Publications Database
Research on Alpha-gal Syndrome
(the Mammalian Meat Allergy)
With this publications database, we hope to consolidate all the evidence-based research on alpha-gal syndrome, as well as select publications on related topics such as:
- pork-cat syndrome and other mammalian meat allergies
- other carbohydrate allergies
- cross-reactive carbohydrate determinants
- the role of ecto- and endoparasites in inducing food allergy
- vector management and ecology
- the evolution of the α-gal immune response
- allergy and autoimmune disease
- hypersensitivity reactions to biologics
- co-factors
- idiopathic anaphylaxis
- airborne reactions to food allergens
- carrageenan, mammalian byproducts, cross-contamination of meat products, and other relevant food and food industry issues
- viral glycan shields and the development of drugs and vaccines employing the α-gal immune response
- xenotransplantation and the development of knock-out pigs
Some gray literature and relevant government, industry, and nonprofit documents were included.
The database was created by Lee Ann Kendrick and Sharon Forsyth, who also manage and update it. Much thanks to Matthew von Hendy of Green Heron Research Resources and John Bianchi of Revivicor for their assistance.
Stars indicate publications flagged as important or of interest in one or more review articles by Commins SP, Hilger C, Platts-Mills TAE, and van Nunen S, and/or deemed as such by the database manager.
* of interest
** of significant interest
† of special relevance to emergency care/perioperative care/hospitalization/pharmacy
‡ of special relevance to diagnosis and management
§ key review articles
Please report errors or omissions to alphagalinformation@gmail.com.
| AUTHORS | DATE | TITLE & ABSTRACT | PUBLICATION/LINK | KEYWORDS |
|---|---|---|---|---|
| Abreu C, Bartolomé B, Cunha L, Falcão H. | 2018 | Galactose-alpha-1,3-galactose allergy: a rare syndrome and an atypical presentation. Summary: Allergies to red meat associated with galactose-alpha-1,3-galactose, commonly known as alpha-gal, are rare and have only recently been described. At this time, the literature reports only one case documented in Portugal. In this study, we report the case of a 76-year-old male with an immediate reaction following the ingestion of red meat. Rigorous diagnostic exams, including prick test, prick-to-prick tests, serum specific IgE and SDS-PAGE IgE-immunoblotting, were performed. The alpha-gal epitope IgE re-turned a value of 35.3 kUA/L, leading the authors to believe that this is an atypical case of alpha-gal allergy. |
European annals of allergy and clinical immunology. 2018 Jul;50(4):190-2. | Bartolome; Falcao; Europe; Portugal; rapid onset reaction; immediate reaction; no tick bite; unknown vector |
| Abreu C, Cunha L, Bartolomé B, Falcão H. | 2015 | Anaphylaxis after consumption of red meat in patient with IgE antibodies specific for galactose-alpha-1,3-galactose. | Allergy: European Journal of Allergy and Clinical Immunology. 2015 Sep;70:616-7. | Bartolome Falcao |
| Adams CB, Street DS, Crass M, Bossaer JB. | 2016 | Low rate of cetuximab hypersensitivity reactions in Northeast Tennessee: An Appalachian effect? Purpose: Cetuximab is a monoclonal antibody with a known risk of hypersensitivity reactions. Early studies showed hypersensitivity reaction rates of 3%, but there appears to be a higher incidence in the southeastern United States. To confirm the findings from nearby institutions that cetuximab-associated hypersensitivity reactions occur in approximately 20% of patients in the southeastern United States. Methods: A retrospective chart review was conducted at Johnson City Medical Center in Johnson City, Tennessee. Each patient's first infusion was analyzed for hypersensitivity reaction, as well as for demographic information such as allergy and smoking history, pre-medications, and malignancy type. Results: Data from the first infusion of cetuximab were collected for a total of 71 patients with various malignancies. The overall rate of grade 3 or higher hypersensitivity reaction was 1.4%, and total rate of hypersensitivity reaction was 8.5%. These findings more closely correlate to the early clinical trials and package insert. Both severe (p=0.001) and any-grade (p=0.002) hypersensitivity reaction occurred less frequently in one Southeastern Appalachian medical center compared to academic medical centers directly to the east and west. Conclusions: Patients in southern Appalachia may be less likely to develop cetuximab hypersensitivity reactions compared to surrounding areas in the Southeastern U.S. These results lend support to the theory that exposure to lonestar ticks (Amblyomma americanum) may be responsible for the development of IgE antibodies to cetuximab that cause hypersensitivity reactions. The development of quick and reliable bedside predictors of cetuximab hypersensitivity reactions may aid clinicians considering the use of cetuximab. |
Journal of Oncology Pharmacy Practice. 2016 Dec;22(6):784-9. | pharmacy; pharmaceutical; medication; biologic; biological agent; monoclonal antibody; mAb; cetuximab; prevalence; Tennessee; Appalachia |
| Adegoke A, Kumar D, Budachetri K, Karim S. | 2021 | Changes in microbial composition, diversity, and functionality in the Amblyomma maculatum microbiome following infection with Rickettsia parkeri. Background: Ticks are the primary vectors for emerging and resurging pathogens of public health significance worldwide. Examining tick bacterial composition, diversity, and functionality across developmental stages and tissues is necessary for designing new strategies to control ticks and prevent tick-borne diseases. Methods: A high-throughput sequencing approach was used to determine the influence of blood meal and Rickettsia parkeri infection on changes in Amblyomma maculatum microbiome composition, diversity, and functionality across the developmental timeline and in different tissues. Quantitative insight into microbial ecology analysis allowed us to determine microbial population structure, composition, and diversity. A non-metric multidimensional scaling, the sparse correlations for compositional data (SparCC) module, and phylogenetic investigation of communities by reconstruction of unobserved states 2 (PICRUSt2) software were used in the assessment. . Results: The Amblyomma maculatum microbiome comprises ten bacterial genera present across tick life cycle stages. Among the top ten bacterial genera (the core tick microbiome), Rickettsia, Francisella, and Candidatus Midichloria are the key players, with positive interactions within each developmental stage and adult tick organ tested. The bacterial abundances, based on the number of operational taxonomic units (OTUs), increase with blood meal in each stage, helping bacterial floral growth. The growth in bacterial numbers is related to highly abundant energy metabolism orthologs with blood meal, according to functional analysis. Whereas R. parkeri had a positive correlation with Candidatus Midichloria during the tick life cycle, based on the increased number of OTUs and network analysis, this was due to an increased level of metabolic activity. Interestingly, R. parkeri replaces Francisella, based on the lower level of OTUs representing Francisella in R. parkeri-infected ticks (in all stages/organs) and negatively correlated according to network and linear discriminant analysis effect size (LEfSe). br> Conclusions: We found that Rickettsia and Francisella predominate in the core microbiome of the Gulf Coast tick, whereas Candidatus Midichloria and Cutibacterium levels increase with infection. Network analysis and functional annotation suggest that R. parkeri interacts positively with Candidatus Midichloria and negatively with Francisella and that metabolic profiles are upregulated with blood meal and R. parkeri infection. Overall, this is the first study to determine the combinatorial outcome of blood meal and pathogen interaction on microbiome composition over the developmental stages of Am. maculatum. This new study expands on our existing knowledge of the Am. maculatum microbiome and further highlights the need to investigate pathogen–symbiont interactions between R. parkeri and Francisella or Candidatus Midichloria to facilitate the development of strategies for controlling tick-transmitted diseases. |
bioRxiv 2021.10.25.465777 | Amblyomma maculatum; tick biome |
| Afshan T, Kelbel T. | 2019 | M301 ALLERGIC REACTION WHILE MAKING BURGERS—BLAME IT ON THE DOG!. Introduction: A 5-year-old girl with history of significant eczema, severe dog allergy (IgE>100), and anaphylactic allergy to egg and treenuts developed urticaria on her bilateral arms after preparing hamburger patties. No other ingredients, such as egg, were handled. She had previously tolerated cooked beef and had no history of milk allergy. Case Description: Why, in the absence of milk allergy, was this patient able to tolerate cooked beef ingestion but developed urticaria after raw beef exposure? Diagnostic Plan: Initial diagnostics for beef allergy included beef extract skin testing and beef IgE blood testing, both of which were negative. IgE blood tests for α-Gal, pork, and venison were also negative. The patient passed an oral food challenge to cooked beef. Subsequent skin testing for raw beef was positive (5mm x 10mm). Discussion: Mammalian meat allergy is overall rare, and is frequently associated with α-Gal allergy. A relationship between mammalian meat and epithelia has been described infrequently and is thought to be due to serum albumin cross-reactivity. There is one previous case of an adult cook who developed wheezing and contact urticaria after exposure to raw beef, had previously tolerated cooked beef ingestion, and was subsequently found to have positive skin testing to raw beef. Given structural similarities between mammalian albumins and prior described relationships (i.e. cat and pork), further study would be beneficial to better understand this possible connection. Conclusion: To the best of our knowledge, this is the first pediatric case of raw beef allergy coinciding with severe dog allergy. |
Annals of Allergy, Asthma & Immunology. 2019 Nov 1;123(5):S124. | |
| Ailsworth S, Noth A, Patel J, Workman L, Keshavarz B, Nelson M, Platts-Mills T, Susi A, Nylund C, Wilson J. | 2023 | Association of Sex and ABO-blood Group with Alpha-Gal Sensitization in a Cohort of Military Personnel. Rationale: IgE antibodies to galactose-alpha-1,3-galactose (alpha-gal) are strongly linked with tick bites and cause a syndrome of mammalian meat allergy. Previous reports suggest that male sex is associated with alpha-gal sensitization, whereas B blood group is protective. We sought to investigate these associations in a large military cohort. Methods: Baseline and follow-up serum samples (median 3.5 years) were collected and stored in the Department of Defense Serum Repository from 3000 personnel stationed at 10 military bases in the central/eastern USA. Alpha-gal IgE (cut-off 0.1 kU/L) was measured by ImmunoCAP and ABO-blood group assessed by reverse-typing in a subset of the cohort. Results: Of the 3000 subjects, median age was 19 years (IQR 18-22), 2456 (82%) were male, 179 (6.0%) were sensitized to alpha-gal at baseline and 169 (5.6%) had incident alpha-gal sensitization (defined as subjects who sero-converted or had levels increase from baseline to follow-up). 6.6% of males versus 3.3% of females were sensitized at baseline, p=0.004. Adjusted for age, race and home state the odds ratio for sensitization was 1.8 in males (95%CI 1.1-3.0). Incident alpha-gal IgE was higher in males (6.4%) than females (2.4%), p<0.001. Adjusted for age, race and military branch the odds ratio for incident alpha-gal was 1.7 in males (95%CI 1.0-3.3). Using a nested control cohort (n=169) matched for age, sex, race and geography, incident alpha-gal subjects trended toward a lower frequency of B/AB blood types (12% vs 16%), but this was not significant (p=0.28). Conclusions: Alpha-gal sensitization is significantly associated with male sex, but not ABO-blood group status. |
Journal of Allergy and Clinical Immunology. 2023 Feb 1;151(2):AB93. | Epidemiology, military, blood type, prevalence, occupational medicine |
| Airaksinen L, Suojalehto H, Lindström I, Sund J, Pallasaho P, Puustinen A. | 2022 | Characterization of relevant bovine dander allergen components. |
J Investig Allergol Clin Immunol. 2024;34(1):1. | Finland; occupational allergy; cattle farmer; cows |
| Akarsu A, Soyer O, Sekerel BE. | 2020 | Hypersensitivity Reactions to Biologicals: from Bench to Bedside. Purpose of Review: Biologic agents are new treatment options for chronic inflammatory diseases and cancers. As a result of their unique mechanism of action, they are more effective and less toxic treatment option and their clinical usage is increasing. While they are more commonly used, various adverse effects have been observed including life-threatening ones, including anaphylaxis. The aim of this review is to distinguish the anaphylaxis from other hypersensitivity reactions (HSR) and provide a management algorithm for the anaphylactic reactions induced by biological agents. Recent Findings: Many case reports and series have been published regarding anaphylaxis and other hypersensitivity reactions (concerning cytokine release syndrome, acute infusion–related reactions) due to biologic agents. Although acute treatment of HSR varies according to the clinical presentation, desensitization with the drug is the major management option for subsequent administrations in the case of anaphylactic reactions. . Summary: Anaphylaxis and other immediate onset hypersensitivity reactions are occasionally difficult to differentiate from each other, and mixed-type reactions may be observed. Immediate management of anaphylaxis includes discontinuation of infusion, immediate administration of adrenaline, antihistamines, corticosteroids, and other treatment options depending on the symptoms. After 30–120 min of the reaction, a blood sample for serum tryptase levels should be obtained and after 4–6 weeks skin testing with the culprit drug should be performed for decision of long-term management via either graded challenge or desensitization. |
Current Treatment Options in Allergy. 2020 Jan 18:1-3. | review article; biologic; biological agent; mAb; monoclonal antibody; pharmacy; pharmaceutical |
| Akella K, Patel H, Wai J, Roppelt H, Capone D. | 2017 | Alpha Gal-Induced Anaphylaxis to Herpes Zoster Vaccination. INTRODUCTION: Reported incidence of tick borne illness has progressively risen over the last decade. Galactose-alpha-1,3- galactose (alpha gal) allergy is a novel presentation of a tick borne illness induced by the Lone Star Tick, which is a well known vector for ehrlichiosis, tularemia, and Southern Tick-associated Rash Illness (STARI). Individuals with tick borne illnesses in the Lone Star Tick distribution of southern, midwestern and northeastern states are at greater risk for developing this condition. Three major hypotheses exist to describe how ticks might induce an IgE response through transmission of alpha gal: 1) alpha gal may be a component of tick saliva, 2) alpha gal may be residual from prior blood meal, and 3) alpha gal may be transmitted through commensal organism transmission. Clinical presentation of alpha gal allergy includes gastrointestinal symptoms, itching and urticaria, and delayed anaphylaxis. There has been one prior report of alpha gal induced anaphylaxis after administration of herpes zoster vaccination in the literature. We describe a second, unique presentation of this allergic condition observed at our institution. CASE PRESENTATION: A 73 year old female with a past medical history of hypertension, chronic hepatitis C, and alpha gal allergy presented to our Emergency Department for near syncope after epinephrine administration for upper lip, mouth and tongue swelling experienced 45 minutes after obtaining her herpes zoster vaccination. Review of the vaccination contents revealed use of porcine gelatin - a meat product felt to have induced an IgE response in the setting of alpha gal allergy. The patient was admitted, managed with intravenous fluids, and discharged the following morning. DISCUSSION: To increase physician awareness of alpha gal allergy and increased incidence in populations exposed to tick-borne diseases. We suggest avoiding administering the herpes zoster vaccine in patients with a history of a tick borne illness. CONCLUSIONS: Alpha gal allergy is a relatively novel presentation of tick borne illness induced by the Lone Star Tick - commonly found in the southern, midwest and northeastern United States. We report an unusual case of alpha gal allergy with anaphylaxis induced by herpes zoster vaccination due to use of porcine gelatin. |
Chest. 2017 Oct 1;152(4):A6. | pharmacy; vaccination; vaccine; herpes zoster; primary care; management |
| Altman MO, Gagneux P. | 2019 | Absence of Neu5Gc and presence of anti-Neu5Gc antibodies in humans—an evolutionary perspective. The glycocalyx of human cells differs from that of many other mammals by the lack of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and increased abundance of its precursor N-acetylneuraminic acid (Neu5Ac). Most humans also have circulating antibodies specifically targeting the non-human sialic acid Neu5Gc. Recently, several additional mammalian species have been found to also lack Neu5Gc. In all cases, loss-of-function mutations in the gene encoding the sialic acid-modifying enzyme CMAH are responsible for the drastic change in these species. Unlike other glycan antigens, Neu5Gc apparently cannot be produced by microbes, raising the question about the origin of these antibodies in humans. Dietary exposure and presentation on bacteria coating themselves with Neu5Gc from the diet are distinct possibilities. However, the majority of the non-human species that lack Neu5Gc do not consume diets rich in Neu5Gc, making it unlikely that they will have been immunized against this sialic acid. A notable exception are mustelids (ferrets, martens and their relatives) known for preying on various small mammal species rich in Neu5Gc. No studies exist on levels of anti-Neu5Gc antibodies in non-human species. Evolutionary scenarios for the repeated, independent fixation of CMAH loss-of-function mutations at various time points in the past include strong selection by parasites, especially enveloped viruses, stochastic effects of genetic drift, and directional selection via female immunity to paternal Neu5Gc. Convergent evolution of losses of the vertebrate-specific self-glycan Neu5Gc are puzzling and may represent a prominent way in which glycans become agents of evolutionary change in their own right. Such change may include the reconfiguration of innate immune lectins that use self-sialic acids as recognition patterns. |
Frontiers in immunology. 2019 Apr 30;10:789. | glycan antigen; xenoglycan; sialic acid; Neu5Gc; Neu5Ac; carbohydrate; evolution |
| Altmann F. | 2016 | Coping with cross-reactive carbohydrate determinants in allergy diagnosis. A relevant proportion of allergy diagnosis is accomplished by in vitro determination of specific immunglobulin E (sIgE) to extracts from suspected allergens. Such extracts inevitably contain glycoproteins, which may react with patients’ IgE. In the case of plant and insect allergens, the relevant epitope structure is an alpha-1,3-fucose on the Asn-linked sugar residue of so-called N-glycans. Due to their wide distribution, N-glycans carrying this epitope are known as “cross-reactive carbohydrate determinant(s)” (CCD[s]). About 15 years of awareness allow the conclusion that anti-CCD IgE does not cause noticeable clinical symptoms. In consequence, diagnostic results arising from CCD reactivity must be rated as false positives. With up to 30 % of CCD reactive patients, this can be regarded as a serious problem. Another cross-reactive carbohydrate determinant became notorious as a potential cause of anaphylactic reactions to a recombinant glycoprotein drug carrying alpha-1,3-galactose. This galactose-containing determinant (GalCD, galactose containing cross-reactive carbohydrate determinant) was supposed as a trigger for delayed allergic reactions to red meat in several cases. Thus, alpha-1,3-galactose may have clinical relevance in certain cases – possibly as a result of tick bites. Often, however, GalCDs probably cause false-positive results with milk and meat extracts. No clear evidence for the role of other non-human carbohydrate structures such as N-glycolylneuraminic acid as CCD has been presented so far. Remedies for sIgE based in vitro diagnosis come in the form of non-glycosylated recombinant allergen components or of specific CCD inhibitors. The high potential of recombinant allergens is optimally realized in the context of component resolved diagnosis using allergen arrays with more than 100 components, whereas CCD inhibitors increase the specificity of conventional extract-based diagnosis. Reagents for the detection and inhibition of CCDs from plants and insects have been developed, whereas tools for GalCDs of milk and meat lag behind. |
Allergo journal international. 2016 Jun 1;25(4):98-105. | cross-reactive carbohydrate determinant; CCD |
| Altmann F. | 2007 | The role of protein glycosylation in allergy. The asparagine-linked carbohydrate moieties of plant and insect glycoproteins are the most abundant environmental immune determinants. They are the structural basis of what is known as cross-reactive carbohydrate determinants (CCDs). Despite some structural variation, the two main motifs are the xylose and the core-3-linked fucose, which form the essential part of two independent epitopes. Plants contain both epitopes, insect glycoproteins only fucose. These epitopes and other fucosylated determinants are also found in helminth parasites where they exert remarkable immunomodulatory effects. About 20% or more of allergic patients generate specific anti-glycan IgE, which is often accompanied by IgG. Even though antibody-binding glycoproteins are widespread in pollens, foods and insect venoms, CCDs do not appear to cause clinical symptoms in most, if not all patients. When IgE binding is solely due to CCDs, a glycoprotein allergen thus can be rated as clinical irrelevant allergen. Low binding affinity between IgE and plant N-glycans now drops out as a plausible explanation for the benign nature of CCDs. This rather may result from blocking antibodies induced by an incidental ‘immune therapy’ (‘glyco-specific immune therapy’) exerted by everyday contact with plant materials, e.g. fruits or vegetables. The need to detect and suppress anti-CCD IgE without interference from peptide epitopes can be best met by artificial glycoprotein allergens. Hydroxyproline-linked arabinose (single β-arabinofuranosyl residues) has been identified as a new IgE-binding carbohydrate epitope in the major mugwort allergen. However, currently the occurrence of this O-glycan determinant appears to be rather restricted. |
International archives of allergy and immunology. 2007;142(2):99-115. | Glycan antigen; xenoglycan; sialic acid; Neu5Gc; Neu5Ac; carbohydrate |
| Altrich ML, Blum SP, Foster SM. | 2015 | Delayed Anaphylaxis to Mammalian Meat: A Fascinating Disease and Captivating Story. Delayed anaphylaxis to mammalian meat is a newly recognized IgE-mediated syndrome associated with Lone Star tick bites. IgE-mediated anaphylaxis classically occurs within one hour of exposure to the allergen, which is typically a protein epitope. However, in this disease, circulating antibodies to a carbohydrate, alpha-gal (galactose-alpha-1,3-galactose), stimulate the anaphylactic cascade with hives, diarrhea, abdominal cramps, respiratory distress and anaphylactic shock developing after ingestion of beef, pork or lamb meat. The delayed onset of symptoms three to six hours after ingestion of meat is unique. Recognition and understanding of this disease is important for treating and educating patients with suggestive symptoms. Avoidance of red meat is the recommended therapy. |
Journal of Allergy and Clinical Immunology. 2015 Feb 1;135(2):AB37. | North America; United States; prevalence |
| Altshuler E, Krikpatrick J, Aryan M, Miralles F. | 2021 | Mammalian meat allergy emerges after tick bite: the alpha-gal syndrome. Alpha-gal syndrome (AGS) is a hypersensitivity reaction to mammalian meat that develops after tick bite exposure. AGS was first described in 2009 and testing for the allergy has become available in the last decade. We report the case of a 56-year-old farmer with a history of frequent lone star tick bites who presented with a 7-year history of diffuse urticaria occurring hours after eating red meat. AGS is likely underdiagnosed because of the unusual presentation of the allergy, historic lack of available testing, and deficiency of physician knowledge about the condition. Recognition of AGS is important both to help alleviate symptom burden and to avoid iatrogenesis. Patients with AGS should not receive products containing mammalian products, such as cat-gut suture, porcine-derived heart valves, and bovine-derived vaccines. Patients with AGS may present in a variety of clinical environments and physicians of all kinds should be able to recognise the symptoms. |
BMJ Case Reports CP. 2021 Nov 1;14(11):e245488. | Florida |
| Alvarez-Perea A, Caralli ME, Zubeldia JM, Baeza ML. | 2014 | Pork-cat syndrome as a cause of occupational asthma. We report the case of a 30-year-old woman with a family history of atopy. At the age of 13, soon after receiving a cat, she began to experience perennial ocular and nasal symptoms, as well as cough, wheeze, and dyspnea, all of which worsened in spring. At age 14, she was diagnosed with allergic rhinoconjunctivitis and mild intermittent asthma caused by pollen and dander. Her allergy improved when the cat was removed, and symptoms remained limited to mild rhinoconjunctivitis in springtime, although she still had mild asthma throughout the year when practicing sports. When she was 20, she started working at a grocery store selling cured meats. One of her duties was to cut pork bones (cured and cooked ham). From that point, her rhinoconjunctivitis worsened and her asthma attacks resumed. These manifestations were exacerbated at her workplace, especially when she had to cut pork bones. Her asthma continued to deteriorate, and she experienced 3-4 exacerbations per year that forced her to be absent from work. She frequently needed aerosol therapy after work, although she felt better on days off work and was almost asymptomatic during vacations. In 2010-2011, she was admitted to hospital on 4 occasions, forcing her to miss work for 1-2 months each time. Her asthma was controlled with oral corticosteroids. |
J Investig Allergol Clin Immunol. 2014 Jan 1;24(3):192-211. | airborne reactions; pork-cat syndrome; occupational medicine |
| Amoah AS, Asuming-Brempong EK, Obeng BB, Versteeg SA, Larbi IA, Aryeetey Y, Platts-Mills TA, Mari A, Brzezicka K, Gyan BA, Mutocheluh M. | 2018 | Identification of dominant anti-glycan IgE responses in school children by glycan microarray. Letter to the editor In helminth-endemic areas, elevated levels of cross-reactive IgE to environmental and food allergens are often seen that do not translate into positive skin prick test results or allergy symptoms. 1 Among Ghanaian children, such cross-reactivity was shown to be associated with Schistosoma haematobium infection and dominated by high IgE against cross-reactive carbohydrate determinants (CCDs). 2 The specific carbohydrate motifs involved in this IgE recognition were not determined. |
Journal of Allergy and Clinical Immunology. 2018 Mar 1;141(3):1130-3. | |
| Andrade AL, Riccetto AG, Vilela MM, de Oliveira DN, Catharino RR, Nolasco da Silva MT. | 2018 | Anaphylactic reaction to galactose‐derived oligosaccharide residues from lactose used as a drug excipient. Inhaled steroids are currently the most widely used and recommended medicines for the management of persistent asthma because of their high local and anti-inflammatory efficacy.1 There are three main presentations of the drug: aerosol spray (hydrofluoroalkane – HFA - as a propellant), liquid solution and dry powder inhaler. Dry powder devices are often preferred over HFA sprays in patients over 6 years of age, both for environmental issues and for the intrinsic advantages of the technique, such as ease of use and greater uptake and metabolism of the drug.1,2 This article is protected by copyright. All rights reserved. |
Pediatric Allergy and Immunology. 2018 Mar 1;29(2):207-10. | |
| Anemüller W, Mohr M, Brans R, Homann A, Jappe U. | 2018 | Alpha-Gal-assoziierte verzögerte Anaphylaxie gegen rotes Fleisch als Berufskrankheit. Bei einem 30-jährigen Koch mit rezidivierenden verzögerten Angioödemen konnte anamnestisch und laborexperimentell als Ursache die Sensibilisierung gegen das Kohlenhydratepitop Galactose-alpha-(1,3)-Galactose (alpha-Gal) aufgedeckt werden. Mit der Diagnose einer verzögerten Anaphylaxie bei Sensibilisierung gegen alpha-Gal erfolgte aufgrund des beruflichen Bezuges die Meldung an die Berufsgenossenschaft mittels Hautarztbericht BK 5101. Hierauf wurde dem Patienten fristlos gekündigt. Als Konsequenz zeigten wir eine Berufskrankheit an. Diese Kasuistik stellt die Bedeutung der unterdiagnostizierten, potenziell lebensbedrohlichen Allergie gegen das Disaccharid alpha-Gal des roten Fleisches als Berufskrankheit dar. English translation: Alpha-gal associated delayed red meat anaphylaxis as an occupational disease In a 30-year-old chef with recurrent delayed angioedema history as well as the experimental detection of IgE antibodies to galactose-alpha (1,3) -galactose (alpha-gal) pointed to alpha gal as the causative agent. The diagnosis, therefore, was delayed by anaphylaxis due to alpha-gal. Because of the potential relationship to his profession, we have submitted a dermatologist's report BK 5101 to the liability and insurance association, whereupon his contract of employment without notice. As a result, we reported an occupational disease. This case demonstrates underdiagnosed, potential life-threatening allergy to the disaccharide alpha gal in red meat as to occupational disease. |
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2018 Oct;69(10):848-52. | Anemuller; occupational medicine; chef |
| Angiolillo A, Gandaglia A, Arcaro A, Carpi A, Gentile F, Naso F, Di Costanzo A. | 2021 | Altered Blood Levels of Anti-Gal Antibodies in Alzheimer’s Disease: A New Clue to Pathogenesis?. Alzheimer’s disease is a neurodegenerative disorder whose pathological mechanisms, despite recent advances, are not fully understood. However, the deposition of beta amyloid -peptide and neuroinflammation, which is probably aggravated by dysbiotic microbiota, seem to play a key role. Anti-Gal are the most abundant xenoreactive natural antibodies. They are supposed to stem from immunization against the gut microbiota and have been implicated in the pathogenesis of several diseases, including multiple sclerosis. These antibodies target the alpha-Gal epitope, expressed on the terminal sugar units of glycoprotein or glycolipid of all mammals except apes, Old World monkeys and humans. The alpha-Gal is constitutively expressed in several bacteria constituting the brain microbiota, and alpha-Gal-like epitopes have been detected in gray matter, amyloid plaque, neurofibrillary tangles and corpora amylacea of the human brain, suggesting a potential link between anti-Gal and Alzheimer’s disease etiopathogenesis. For the first time, our study searched for possible alterations of anti-Gal immunoglobulin levels in Alzheimer’s disease patients. IgG and IgM blood levels were significantly lower, and IgA significantly higher in patients than in healthy subjects. These results suggest that such immunoglobulins might be implicated in Alzheimer’s disease pathogenesis and open new scenarios in the research for new biomarkers and therapeutic strategies. |
Life. 2021 Jun;11(6):538. | Brain; Alzheimer's; anti-gal; autoimmune |
| Ankersmit HJ, Copic D, Simader E. | 2017 | When meat allergy meets cardiac surgery: A driver for humanized bioprosthesis. Virginia cardiothoracic surgeons, recently described 2 patients who underwent implantation of a bioprosthetic aortic valve and postoperatively developed a meat allergy associated with a gal-specific IgE immune response. Both patients developed premature degeneration of their bioprosthesis that required reoperation and implantation of a mechanical valve in the aortic position.10 What can we learn as academic surgeons from this scientific story? (1) Big Pharma has not reacted to academic work to provide more durable gal-deficient bioprosthesis. Cardiac surgeons and cardiologists are continuing to implant valves that are known to induce a systemic immune response, leading to precocious degeneration. Furthermore, the uncritical lowering of age limits for biovalve replacement has severe consequences.11,12 (2) Academic research pertaining to the alpha-gal immune response in cardiac surgery is rather meek: A PubMed search in November 2016 with the key words ‘‘alpha-gal’’ and ‘‘valve’’ brought up only 40 citations. (3) Only the very avant-garde centers, such as the Hannover and Seoul Group, are trying to tackle this important question by means of detergent-based decellularization procedures13,14 or by using alpha-galactosidase.15 Tissueengineering research is ongoing in most academic centers of relevance, but commercial producers must instigate the manufacture of such ‘‘humanized’’ bioprostheses with potentially longer life spans. The first successful endeavors in that direction have been reported.16 Allergy and cardiac surgery do not particularly fit together, but in my opinion these ‘‘case insights’’ from patients with meat allergy with valve degeneration will lead to commercially available gal-deficient bioprostheses for future generations of patients with valve disease. Another speculation is that regulatory affairs in the European Union or the Food and Drug Administration in the United States will force the industry to provide such valves, and then ignorance will be overcome. The valve industry takes pride in being innovative at annual cardiac surgery meetings. Will we wait for another decade for action? |
The Journal of thoracic and cardiovascular surgery. 2017 Oct 1;154(4):1326-7. | cardiac surgery; cardiothoracic surgery; bioprosthetic heart valve |
| Apari P, Földvári G | 2022 | Tick bite induced α‐gal syndrome highlights anticancer effect of allergy. Tick bite induced α-gal syndrome (AGS) following consumption of mammalian meat is a recently described intriguing disease occurring worldwide. Here we argue that AGS and delayed allergy in general is an adaptive defence method against cancer. Our hypothesis synthesizes two lines of supporting evidence. First, allergy has been shown to have direct anti-cancer effects with unknown mechanism. Second, eating processed meat was shown to be linked to developing cancer. Humans lost their genes encoding molecules α-gal 30 MYA and Neu5Gc 2 MYA, the latter co-occurring with the start of using fire. These molecules are acquired from external sources, as tick bite for α-gal and mammalian meat for Neu5Gc, the latter accumulating in tumors. The resulting specific delayed allergic response is a molecular adaptation to fight cancer. By further testing and applying our hypothesis, new avenues in cancer research and therapy will open that might save lives and decrease human suffering. |
BioEssays. 2022 Jan;44(1):2100142. | cancer |
| Apostolovic D, Bigdeli N, Starkhammar M, van Hage M. | 2019 | Red meat allergic patients have specific TH2 derived cellular and humoral responses against Ixodes ricinus tick proteins supporting the link to alpha-gal allergy. | ALLERGY. 2019 Aug 1; 4: 155-156. | Europe; Sweden; vector; Ixodes ricinus |
| Apostolovic D, Grundström J, Kiewiet MB, Perusko M, Hamsten C, Starkhammar MH, Paulie S, van Hage M. | 2023 | Th2-skewed T cells correlate with B cell response to α-Gal and tick antigens in α-Gal syndrome. Tick bites have been shown to transmit a novel form of severe food allergy, the galactose-α-1,3-galactose (α-Gal) syndrome (AGS). Cellular responses to α-Gal in AGS patients have to date not been thoroughly scrutinized. Therefore, we investigated T and B cell proliferation, activation and cytokine profiles in response to tick protein extract (TE) and α-Gal-free TE in AGS patients and healthy controls. T and B cells from both patients and controls proliferated in response to TE, but significantly more in the patients. B cell proliferation, but not T cell proliferation, in AGS patients was reduced by removing α-Gal from the TE. In addition, TE induced a clear Th2 cytokine profile in AGS patients. Expression of CD23 by B cells correlated only to T cell proliferation. However, both B cell proliferation and CD23 expression were reduced when CD40L and IL-4 were blocked. A large proportion of the IgG1 and IgE antibodies binding TE in AGS patients were directed against the α-Gal epitope. We have for the first time investigated T and B cell responses to α-Gal carrying tick proteins in AGS patients, which will be essential for the understanding of the immune response against an allergenic carbohydrate transmitted by ticks. |
The Journal of Clinical Investigation. 2023 Jan 26. | cellular mechanisms; B cells; T cells |
| Apostolovic D, Krstic M, Mihailovic J, Starkhammar M, Velickovic TC, Hamsten C, van Hage M. | 2017 | Peptidomics of an in vitro digested a-Gal carrying protein revealed IgE-reactive peptides. The mammalian carbohydrate galactose-α1,3-galactose (α-Gal) causes a novel form of food allergy, red meat allergy, where patients experience severe allergic reactions several hours after red meat consumption. Here we explored gastric digestion of α-Gal glycoproteins using an in vitro model. Bovine thyroglobulin (BTG), a typical α-Gal carrying glycoprotein, was digested with pepsin. The resulting peptides were characterized by SDS PAGE, immunoblot and ImmunoCAP using sera from 20 red meat allergic patients. During pepsinolysis of BTG, a wide range of peptide bands was observed of which 14 to 17 kDa peptides remained stable throughout the gastric phase. The presence of the α-Gal epitope on the obtained peptides was demonstrated by an anti-α-Gal antibody and IgE from red meat allergic patients. The α-Gal digests were able to inhibit up to 86% of IgE reactivity to BTG. Importantly, basophil activation test demonstrated that the allergenic activity of BTG was retained after digestion in all four tested patients. Mass spectrometry-based peptidomics revealed that these peptides represent mostly internal and C-terminal parts of the protein, where the most potent IgE-binding α-Gal residues were identified at Asn1756, Asn1850 and Asn2231. Thus allergenic α-Gal epitopes are stable to pepsinolysis, reinforcing their role as clinically relevant food allergens. |
Scientific reports. 2017 Jul 12;7(1):1-0. | proteins; peptides; digestion; stability Sweden; Europe |
| Apostolovic D, Mihailovic J, Commins SP, Wijnveld M, Kazimirova M, Starkhammar M, Stockinger H, Platts-Mills TA, Cirkovic VT, Hamsten C, van Hage M. | 2020 | Allergenomics of the tick Ixodes ricinus reveals important alpha-Gal-carrying IgE-binding proteins in red meat allergy. Letter to the editor. |
Allergy. 2020 Jan;75(1):217. | Europe; Sweden; vectors; Ixodes ricinus; |
| Apostolovic D, Rodrigues R, Thomas P, Starkhammar M, Hamsten C, van Hage M. | 2018 | Immunoprofile of α‐Gal‐ and B‐antigen‐specific responses differentiates red meat‐allergic patients from healthy individuals. Background: The galactose--1,3-galactose (-Gal) epitope is involved in red meat allergy. As -Gal is structurally similar to the blood group B-antigen, we explored the relationship between the immune responses to -Gal- and the B-antigen in red meat-allergic patients compared to healthy A/O or B blood donors. Methods: Sera from 51 red meat-allergic patients IgE-positive to -Gal and 102 healthy blood donors (51 blood group A/O; 51 blood group B) were included. -Gal- and B-antigen-specific IgE (ImmunoCAP) and IgG/IgG (1-4) (ELISA) responses were determined. Basophil activation tests were performed. Results: Fifteen healthy donors were IgE positive to -Gal, of which 3 had blood group B. The allergic patients had significantly higher -Gal IgE levels compared to the healthy donors. The majority of the allergic patients, but none of the healthy donors, had IgE against the B-antigen. Inhibition studies revealed cross-reactivity between -Gal and the B-antigen. The biological activity of the B-antigen was confirmed by basophil activation tests. Anti--Gal IgG (1) and IgG (4) levels were significantly higher in the patients compared to the healthy donors. Moreover, the IgG response to the B-antigen was comparable between the allergic patients and healthy A/O donors. Conclusion: Red meat-allergic patients showed significantly higher -Gal IgE, IgG (1), and IgG (4) levels, reflecting a Th2 response, compared to healthy blood donors. Blood group B donors had significantly reduced antibody responses to -Gal, due to similarities with the B-antigen, resulting in a lower risk of sensitization to -Gal and development of red meat allergy. |
Allergy. 2018 Jul;73(7):1525-31. | Europe; Sweden; Blood group |
| Apostolovic D, Tran TA, Hamsten C, Starkhammar M, Cirkovic Velickovic T, van Hage M. | 2014 | Immunoproteomics of processed beef proteins reveal novel galactose-alpha-1,3-galactose-containing allergens. BACKGROUND: Red meat allergy presents a novel form of food allergy with severe delayed allergic reactions where IgE antibodies are directed against the carbohydrate alpha-Gal epitope. Food preparation and processing can influence the allergenicity of proteins. The aim of this study was to characterize the proteomic profile of different beef preparations and to investigate their alpha-Gal reactivity and potential allergenicity. METHODS: Extracts from raw, boiled, fried, and medium rare prepared beef were assessed by 2D PAGE for the comparison of protein profiles. IgE-binding proteins were identified using immunoblot-coupled proteomic analysis using sera from red meat-allergic patients. Presence of the alpha-Gal epitope was verified using anti-alpha-Gal antibody and IgE inhibition immunoblot with alpha-Gal. RESULTS: Multiple IgE-binding proteins were detected in the different beef preparations, many of which were also recognized by the anti-alpha-Gal antibody. Protein spots reacting with IgE in patient sera were analyzed by MS/MS, resulting in identification of 18 proteins with high identification scores. Seven of the 18 beef allergens identified using meat-allergic patient sera were also recognized by the anti-alpha-Gal monoclonal antibody, and four of them were stabile to thermal treatment. Furthermore, a dose-dependent inhibition of red meat-allergic patients' IgE to beef by alpha-Gal was demonstrated. CONCLUSIONS: We show that the alpha-Gal epitope is commonly present in IgE-reactive beef proteins recognized by meat-allergic patients. Seven novel alpha-Gal-containing IgE-binding proteins were identified, of which four were stable to heat treatment. Thus, the allergenicity of red meat proteins is preserved even upon different thermal cooking. |
Allergy. 2014 Oct;69(10):1308-15. | Europe; Sweden; proteins; beef; cooking; thermal stability; |
| Apostolovic D, Tran TA, Sánchez‐Vidaurre S, Cirkovic Velickovic T, Starkhammar M, Hamsten C, van Hage M. | 2015 | Red meat allergic patients have a selective IgE response to the α-Gal glycan. Galactose-alpha-1,3-galactose (alpha-Gal) is a mammalian carbohydrate with significance in a novel type of food allergy. Patients with IgE against alpha-Gal report severe allergic symptoms 3-6 h after consumption of red meat. We investigated whether IgE from red meat allergic patients recognizes other mammalian glycans than alpha-Gal or glycans from the plant kingdom and insects of importance in allergy. We found that none of the 24 red meat allergic patients investigated had an IgE antibody response against the other abundant mammalian glycan N-glycolylneuraminic acid or against cross-reactive carbohydrate determinants from plant or venom sources (nCup a 1, nArt v 1, and MUXF3). Deglycosylation of an alpha-Gal-containing protein, bovine thyroglobulin, significantly reduced the IgE response. In conclusion, we show that red meat allergic patients have a selective IgE response to the alpha-Gal glycan found in red meat. Other common glycans reactive in allergic disease are not targets of red meat allergic patients' IgE. |
Allergy. 2015 Nov;70(11):1497-500. | Europe; Sweden; Sanchez-Vidaurre; glycan; cross-reactive carbohydrate determinant; Neu5Gc; N-glycolylneuraminic acid |
| Apostolovic D, Tran TA, Starkhammar M, Sánchez-Vidaurre S, Hamsten C, Van Hage M. | 2016 | The red meat allergy syndrome in Sweden. In the last decade, a novel type of food allergy presenting with severe allergic reactions several hours after consumption of red meat has been recognized. The allergic responses are due to IgE antibodies directed against the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) found in mammalian meat. This review presents the red meat allergy syndrome in Sweden, discusses the features of the immune response to carbohydrates, and highlights the presence of heat stable α-Gal-containing proteins in meat. The number of diagnosed red meat allergy cases in Sweden has increased significantly over the past few years. All patients have been tick bitten. Our recent work has shown that α-Gal is present in the European tick Ixodes ricinus (I. ricinus), thus potentially explaining the strong association between anti-α-Gal IgE and tick bites, with development of red meat allergy as a secondary phenomenon. Further studies using immunoproteomics have identified novel α-Gal-containing meat proteins that bound IgE from red meat allergic patients. Four of these proteins were stable to thermal processing pointing to the fact that the allergenicity of red meat proteins is preserved in cooked meat. In keeping with the fact that the α-Gal epitope is structurally related to the blood group B antigen, a positive association with the B-negative blood groups among our red meat allergic patients was noted. A selective IgE reactivity to the pure carbohydrate moiety was observed when investigating the specificity of the α-Gal immune response. IgE from red meat allergic patients does not recognize the other major mammalian carbohydrate, N-glycolylneuraminic acid (Neu5Gc), also present in high amounts in red meat. Furthermore, neither common cross-reactive carbohydrate determinants (CCDs) from plants nor venoms are targets of the IgE response in these patients. . Taken together, the α-Gal carbohydrate has shown to be a potentially clinically relevant allergen that should be taken into account in the diagnosis of food allergy. Many new findings in the field of red meat allergy have been obtained during the past years, but further efforts to understand the process of digestion, absorption, and delivery of α-Gal-containing molecules to the circulation are needed. |
Allergo Journal. 2016 Mar 1;25(2):29-34. | Europe; Sweden; Sanchez-Vidaurre; review article; Europe; Scandanavia; Sweden |
| Araujo RN, Franco PF, Rodrigues H, Santos LC, McKay CS, Sanhueza CA, Brito CR, Azevedo MA, Venuto AP, Cowan PJ, Almeida IC, Finn MG, Marques MF. | 2016 | ** Amblyomma sculptum tick saliva: alpha-Gal identification, antibody response and possible association with red meat allergy in Brazil. The anaphylaxis response is frequently associated with food allergies, representing a significant public health hazard. Recently, exposure to tick bites and production of specific IgE against α-galactosyl (α-Gal)-containing epitopes has been correlated to red meat allergy. However, this association and the source of terminal, non-reducing α-Gal-containing epitopes have not previously been established in Brazil. Here, we employed the α-1,3-galactosyltransferase knockout mouse (α1,3-GalT-KO) model and bacteriophage Qβ-virus like particles (Qβ-VLPs) displaying Galα1,3Galβ1,4GlcNAc (Galα3LN) epitopes to investigate the presence of α-Gal-containing epitopes in the saliva of Amblyomma sculptum, a species of the Amblyomma cajennense complex, which represents the main tick that infests humans in Brazil. We confirmed that the α-1,3-galactosyltransferase knockout animals produce significant levels of anti-α-Gal antibodies against the Galα1,3Galβ1,4GlcNAc epitopes displayed on Qβ-virus like particles. The injection of A. sculptum saliva or exposure to feeding ticks was also found to induce both IgG and IgE anti-α-Gal antibodies in α-1,3-galactosyltransferase knockout mice, thus indicating the presence of α-Gal-containing epitopes in the tick saliva. The presence of α-Gal-containing epitopes was confirmed by ELISA and immunoblotting following removal of terminal α-Gal epitopes by α-galactosidase treatment. These results suggest for the first known time that bites from the A. sculptum tick may be associated with the unknown etiology of allergic reactions to red meat in Brazil. |
International journal for parasitology. 2016 Mar 1;46(3):213-20. | Latin America; Brazil; vectors; tick species; Amblyomma sculptum; tick saliva |
| Archer-Hartmann SA, Crispell G, Karim S, Dharmarajan G, Azadi P. | 2018 | Tick Bites and Hamburgers: N-Glycosylation analysis of saliva and salivary glands from the ticks responsible for Alpha-Gal Syndrome. | GLYCOBIOLOGY. 2018 Dec 1; 28(12):1080-1081. | vectors; tick saliva |
| Arkestål K, Sibanda E, Thors C, Troye-Blomberg M, Mduluza T, Valenta R, Grönlund H, van Hage M. | 2011 | Impaired allergy diagnostics among parasite-infected patients caused by IgE antibodies to the carbohydrate epitope galactose-α-1,3-galactose. BACKGROUND: The carbohydrate epitope galactose-alpha 1,3-galactose (alpha-Gal) is abundantly expressed on nonprimate mammalian proteins. We have recently shown that alpha-Gal is responsible for the IgE binding to cat IgA, a newly identified cat allergen (Fel d 5). OBJECTIVE: We sought to investigate the diagnostic relevance of IgE antibodies to Fel d 5 and alpha-Gal among parasite-infected patients from central Africa without cat allergy compared with patients with cat allergy from the same region. METHODS: Sera from 47 parasite-infected patients and 31 patients with cat allergy were analyzed for total IgE and IgE antibodies against cat dander extract (CDE) by using the ImmunoCAP system. Inhibition assay was performed with alpha-Gal on solid phase-bound CDE. The presence of IgE specific for the major cat allergen Fel d 1, Fel d 5, and alpha-Gal was analyzed by means of ELISA. RESULTS: Among the 47 parasite-infected patients, 85% had IgE antibodies against alpha-Gal (OD; median, 0.175; range, 0.102-1.466) and 66% against Fel d 5 (OD; median, 0.13; range, 0.103-1.285). Twenty-four of the parasite-infected patients were sensitized to CDE, and 21 of them had IgE antibodies to Fel d 5 and alpha-Gal. There was no correlation between IgE levels to CDE and rFel d 1 among the parasite-infected patients but a strong correlation between CDE and Fel d 5 and alpha-Gal (P < .001). Among the group with cat allergy, only 5 patients had IgE to alpha-Gal, and nearly 75% (n = 23) had IgE to rFel d 1 (median, 7.07 kU(A)/L; range, 0.51-148.5 kU(A)/L). In contrast, among the patients with cat allergy, there was a correlation between IgE levels to CDE and rFel d 1 (P < .05) but no correlation between CDE and Fel d 5 and alpha-Gal. CONCLUSION: IgE to alpha-Gal causes impaired allergy diagnostics in parasite-infected patients. Screening for IgE to rFel d 1 and other allergens without carbohydrates might identify patients with true cat sensitization/allergy in parasite-infested areas. |
Journal of Allergy and Clinical Immunology. 2011 Apr 1;127(4):1024-8. | Arkestal Gronlund; Africa; Zimbabwe; cat allergy; non-tick vector; parasite; helminth; geohelminth; Ascaris lumbricoides; Ascaris lumbricoides; Necator americanus; hookworm; Ancylostoma duodenaleschistosome; schistosomiasis |
| Armentia A, Martin-Gil FJ, Pascual C, Martin-Esteban M, Callejo A, Martinez C | 2006 | Anisakis simplex allergy after eating chicken meat. Background: Allergic reactions to food can be produced by contaminants that induce sensitization. Among these, Anisakis simplex can cause seafood infestation, and allergic symptoms (urticaria–angioedema, anaphylaxis, and asthma) can follow the eating or handling of affected fish. Although seafood is the principal source of human infections by this parasite, we have found allergic symptoms in 8 patients previously diagnosed as having A simplex sensitization after they ate chicken meat. Chicken feed usually has a high proportion of fishmeal, which might possibly be contaminated by this nematode. Objective: The aim of our study was to determine whether parasite proteins present in chicken meat could be responsible for the symptoms reported by these subjects. Methods: We carried out in vivo tests (prick, bronchial challenge, and double-blind placebo-controlled challenge with meat chicken) in these 8 patients. We performed immunoblotting using the sera from the 8 patients and controls in order to detect A simplex sensitization. We also investigated the presence of A simplex proteins in sera from chickens fed with fishmeal and in other sera from chickens fed only with cereals. We excluded sensitization to other chicken nematodes by serologic methods. Results: All 8 patients presented positive prick and challenges to A simplex. When we used serum from chickens fed with fishmeal as the antigen in blotting, patients 3, 4, 5, 6, 7, and 8 recognized a band of 16 kd, also obtained when using pools of fish–shellfish and A simplex larva. No detection was observed with sera from chickens fed with only cereals. Conclusion: We provide evidence, based on in vivo and in vitro tests, that subjects highly sensitized to A simplex can detect the presence of Anisakis species allergens in chicken meat. |
Journal of Investigational Allergology and Clinical Immunology. 2006 Jan 1;16(4):258. | Chicken diet |
| Armstrong P, Binder A, Amelio C, Kersh G, Biggerstaff B, Beard C, Petersen L, Commins S. | 2019 | Descriptive Epidemiology of Patients Diagnosed with Alpha-gal Allergy—2010–2019. Rationale: Alpha-gal allergy is an immunoglobulin E (IgE) mediated allergy to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate found in mammalian meat. Clinical presentation ranges from hives to anaphylaxis, and episodes typically occur 3–6 hours after ingestion of meat. Exposure to the Lone Star tick (Amblyomma americanum) has been implicated as the primary risk factor for developing alpha-gal allergy. Methods: We performed a retrospective, descriptive analysis of randomly selected patients with alpha-gal allergy, with at least one positive (IgE ≥ 0.1) test, who presented for care during 3/2010–3/2019. Data were collected through medical chart review and analyzed using SAS v9.4 (Cary, NC). Results: Of 100 patients, median age at onset was 53 years (IQR 42-60), 56% were female, and 95% reported Caucasian race. Pre-existing food allergies were rare. Nearly all (86, 97%) reported history of tick or chigger bite prior to onset. On average, patients experienced 3 episodes before diagnosis. Common symptoms included hives (63%), abdominal pain (39%), and nausea/vomiting (33%). The most commonly reported triggers were beef (42%), dairy (33%), pork (26%) and red meat (26%). Conclusions: Alpha-gal allergy occurs predominantly in Caucasian adults. Previously noted trends, such as report of tick bite, and lack of prior food allergies were also seen in this cohort. Hives is the most commonly reported symptom; however, gastrointestinal involvement remains prominent. Dairy was reported as a trigger in a larger proportion of patients than has been seen in other studies. Continued understanding of this condition is important for detection and clinical management. |
Journal of Allergy and Clinical Immunology. 2020 Feb 1;145(2):AB145. | CDC; epidemiology; symptoms; triggers; dairy; gastrointestinal; GI |
| Arnold DF, Misbah SA. | 2008 | Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. TO THE EDITOR: Chung and colleagues (March 13 issue)1 found IgE antibodies to galactose-α-1,3-galactose in pretreatment serum samples from 17 of 25 patients who had hypersensitivity reactions to cetuximab, whereas IgE antibodies were found in only 1 of 51 patients who did not have a hypersensitivity reaction. If, as suggested, the presence of such antibodies in pretreatment samples is predictive of anaphylaxis, pretreatment testing would help in minimizing the risk of anaphylaxis associated with cetuximab. It would be important to know whether skin testing was done in the study patients, and if so, whether the results were concordant with the presence of IgE antibodies to cetuximab. |
The New England journal of medicine. 2008 Jun 1;358(25):2735-author. | biologics; biological agents; monoclonal antibody; mAb; cetuximab; |
| Arroyo A, Tourangeau, L. | 2015 | Regional anaphylaxis: Not so regional? A case of IgE antibodies to Alpha-Gal after tick bite in California. | ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY. 2015 Nov 1; 115(5):A71-A71. | geography; distribution; West Coast; California; prevalence |
| Arthur CM, Zerra PE, Shin S, Wang J, Song X, Doering CB, Meeks S, Lollar P, Stowell SR. | 2021 | Non-Human Glycans Can Regulate Anti-FVIII Antibody Formation in Mice. |
Blood. 2021 May 21. | medical products; drugs, hemophilia; Recombinant Factor VIII (FVIII) |
| Asaumi T, Ebisawa M. | 2018 | How to manage food dependent exercise induced anaphylaxis (FDEIA). Purpose of review: In recent years, the number of reports on food-dependent exercise-induced anaphylaxis (FDEIA) has been increasing. This review aims to describe the standard management of FDEIA including provocation tests and identify the issues that remain unclear. Recent findings: Provocation tests with aspirin for FDEIA enable us to confirm the definitive diagnosis and to make differential diagnosis. In some cases, FDEIA symptoms can be induced by aspirin and the causative food without exercise. Exercise may only be an augmenting factor of FDEIA, similar to aspirin or alcohol. Summary: The mechanisms of FDEIA development remain unclear. It has been suggested that in FDEIA, exercise lowers the threshold of a food allergy. Further research is needed to elucidate the mechanism of FDEIA and to establish strategies for effective disease management. |
Current opinion in allergy and clinical immunology. 2018 Jun 1;18(3):243-7. | cofactor |
| Atkins J. | 2020 | Regulating the Impending Transformation of the Meat Industry:" Cultured Meat". |
J. Tech. L. & Pol'y. 2019;24:1. | Cultured meat; cell-based meat; law; legal; FDA; USDA |
| Atkinson C, Hatch, R. | 2018 | Resolution of galactose alpha 1-3 galactose (Alpha-Gal) anaphylaxis after tick and hooved meat avoidance. Introduction: Anaphylatic reactions to Alpha-Gal carbohydrate epitope commonly present in meat of hooved animals and are recognized as an important cause of delayed anaphylaxis. Tick bites appear to be a necessary cofactor in developing sensitization to Alpha-Gal. Case Description: Our patient is a 53-year-old female living in Oklahoma who presented to the clinic in 2011 with a two-year history of pruritis, hives, throat tightness, and facial swelling. Symptoms occurred at night after consuming corn or potato chips which had previously been tolerated. Prior to presentation, she had labs drawn which showed elevated counts to pork and beef. It was discovered that six hours after consuming meat she had these episodes and reported having tick bites from her dogs. Percutaneous tests with allergenic extracts showed minimal activity to fresh beef and lamb. Alpha-gal specific IgE was elevated at 65.8 kU/L and she was advised to avoid all meat products except poultry and fish. At four-month follow-up, she continued to avoid pork and beef without further events and had no new tick bites. She had her dogs and home treated for ticks and moved to a new house. At six years after presentation, she reintroduced small amounts of well cooked meat products without problems. Alpha-Gal specific IgE was 0.47 kU/L and continued to decline despite continued meat consumption. . Discussion: This case implies that, at least in this patient, both tick bites and meat exposure are necessary to maintain sensitization. Reintroducing the meat alone without tick exposure did not result in re-sensitization. |
Annals of Allergy, Asthma & Immunology. 2018 Nov 1;121(5):S117. | Oklahoma; vector; tick; sero-reversion |
| Atwal D, Safar AM, Govindarajan R, Makhoul I. | 2019 | Severe first infusion reaction related to cetuximab in cancer patients in Arkansas. Introduction: Cetuximab, a chimeric monoclonal antibody, is a commonly used anticancer drug that prevents binding of epidermal growth factor to epidermal growth factor receptor. It has been widely used in a variety of cancers since its initial approval by the FDA in 2004. Despite its efficacy, it has met with some genuine concerns especially regarding the anaphylactoid reactions occurring after first infusions. Cetuximab-related first infusion reaction has been found to be much more prevalent in the Southeastern United States with several studies from the southern United States supporting it. The purpose of our study was to determine the rate of first infusion reaction in the state of Arkansas and the factors that could predispose to first infusion reaction.Methods and results: We performed a retrospective chart review of consecutive patients who received cetuximab between January 2004 and December 2016 at the University of Arkansas for Medical Sciences. We included a total of 220 patients in our analysis out of which 32 (14.5%) developed cetuximab-related first infusion reaction. There was a statistically significant increased risk in males versus females (18.2% vs. 8.4%, P = 0.045) and trend toward significance for the difference between Caucasians and Blacks (16.5% vs. 7.1%, P = 0.054).Conclusion: There is increased incidence of cetuximab-related first infusion reaction in Arkansas which is much higher than the national average but comparable to the incidence in other neighboring states in the Southeastern United States. This increased incidence tends to cluster in Caucasian males. Safer alternatives should be preferred for treatment of cancers particularly in the Southeastern United States whenever possible. |
Journal of Oncology Pharmacy Practice. 2019 Jul;25(5):1130-4. | pharmacy; pharmaceutical; medication; biologic; biological agent; monoclonal antibody; mAb; cetuximab; demographics; race |
| Avila SA, Wojno T. | 2022 | Alpha-Gal Syndrome: A New Etiology for Periorbital Edema. Alpha-gal syndrome is characterized by an IgE-mediated hypersensitivity response to the carbohydrate galactose-alpha-1,3-galactose. It can manifest as both an immediate drug allergy to pharmaceuticals containing alpha-gal as well as a delayed hypersensitivity response to the ingestion of mammalian meat products. In the United States, sensitization to alpha-gal is thought to occur from tick bites and can cause severe angioedema, most commonly periorbitally and periorally, with high rates of anaphylaxis. We present a unique case of chronic periorbital edema in a carnivorous individual after acquiring a new red meat allergy from Alpha-Gal Syndrome. |
Ophthalmic Plastic and Reconstructive Surgery. 2022 Feb 15. | Ophthalmology; edema; nocturnal symptoms |
| Backer E, Carroll J. | 2016 | 1742: Delayed anaphylaxis following mammalian meat consumption: An Evolving vector-born process. Our patient is a 69-year-old male who presented with an anaphylactic reaction. He has no known allergies or co-morbidities. A history revealed consumption of steak 6 hours before symptom onset of generalized urticaria, angioedema and dyspnea. |
Critical Care Medicine. 2016 Dec 1;44(12):511. | Emergency medicine; critical care; first responder |
| Backer E, Carroll J. | 2016 | A Case of Unexplained Shock Following Steak Consumption. INTRODUCTION: Delayed anaphylaxis following red meat consumption is a novel phenomenon in the Southwestern United States. This presentation will illustrate a case of IgE mediated activity against the galactose-a-1,3-galactose (alpha-gal) epitope. This carbohydrate determinant is common in humans and isotope switching to alpha-gal IgE occurs following ectoparasite exposure. First described in 2009, early case reports led to identification of the Amblyomma americanum, or lone star tick, as the sensitizing exposure. We present the first reported case of anaphylaxis in New Hampshire from red meat consumption following alpha-gal sensitization. CASE PRESENTATION: Our patient is a 69-year-old male who presented with an anaphylactic reaction. He has no known allergies or co-morbidities. A history revealed consumption of steak 6 hours before symptom onset of generalized urticaria, angioedema and dyspnea. Treatment included anti-histamines, steroids, and epinephrine. It was later divulged he sustained a tick bite 5 weeks prior to this admission. Further work-up identified a total IgE of 129 kU/L and an elevated alpha-gal IgE of 10 kU/L (normal #0.34 kU/L). His history and serologic testing allowed us to confirm a diagnosis of delayed anaphylaxis due to a red meat allergy. He made a full recovery, and received follow-up in our Allergy clinic and counseling on red meat avoidance. DISCUSSION: IgE sensitization to the oligosaccharide alpha-gal following exposure to the lone star tick is described largely in the southeastern United States. After red meat ingestion, a delayed anaphylactic reaction may occur. The diagnosis should be suspected when caring for the patient with anaphylaxis of unclear etiology, and is confirmed using an IgE specific immunoassay. Treatment in the acute setting is supportive, and long-term care includes avoidance of mammalian meats and prevention of further tick exposure. CONCLUSIONS: This case demonstrates a vector-associated sensitivity leading to delayed anaphylaxis following consumption of mammalian meat. It is the first documented occurrence in our state, supporting the described geographic spread of the lone start tick. Practitioners should maintain this condition on their differential as it becomes increasingly recognized in non-endemic regions. |
Chest. 2016 Oct 1;150(4):1139A. | Northeast; New Hampshire; idiopathic anaphylaxis |
| Baczako A, Ollert M, Biedermann T, Darsow U. | 2015 | Recurrent anaphylaxis in an 18-year old-a case of alpha-gal allergy: 1196. No abstract available |
Not available | |
| Baker MG, Sampson HA. | 2018 | Phenotypes and endotypes of food allergy: A path to better understanding the pathogenisis and prognosis of food allergy. Key Messages • Proper identification of phenotypes and endotypes of IgE-mediated food allergy may allow for more meaningful investigation of underlying pathobiologic mechanisms that can ultimately improve our approach to treatment. • Both phenotype and endotype are determined by genotype, inherited epigenetic factors and environmental factors. • Proposed phenotypes and respective endotypes include: Classic (persistent, transient, food-dependent exercise-induced, NSAID-dependent, alcohol-dependent), Intermittent and Cross-Reactive, Aerosol Sensitization (local reactions to aerosolized cross reactant antigens, systemic reactions to aerosolized forms of food-specific antigens), α-Gal syndrome and Sensitized Nonreactive. • A formalized cluster analysis of patients with food allergy to refine phenotype and endotype identification remains an area of opportunity in our field. |
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology. 2018 Mar;120(3):245. | |
| Bakhtiar M, Leong K, Kwok F, Hui M, Tang M, Joseph C, Bathumana‐Appan P, Nagum A, Yadzir ZHM, Murad, S. | 2017 | † P66: ALLERGIC REACTION TO BOVINE GELATIN COLLOID: THE ROLE OF IMMUNOGLOBULIN E TOWARDS GALACTOSE-ALPHA-1,3-GALACTOSE: IMPLICATIONS BEYOND RED MEAT ALLERGIES. Background: The bovine gelatin colloid is a recognised cause of adverse reactions, albeit uncommon. It is noteworthy that many patients with red‐meat‐derived gelatin allergy may have negative specific Immunoglobulin E (sIgE) antibody to the conventional red‐meat‐derived gelatin immunoassay. Bovine gelatin colloids have been shown to contain about 0.44 ± 0.2 mcg/g to 0.52 ± 0.1 mcg/g of galactose‐alpha‐1,3‐galactose (alpha‐gal). It has been demonstrated that sIgE towards the alpha‐gal moiety may cause life‐threatening anaphylactic reactions with wide ranging implications. Method: We describe three patients with an allergic reaction to bovine gelatin colloid who had positive skin test to Gelofusine and sIgE to alpha‐gal but negative sIgE to bovine gelatin. . Report: All three patients presented with suspected perioperative anaphylaxis. None of them had any history of asthma, allergic rhinitis, atopic eczema, drug, latex, cow’s milk and/or cat allergy. Two patients had history suggestive of beef allergy but none reported any allergy to gelatin containing food. They were all investigated via skin and in vitro tests after an eventful course of general anaesthesia. Skin testing to cetuximab was not performed due to costs consideration. All patients had a positive intradermal test to Gelofusine. Results for sIgE to bovine gelatin and alpha‐gal were negative (≤0.1 kU/L) and positive (range 0.25–14.8 kU/L) respectively, for all patients. Two patients had positive sIgE to beef, mutton and cow’s milk (range 0.26–1.22 kU/L). Cat dander sIgE was positive for one patient (0.12 kU/L). Total IgE was raised in all patients (range 214–1483 kU/L). Baseline tryptase level of all patients was not raised (range 3.73–4.98 μg/L). . Conclusion: It appears that the diagnosis of alpha‐gal‐related gelatin sensitisation and allergy may readily be missed by a conventional gelatin sIgE assay. Possibly, the allergenic target for the gelatin immunoassay does not include the alpha‐gal moiety. |
Internal Medicine Journal. 2017 Sep;47:24. | perioperative care; gelatin; gelatine; plasma volume expander; plasma volume substitute |
| Bandino ML, Gomez R, Waibel K. | 2013 | SAFETY OF ZOSTER LIVE VACCINE IN AN ADULT WITH alpha-GAL ALLERGY. No abstract available |
Annals of Allergy Asthma & Immunology 2018; 111 (5), A71-A71. | vaccination; vaccine; herpes zoster |
| Bansal RA, Bahal S, O’Brien R, Miller J, Bansal AS, Yong PF. | 2021 | The first reported cases of meat allergy following tick bites in the UK. Allergic reactions frequently involve the production of immunoglobulin E (IgE) antibodies to proteins. However, reactions directed against carbohydrate moieties are increasingly being recognised. Tick bites can contribute to the development of immunoglobulin E to the galactose-1,3-galactose (alpha-gal) moiety on tick salivary proteins. These IgE molecules can cross-react with alpha-gal found in red meats, causing Type I IgE-mediated hypersensitivity reactions to these foods. We present three cases of delayed reactions to beef, pork and lamb in patients with prior tick bites and in the presence of a positive-specific IgE to alpha-gal. Patients were advised to avoid red meat consumption and to carry emergency treatment in the form of anti-histamines with or without adrenaline autoinjector devices. This is the first published report of red meat allergy caused by tick bites suffered in the UK |
JRSM open. 2021 Apr;12(4):2054270421996131. | Europe; UK |
| Barbaud A, Granel F, Waton J, Poreaux C. | 2011 | † How to manage hypersensitivity reactions to biological agents? Biological agents induce cutaneous adverse drug reactions (CADR) different from those observed with xenobiotics. Type alpha is the cytokine release syndrome, type beta are hypersensitivity reactions and type gamma is a cytokine imbalance syndrome. Infusion-reactions, anaphylactoid reactions occur with various biological agents administered intravenously. In non-severe cases the infusion rate has to be reduced, in severe reactions, the treatment must be stopped, and resuscitation carried out with corticosteroids and epinephrine. Reactions may be due to an alpha syndrome but a true allergy could be involved as demonstrated in some patients with IgE antibodies to the galactose-alpha-1,3-galactose portion of the cetuximab or anti infliximab-IgE. Some desensitisation protocols have been published. Non allergic itching and eczema-like lesions are frequent with epidermal growth factor receptor inhibitors. Rash or desquamation was observed in 40% of cases with antiangiogenic agents, 90% of patients treated with imatinib have rashes, oedema or pruritus and a non-allergic periorbital oedema. Severe CADR, such as Stevens-Johnson syndrome, can be provoked. Delayed readings of intradermal tests could be of value in managing patients with a maculopapular rash due to interferon. Anaphylaxis attributed to omalizumab seems to be rare (0.2%) and skin rashes occur in 7% of cases. Anaphylactoid reactions occur in 1% of patients treated with natalizumab. In the case of anti-natalizumab antibody-mediated reactions, treatment should be stopped. These allergic-like side effects of new biological agents must be known and reported to Pharmacovigilance agency networks. |
European Journal of Dermatology. 2011 Oct 1;21(5):667-74. | biologic; mAb; monoclonal antibody; biological agent |
| Bardash Y, Tham T, Olson C, Khaymovich J, Costantino P. | 2019 | Anaphylactoid hypersensitivity reaction from intra-arterial cetuximab: Clinical considerations and management. Intra-arterial infusion of drugs shows promising results in terms of safety and efficacy. Intra-arterial cetuximab, a monoclonal antibody treatment, is currently being tested for its use in head and neck cancers. We present the case of a 45-year-old Asian male who developed an anaphylactoid hypersensitivity reaction, manifesting itself in the form of bronchospasm, tachycardia, and hypotension, during intra-arterial infusion of cetuximab. The symptoms were quickly diagnosed, and the patient was treated accordingly. Despite the safety profile of cetuximab and the decreased risk of systemic effects with intra-arterial infusion versus intravenous infusion, severe hypersensitivity reactions are still a risk in intra-arterial cetuximab infusions. Consequently, proper planning and care must be taken to prophylactically prevent and in the case of a reaction, treat the reaction accordingly. The case presented herein is, to the best of our knowledge, the first recorded moderate-to-severe infusion reaction in a patient receiving intra-arterial cetuximab treatment for head and neck cancer. |
SAGE open medical case reports. 2019 Jan;7:2050313X18823447. | |
| Barreiro LB, Chervonsky A. | 2021 | My Old World chap, this α-gal is not for you. 30 million years ago, ancestors of Old World primates lost the ability to produce α-gal. In this issue of Cell Host & Microbe, Singh et al. (2021) show that the loss is associated with increased resistance to sepsis, but that this advantage comes alongside a cost of accelerated reproductive senescence. |
Cell Host & Microbe. 2021 Mar 10;29(3):315-7. | Evolution; catarrhine primates |
| Baumgart KW, Broadfoot AJ, Van Nunen SA. | 2019 | Sensitisation and sero-reversion to tick bite induced galactose-1,3-alpha-galactose, meat and dairy sensitisation in New South Wales, Australia. | Allergy. 2019 Aug; 74:509-509. | Asia; Aulstralia; sensitization; sero-reversion |
| Beaman MH. | 2018 | Non-infectious illness after tick bite. Tick bites are common and may have non-infectious complications. Reactions range from local reactions to systemic syndromes, tick paralysis, mammalian meat allergy and tick anaphylaxis. Management revolves around prevention with vector avoidance and immediate removal of the tick if bitten. Treatment of bite reactions is usually symptomatic only with antihistamines or corticosteroids. Adrenaline may be indicated for severe cases. |
Microbiology Australia. 2018 Nov 27;39(4):212-5. | Australia; tick paralysis; tick anaphylaxis |
| Beaudouin E, Thomas H, Nguyen-Grosjean VM, Picaud J, Moumane L, Richard C, Léon A, Jacquenet S, Sabouraud-Leclerc D, Renaudin JM, Barbaud A, Moneret-Vautrin DA. | 2015 | Allergie à galactose-α-1,3 galactose (α-Gal) : une observation singulière et revue bibliographique. Résumé Les auteurs rapportent une observation singulière induite par galactose-α-1,3 galactose (α-Gal) et se proposent de faire ainsi une revue bibliographique sur le sujet. English translation: Allergy to galactose-α-1,3 galactose (α-Gal): Case report and literature review. The authors report a singular case about mammalian meat anaphylaxis due to galactose-alpha-1,3 galactose (alpha-Gal) and review the current literature. |
REVUE FRANCAISE D ALLERGOLOGIE. 2015;55(7):492-7. | review article; Europe; France |
| Beauti S. | 2021 | Molecular Characterization of Tick Galectin in Context of α-Gal Syndrome. α-Gal Syndrome (AGS) is a tick-borne delayed hypersensitivity reaction that occurs 3-6 hours after red meat consumption. It is induced by oligosaccharide galactose-α-1,3-galactose (α-gal) found in the Lone Star tick, Amblyomma americanum, and all mammalian-derived foods. α-gal specific IgE (sIgE) antibodies are produced after α-gal transmission from the tick bite and activates after subsequent red meat consumption. Previously, an immune-affinity approach utilized α-Gal antibody to isolate and identify covalently linked tick saliva antigens to α-gal followed by Liquid Chromatography-tandem Mass Spectrometry (LS-MS/MS) analysis. The identified antigen included tick salivary Galectin, a carbohydrate-binding protein involved in many physiological functions such as inflammation and immune responses. The goal of this study is to characterize the A. americanum Galectin protein and its involvement in AGS. Our qRT-PCR results revealed decreased gene expression of Galectin in different stages of the bloodmeal. We utilized an RNA interference (RNAi) approach to silence Galectin gene expression and assessed the functional consequences of gene depletion on tick behavior, phenotype, and tick molting. The silencing of Galectin did not have a significant impact on α-gal. However, Galectin knockdown (KD) did cause a significant downregulation in galactose metabolism related genes. Galectin-silenced ticks showed impaired oviposition and increased microbial load. We are currently conducting experiments to further characterize the role of Galectin in microbial maintenance, galactose metabolism and reproductive development to determine possible links between Galectin and α-gal. |
Mississippi Undergraduate Honors Conference 2021 The Certainty of Uncertainty: Research in an Ever-Changing World. 2. | tick galectin |
| Behmer RG, Thomas RS, Jarawan HT. | 2022 | Urticarial Rash in a Patient with Alpha-Gal Syndrome Caused by Subcutaneous Heparin at Prophylactic Dosing: A Case Report. Introduction: We report a patient with a history of red meat allergy, or alpha-gal syndrome, who had an urticarial rash after exposure to unfractionated heparin at a dose typically used for prophylaxis of deep venous thrombosis. Although anaphylactic reactions have been reported with systemic intravenous heparin, we believe this case is the first report of an immunoglobulin E–mediated reaction to subcutaneous heparin at prophylactic dosing. > Clinical Findings: An 85-year-old male had a 3-year history of red meat allergy and was intolerant of pork and beef. He developed an immunoglobulin E–mediated allergic reaction to subcutaneous heparin at a dose of 5000 units twice daily. > Clinical Course: The patient presented to the emergency department after a fall. He had back pain and was diagnosed with a compression fracture. He was admitted to the hospital because he was unable to safely ambulate. He was treated with subcutaneous unfractionated heparin to prevent deep venous thrombosis as part of routine care. Twenty-four hours after exposure to heparin, he developed an urticarial rash. The rash resolved promptly after discontinuing heparin and excluding other potential allergic triggers. > Conclusions: In patients with alpha-gal syndrome, unfractionated heparin via a subcutaneous route at prophylactic dosing can precipitate immunoglobulin E–mediated systemic reactions and should be avoided. |
Journal of Maine Medical Center. 2022;4(2):9. | surgery; perioperative; medical products; heparin |
| Bellamy P, Sanderson WT, Winter K, Stringer JW, Kussainov N, Commins SP. | 2020 | Prevalence of Alpha-gal Sensitization among Kentucky Timber Harvesters and Forestry and Wildlife Practitioners. This study shows that persons in occupations such as timber harvesting and forestry and wildlife practitioners who encounter frequent exposure to ticks may have a high prevalence of sensitization to the sugar molecule galactose-α-1,3-galactose. Clinicians who treat patients in occupations with frequent exposure to ticks, or with mild to severe gastrointestinal reactions when they eat red meat, should assess sensitization to galactose-α-1,3-galactose. |
The Journal of Allergy and Clinical Immunology: In Practice. 2020 Dec 17. | |
| Beltrán-Cárdenas CE, Granda-Restrepo DM, Franco-Aguilar A, Lopez-Teros V, Arvizu-Flores AA, Cárdenas-Torres FI, Ontiveros N, Cabrera-Chávez F, Arámburo-Gálvez JG. | 2021 | Prevalence of Food-Hypersensitivity and Food-Dependent Anaphylaxis in Colombian Schoolchildren by Parent-Report. Background and objectives: The epidemiology of food allergy (FA) and food-dependent anaphylaxis remains unknown in Colombia. Our aim was to estimate by parent-report the prevalence of FA and food-dependent anaphylaxis in a Colombian population of schoolchildren. Materials and methods: A printed questionnaire was sent to parents of schoolchildren aged 5–12 years old from Medellín, Colombia in order to collect FA-related data. Results: Nine hundred and sixty-nine (969) parents returned the questionnaire with valid responses (response rate, 52.5%). The estimated prevalence rates (95% CI) were: adverse food reactions 12.79% (10.76–15.07), “perceived FA, ever” 10.93% (9.08–13.08), “physician-diagnosed FA, ever” 4.33% (3.14–5.81), “immediate-type FA, ever” 6.81% (5.30–8.58), “immediate-type FA, current” 3.30% (2.26–4.63), and food-dependent anaphylaxis 1.85% (1.10–2.92). The most frequently reported food allergens were milk (1.44%), fruits (0.41%), meat (0.41%), and peanut (0.3%). Sixty-one percent of “food-dependent anaphylaxis” cases sought medical attention, but only eleven percent of the cases reported the prescription of an epinephrine autoinjector. Conclusions: FA and food-dependent anaphylaxis are not uncommon among schoolchildren from Colombia. The prescription of epinephrine autoinjectors should be encouraged among health personnel for the optimal management of suspected cases of food-dependent anaphylaxis. Excerpts: "The main triggers of FA reactions in Colombian schoolchildren were milk, fruits, meat, and peanut." "Notably, the presence of 26 species of ticks of the genus Amblyomma has been reported in Colombia and at least 7 of these species are common in the Medellín area (on Antioquia department) [32]. However, a potential high prevalence of alpha-Gal sensitization or meat allergy due to the alpha-Gal allergenic epitope will require evaluations with objective diagnostic criteria. At the moment, our results highlight the need for future studies to evaluate alpha-gal sensitization in this population." |
Medicina. 2021 Feb;57(2):146. | Latin America; Colombia; Amblyomma |
| Bensinger A, Green P. | 2019 | Mammalian Meat Allergy Masquerading as IBS-D: 1846. INTRODUCTION: Mammalian meat allergy, often referred to as alpha gal allergy, is a recently discovered and increasingly prevalent condition with a wide range of clinical manifestations resulting from an allergic reaction mediated by IgE antibodies directed against galactose-alpha-1,3-galactose. Patients can frequently experience nausea, diarrhea, indigestion, urticaria, angioedema or anaphylaxis typically arising three to six hours after ingestion of mammalian protein. Interestingly, patients have longstanding tolerance to mammalian meats years before symptom onset and were bitten by the lone star tick, Amblyomma americanum, prior to symptom onset. We present a case of mammalian meat allergy diagnosed after the discovery of a tick on a patient’s lower extremity during a colonoscopy. CASE DESCRIPTION/METHODS: A 64-year-old female with a history of IBS-D presented to our clinic several years of chronic urticaria, diarrhea, nausea and abdominal pain, typically occurring after food intake. An extensive workup of chronic diarrhea was largely unrevealing. However, during a colonoscopy a tick was discovered on the patient’s inner thigh and was removed. Given her symptom complex, additional blood work was pursued and revealed elevated levels of serum alpha gal IgE. Further history revealed multiple prior tick bites with severe localized skin reactions in the past. At a follow-up visit after avoidance of mammalian meat and byproducts, the patient reported a 90% improvement in her symptoms, with just one formed bowel movement per day. She continued to have some bloating and abdominal pressure, but overall her symptoms were drastically improved with a modified diet. DISCUSSION: This case illustrates the challenges in identifying alpha gal allergy, a unique and frequently misdiagnosed allergic condition that is increasing in prevalence. The clinical presentation of alpha gal is unique when compared to other food allergies as there are a lack of immediate oral symptoms and episodes only occur after lone star tick exposure. Additionally, onset of symptoms occurs three to six hours after mammalian meat consumption, making its association difficult to uncover. The case also highlights the importance of taking a thorough history, with higher suspicion in patients with recurrent episodes of urticaria, angioedema, gastroenteritis, or anaphylaxis without an obvious cause. Thus, improved awareness of alpha gal allergy is essential, particularly for providers located in endemic areas like the southeastern United States. |
American Journal of Gastroenterology. 2019 Oct 1;114(2019 ACG Annual Meeting Abstracts):S1036-7. | gastroenterology; gastrointestinal symptom; GI; IBD; IBS; differential; misdiagnosis |
| Berends AMA, & Elberink JNGO. | 2017 | The alpha-gal syndrome: an allergic reaction to mammalian meat secondary to a tick bite. / Het alfa-galsyndroom, allergische reacties op vlees: allergie voor zoogdierenvlees secundair aan een tekenbeet. Here we present the case of a 68-year-old patient with alpha-gal syndrome. This is a delayed-onset allergic reaction, characteristically occurring 2-6 hours after ingestion of mammalian meat products. The reaction occurs because the patient has developed IgE antibodies to a mammalian oligosaccharide epitope, galactose-α-1,3-galactose (alpha-gal); tick bites induce this IgE antibody response. Presentation varies from chronic urticaria to life-threatening anaphylaxis. The alpha-gal syndrome is usually self-limiting as long as there are no new tick bites. Clinicians should be aware of this syndrome, which is often not recognized as such. |
Nederlands Tijdschrift Voor Geneeskunde. 2017; 161:D1062. | Europe; Netherlands |
| Berg EA, Platts-Mills TAE, Commins SP. | 2014 | Drug allergens and food-the cetuximab and galactose-alpha-1,3-galactose story. Objective: A novel form of food allergy has been described that initially became apparent from IgE reactivity with the drug cetuximab. Ongoing work regarding the etiology, distribution, clinical management, and cellular mechanisms of the IgE response to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) is reviewed. Data Sources: Brief review of the relevant literature in peer-reviewed journals. Study Selection: Studies on the clinical and immunologic features, pathogenesis, epidemiology, laboratory evaluation, and management of IgE to alpha-gal are included in this review. Results: Recent work has identified a novel IgE antibody response to the mammalian oligosaccharide epitope, alpha-gal, that has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Study results have suggested that tick bites are a cause of IgE antibody responses to alpha-gal in the United States. Patients with IgE antibody to alpha-gal continue to emerge, and, increasingly, these cases involve children. Nevertheless, this IgE antibody response does not appear to pose a risk for asthma but may impair diagnostic testing in some situations. Conclusion: The practicing physician should understand the symptoms, evaluation, and management when diagnosing delayed allergic reactions to mammalian meat from IgE to alpha-gal or when initiating treatment with cetuximab in patients who have developed an IgE antibody response to alpha-gal. |
Annals of Allergy, Asthma & Immunology. 2014 Feb 1;112(2):97-101. | review article; primay care; oncology; cetuximab |
| Bernth Jensen JM, Laursen NS, Jensen RK, Andersen GR, Jensenius JC, Sørensen UBS, Thiel S. | 2020 | Complement activation by human IgG antibodies to galactose‐α‐1, 3‐galactose. Some human antibodies may paradoxically inhibit complement activation on bacteria and enhance pathogen survival in humans. This property was also claimed for IgG antibodies reacting with terminal galactose‐α‐1,3‐galactose (Galα3Gal; IgG anti‐αGal), a naturally occurring and abundant antibody in human plasma that targets numerous different pathogens. To reinvestigate these effects, we used IgG anti‐αGal affinity isolated from a pool of normal human IgG and human hypogammaglobulinaemia serum as a complement source. Flow cytometry was performed to examine antibody binding and complement deposition on pig erythrocytes, Escherichia coli O86 and Streptococcus pneumoniae serotype 9V. Specific nanobodies were used to block the effect of single complement factors and to delineate the complement pathways involved. IgG anti‐αGal was capable of activating the classical complement pathway on all the tested target cells. The degree of activation was exponentially related to the density of bound antibody on E. coli O86 and pig erythrocytes, but more linearly on S. pneumoniae 9V. The alternative pathway of complement amplified complement deposition. Deposited C3 fragments covered the activating IgG anti‐αGal, obstructing its detection and highlighting this as a likely general caveat in studies of antibody density and complement deposition. The inherent capacity for complement activation by the purified carbohydrate reactive IgG anti‐αGal was similar to that of normal human IgG. We propose that the previously reported complement inhibition by IgG anti‐αGal relates to suboptimal assay configurations, in contrast to the complement activating property of the antibodies demonstrated in this paper. |
Immunology. 2020 Jul 14. | |
| Bernth Jensen JM, Petersen MS, Ellerman-Eriksen S, Møller BK, Jensenius JC, Sørensen UB, Thiel S | 2020 | Abundant human anti-Galα3Gal antibodies display broad pathogen reactivity. Antibodies of the IgG class to terminal Galα3Gal (IgG anti-αGal) is abundant in human plasma and are reported to bind most sepsis-causing Gram-negative bacteria. However, these seminal findings, made more than two decades ago, have not been reexamined. Our aim was to assess IgG anti-αGal´s pathogen reactivity. We affinity purified IgG anti-αGal from a therapeutic grade normal human IgG pool applying two rounds of positive selection with Galα3Gal-coupled beads and included removal of column matrix reactive antibodies. The purified antibodies were rigorously characterized in terms of specificity and purity in various solid-phase immunoassays. We used flow cytometry to study reactivity against 100 consecutive clinical isolates diagnosed as cause of sepsis in humans. We found that the purified IgG anti-αGal displays high specificity for Galα3Gal. Also, IgG anti-αGal at 5 mg/L bound 56 out of 100 pathogens with predilection for Gram-positive bacteria binding 39 out of 52 strains. We confirm that although IgG anti-αGal comprise a small fraction of the human antibody pool (~0.1%), these antibodies targets an impressively large part of pathogens causing invasive disease. |
Scientific reports. 2020 Mar 12;10(1):1-3. | |
| Bernth Jensen JM, Skeldal S, Petersen MS, Møller BK, Hoffmann S, Jensenius JC, Sørensen UBS, Thiel S. | 2020 | The human natural anti‐αGal antibody targets common pathogens by broad‐spectrum polyreactivity. Naturally occurring antibodies are abundant in human plasma, but their importance in the defense against bacterial pathogens is unclear. We studied the role of the most abundant of such antibodies, the antibody against terminal galactose‐α‐1,3‐galactose (anti‐αGal), in the protection against pneumococcal infections (Streptococcus pneumonia). All known pneumococcal capsular polysaccharides lack terminal galactose‐α‐1,3‐galactose, yet highly purified human anti‐αGal antibody of the IgG class reacted with 48 of 91 pneumococcal serotypes. Anti‐αGal was found to contain multiple antibody subsets that possess distinct specificities beyond their general reactivity with terminal galactose‐α‐1,3‐galactose. These subsets in concert targeted a wide range of microbial polysaccharides. We found that anti‐αGal constituted up to 40% of the total antibody reactivity to pneumococci in normal human plasma, that anti‐αGal drives phagocytosis of pneumococci by human neutrophils, and that the anti‐αGal level was 2‐fold lower in patients prone to pneumococcal infections compared to controls. Moreover, during a 48‐year period in Denmark, the 48 anti‐αGal‐reactive serotypes caused fewer invasive pneumococcal infections (n = 10,927) than the 43 non‐reactive serotypes (n = 18,107), supporting protection on the population level. Our findings explain the broad‐spectrum pathogen reactivity of anti‐αGal and support that these naturally occurring polyreactive antibodies contribute significantly to human protective immunity. |
Immunology.2020 Dec 19. | |
| Bernth-Jensen JM, Møller BK, Jensenius JC, Thiel S. | 2011 | Biological variation of anti-alpha Gal-antibodies studied by a novel Time-Resolved ImmunoFluorometric Assay. As much as one percent of antibodies in human plasma are reported to be specific for the non-human disaccharide structure alphaGal. Various microbes express alphaGal. However, the implications of anti-alphaGal antibodies for the anti-microbial defenses are poorly established. With the perspective of studying the biological importance of the antibodies, we have established a sensitive Time-Resolved ImmunoFluorometric Assay (TRIFMA) for quantification of such antibodies. Two versions were developed, one for IgM antibodies and one for IgG antibodies. Samples were collected from plasma donations of healthy adults (n=120) of known gender (60+60), AB0-type (0: 15+15, A: 15+15, B: 15+15, and AB: 15+15) and age (19-64 yrs). We subsequently examined the potential association between antibody concentration and AB0-type, gender, age, and titers of antibodies to blood type antigens. We found that IgG and IgM anti-alphaGal concentrations are, 1) stable over time within the individual, 2) vary more than 400-fold between individuals, 3) negatively correlated with age for IgM but not for IgG antibodies, 4) IgM antibodies are 2-fold higher in females whereas no gender difference was observed for the IgG antibodies, 5) inter-mutual correlated, 6) lowest in individuals expressing B-antigen, and 7) AB0-type A individuals may constitute an intermediate group. Our established method and findings pave the way for further studies of the involvement of anti-alphaGal antibodies in immunity and may be a method to examine the potential of an individual to mount an anti-carbohydrate response. |
Journal of immunological methods. 2011 Oct 28;373(1-2):26-35. | Moller; antibody; IgG; IgM; blood type; demographics; age |
| Berry DC, Britton L, Joseph LM, Jessup A. | 2019 | Alpha-gal: a delayed onset of anaphylaxis and uncoverSensitisation and sero-reversion to tick bite induced galactose-1,3-alpha-galactose, meat and dairy sensitisation in New South Wales, Australia.ing the cause. The current literature on alpha-gal delayed anaphylaxis indicates that it is increasing in incidence. • This article contributes key factors and assessment findings relevant to delayed anaphylaxis. • Key implications for emergency nursing practice found in this article include the importance of nurses' eliciting histories of tick bites and patients' dietary intake within the last 6 hours before presentation to emergency departments. |
2019 Sep 1;45(5):567-9. | nursing; emergency care; first responders |
| Bianchi J, Kuravi K, WALTERS A, Commins S, Sorrells L. | 2023 | Quantitative and qualitative assessment of alpha a-gal in food products. Rationale: Large populations in selected regions are sensitized to galactose-alpha 1,3-galactose (alpha-gal). Sensitized individuals that are exposed to alpha-gal via consumption of mammalian food products are well documented to experience adverse events including GI distress and anaphylaxis. The objective of this study was to characterize relative concentration of alpha α-gal in various food products. Methods: Characterization of alpha α-gal was determined via ELISA, Western and IHC assays. The various food products evaluated included bacon, ham, and dietary supplements (collagen, whey, and pepsin). Porcine a-gal knockout (devoid of a-gal aka GalSafe) derived tissue or products served as negative controls. Results: Analytical analysis indicated presence of alpha-gal in all products from standard mammalian sources (pigs and cows) with relative concentrations exceeding 10 million epitopes per mg. Alpha-gal is undetectable in the negative control(porcine alpha-gal knockout). . Conclusions: Alpha-gal persist at very high concentrations in all mammalian derived food products evaluated. Products sourced from alpha gal knockout pigs had no detectable levels of alpha gal AGS patients did not experience any adverse events upon consumption of porcine a-gal knockout (devoid of a-gal aka GalSafe) food. |
Journal of Allergy and Clinical Immunology. 2023 Feb 1;151(2):AB96. | Food; dietary supplements (collagen, whey, and pepsin) |
| Bianchi J, Walters A, Fitch ZW, Turek, JW. | 2020 | † **Alpha-gal syndrome: Implications for cardiovascular disease Alpha-gal syndrome (AGS) refers to a potentially life-threatening allergy to the molecule galactose-α1,3-galactose (gal), which is expressed on most mammalian tissues but, importantly, is not expressed by humans. This syndrome can manifest as an allergic reaction to mammalian meat products, but other sources of mammalian tissue can also provoke an immune response, including injectable and implantable medical products. This syndrome has been linked to coronary atherosclerosis, and medical products that express gal are routinely used in cardiology and cardiac surgery. This article seeks to discuss potential implications of alpha syndrome as it relates to cardiovascular health and to heighten awareness in the cardiovascular community about this emerging public health issue. |
Global Cardiology Science and Practice. 2020 Feb 9;2019(3). | Perioperative care; cardiac surgery; cardiovacular surgery; cardiology; prevalence; atherosclerosis; CAD coronary artery disease |
| Bianchi J, Walters A, KURAVI K, Sorrells L, Choudhary S, Commins S. | 2022 | Evaluation of an Allergen Free Pig for AGS Patients. Rationale: Allergists have identified populations with high titers of anti-alpha-gal (galactose-alpha1,3-galactose) IgE due to a tick bite that adversely react after exposure to alpha-gal (e.g. alpha-gal syndrome (AGS)). Alpha-gal is present in all mammalian derived food and therapeutic products. Our objective was to characterize tissues from a line of engineered pigs (Gal KO), that is devoid of the allergen, alpha-gal. Methods: In vitro and in vivo comparison of selected tissues from standard and Gal KO pigs. Evaluation consisted of analyte, sensory, and immunohistochemistry analysis. Further, a challenge study was performed in a Gal KO murine model with high titers of alpha-gal IgE. Results: Analytes demonstrated the nutrient values of Gal KO food products are consistent to food products from standard pigs as well as nutrient values published in USDA databases. Gal KO pork samples were consistent with sensory attributes from standard pork samples. Immunohistochemistry revealed sera from AGS patients did not react to Gal KO pork samples. Gal KO mice sensitized with tick extract and subsequently challenged to kidney extract indicate substantial response to standard pig kidney and undetectable response to Gal KO pig kidney. Conclusions: The tissue characteristics of the Gal KO pig are consistent to the standard pig except for undetectable alpha-gal. Food and therapeutic products derived from Gal KO pigs have the potential to be a safer alternative for derivation of food or human therapeutics in the AGS population than currently available mammalian sourced material. |
Journal of Allergy and Clinical Immunology. 2022 Feb 1;149(2):AB202. | knock-out pig; GalSafe pig; food; pork |
| Bickerton M, Toledo A. | 2020 | Multiple pruritic tick bites by Asian Longhorned tick larvae (Haemaphysalis longicornis). This study presents the first report of multiple human bites by larvae of Haemaphysalis longicornis Neumann in the U.S. An adult male working on a public park in Hackensack City (New Jersey) removed eight attached larvae from the arm, armpit, and back. The worker developed small erythematous pruritic lesions that self resolved in two weeks. No other symptoms were associated with the bite. The Asian longhorned tick is not considered an anthropophilic tick species. Still, the parthenogenetic population present in the eastern U.S can reach high numbers in small areas increasing the risk of tick bites to non-specific hosts, including humans. Public health practitioners should become familiar with the Asian longhorned tick, and vectorial competence studies should be carried out to determine the risk of tick-borne disease transmission to humans. |
International Journal of Acarology. 2020 Aug 12:1-4. | vector; tick; Haemaphylis longicornis |
| Biedermann T, Fischer J, Yazdi A. | 2015 | ‡ Mammalian meat allergy: a diagnostic challenge. Introduction: The first national report in the lay press on galactose--1,3-galactose-mediated meat allergy (or red meat allergy) appeared in the German newspaper “Der Spiegel” in December 2012 [1]. Since then, awareness of this clinical picture has increased significantly, not least among affected patients, and it is not infrequent for affected individuals to take the initiative in terms of obtaining a diagnosis. The present report uses the case of an affected female patient as a basis to convey the fundamentals and procedures involved in a disease recognition and diagnosis that has become better understood and more readily diagnosed in recent years, as well as to emphasize the significance of skin tests. |
Allergo journal international. 2015 May 1;24(3):81-3. | Europe; Germany; diagnosis |
| Biedermann T, Röcken, M. | 2012 | Delayed appearance of symptoms in immediate hypersensitivity: type I sensitization to galactose-alpha-1,3-galactose. Delayed immediate-type allergy to innards and red meat can be mediated by IgE antibodies to galactose-alpha-1, 3-galactose (alpha-Gal). Apart from humans and Old World apes, alpha-Gal is ubiquitously expressed in glycoproteins and glycolipids. Thus, as alpha-Gal is immunogenic for humans, they can be easily sensitized even through a tick bite. Anti-alpha-Gal IgG represents approximately 1% of total IgG; IgE antibodies to alpha-Gal are comparably rare. However, in these patients, consuming red meat and especially innards can lead to the development of immediate type reactions such as urticaria. Cetuximab is a humanized IgG1 antibody containing murine alpha-Gal. Therefore, allergic reactions may occur with its first administration. |
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2012 Apr;63:76-9. | Rocken |
| Bilò MB, Martini M, Tontini C, Mohamed OE, Krishna MT. | 2019 | Idiopathic anaphylaxis. Idiopathic anaphylaxis (IA) or spontaneous anaphylaxis is a diagnosis of exclusion when no cause can be identified. The exact incidence and prevalence of IA are not known. The clinical manifestations of IA are similar to other known causes of anaphylaxis. A typical attack is usually acute in onset and can worsen over minutes to a few hours. The pathophysiology of IA has not yet been fully elucidated, although an IgE-mediated pathway by hitherto unidentified trigger/s might be the main underlying mechanism. Elevated concentrations of urinary histamine and its metabolite, methylimidazole acetic acid, plasma histamine and serum tryptase have been reported, consistent with mast cell activation. There is some evidence that corticosteroids reduce the frequency and severity of episodes of IA, consistent with a steroid-responsive condition. Important differential diagnoses of IA include galactose alpha-1,3 galactose (a carbohydrate contained in red meat) allergy, pigeon tick bite (Argax reflexus), wheat-dependent exercise-induced anaphylaxis, Anisakis simplex allergy and mast cell disorders. Other differential diagnoses include "allergy-mimics" such as asthma masquerading as anaphylaxis, undifferentiated somatoform disorder, panic attacks, globus hystericus, vocal cord dysfunction, scombroid poisoning, vasoactive amine intolerance, carcinoid syndrome and phaeochromocytoma. Acute treatment of IA is the same as for other forms of anaphylaxis. Long-term management is individualized and dictated by frequency and severity of symptoms and involves treatment with H1 and H2 receptor blockers, leukotriene receptor antagonist and consideration for prolonged reducing courses of oral corticosteroids. Patients should possess an epinephrine autoinjector with an anaphylaxis self-management plan. There are anecdotal reports regarding the use of omalizumab. For reasons that remain unclear, the prognosis of IA is generally favourable with appropriate treatment and patient education. If remission cannot be achieved, the diagnosis should be reconsidered. |
Clinical & Experimental Allergy. 2019 Jul;49(7):942-52. | Bilo; idiopathic anaphylaxis |
| Binder A, Armstrong P, Wachs T, Commins S, Beard C, Petersen L, Altrich M, Kersh G. | 2020 | **Trends in Alpha-gal Allergy Diagnostic Testing in the United States, 2010–2018. RATIONALE: Alpha-gal allergy is an immunoglobulin E (IgE) mediated allergy to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate found in mammalian meat. National data on incidence and distribution are not available, but case reports commonly originate from the southeastern United States, and suggest exposure to the Lone Star tick (Amblyomma americanum) as a risk factor. METHODS: We performed a retrospective analysis of alpha-gal IgE tests performed during 2010–2018 by Viracor Eurofins laboratories. Results≥ 0.1 kU/L were considered positive. We mapped data according to U.S. Census division to identify geographic differences in testing and prevalence. . RESULTS: During 2010–2018, 39% of all tests performed were positive. The number of tests performed annually increased 81-fold between 2010 and 2018; however, percent positivity remained stable, ranging from a peak of 56%in 2010 to 36%in 2016. Sourcelocation was provided for 46% of specimens;the percent positive was highest in the Mid-Atlantic (54%), and lowest in the Pacific (6%).. CONCLUSIONS: The rate of alpha-gal allergy testing increased steadily since 2010, but the proportion of positive samples remained stable. This suggests increased awareness and utilization, with capture of positive results, as opposed to largely inappropriate testing. Geographic distribution of positive results corresponds with the known range of Lone Star ticks. While the findings provide valuable information on the scope and distribution of IgE-positive patients, clinical information was not linked to these results. Systematic collection of clinical and laboratory data together would provide valuable insight into the burden of disease caused by alpha-gal allergy |
Journal of Allergy and Clinical Immunology. 2020 Feb 1;145(2):AB144. | prevalence |
| Binder AM, Cherry‐Brown D, Biggerstaff BJ, Jones ES, Amelio CL, Beard CB, Petersen LR, Kersh GJ, Commins SP, Armstrong PA. | 2022 | Clinical and Laboratory Features of Patients Diagnosed with Alpha‐gal Syndrome—2010–2019. Background: Alpha-gal syndrome (AGS) is an IgE-mediated allergy to galactose-alpha-1,3-galactose. Clinical presentation ranges from hives to anaphylaxis; episodes typically occur 2-6 hours after exposure to alpha-gal-containing products. In the United States, lone star tick bites are associated with development of AGS. To characterize features of AGS, we evaluated a cohort of patients presenting for care at the University of North Carolina, focusing on symptoms, severity, and identifying features unique to specific alpha-gal-containing product exposures. Methods: We performed a chart review and descriptive analysis of 100 randomly selected patients with AGS during 2010-2019. Results: Median age at onset was 53 years, 56% were female, 95% reported White race, 86% reported a history of tick bite, and 75% met criteria for anaphylaxis based on involvement of ≥2 organ systems. Those reporting dairy reactions were significantly less likely to report isolated mucocutaneous symptoms (3% vs 24%; ratio [95% CI]: 0.1 [0.1, 0.3]) than those who tolerated dairy, and were more likely to report gastrointestinal symptoms (79% vs 59%; ratio [95% CI]: 1.3 [0.7, 2.6]), although this difference was not statistically significant. Dairy-tolerant patients demonstrated higher alpha-gal sIgE titers (as a percentage of total IgE) than dairy-reactive patients (GM 4.1[95% CI: 2.7, 6.1] vs. GM 2.5 [95% CI: 1.3, 4.8], respectively; ratio - 1.6 [95% CI: -1.0, 3.9]). Conclusion: While tick exposure is common in the southern United States, nearly all AGS patients reported a tick bite. Gastrointestinal symptoms were prominent among those reporting reactions to dairy. Anaphylaxis was common, underscoring the severity and need to raise awareness of AGS among patients and providers. |
Allergy. 2022 Sep 30. | clinical features |
| Binder AM, Commins S, Altrich ML, Wachs T, Biggerstaff BJ, Beard CB, Petersen LR, Kersh GJ, Armstrong PA. | 2021 | Diagnostic Testing for Galactose-alpha-1, 3-galactose (Alpha-gal), United States, 2010–2018. Background: Alpha-gal syndrome (AGS) is an emerging immunoglobulin E (IgE)mediated allergy to galactose-alpha-1,3-galactose (alpha-gal). The geographic distribution and burden of AGS in the United States is unknown. Objective: To characterizes alpha-gal IgE testing patterns and describes trends and distribution during 2010–2018 in the United States. Methods: This retrospective analysis included all persons tested for alpha-gal IgE antibodies by Viracor-IBT Laboratories (Lee’s Summit, MO), the primary site of testing in the United States. Data included age and sex of person tested, specimen state of origin, collection date, and result value; persons with at least one positive test (≥0.1 kU/L) were compared to negatives. Proportions tested and with positive test results were calculated using U.S. Census population estimates. Results: Overall, 122,068 specimens from 105,674 persons were tested for alpha-gal IgE during July 1, 2010–December 31, 2018. Nearly one-third (34,256, 32.4%) had at least one positive result. The number of persons testing positive increased 6-fold from 1,110 in 2011 to 7,798 in 2018. Of those testing positive, mean [SD] age was 46.9 [19.8] years; males were more likely to test positive than females (43.3% vs 26.0%). Arkansas, Virginia, Kentucky, Oklahoma, and Missouri had the highest number of persons who were tested and had a positive result per 100,000 population. Conclusion: More than 34,000 persons, most presumably symptomatic, have tested positive for IgE antibodies to alpha-gal, suggesting AGS is an increasingly recognized public health problem. The geographic distribution of persons who tested positive is consistent with exposure to Amblyomma americanum ticks. |
Annals of Allergy, Asthma & Immunology. 1920. | prevalence; testing; united states |
| Binetruy F, Buysse M, Lejarre Q, Barosi R, Villa M, Rahola N, Paupy C, Ayala D, Duron O. | 2020 | Microbial community structure reveals instability of nutritional symbiosis during the evolutionary radiation of Amblyomma ticks. |
Molecular Ecology. 2020 Mar;29(5):1016-29. | |
| Bircher AJ, Hofmeier KS, Link S, Heijnen I. | 2017 | Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review. Until recently, food allergies to mammalian meats have been considered to be very rare. The observation that patients not previously exposed to the monoclonal chimeric antibody cetuximab suffered from severe anaphylaxis upon first exposure, led to the identification of galactose-alpha-1,3-galactose as a new relevant carbohydrate allergen. These patients later often suffered from anaphylactic reactions to red meat. Epidemiological data indicated that bites by the tick Amblyomma americanum in the USA, later also by Ixodes species in other continents, resulted in sensitisation to alpha-gal. On the other hand, in African patients with parasitic disorders, a high prevalence of anti-alpha-gal IgE, without clinical relevance, has been reported. In our four cases, one patient with a late onset of meat allergy had a history of a tick bite. The other three patients had symptoms from childhood or at a juvenile age. This indicates that in some patients, other ways of sensitisation may also take place. However, in patients without atopy, tick bite-induced IgE to alpha-gal may be more relevant. Diagnosis is based on a history of delayed onset of anaphylaxis. Skin tests with commercially available meat test solutions are often equivocal or negative; skin tests with raw meat and particularly pork kidney are more sensitive. Determination of specific IgE to alpha-gal is commercially available. The highest sensitivity is observed with skin and basophil activation tests with cetuximab which is, however, limited by its high costs. |
European Journal of Dermatology. 2017 Jan 1;27(1):3-9. | review article; Europe; Switzerland; co-factor; cofactor; alcohol; organ; lung; goat; vector of sensitization |
| Bircher AJ, Scherer K. | 2009 | Hypersensitivity reactions due to agents that modify the biological response (biologicals). Adverse reactions induced by biological agents which are being used increasingly in the therapy of inflammatory diseases, autoimmune disorders and tumors are being observed more and more frequently. This is a consequence of both the growing number of indications and the increasing number of these substances. They have an intrinsic immunologic effect, due to their structure, to their structural similarity to physiological proteins, as well as to their capacity to act directly on the immune system. In addition, they can induce the production of anti-allotype or anti-idiotype antibodies, especially when they have an extensive murine sequence, but also through their humanized or human antibody components. The adverse reactions which they induce also depend on the structure of their target, which they can activate, inhibit or modify by other mechanisms. The principal adverse reactions are of type alpha, with a "cytokine release syndrome", or of type beta, with the production of IgG or IgE antibodies and subsequent immediate type reactions such as urticaria, anaphylaxis or serum sickness. Pre-existing antibodies directed against some of these agents may have been generated by ubiquitous crossreacting epitopes. Local reactions occur frequently at the subcutaneous injection site of these agents; these reactions can sometimes be avoided by modifying the injection technique. The means of diagnosing such reactions are currently limited and their value has not yet been established on a large number of subjects. Continuation of this therapy is generally contraindicated due to the risk of severe complications. |
REVUE FRANCAISE D ALLERGOLOGIE. 2009 Apr 1;49(3):296-9. | pharmaceutical;; pharmacy; medication; biologic; biological agent |
| Blackburn CM, Pattarabanjird T, Qiao H, Drago F, Marshall M, Erickson LD, McNamara CA. | 2022 | Uncovering Mechanisms Between Oligosaccharide Galactose-alpha 1, 3-galactose (alpha-gal) Sensitization And Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. Recent work by our group and others have shown individuals with IgE to the oligosaccharide allergen present in mammalian products (α-gal) have increased atheroma burden with increased necrosis and calcification compared to those without α -gal specific IgE. These data suggest α -gal specific IgE increase plaque severity and vulnerability, yet the mechanisms that promote production of IgE to α -gal are unknown. Previous work from our group utilized multi-omics single cell analysis of circulating PBMCs from subjects with coronary angiography at UVA and showed subjects with IgE α -gal sensitization had a higher frequency of CCR6hi switched memory (SWM) B cells and that the CCR6 ligand, CCL20, increased class switching to IgE. To determine mechanisms whereby CCR6 may mediated class switching to IgE, we enriched total B cells from healthy donor peripheral blood mononuclear cells and stimulated with 20ng/ml human IL-4 and 10μg/ml agnostic anti-human CD40 with or without 20ng/ml CCL20 for 3 days. After 3 days of treatment, cells were collected and stained with a 15-color panel and analyzed via flow cytometry. Cells were analyzed for surface expression of CD20 and CD3 to gate total B cells. Gated B cells were further separated into CD27+/IgM-/IgD- to define SWM B cell population. CCL20 treatment did not increase the total percent of SWM B cells; however, there was a 2-3-fold increase in CCR6+ SWM B cells compared to CCR6- SWM B cells. CCL20 treated CCR6+ SWM B cells have an average of 7% increase of phosphorylated mTOR in total SWM B cells compared to nonCCL20 treated CCR6+ SWM B cells. These results suggest CCL20 stimulation induces mTOR phosphorylation and activation. Thus, mTOR activation and downstream mediators may be necessary for α -gal induced B cell class switching. From these preliminary studies, we conclude that CCL20 stimulation increases the percent pmTOR+ SWM B cells. We will continue to investigate downstream mTOR mediators in regard to B cell class switching after CCL20 stimulation and how α-gal sensitization augments B cell IgE class switching and increases atherosclerosis with our novel α -gal-/- Apoe-/- mouse. |
May;42(Suppl_1):A525-. | CAD; atheroclerosis; cardiac; cardiovascular; coronary artery disease |
| Błaszak B, Gozdecka G, Shyichuk A. | 2018 | Carrageenan as a functional additive in the production of cheese and cheese-like products. Carrageenan is a well-known gelling agent used in the food industry. The present review of patent and scientific literature shows that carrageenan is a useful additive in the cheese production process. The gel-strengthening properties of carrageenan are as a result of the fairly strong bonds it forms with casein macromolecules. However, carrageenan-casein interaction is dependent on pH. Different carrageenan types have different charge levels (the most charged is the helix form of lambda-carrageenan), which affects the carrageenan casein aggregates. The correct concentration of carrageenan and temperature treatment can improve cheese yield and whey protein recovery, which is desirable for cheese producers. Even small amounts of this hydrocolloid can increase cheese firmness and maintain cheese structure after cheese curd heating. Carrageenan improves cheese structure and other properties, such as ease of grating or slicing, which are very importantfor customers. Some modifications to cheese composition can destroy the natural cheese structure, but the addition of carrageenan can be useful for creating modified cheese-like products with desirable attributes. Carrageenan can be a good replacement for emulsifying salts, to stabilize cheese fat without disturbing the Ca:P ratio. The replacement of emulsifying salts with carrageenan (as little as 1%) results in a homogenous cheese product. For that reason, carrageenan is a useful additive for maintaining the organoleptic and structural values of fat-free cheese. Carrageenan can also stabilize the structure in cheese-like products and replace casein in cheese imitations. |
Acta Scientiarum Polonorum Technologia Alimentaria. 2018 Jun 30;17(2):107-16. | carrageenan |
| Blessmann J, Hanlodsomphou S, Santisouk B, Choumlivong K, Soukhaphouvong S, Chanthilat P, Brockow K, Biedermann T. | 2020 | Serum IgE against galactose-alpha-1, 3-galactose is common in laotian patients with snakebite envenoming but not the major trigger for early anaphylactic reactions to antivenom. Snake antivenom is the only specific treatment for snakebite envenoming, but life-threatening anaphylaxis is a severe side effect and drawback for the use of these typically mammalian serum products. The present study investigates the hypotheses whether serum IgE antibodies against the epitope galactose-alpha-1,3-galactose (α-gal) located on the heavy chain of non-primate mammalian antibodies are a possible cause for hypersensitivity reactions to snake antivenom. Serum samples from 55 patients with snakebite envenoming were obtained before administration of snake antivenom and tested for serum IgE (sIgE) against α-gal and total IgE. Early anaphylactic reactions (EARs) during the first 3 h after antivenom administration were classified into mild, moderate or severe and correlated with the presence of sIgE against α-gal. Fifteen (27%) out of 55 patients (37 male, 18 female, median 34 years, range 9–90 years) developed EARs after antivenom administration. Eleven, three and one patients had mild, moderate and severe EARs, respectively. Serum IgE against α-gal was detected in 17 patients (31%); in five (33%) out of 15 patients with EARs and in 12 (30%) out of 40 patients without EAR (Odds Ratio = 1.2; 95%-confidence interval: 0.3–4.2) with no correlation to severity. Although the prevalence of serum IgE against α-gal was high in the study population, very high levels of total IgE in the majority of patients question their clinical relevance and rather indicate unspecific sIgE binding instead of allergy. Lack of correlation between α-gal sIgE and EARs together with significantly increased total IgE levels suggest that sIgE against α-gal is not the major trigger for hypersensitivity reactions against snake antivenom. |
Toxicon: X. 2020; 100054. | Asia; Laos; prevalence; pharmacy; pharmaceutical; medical product; antivenom; helminth; endoparasite |
| Böer U, Schridde A, Anssar M, Klingenberg M, Sarikouch S, Dellmann A, Harringer W, Haverich A, Wilhelmi M. | 2015 | The Immune Response to Crosslinked Tissue is Reduced in Decellularized Xenogeneic and Absent in Decellularized Allogeneic Heart Valves. Background: The degeneration and failure of xenogeneic heart valves, such as the Matrix P Plus valve (MP-V) consisting of decellularized porcine valves (dec-pV) and equine glutaraldehyde-fixed conduits (ga-eC) have been linked to tissue immunogenicity accompanied by antibody formation. In contrast, decellularized allograft valves (dec-aV) are well-tolerated. Here, we determined tissue-specific antibody levels in patients after implantation of MP-V or dec-aV and related them to valve failure or time period after implantation. Methods and Results: Specific antibodies toward whole tissue-homogenates or alphaGal were determined retrospectively by ELISA analyses from patients who received MP-V with an uneventful course of 56.1 ± 5.1 months (n = 15), or with valve failure after 25.3 ± 14.6 months (n = 3), dec-aV for various times from 4 to 46 months (n = 14, uneventful) and from healthy controls (n = 4). All explanted valves were assessed histopathologically.MP-V induced antibodies toward both tissue components with significantly higher levels toward ga-eC than toward dec-pV (68.7 and 26.65 μg/ml IgG). In patients with valve failure, levels were not significantly higher and were related to inflammatory tissue infiltration. Anti-Gal antibodies in MP-V patients were significantly increased in both, the uneventful and the failure group. In contrast, in dec-aV patients only a slight tissue-specific antibody formation was observed after 4 months (6.24 μg/ml) that normalized to control levels after 1 year. Conclusions: The strong humoral immune response to glutaraldehyde-fixed tissues is reduced in decellularized xenogeneic valves and almost absent in decellularized allogeneic tissue up to 4.5 years after implantation. |
The International journal of artificial organs. 2015 Apr;38(4):199-209. | Boer |
| Boni E, Incorvaia C. | 2020 | Near-fatal anaphylaxis with Kounis syndrome caused by Argas reflexus bite: a case report. Background: The pigeon tick Argas reflexus is a temporary parasite of pigeons. It bites during night hours and lies briefly on its prey, as long as it takes the blood meal. When pigeons are not accessible, ticks look for other hosts, invading nearby flats and biting humans. Case presentation: We present the case of a woman aged 46 years who experienced severe anaphylaxis during the night which required emergency medical treatment, tracheal intubation and hospitalization in intensive care unit. Kounis syndrome was documented by transient ST depression and elevation of troponin. The allergological work up ruled out hypersensitivity to drugs, latex and foods containing alpha-gal, which is a cause of anaphylaxis. Basal serum tryptase was in normal range (8.63 ng/ml). When questioned about the presence of ticks, the patient brought into view various specimens of ticks that were recognized by an entomologist as Argas reflexus. Conclusions: An in vitro diagnosis of allergy to Argas reflexus is currently not feasible because, though the major allergen Arg r 1 has been isolated, allergen extracts are not commercially available. Therefore, the diagnosis of anaphylaxis from Argas reflexus, when other causes of anaphylaxis are excluded, must rely only on history and clinical findings, as well as on the presence of pigeons and/or pigeon ticks in the immediate domestic environment. |
Clinical and Molecular Allergy. 2020 Dec;18(1):1-3. | vectors; mites; ectoparasites; arthropods |
| Borsani B, De Santis R, Perico V, Penagini F, Pendezza E, Dilillo D, Bosetti A, Zuccotti GV, D’Auria E. | 2021 | The Role of Carrageenan in Inflammatory Bowel Diseases and Allergic Reactions: Where Do We Stand?. Carrageenan (CGN) is a high molecular weight polysaccharide extracted from red seaweeds, composed of D-galactose residues linked in β-1,4 and α-1,3 galactose-galactose bond, widely used as a food additive in processed foods for its properties as a thickener, gelling agent, emulsifier, and stabilizer. In recent years, with the spread of the Western diet (WD), its consumption has increased. Nonetheless, there is a debate on its safety. CGN is extensively used as an inflammatory and adjuvant agent in vitro and in animal experimental models for the investigation of immune processes or to assess the activity of anti-inflammatory drugs. CGN can activate the innate immune pathways of inflammation, alter the gut microbiota composition and the thickness of the mucus barrier. Clinical evidence suggests that CGN is involved in the pathogenesis and clinical management of inflammatory bowel diseases (IBD), indeed food-exclusion diets can be an effective therapy for disease remission. Moreover, specific IgE to the oligosaccharide α-Gal has been associated with allergic reactions commonly referred to as the “α-Gal syndrome”. This review aims to discuss the role of carrageenan in inflammatory bowel diseases and allergic reactions following the current evidence. Furthermore, as no definitive data are available on the safety and the effects of CGN, we suggest gaps to be filled and advise to limit the human exposure to CGN by reducing the consumption of ultra-processed foods. |
Nutrients. 2021 Oct;13(10):3402. | carrageenan |
| Bosques CJ, Collins BE, Meador JW, Sarvaiya H, Murphy JL, DelloRusso G, Bulik DA, Hsu IH, Washburn N, Sipsey SF, Myette JR. | 2010 | Chinese hamster ovary cells can produce galactose-α-1, 3-galactose antigens on proteins. Chinese hamster ovary (CHO) cells are widely used for the manufacture of biotherapeutics, in part because of their ability to produce proteins with desirable properties, including ‘human-like’ glycosylation profiles. For biotherapeutics production, control of glycosylation is critical because it has a profound effect on protein function, including half-life and efficacy. Additionally, specific glycan structures may adversely affect their safety profile. For example, the terminal galactose-α-1,3-galactose (α-Gal) antigen can react with circulating anti α-Gal antibodies present in most individuals1. It is now understood that murine cell lines, such as SP2 or NSO, typical manufacturing cell lines for biotherapeutics, contain the necessary biosynthetic machinery to produce proteins containing α-Gal epitopes2–4. Furthermore, the majority of adverse clinical events associated with an induced IgE-mediated anaphylaxis response in patients treated with the commercial antibody Erbitux (cetuximab) manufactured in a murine myeloma cell line have been attributed to the presence of the α-Gal moiety4. Even so, it is generally accepted that CHO cells lack the biosynthetic machinery to synthesize glycoproteins with α-Gal antigens5. Contrary to this assumption, we report here the identification of the CHO ortholog of N-acetyllactosaminide 3-α-galactosyltransferase-1, which is responsible for the synthesis of the α-Gal epitope. We find that the enzyme product of this CHO gene is active and that glycosylated protein products produced in CHO contain the signature α-Gal antigen because of the action of this enzyme. Furthermore, characterizing the commercial therapeutic protein abatacept (Orencia) manufactured in CHO cell lines, we also identified the presence of α-Gal. Finally, we find that the presence of the α-Gal epitope likely arises during clonal selection because different subclonal populations from the same parental cell line differ in their expression of this gene. Although the specific levels of α-Gal required to trigger anaphylaxis reactions are not known and are likely product specific, the fact that humans contain high levels of circulating anti-α-Gal antibodies suggests that minimizing (or at least controlling) the levels of these epitopes during biotherapeutics development may be beneficial to patients. Furthermore, the approaches described here to monitor α-Gal levels may prove useful in industry for the surveillance and control of α-Gal levels during protein manufacture. |
Nature biotechnology. 2010 Nov;28(11):1153-6. | Pharmaceutical; pharmacy; biologic; biological agent; Chinese hamster ovary; CHO |
| Boussamet L, Montassier E, Soulillou JP, Berthelot L. | 2021 | α1-3Gal antigen in gut microbiota, a potential new environmental factor in multiple sclerosis. |
Clinical Immunology. 2021 Feb 6:108693. | Autoimmune disease; multiple sclerosis; IgG; microbiota; microbiome |
| Boussamet L, Montassier E, Soulillou JP, Berthelot L. | 2021 | Anti α1-3Gal antibodies and Gal content in gut microbiota in immune disorders and multiple sclerosis Recent observations suggest that Gal antigen content in gut microbiota and anti-Gal antibody response may influence inflammation in immune related disorders. In this review we summarized the current knowledge on antibody response to the Gal epitope in various immune disorders. We discuss the origin of Gal antigen associated to gut microbiota. In multiple sclerosis, the possible mechanisms by which the altered microbiota and/or circulating anti-Gal level could affect the immune response in this disease are presented. |
Red.;84:85 | Autoimmune disease; multiple sclerosis; IgG; microbiota; microbiome |
| Boyce RM, Schulz A, Mansour O, Giandomenico D, Farel CE, Commins SP. | 2022 | Alpha-gal Syndrome in the Infectious Diseases Clinic: A series of five cases in central North Carolina. Background: Alpha-gal syndrome (AGS) is a recently described allergy to galactose-α-1,3-galactose, an oligosaccharide present in mammalian meat. AGS can present with angioedema, urticaria, and anaphylaxis arising 3-6 hours after ingestion, although symptoms such as gastrointestinal distress, fatigue, and arthralgias are also reported. Because AGS appears to be associated with tick bites, patients may present to Infectious Diseases (ID) clinics for evaluation. Methods: We documented a series of five patients referred to the University of North Carolina ID clinic between 2020–2022 for various tick-borne infections that were found to have symptoms and laboratory testing consistent with AGS. Patients were subsequently referred to the Allergy and Immunology clinic. Results: Patients were referred to the ID clinic for persistent symptoms following positive tick-borne disease testing or presumed tick-borne infection. All patients had an elevated alpha-gal IgE and clinical presentation consistent with AGS. Common symptoms included episodic gastrointestinal distress (e.g., cramping, nausea, diarrhea), fatigue, arthralgias, and subjective cognitive impairment, but a notable absence of severe anaphylaxis. Four patients were seen by at least one non-allergy specialist prior to referral to ID. Patients reported substantial improvement in their symptoms following dietary restriction. Conclusions: ID physicians should be aware of AGS as a cause of persistent, non-specific symptoms following a tick exposure or tick-borne illness. Further research is needed to determine the prevalence of alpha-gal sensitization and AGS following tick-borne bites. |
InOpen Forum Infectious Diseases 2022 Dec 12. | Infectious disease; tick-borne disease; chronic tick-borne illness; chronic Lyme; GI; arthralgia; joint; arthritis; brain fog; cognitive; post-acute; Rickettsia; Ehrlichia; Borrelia burgdorferi |
| Boylston TD. | 2019 | Byproducts from Butter and Cheese Processing. | Byproducts from Agriculture and Fisheries: Adding Value for Food, Feed, Pharma, and Fuels. 2019 Oct 14:107-21. | |
| Bradfisch F, Pietsch M, Forchhammer S, Strobl S, Stege HM, Pietsch R, Carstens S, Schäkel K, Yazdi A, Saloga J. | 2019 | Case series of anaphylactic reactions after rabies vaccinations with gelatin sensitization. Side effects due to allergic reactions to vaccine antigen or to additives such as chicken protein or gelatin have been known for some time. Recent findings regarding reactions mediated via the carbohydrate epitope galactose-alpha-1,3-galactose (alpha-gal), a constituent of animal gelatin, broaden the spectrum of gelatin-related allergies. This case series presents four patients who developed anaphylactic reactions following rabies vaccination using the vaccine Rabipur®. After appropriate allergy testing by skin prick testing and the determination of specific IgE to allergens in the vaccine, triggering by alpha-gal could be excluded and an allergy to gelatin was detected. The absence of allergic symptoms following the consumption of gelatin could potentially be explained through intestinal hydrolysis resulting in a loss of allergenic potency. Further implications related to the use of gelatin-containing infusions in emergency medicine are discussed. |
Allergo Journal International. 2019;28(4):103-6. | Primary care; vaccination; vaccine; gelatin; gelatine; rabipur; rabies |
| Brady SP, Novack D, Kulczycki A. | 2015 | Recurrent Anaphylaxis Due to Delayed Allergy to Mammalian Meat in a Patient with Mastocytosis. RATIONALE: Mastocytosis and delayed allergy to mammalian meat are under-recognized and potentially life-threatening conditions. We describe a patient with mastocytosis and delayed allergy to mammalian meat whose diagnoses came to light after several episodes of severe anaphylaxis. METHODS: Measurement of serum tryptase and IgE to galactose-alpha-1,3-galactose alpha-gal) were performed at Mayo Clinic, Rochester, MN. Bone Marrow biopsy was performed at Barnes-Jewish Hospital, St. Louis, MO. RESULTS: A 52-year-old man presented with a several year history of recurrent syncope. Symptoms proceeding syncope included nausea, vomiting, abdominal cramping, flushing, itching and lightheadedness. Prolonged unresponsiveness, hypotension and bradycardia accompanied each event, once requiring intubation and mechanical ventilation. Cardiac work-up was unrevealing. A pacemaker was placed for presumed symptomatic sinus bradycardia. Detailed history later revealed ingestion of beef and pork several hours prior to each event, as well as exposure to tick bites. IgE to alpha-gal was 1.93 kU/L (reference range <0.35kU/L), suggesting that an allergy to alpha-gal triggered these events. Baseline serum tryptase was 30 ng/mL (reference range <11.5ng/mL) and bone marrow biopsy was diagnostic for mastocytosis. The patient was prescribed an epinephrine auto-injector, placed on cetirizine, ranitidine and montelukast, and instructed to limit exposure to ticks and mammalian meat. The patient has had no further episodes. CONCLUSIONS: We believe this is one of the first cases described of life-threatening anaphylaxis secondary to delayed allergy to mammalian meat in a patient with mastocytosis. This case highlights the importance of including these rare entities in the differential diagnosis of unexplained syncope. |
Journal of Allergy and Clinical Immunology. 2015;135(2):AB206. | mastocytosis; mast cell disorder; cardiac; syncope |
| Brestoff JR, Tesfazghi MT, Zaydman MA, Jackups R, Kim BS, Scott MG, Gronowski AM, Grossman BJ. | 2018 | The B antigen protects against the development of red meat allergy. ...Collectively, these findings suggest that expressing the B antigen may be protective against allergic sensitization to a-Gal and the development of RMA. Although patients who express the B antigen can undergo allergic sensitization to a-Gal and develop RMA, the likelihood of sensitization, degree of sensitization, and probability of disease appear to be markedly lower than in patients without the B antigen. To our knowledge, RMA is the first example where an ABO antigen may modulate the risk and perhaps the pathogenesis of a food allergy |
The Journal of Allergy and Clinical Immunology: In Practice. 2018; 6(5):1790-1. | blood type; B antigen; |
| Brestoff JR, Zaydman MA, Scott MG, Gronowski AM. | 2017 | ‡ Diagnosis of red meat allergy with antigen-specific IgE tests in serum. Letter to the editor ...Taken together, these findings indicate that the α-gal-bTG IgE test is the most useful for establishing a diagnosis of red meat allergy, although α-gal-biotin, beef, and pork IgE are also effective. The diagnostic value of the beef and pork IgE tests may relate to the presence of α-gal in beef and pork extracts used for IgE capture.1 Despite their favorable performance characteristics, these tests should be used and interpreted carefully. For example, none of these antigen-specific IgE tests can distinguish red meat allergy from tick allergy6 or cetuximab hypersensitivity,7 and pork IgE cannot discriminate between red meat allergy and pork-cat syndrome.8 In addition, 85% of helminth-infected patients have elevated α-gal IgE concentrations without evidence of red meat allergy.9 Therefore, the diagnostic value and interpretation of these tests depend on clinical context. We recommend measuring α-gal or beef IgE concentrations for diagnosis of red meat allergy only in patients who present with symptoms related to red meat exposure or who present with recurrent idiopathic anaphylaxis, angioedema, urticaria, or gastrointestinal symptoms. False positives should be considered in the above clinical scenarios or if the patient's symptoms do not improve after avoiding meat ingestion and/or if challenging with offending meats fails to elicit symptoms. |
Journal of Allergy and Clinical Immunology. 2017 Aug 1;140(2):608-10. | Primary care; diagnosis |
| Brockow K, Kneissl D, Valentini L, Zelger O, Grosber M, Kugler C, Werich M, Darsow U, Matsuo H, Morita E, Ring J. | 2015 | Using a gluten oral food challenge protocol to improve diagnosis of wheat-dependent exercise-induced anaphylaxis. Background: Oral wheat plus cofactors challenge tests in patients with wheat-dependent exercise-induced anaphylaxis (WDEIA) produce unreliable results. Objective: We sought to confirm WDEIA diagnosis by using oral gluten flour plus cofactors challenge, to determine the amount of gluten required to elicit symptoms, and to correlate these results with plasma gliadin levels, gastrointestinal permeability, and allergologic parameters. Methods: Sixteen of 34 patients with a history of WDEIA and ω5-gliadin IgE underwent prospective oral challenge tests with gluten with or without cofactors until objective symptoms developed. Gluten reaction threshold levels, plasma gliadin concentrations, gastrointestinal permeability, sensitivities and specificities for skin prick tests, and specific IgE levels were ascertained in patients and 38 control subjects. Results: In 16 of 16 patients (8 female and 8 male patients; age, 23-76 years), WDEIA was confirmed by challenges with gluten alone (n = 4) or gluten plus cofactors (n = 12), including 4 patients with previous negative wheat challenge results. Higher gluten doses or acetylsalicylic acid (ASA) plus alcohol instead of physical exercise were cofactors in 2 retested patients. The cofactors ASA plus alcohol and exercise increased plasma gliadin levels (P < .03). Positive challenge results developed after a variable period of time at peak or when the plateau plasma gliadin level was attained. Positive plasma gliadin threshold levels differed by greater than 100-fold and ranged from 15 to 2111 pg/mL (median, 628 pg/mL). The clinical history, IgE gliadin level, and baseline gastrointestinal level were not predictive of the outcomes of the challenge tests. The challenge-confirmed sensitivity and specificity of gluten skin prick tests was 100% and 96%, respectively. Conclusion: Oral challenge with gluten alone or along with ASA and alcohol is a sensitive and specific test for the diagnosis of WDEIA. Exercise is not an essential trigger for the onset of symptoms in patients with WDEIA. |
Journal of Allergy and Clinical Immunology. 2015 Apr 1;135(4):977-84. | Wheat-dependent exercise-induced anaphylaxis omega-5-gliadin gluten anaphylaxis cofactors plasma gliadin levels threshold levels oral challenge test |
| Browning R, Le V, Jerath M. | 2022 | Alpha-Gal Allergy and Mast Cell Hyperactivity Overlap. Rationale: Galactose-alpha-1,3-galactose (alpha-gal) allergy is often initially misdiagnosed as chronic urticaria or idiopathic anaphylaxis (here collectively referred to as mast cell hyperactivity [MCH]). However, a subset of alpha-gal allergic patients also have concurrent MCH. Here we compare characteristics of these populations. Methods: Within our practice, we identified a cohort of 65 patients with alpha-gal allergy, fourteen of whom also have MCH. Medical record review was performed to compare age, gender, alpha-gal IgE, other atopic conditions, comorbidities, and tick bite history. Results: Patients with alpha-gal allergy and MCH, as compared to those with alpha-gal allergy alone, were more likely to have GERD (64% vs 33%, p=0.03), migraine (21% vs 4%, p=0.03), psychiatric diagnosis (57% vs 27%, p=0.04), multiple psychiatric diagnoses (34% vs 12%, p=0.03), and stinging insect allergy (33% vs 2%, p=0.001). Although both groups were equally likely to have other atopic disease (79% vs 76%, p=0.87), those with MCH were more likely to have multiple other atopic conditions (50% vs 20%, p=0.02). There was no significant difference in average age (42.5 vs 48.6 years, p=0.26), initial alpha-gal IgE (6.41 vs 16.05, p=0.21), diabetes (7% vs 8%, p=0.93), hypertension (7% vs 24%, p=0.18), or cardiovascular disease (0% vs 12%, p=0.18). Although the difference was not significant, patients with both alpha-gal and MCH are more likely to be female (71% vs 53%, p=0.22). Greater than 90% of both groups reported previous tick bite. Conclusions: Combined alpha-gal and MCH is associated with increased prevalence of GERD, migraine, psychiatric conditions, and multiple other atopic conditions. |
Journal of Allergy and Clinical Immunology. 2022 Feb 1;149(2):AB201. | mast cell; comorbidity |
| Brzozowska M, Mokrzycka N, PoreBski G. | 2021 | Alpha-gal syndrome: the first report in Poland. |
Central-European Journal of Immunology. 2021;46(3):398. | Europe; Poland |
| Browning R, Kalaidina E, Saligrama P, Lee I, Mantia T, Jerath M, Kendall P. | 2023 | Increased Population of CD19+ CCR6+ Cells Expressing Intracellular IgE in Alpha-Gal Allergic Patients. ABSTRACT |
Journal of Allergy and Clinical Immunology. 2023 Feb 1;151(2):AB92. | cellular mechanisms; immunology; immunophenotype |
| Burk CM, Beitia R, Lund PK, Dellon ES. | 2016 | High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy. Eosinophilic esophagitis (EoE) is an antigen/allergy-mediated chronic inflammatory condition. The rapid rise in the number of cases of EoE suggests an as-yet undiscovered environmental trigger. This study tested the hypothesis that immunoglobulin E (IgE) to galactose-alpha-1,3-galactose (alpha-gal), a newly recognized sensitization induced by a tick bite that causes mammalian meat allergy, is a risk factor for EoE. We conducted a case-control study using prospectively collected and stored samples in the University of North Carolina EoE Patient Registry and Biobank. Serum from 50 subjects with a new diagnosis of EoE and 50 non-EoE subjects (either with gastroesophageal reflux disease or dysphagia from non-EoE etiologies) was tested for alpha-gal-specific IgE using an ImmunoCAP-based method. Specific IgE > 0.35 kUA /L was considered a positive result. Subjects with EoE were a mean of 35 years old, 68% were male, and 94% were white. Non-EoE controls were a mean of 42 years, 50% were male, and 78% were white. A total of 22 (22%) subjects overall had alpha-gal-specific IgE > 0.35 kUA /L. Of the EoE cases, 12 (24%) were positive, and of the non-EoE controls, 10 (20%) were positive (p=0.63). Neither the proportion sensitized nor the absolute values differed between EoE and non-EoE subjects. We found a similar but high rate of alpha-gal sensitization in patients with EoE as found in non-EoE controls who were undergoing endoscopy. While our data do not support alpha-gal sensitization as a risk factor for EoE, the high rates of sensitization observed in patients undergoing upper endoscopy for symptoms of esophageal dysfunction is a new finding. |
Diseases of the Esophagus. 2016 Sep 1;29(6):558-62. | eosinophilic esophagitis; EE |
| Burrows AG, Ellis AK. | 2021 | Idiopathic anaphylaxis: Diagnosis and management.> Introduction: Idiopathic anaphylaxis (IA) is a diagnosis of exclusion and is based on the inability to identify a causal relationship between a trigger and an anaphylactic event, despite a detailed patient history and careful diagnostic assessment. The prevalence of IA among the subset of people who experienced anaphylaxis is challenging to estimate and varies widely, from 10 to 60%; most commonly noted is ∼20% in the adult anaphylactic population. Comorbid atopic conditions, such as food allergy, allergic rhinitis, and asthma, are present in up to 48% of patients with IA. Improved diagnostic technologies and an increased understanding of conditions that manifest with symptoms associated with anaphylaxis have improved the ability to determine a more accurate diagnosis for patients who may have been initially diagnosed with IA. Methods: Literature search was conducted on PubMed, Google Scholar and Embase. Results: Galactose-α-1,3-galactose (α-gal) allergy, mast cell disorders, and hereditary a-tryptasemia are a few differential diagnoses that should be considered in patients with IA. Unlike food allergy, when anaphylaxis occurs within minutes to 2 hours after allergen consumption, α-gal allergy is a 3–6-hour delayed immunoglobulin E–mediated anaphylactic reaction to a carbohydrate epitope found in red meat (e.g., beef, lamb, pork). The more recently described hereditary α-tryptasemia is an inherited autosomal dominant genetic trait caused by increased germline copies of tryptase human gene alpha-beta 1 (TPSAB1), which encodes α tryptase and is associated with elevated baseline serum tryptase. Acute management of IA consists of carrying an epinephrine autoinjector to be administered immediately at the first signs of anaphylaxis. Long-term management for IA with antihistamines and other agents aims to potentially reduce the frequency and severity of the anaphylactic reactions, although the evidence is limited. Biologics are potentially steroid-sparing for patients with IA; however, more research on IA therapies is needed. Conclusion: The lack of diagnostic criteria, finite treatment options, and intricacies of making a differential diagnosis make IA challenging for patients and clinicians to manage |
InAllergy & Asthma Proceedings 2021 Nov 1 (Vol. 42, No. 6). | Idiopathic anaphylaxis |
| Bylsma LC, Dean R, Lowe K, Sangaré L, Alexander DD, Fryzek JP. | 2019 | The incidence of infusion reactions associated with monoclonal antibody drugs targeting the epidermal growth factor receptor in metastatic colorectal cancer patients: A systematic literature review and meta-analysis of patient and study characteristics. BACKGROUND: Systemic cancer therapies may induce infusion reactions (IRs) or hypersensitivities. Metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies, including cetuximab and panitumumab, may be subject to these reactions. We conducted a meta-analysis to estimate the IR incidence in this population and identify variations in this incidence by patient or study characteristics. METHODS: A systematic review was conducted to identify observational studies or clinical trials of mCRC patients treated with anti-EGFR therapies that reported occurrences of IRs, hypersensitivity, or allergy/anaphylaxis. The objective of the study was to estimate the incidence of IRs. Random effects models were used to meta-analyze the incidence of IRs overall and stratified by therapy type, study design, geographic location, RAS or KRAS mutation status, grade of reaction severity, and terminology used to describe the reaction. RESULTS: The pooled estimate for IR incidence was 4.9% (95% confidence interval: 3.6%-6.5%). Lower-grade reactions were more common than higher-grade reactions overall and the incidence of reactions among cetuximab patients was nearly four times that of panitumumab patients (6.1% vs 1.6%). CONCLUSIONS: IRs occur in approximately 5% of mCRC patients treated with anti-EGFR therapies, and the incidence varies significantly by grade of severity and therapy type. Studies evaluating these outcomes should consider investigating survival outcomes by IR status to determine its prognostic relevance. |
Cancer medicine. 2019 Sep;8(12):5800-9. | Cancer; mAb; monoclonal antibody; biologic; biological agent; perioperative; review article |
| Caballero ML, Krantz MS, Quirce S, Phillips E, Stone Jr CA. | 2021 | Hidden Dangers: Recognizing Excipients as Potential Causes of Drug and Vaccine Hypersensitivity Reactions Excipients are necessary as a support to the active ingredients in drugs, vaccines and other products and they contribute to their stability, preservation, pharmacokinetics, bioavailability, appearance and acceptability. For both drugs and vaccines these are rare reactions however for vaccines they are the primary cause of immediate hypersensitivity. Suspicion for these “hidden dangers” should be high in particular when anaphylaxis has occurred in association with multiple chemically distinct drugs. Common excipients implicated include gelatin, carboxymethylcellulose (CMC), polyethylene glycols (PEG) and products related to PEG in immediate hypersensitivity reactions (IHRs); and propylene glycol (PG), in delayed hypersensitivity reactions (DHRs). Complete evaluation of a suspected excipient reaction requires detailed information from the product monograph and package insert to identify all ingredients that are present and to understand the function and structure for these chemicals. This knowledge helps develop a management plan that may include allergy testing to identify the implicated component and to give patients detailed information for future avoidance of relevant foods, drugs and vaccines. Excipient reactions should be particularly considered for specific classes of drugs where they have been commonly found to be the culprit (e.g. corticosteroids, injectable hormones, immunotherapies, monoclonal antibodies, and vaccines). We provide a review of the evidence-based literature outlining epidemiology and mechanisms of excipient reactions and provide strategies for heightened recognition and allergy testing. |
The Journal of Allergy and Clinical Immunology: In Practice. 2021 Mar 15 | Drugs; medical products; gelatin |
| Cabezas Cruz A, Valdés JJ, De La Fuente J. | 2016 | Control of vector-borne infectious diseases by human immunity against α-Gal. The World Health Organization estimates that 1 billion individuals suffer from vector-borne diseases (VBDs), accounting for 17% of all infectious diseases worldwide, and 1 million of these individuals die annually due to VBDs. In addition, recent reports highlight a disturbing picture regarding the current situation of VBDs in the continental Europe [1], UK [2], and China [3]. These diseases are caused by pathogens transmitted by arthropod vectors such as ticks (e.g. Lyme disease caused by Borrelia burgdorferi, human granulocytic anaplasmosis caused by Anaplasma phagocytophilum, and tick-borne encephalitis (TBE) caused by TBE virus), mosquitoes (e.g. malaria caused by Plasmodium spp. and dengue fever caused by dengue virus), phlebotomine sand flies (e.g. various forms of human leishmaniasis caused by Leishmania spp.), tsetse flies (e.g. sleeping sickness caused by Trypanosoma brucei), and Triatomine bugs (e.g. Chagas disease caused by Trypanosoma cruzi) [4,5]. Effective vaccination strategies to control most of the VBDs have not been successfully developed or implemented, and the use of insecticides and/or chemotherapy has resulted in an increasing number of insecticide-resistant vectors and drug-resistant pathogens [4]. Therefore, alternative strategies for control of VBDs are urgently needed. In the context of the increasing burden of emerging VBDs worldwide, we propose the use of probiotics composed of bacteria producing the carbohydrate α-Gal as dietary supplements to control VBDs. Although previous studies have shown that anti-α-Gal antibodies in human serum do not induce 100% killing of Plasmodium [22], the use of probiotics containing bacteria-producing α-Gal may alter host natural response to this carbohydrate resulting in increased protection to parasite infection. Considering the results of previous studies [11,19,20], while probiotics such as Lactobacillus spp. may constitute the appropriate carrier of α-Gal in probiotic-based vaccines against vector-borne pathogens, the combination with TLR4 agonists may be needed to develop a potent and protective immune response against this carbohydrate. Future studies should focus on the characterization of the mechanisms involved in the immune response to α-Gal. This antibody response may be effective against different vector-borne pathogens that contain α-Gal on their surface. Therefore, the probiotics-based vaccines exploiting this major evolutionary adaptation may constitute an effective strategy to reduce the impact of VBDs on human health. Although the road to probiotic-based vaccines appears to be challenging, the rational design of vaccines exploiting the special immunity of human to α-Gal may be our best strategic move to win our battle against VBDs. |
Expert Review of Vaccines. 2016 Apr 19;15(8) 953-5. | |
| Cabezas-Cruz A, de la Fuente J, Fischer J, Hebsaker J, Lupberger E, Blumenstock G, Aichinger E, Yazdi AS, Enkel S, Oehme R, Biedermann T. | 2017 | Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the alpha-Gal syndrome? Comment on: Prevalence of type I sensitization to alpha-gal in forest service employees and hunters. Fischer J, Lupberger E, Hebsaker J, Blumenstock G, Aichinger E, Yazdi AS, Reick D, Oehme R, Biedermann T. Allergy. 2017 Oct;72(10):1540-1547. doi: 10.1111/all.13156. Epub 2017 May 10. PMID: 28273338 |
Allergy 2017; 72(12): 2044-2047. | |
| Cabezas-Cruz A, de la Fuente J. | 2020 | Immunity to α-Gal: toward a single-antigen pan-vaccine to control major infectious diseases. Infectious diseases constitute a growing burden for human health worldwide. In particular, vector-borne diseases account for 17% of all infectious diseases and kill about 1 million people annually.(1) These diseases are caused by a diverse group of pathogens including viruses, bacteria, and protozoa that are transmitted by arthropod vectors such as ticks, mosquitoes, sandflies, kissing bugs, and tsetse flies.(1) Among the nonviral vector-borne diseases, malaria, leishmaniasis, Chagas disease, sleeping sickness, and Lyme disease represent the highest burden to human health. Further, vaccines are not available for the prevention and control of these diseases.(2) Among non-vector-borne diseases, tuberculosis caused by mycobacteria of the Mycobacterium tuberculosis complex is one of the world’s most common causes of death from infectious diseases.(3) All pathogens producing these deadly diseases have something in common: the galactose-alpha-1,3-galactose (α-Gal) epitope exposed on their surface (Table 1). During evolution, humans lost the ability to synthesize the carbohydrate α-Gal, which resulted in an almost unique capacity to produce high antibody titers against α-Gal.(4) The immunity to α-Gal may neutralize the pathogens with α-Gal on their surface, and therefore the induction of this protective immune response may constitute an effective intervention for the prevention and control of infectious diseases.(5) The study of the anti-α-Gal immunity will provide the basis to develop a single-antigen “pan-vaccine” to control major infectious diseases. |
ACS Central Science. 2017; 3(11): 1140-2. | pan-vaccine |
| Cabezas-Cruz A, de la Fuente, J. | 2017 | Immunity to α-Gal: The Opportunity for Malaria and Tuberculosis Control. Among all infectious diseases, malaria and tuberculosis constitute leading causes of morbidity and mortality of human populations in developed and undeveloped countries. In 2015, the WHO reported that 10.4 million people had tuberculosis and 1.8 million of them died from the disease. Despite a reduction of malaria cases between 2000 and 2015, the WHO reported 212 million cases and 429,000 deaths due to this disease in 2015 alone. Drug resistance to first-line antimalarial drugs (e.g., chloroquine, sulfadoxine–pyrimethamine, and artemisinin) is a major constrain of malaria control Sub-Saharan Africa. Likewise, multidrug-resistant tuberculosis is a growing problem worldwide. Thus, the control of these diseases is among the most challenging tasks of public health worldwide. Drug overuse and misuse are recognized as the main drivers of drug resistance in parasites and pathogenic bacteria. The identification of genetic factors affecting the susceptibility to these infectious diseases is essential toward reducing drug overuse and inappropriate treatment regimes. In this opinion, we propose that blood groups, a major driver of anti-α-Gal immunity and malaria and tuberculosis incidence, can be used to tailor anti-malaria and anti-tuberculosis vaccination. Blood group A and O individuals, that can potentially develop strong anti-α-Gal immunity, could be immunized with probiotic-based vaccines to enhance the natural levels of anti-α-Gal antibodies. This immunity could lead to protection against these diseases which in turn would reduce the use of anti-malaria and anti-tuberculosis drugs. |
Frontiers in immunology. 2017 Dec;8:1733. | |
| Cabezas-Cruz A, Espinosa PJ, Alberdi P, Šimo L, Valdés JJ, Mateos-Hernández L, Contreras M, Rayo MV, de la Fuente J. | 2018 | Tick galactosyltransferases are involved in alpha-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development. The carbohydrate Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R (alpha-Gal) is produced in all mammals except for humans, apes and old world monkeys that lost the ability to synthetize this carbohydrate. Therefore, humans can produce high antibody titers against alpha-Gal. Anti-alpha-Gal IgE antibodies have been associated with tick-induced allergy (i.e. alpha-Gal syndrome) and anti-alpha-Gal IgG/IgM antibodies may be involved in protection against malaria, leishmaniasis and Chagas disease. The alpha-Gal on tick salivary proteins plays an important role in the etiology of the alpha-Gal syndrome. However, whether ticks are able to produce endogenous alpha-Gal remains currently unknown. In this study, the Ixodes scapularis genome was searched for galactosyltransferases and three genes were identified as potentially involved in the synthesis of alpha-Gal. Heterologous gene expression in alpha-Gal-negative cells and gene knockdown in ticks confirmed that these genes were involved in alpha-Gal synthesis and are essential for tick feeding. Furthermore, these genes were shown to play an important role in tick-pathogen interactions. Results suggested that tick cells increased alpha-Gal levels in response to Anaplasma phagocytophilum infection to control bacterial infection. These results provided the molecular basis of endogenous alpha-Gal production in ticks and suggested that tick galactosyltransferases are involved in vector development, tick-pathogen interactions and possibly the etiology of alpha-Gal syndrome in humans. |
Scientific reports. 2018;8(1):1-8. | |
| Cabezas-Cruz A, Hodžić A, Mateos-Hernández L, Contreras M, de la Fuente J. | 2021 | Tick–human interactions: from allergic klendusity to the α-Gal syndrome. Ticks and the pathogens they transmit, including bacteria, viruses, protozoa, and helminths, constitute a growing burden for human and animal health worldwide. The ability of some animal species to acquire resistance to blood-feeding by ticks after a single or repeated infestation is known as acquired tick resistance (ATR). This resistance has been associated to tick-specific IgE response, the generation of skin-resident memory CD4+ T cells, basophil recruitment, histamine release, and epidermal hyperplasia. ATR has also been associated with protection to tick-borne tularemia through allergic klendusity, a disease-escaping ability produced by the development of hypersensitivity to an allergen. In addition to pathogen transmission, tick infestation in humans is associated with the α-Gal syndrome (AGS), a type of allergy characterized by an IgE response against the carbohydrate Galα1-3Gal (α-Gal). This glycan is present in tick salivary proteins and on the surface of tick-borne pathogens such as Borrelia burgdorferi and Anaplasma phagocytophilum, the causative agents of Lyme disease and granulocytic anaplasmosis. Most α-Gal-sensitized individuals develop IgE specific against this glycan, but only a small fraction develop the AGS. This review summarizes our current understanding of ATR and its impact on the continuum α-Gal sensitization, allergy, and the AGS. We propose that the α-Gal-specific IgE response in humans is an evolutionary adaptation associated with ATR and allergic klendusity with the trade-off of developing AGS. |
Biochemical Journal. 2021 May 14;478(9):1783-94. | |
| Cabezas-Cruz A, Hodžić A, Román-Carrasco P, Mateos-Hernández L, Duscher GG, Sinha DK, Hemmer W, Swoboda I, Estrada-Peña A, De La Fuente J. | 2019 | Environmental and Molecular Drivers of the alpha-Gal Syndrome. The alpha-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody (Ab) response against the carbohydrate Galalpha1-3Galbeta1-4GlcNAc-R (alpha-Gal), which is present in glycoproteins from tick saliva and tissues of non-catarrhine mammals. Recurrent tick bites induce high levels of anti-alpha-Gal IgE Abs that mediate delayed hypersensitivity to consumed red meat products in humans. This was the first evidence that tick glycoproteins play a major role in allergy development with the potential to cause fatal delayed anaphylaxis to alpha-Gal-containing foods and drugs and immediate anaphylaxis to tick bites. Initially, it was thought that the origin of tick-derived alpha-Gal was either residual blood meal mammalian glycoproteins containing alpha-Gal or tick gut bacteria producing this glycan. However, recently tick galactosyltransferases were shown to be involved in alpha-Gal synthesis with a role in tick and tick-borne pathogen life cycles. The tick-borne pathogen Anaplasma phagocytophilum increases the level of tick alpha-Gal, which potentially increases the risk of developing AGS after a bite by a pathogen-infected tick. Two mechanisms might explain the production of anti-alpha-Gal IgE Abs after tick bites. The first mechanism proposes that the alpha-Gal antigen on tick salivary proteins is presented to antigen-presenting cells and B-lymphocytes in the context of Th2 cell-mediated immunity induced by tick saliva. The second mechanism is based on the possibility that tick salivary prostaglandin E2 triggers Immunoglobulin class switching to anti-alpha-Gal IgE-producing B cells from preexisting mature B cells clones producing anti-alpha-Gal IgM and/or IgG. Importantly, blood group antigens influence the capacity of the immune system to produce anti-alpha-Gal Abs which in turn impacts individual susceptibility to AGS. The presence of blood type B reduces the capacity of the immune system to produce anti-alpha-Gal Abs, presumably due to tolerance to alpha-Gal, which is very similar in structure to blood group B antigen. Therefore, individuals with blood group B and reduced levels of anti-alpha-Gal Abs have lower risk to develop AGS. Specific immunity to tick alpha-Gal is linked to host immunity to tick bites. Basophil activation and release of histamine have been implicated in IgE-mediated acquired protective immunity to tick infestations and chronic itch. Basophil reactivity was also found to be higher in patients with AGS when compared to asymptomatic alpha-Gal sensitized individuals. In addition, host resistance to tick infestation is associated with resistance to tick-borne pathogen infection. Anti-alpha-Gal IgM and IgG Abs protect humans against vector-borne pathogens and blood group B individuals seem to be more susceptible to vector-borne diseases. The link between blood groups and anti-alpha-Gal immunity which in turn affects resistance to vector-borne pathogens and susceptibility to AGS, suggests a trade-off between susceptibility to AGS and protection to some infectious diseases. The understanding of the environmental and molecular drivers of the immune mechanisms involved in AGS is essential to developing tools for the diagnosis, control, and prevention of this growing health problem. |
Front Immunology 2019; 10: 1210. | |
| Cabezas-Cruz A, Mateos-Hernández L, Alberdi P, Villar M, Riveau G, Hermann E, Schacht AM, Khalife J, Correia-Neves M, Gortazar C, De La Fuente J. | 2017 | Effect of blood type on anti-alpha-Gal immunity and the incidence of infectious diseases. The identification of factors affecting the susceptibility to infectious diseases is essential toward reducing their burden on the human population. The ABO blood type correlates with susceptibility to malaria and other infectious diseases. Due to the structural similarity between blood antigen B and Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R (alpha-Gal), we hypothesized that self-tolerance to antigen B affects the immune response to alpha-Gal, which in turn affects the susceptibility to infectious diseases caused by pathogens carrying alpha-Gal on their surface. Here we found that the incidence of malaria and tuberculosis, caused by pathogens with alpha-Gal on their surface, positively correlates with the frequency of blood type B in endemic regions. However, the incidence of dengue fever, caused by a pathogen without alpha-Gal, was not related to the frequency of blood type B in these populations. Furthermore, the incidence of malaria and tuberculosis was negatively correlated with the anti-alpha-Gal antibody protective response. These results have implications for disease control and prevention. |
Experimental & molecular medicine 2017; 49(3): e301. | |
| Cabezas-Cruz A, Mateos-Hernández L, Chmelař J, Villar M, de la Fuente J. | 2017 | Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat. Tick-induced allergy to red meat is associated with anti-alpha-Gal IgE antibody levels. We propose that tick salivary prostaglandin E2 triggers antibody class switching in mature B cells, increasing the levels of anti-alpha-Gal IgE antibodies. Immune tolerance to alpha-Gal in blood type B individuals might reduce the risk to this allergy. |
Trends Parasitol 2017; 33(7): 495-498. | |
| Cabezas-Cruz A, Mateos-Hernández L, Pérez-Cruz M, Valdés JJ, De Mera IGF, Villar M, de la Fuente J. | 2015 | Regulation of the Immune Response to alpha-Gal and Vector-borne Diseases. Vector-borne diseases (VBD) challenge our understanding of emerging diseases. Recently, arthropod vectors have been involved in emerging anaphylactic diseases. In particular, the immunoglobulin E (IgE) antibody response to the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-gal) following a tick bite was associated with allergies to red meat, cetuximab, and gelatin. By contrast, an anti-alpha-gal IgM antibody response was shown to protect against mosquito-borne malaria. Herein, we highlight the interplay between the gut microbiota, vectors, transmitted pathogens, and the regulation of the immune response as a model to understand the protective or allergic effect of alpha-gal. Establishing the source of alpha-gal in arthropod vectors and the immune response to vector bites and transmitted pathogens will be essential for diagnosing, treating, and ultimately preventing these emerging anaphylactic and other vector-borne diseases. |
Trends Parasitol 2015; 31(10): 470-476. | |
| Cabezas-Cruz A, Valdés J, de la Fuente J. | 2014 | Cancer research meets tick vectors for infectious diseases. Continuous human exploitation of environmental resources and an increase in human outdoor activities have led to more contact with arthropod vectors, promoting an emergence and resurgence of tick-borne pathogens. Clinical trials of cetuximab, a monoclonal antibody that inhibits epidermal growth factor receptor used for treatment of metastatic colorectal cancer, have shown that the drug produces more hypersensitivity than expected, with some fatal cases. Patients who developed these hypersensitivity reactions were deemed to have pre-existing IgE antibodies specific to the alpha-gal present in the variable portion of cetuximab. |
The Lancet. Infectious diseases. 2014 Oct;14(10):916. | |
| Caglayan-Sozmen S, Santoro A, Cipriani F, Mastrorilli C, Ricci G, Caffarelli C. | 2019 | † Hazardous Medications in Children with Egg, Red Meat, Gelatin, Fish, and Cow's Milk Allergy. Childhood food allergies are a growing public health problem. Once the offending food allergens have been identified, a strict elimination diet is necessary in treatment or prevention of most of the allergic reactions. Accidental food ingestion can lead to severe anaphylaxis. Food- derived substances can be used in medications at various stages of the manufacturing process. In this review, the possible roles of medications which may contain egg, red meat, gelatin, and fish allergens on allergic reactions in children with food allergy were evaluated. |
Medicina-Lithuania 2019; 55(8) 501. | Medication; pharmaceutical; pharmacy; vaccination; vaccine; review article; primary care physician; pharmacy; pharmacist; perioperative care |
| Calafiore AM, Haverich A, Gaudino M, Di Mauro M, Fattouch K, Prapas S, Zilla P. | 2022 | Immunoreaction to xenogenic tissue in cardiac surgery: alpha-Gal and beyond. > The ability of the immune system to distinguish self from non-self, reacting only to non-self, is essential for immune homeostasis. The mechanisms by which the immune system recognizes and responds to xenogenic tissue heart valves likely involve the initial activation of the innate immune system, with subsequent adaptive immune activation. The antigenicity of xenogeneic tissue constructs, primarily of porcine and bovine origin, has been extensively investigated and several antigenic epitopes have been identified. Some of them have been more exhaustively studied to avoid or at least reduce the immunoreaction triggered by their presence. |
European Journal of Cardio-Thoracic Surgery. 2022 Feb 25. | Cardiac surgery; bioprosthetic heart valve, xenotransplantation |
| Calamari AM, Poppa M, Villalta D, Pravettoni V. | 2015 | Alpha-gal anaphylaxis: the first case report in Italy. We report the case of a 55-year-old man who went into anaphylactic shock six hours after eating a meal containing meat. He reported having had several tick bites in months before the reaction. The serum specific IgE showed strong positivity to alpha-gal. This is clearly alpha-gal anaphylaxis with delayed onset after meat ingestion caused by tick bite, confirmed by alpha-gal IgE positivity. |
European annals of allergy and clinical immunology. 2015 Sep;47(5):161-2. | Europe; Italy |
| Caponetto P, Biedermann T, Yazdi AS, Fischer J. | 2015 | Panitumumab: A safe option for oncologic patients sensitized to galactose-alpha-1,3-galactose. This case describes the treatment with panitumumab of a patient who is highly sensitized to galactose-α-1,3-galactose but also in need of a treatment with an anti–epidermal growth factor receptor mAb due to chemotherapy-refractory metastatic colorectal cancer. |
Journal of Allergy and Clinical Immunology-in Practice 2015; 3(6): 982-983. | biologic; biological agent; monoclonal antibody; mAb; oncology; colon cancer |
| Caponetto P, Fischer J, Biedermann T. | 2013 | * Gelatin-containing sweets can elicit anaphylaxis in a patient with sensitization to galactose-α-1,3-galactose. Gelatin-containing sweets can elicit anaphylaxis in mammalian meat allergic patients. A warning regarding gelatin-containing foods and medical products should be included in recommendations for patients with IgE recognizing Galactose-α-1,3-Galactose. |
The Journal of Allergy and Clinical Immunology: In Practice. 2013 May 1;1(3):302-3. | oral consumption of gelatin; gelatine; food; organs; intestines; tachycardia; dizziness; prick-to-prick test |
| Carlsson M, Braddock M, Li Y, Wang J, Xu W, White N, Megally A, Hunter G, Colice G. | 2019 | Evaluation of antibody properties and clinically relevant immunogenicity, anaphylaxis, and hypersensitivity reactions in two phase III trials of tralokinumab in severe, uncontrolled asthma. Introduction: Tralokinumab is a monoclonal antibody (mAb) that neutralizes interleukin (IL)-13, a cytokine involved in the pathogenesis of asthma. Objective: The objectives of this study were to characterize the potential immunogenic properties of tralokinumab and report data for anti-drug antibodies (ADAs) and hypersensitivity reactions from two phase III clinical trials. Methods: The oligosaccharide structure of tralokinumab, Fab-arm exchange, and ADAs were characterized by standard techniques. Hypersensitivity adverse events (AEs) were evaluated in two pivotal clinical trials of tralokinumab in severe, uncontrolled asthma: STRATOS 1 and 2 (NCT02161757 and NCT02194699). Results: No galactose-α-1,3-galactose (α-Gal) epitopes were found in the Fab region of tralokinumab and only 4.5% of glycoforms contained α-Gal in the Fc region. Under non-reducing conditions, Fab-arm exchange did not take place with another immunoglobulin (Ig) G4 mAb (mavrilimumab). However, following glutathione reduction, a hybrid antibody with monovalent bioactivity was detected. ADA incidences (titers) were as follows: STRATOS 1—every 2 weeks (Q2 W) 0.8% (26.0), every 4 weeks (Q4 W) 0.5% (26.0), placebo 0.8% (52.0); STRATOS 2—Q2 W 1.2% (39.0), placebo 0.8% (13.0). Participant-reported hypersensitivity AE rates were as follows: STRATOS 1—Q2 W 25.9%, Q4 W 25.0%, placebo 25.5%; STRATOS 2—Q2 W 13.2%, placebo 9.0%. External evaluation for anaphylaxis by Sampson criteria found no tralokinumab-related severe hypersensitivity or anaphylaxis reactions. Conclusion: Preclinical assessments suggested a low likelihood of immunogenicity for tralokinumab. In STRATOS 1 and 2, ADA incidence was low, no differences were found between tralokinumab-treated and placebo groups in reporting of hypersensitivity reactions, and there were no Sampson criteria-evaluated anaphylaxis events with tralokinumab treatment. Together, the results suggest that tralokinumab treatment would not increase the risk for severe hypersensitivity or anaphylactic reactions. |
Drug safety. 2019 Jun 4;42(6):769-84. | pharmacy; pharmaceutical; biologic; biological agent; monoclonal antibody; mAb; tralokinumab; asthma; atopic dermatitis; ulcerative colitis |
| Caron L, Ortolani VG, Bono E, Ratti CP, Iemoli E. | 2022 | Alpha-gal syndrome and delayed anaphylaxis after ingestion of red meat: A case report. |
Allergologie Select. 2022;6:299. | Europe; Italy |
| Carroll JF. | 2003 | A cautionary note: survival of nymphs of two species of ticks (Acari: Ixodidae) among clothes laundered in an automatic washer. |
Journal of medical entomology. 2003 Sep 1;40(5):732-6. | vector; lone star tick; prevention; laundry; dryer |
| Carson AS, Gardner A, Iweala OI. | 2022 | Where’s the Beef? Understanding Allergic Responses to Red Meat in Alpha-Gal Syndrome. Alpha-gal syndrome (AGS) describes a collection of symptoms associated with IgE-mediated hypersensitivity responses to the glycan galactose-alpha-1,3-galactose (alpha-gal). Individuals with AGS develop delayed hypersensitivity reactions, with symptoms occurring >2 h after consuming mammalian (“red”) meat and other mammal-derived food products. The mechanisms of pathogenesis driving this paradigm-breaking food allergy are not fully understood. We review the role of tick bites in the development of alpha-gal–specific IgE and highlight innate and adaptive immune cells possibly involved in alpha-gal sensitization. We discuss the impact of alpha-gal glycosylation on digestion and metabolism of alpha-gal glycolipids and glycoproteins, and the implications for basophil and mast cell activation and mediator release that generate allergic symptoms in AGS. |
The Journal of Immunology. 2022 Jan 15;208(2):267-77. | review |
| Carter MC, Akin C, Castells MC, Scott EP, Lieberman P. | 2020 | Idiopathic anaphylaxis yardstick: Practical recommendations for clinical practice. Anaphylaxis is considered idiopathic when there is no known trigger. The signs and symptoms of idiopathic anaphylaxis (IA) are identical to those of anaphylaxis because of a known cause and can include cutaneous, circulatory, respiratory, gastrointestinal, and neurologic symptoms. Idiopathic anaphylaxis can be a frustrating disease for patients and health care providers. Episodes are unpredictable, and differential diagnosis is challenging. Current anaphylaxis guidelines have little specific guidance regarding differential diagnosis and long-term management of IA. Therefore, the objective of the Idiopathic Anaphylaxis Yardstick is to use published data and the authors' combined clinical experience to provide practical recommendations for the diagnosis and management of patients with IA. |
Annals of Allergy, Asthma & Immunology. 2020 Jan 1;124(1):16-27. | iodpathic anaphylaxis; IA |
| Carter MC, Ruiz‐Esteves KN, Workman L, Lieberman P, Platts‐Mills TAE, Metcalfe DD. | 2018 | Identification of alpha-gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis. IgE antibodies (Ab) specific to galactose-α-1,3-galactose (alpha-gal) are responsible for a delayed form of anaphylaxis that occurs 3-6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha-gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha-gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha-gal are delayed and thus may be overlooked. |
Allergy 2018; 73(5): 1131-1134. | |
| Chakrapani N, Fischer J, Swiontek K, Codreanu-Morel F, Hannachi F, Morisset M, Mugemana C, Bulaev D, Blank S, Bindslev-Jensen C, Biedermann T. | 2022 | α-Gal present on both glycolipids and glycoproteins contributes to immune response in meat-allergic patients. Background: The α-Gal syndrome is associated with the presence of IgE directed to the carbohydrate galactose-α-1,3-galactose (α-Gal) and is characterized by a delayed allergic reaction occurring 2 to 6 hours after ingestion of mammalian meat. On the basis of their slow digestion and processing kinetics, α-Gal–carrying glycolipids have been proposed as the main trigger of the delayed reaction. Objective: We analyzed and compared the in vitro allergenicity of α-Gal–carrying glycoproteins and glycolipids from natural food sources. Methods: Proteins and lipids were extracted from pork kidney (PK), beef, and chicken. Glycolipids were purified from rabbit erythrocytes. The presence of α-Gal and IgE binding of α-Gal–allergic patient sera (n = 39) was assessed by thin-layer chromatography as well as by direct and inhibition enzyme-linked immunosorbent assay. The in vitro allergenicity of glycoproteins and glycolipids from different meat extracts was determined by basophil activation test. Glycoprotein stability was evaluated by simulated gastric and intestinal digestion assays. Results: α-Gal was detected on glycolipids of PK and beef. Patient IgE antibodies recognized α-Gal bound to glycoproteins and glycolipids, although binding to glycoproteins was more potent. Rabbit glycolipids were able to strongly activate patient basophils, whereas lipid extracts from PK and beef were also found to trigger basophil activation, but at a lower capacity compared to the respective protein extracts. Simulated gastric digestion assays of PK showed a high stability of α-Gal–carrying proteins in PK. Conclusion: Both α-Gal–carrying glycoproteins and glycolipids are able to strongly activate patient basophils. In PK and beef, α-Gal epitopes seem to be less abundant on glycolipids than on glycoproteins, suggesting a major role of glycoproteins in delayed anaphylaxis upon consumption of these food sources. |
Journal of Allergy and Clinical Immunology. 2022 Apr 19. | glycolipid; glycoprotein; glycolipid hypothesis |
| Chan GC, Chan CM. | 2022 | Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma. |
Biomolecules. 2022 Feb 24;12(3):358. | pharmaceutical; drugs and medical products; biologic; monoclonal antibody; dinutuximab; dinutuximab beta |
| Chandrasekhar J, Cox K, Loo W, Tung K, Erickson L. | 2018 | Development of a novel mouse model to study tick-borne onset of red meat allergy. Bites from Amblyomma americanum, also known as the lone star tick, cause a life-threatening food allergy that induces IgE-mediated allergic reactions in affected individuals after eating dietary ‘red’ meat such as beef, pork, and lamb. Currently, there is no treatment to prevent or cure red meat allergy. Thus, establishing how lone star ticks cause red meat allergy is important for protecting individuals against this allergy. Our lab has successfully developed a novel mouse model of hypersensitivity to tick exposure to better understand how bites from the lone star tick sensitize the host to produce and maintain allergic IgE. Using this model, we identified increased T follicular helper cell and germinal center B cell responses and elevated serum titers of tick-specific IgE and IgG1 in mice exposed to lone star ticks subcutaneously. Furthermore, these mice generate a hypersensitivity response after oral challenge with red meat, as measured by basophil activation. Finally, we found that both the formation of inflammatory skin lesions at the site of tick exposure and the production of IgE were dependent on CD4+ helper T cells. These findings suggest that contained within the tick are factors that markedly influence priming of CD4+ T cells leading to the production of allergic IgE. Based on these data, we propose that manipulation of the factors within lone star ticks that drive CD4+ helper T cell activity could be used locally in the skin at the tick bite site to prevent the onset of meat allergy and systemically to stop an allergic reaction from progressing to a state of severe hypersensitivity. |
The Journal of Immunology 2001; 104.106. | |
| Chandrasekhar JL, Cox KM, Erickson LD. | 2020 | B Cell Responses in the Development of Mammalian Meat Allergy. Studies of meat allergic patients have shown that eating meat poses a serious acute health risk that can induce severe cutaneous, gastrointestinal, and respiratory reactions. Allergic reactions in affected individuals following meat consumption are mediated predominantly by IgE antibodies specific for galactose-α-1,3-galactose (α-gal), a blood group antigen of non-primate mammals and therefore present in dietary meat. α-gal is also found within certain tick species and tick bites are strongly linked to meat allergy. Thus, it is thought that exposure to tick bites promotes cutaneous sensitization to tick antigens such as α-gal, leading to the development of IgE-mediated meat allergy. The underlying immune mechanisms by which skin exposure to ticks leads to the production of α-gal-specific IgE are poorly understood and are key to identifying novel treatments for this disease. In this review, we summarize the evidence of cutaneous exposure to tick bites and the development of mammalian meat allergy. We then provide recent insights into the role of B cells in IgE production in human patients with mammalian meat allergy and in a novel mouse model of meat allergy. Finally, we discuss existing data more generally focused on tick-mediated immunomodulation, and highlight possible mechanisms for how cutaneous exposure to tick bites might affect B cell responses in the skin and gut that contribute to loss of oral tolerance. |
Frontiers in Immunology. 2020;11. | Induction; mechanism; b cell |
| Chandrasekhar JL, Cox KM, Loo WM, Qiao H, Tung KS, Erickson LD. | 2019 | Cutaneous Exposure to Clinically Relevant Lone Star Ticks Promotes IgE Production and Hypersensitivity through CD4(+) T Cell- and MyD88-Dependent Pathways in Mice. Tick-borne allergies are a growing public health concern and have been associated with the induction of IgE-mediated food allergy to red meat. However, despite the increasing prevalence of tick bite-induced allergies, the mechanisms by which cutaneous exposure to ticks leads to sensitization and the production of IgE Abs are poorly understood. To address this question, an in vivo approach was used to characterize the IgE response to lone star tick proteins administered through the skin of mice. The results demonstrated that tick sensitization and challenge induced a robust production of IgE Abs and supported a role for IgE-mediated hypersensitivity reactions in sensitized animals following oral administration of meat. The induction of IgE responses was dependent on cognate CD4(+) T cell help during both the sensitization phase and challenge phase with cutaneous tick exposure. In addition, IgE production was dependent on B cell-intrinsic MyD88 expression, suggesting an important role for TLR signaling in B cells to induce IgE responses to tick proteins. This model of tick-induced IgE responses could be used to study the factors within tick bites that cause allergies and to investigate how sensitization to food Ags occurs through the skin that leads to IgE production. |
Journal of Immunology. 2019 Aug 15;203(4):813-24. | |
| Charlesworth M, Shelton CL. | 2019 | Should intravenous gelatins have a role in contemporary peri‐operative and critical care?. |
Anaesthesia. 2020 Feb;75(2):266-9. | pharmaceutical; pharmacy; medical products; gelatin; plasma volume expanders |
| Chauhan PS, Saxena A. | 2016 | Bacterial carrageenases: an overview of production and biotechnological applications. Carrageenan, one of the phycocolloids is a sulfated galactan made up of linear chains of galactose and 3,6-anhydrogalactose with alternating α-(1 → 3) and β-(1 → 4) linkages and further classified based on the number and the position of sulfated ester(s); κ-, ι- and λ-carrageenan. Enzymes which degrade carrageenans are called k-, ι-, and λ-carrageenases. They all are endohydrolases that cleave the internal β-(1–4) linkages of carrageenans yielding products of the oligo-carrageenans. These enzymes are produced only by bacteria specifically gram negative bacteria. Majority of the marine bacteria produce these enzymes extracellularly and their activity is in wide range of temperature. They have found potential applications in biomedical field, bioethanol production, textile industry, as a detergent additive and for isolation of protoplast of algae etc. A comprehensive information shall be helpful for the effective understanding and application of these enzymes. In this review exhaustive information of bacterial carrageenases reported till date has been done. All the aspects like sources, production conditions, characterization, cloning and- biotechnological applications are summarized. |
3 Biotech. 2016 Dec 1;6(2):146. | carrageenan |
| Che L, Li X, Zhang X, Zhang YL, Yi J, Ruan X, Ma S, Huang Y. | 2021 | The nature and reported incidence of suspected perioperative allergic reactions: A cross-sectional survey. Study objective: Perioperative allergic reactions (POHs) are common and can lead to severe intraoperative instability and even mortality. In contrast to the situation in developed countries, where databases of perioperative anaphylaxis are well documented and analyzed, relevant data are lacking in China. Therefore, we aimed to conduct a national survey to explore the characteristics of perioperative allergic reactions, as well as the knowledge and attitudes toward management and reporting among anesthesiologists. Design: Cross-sectional survey. Setting: Anesthesia department. Patients: A nationally representative sample comprising anesthesiologists from 12 province-level regions was selected. Measurements: A 20-item questionnaire was designed and validated using the Delphi method. Survey distribution was performed between June 2019 and January 2020 by the Chinese Society of Anesthesiology (CSA), which is the official academic society of Chinese anesthesiologists. Responses were compiled and analyzed. Main results: We received responses from 4389 anesthesiologists across China. The estimated rate of suspected POH was 2/1000 patients (0.2%). On average, an anesthesiologist encountered 2.1 suspected POH cases per year. Neuromuscular blocking agents (NMBAs) were perceived as the most common causative agents, followed by antibiotics and succinylated gelatin. The rates of referral and allergy consultations were very low. Institutional support, including protocol development, cognitive aids, and tool kits, was not ideal. Additionally, the management of POH varied substantially. Most anesthesiologists believed that reporting and documenting POH was necessary. Conclusions: Our survey revealed that POH is commonly encountered by Chinese anesthesiologists, but few patients are referred to allergy specialists or clinics for further investigation. A standardized recommendation based on research and data derived from Chinese patients is required |
Journal of Clinical Anesthesia. 2021 Nov 1;74:110404. | Asia; China; perioperative; medical products; anesthesia; gelatin; Gelofusine |
| Chinuki Y, Ishiwata K, Yamaji K, Takahashi H, Morita E. | 2016 | Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan. Recent studies revealed that Amblyomma or Ixodes tick bites may cause red meat allergy, in which galactose-alpha-1,3-galactose (alpha-Gal) is a major IgE-binding epitope. The incidence of red meat allergy is high in Shimane Prefecture, as is tick-transmitted Japanese spotted fever. Therefore, we speculated that tick bites may cause these meat allergies. The carbohydrate alpha-Gal was detected in the salivary gland protein of Haemaphysalis longicornis (H. longicornis), the vector for Japanese spotted fever, by immunoblotting using anti-alpha-Gal antibody. H. longicornis salivary gland protein-specific IgE was detected in the sera of 24 of 30 patients with red meat allergies. Sensitization to tick salivary gland protein containing alpha-Gal is possibly a major etiology of red meat allergy; the carbohydrate plays a crucial role in its allergenicity. These results further indicate that the alpha-Gal epitope is present not only in Amblyomma or Ixodes, but also in Haemaphysalis. |
Allergy. 2016 Mar;71(3):421-5. | Asia; Japan; vector; tick species; Haemaphysalis longicornis |
| Chinuki Y, Ito K, Morita E. | 2019 | 128 Measurement of galactose-alpha-1,3-galactose-related specific IgE before the first administration of cetuximab can reduce the incidence of cetuximab-induced anaphylactic shock. It is known that the main causative antigenic epitope of cetuximab allergy is galactose-alpha-1,3-galactose (alpha-Gal). In 2013, 13 patients with head and neck cancer received the first administration of cetuximab at Matsue Red Cross Hospital in the western part of Japan, and four of them developed anaphylactic shock (Incidence rate was 31%). In the sera of these patients, both alpha-Gal specific IgE by CAP-FEIA and cetuximab specific IgE by western blotting were detected. Both sensitivity and specificity in 13 patients of these tests were 100%. We therefore aimed to prevent cetuximab-induced anaphylactic shock by performing these tests before the administration. We measured alpha-Gal specific IgE by CAP-FEIA and cetuximab specific IgE by western blotting before the first administration of cetuximab in 206 patients with head and neck cancer, and gave the first dose of cetuximab to the patients who showed either on these two tests. As a result, alpha-Gal-specific IgE was detected in 15 of 206, and cetuximab-specific IgE was detected in 12 of 206. Nine patients showed positive on both tests. Thirty nine of the 188 patients who showed negative either on these two tests have received cetuximab so far, and two of them developed anaphylactic shock (Incidence rate was 5%). Although the incidence rate did not reach to 0%, cetuximab-induced anaphylactic shock could be significantly reduced by prior measurement of alpha-Gal-related specific IgE. The reason why the incidence rate could not be 0% may be because the cutoff value (<0.35kUA/L) we decided was high. |
Journal of Investigative Dermatology. 2019 Sep 1;139(9):S236. | Asia; Japan |
| Chinuki Y, Morita E. | 2019 | Alpha-Gal-containing biologics and anaphylaxis. Cetuximab, the IgG1 subclass chimeric mouse-human monoclonal antibody biologic that targets the epidermal growth factor receptor (EGFR), is used worldwide for the treatment of EGFR-positive unresectable progressive/recurrent colorectal cancer and head and neck cancer. Research has shown that the principal cause of cetuximab-induced anaphylaxis is anti-oligosaccharide IgE antibodies specific for galactose-alpha-1,3-galactose (alpha-Gal) oligosaccharide present on the mouse-derived Fab portion of the cetuximab heavy chain. Furthermore, it has been revealed that patients who are allergic to cetuximab also develop an allergic reaction to mammalian meat containing the same alpha-Gal oligosaccharide owing to cross-reactivity, and the presumed cause of sensitization is tick bites: Amblyomma in the United States, Ixodes in Australia and Europe, and Haemaphysalis in Japan. The alpha-Gal-specific IgE test (bovine thyroglobulin-conjugated ImmunoCAP) or CD63-expression-based basophil activation test may be useful to identify patients with IgE to alpha-Gal in order to predict risk for cetuximab-induced anaphylactic shock. Investigations of cetuximab-related anaphylaxis have revealed three novel findings that improve our understanding of immediate-type allergy: 1) oligosaccharide can serve as the main IgE epitope of anaphylaxis; 2) because of the oligosaccharide epitope, a wide range of cross-reactivity with mammalian meats containing alpha-Gal similar to cetuximab occurs; and 3) tick bites are a crucial factor of sensitization to the oligosaccharide. Nonetheless, taking a medical history of tick bites and beef allergy may be insufficient to prevent cetuximab-induced anaphylaxis, and therefore blood testing with an alpha-Gal-specific IgE test, with high sensitivity and specificity, is necessary to detect sensitization to alpha-Gal. |
Allergology International. 2019;68(3):296-300. | |
| Chinuki Y, Takahashi H, Morita E. | 2022 | IgE antibodies to galactose-α-1, 3-galactose, an epitope of red meat allergen, cross-react with a novel flounder roe allergen. Sensitization to galactose-α-1,3-galactose (alpha-Gal) due to tick bites causes allergies to various red meats and cetuximab [1]. The alpha-Gal syndrome cases have been reported in different countries and the identity of implicated tick species varies geographically [1–4]. We previously described 30 individuals with red meat allergy, 24 of whom were found to have IgE against -Gal-containing water-soluble salivary gland proteins of Haemaphysalis longicornis[4]. Interestingly, most of the patients also experienced allergic reactions after ingesting flounder in winter [5]. In this study, we aimed to clarify the mechanism of flounder allergy found in the patients allergic to red meat. |
J Investig Allergol Clin Immunol. 2022;32(4). | non-mammalian vertebrates; fish; founder eggs roe; cross-react |
| Chinuki Y, Takahashi H, Morita E. | 2013 | *Clinical and biochemical evaluation of twenty patients with red meat allergies. Note: 75% of people who reacted to beef also reacted to flounder eggs. |
Jpn J Dermatol. 2013;123(1807):e14. | flounder; allergen; cross-reactivity; cross-reaction; flounder roe; sushi |
| Chitnavis M, Stein DJ, Commins S, Schuyler AJ, Behm B. | 2017 | First-dose anaphylaxis to infliximab: a case of mammalian meat allergy. Letter to the editor: IgE antibodies to galactose-α-1,3-galactose, identified in patients with mammalian meat allergy, can cross-react with a glycosylated component of infliximab, resulting in anaphylaxis in patients who receive this therapy. |
The Journal of Allergy and Clinical Immunology: In Practice. 2017 Sep 1;5(5):1425-6. | |
| Choi GS, Kim JH, Lee HN, Sung JM, Lee JW, Park HS. | 2009 | Occupational asthma caused by inhalation of bovine serum albumin powder. Bovine serum albumin (BSA), which is present in bovine plasma, is one of the major allergens affecting patients with food allergies induced by milk and meat. It is also commonly used in research laboratories. Although some reports have documented food allergies associated with BSA, BSA-induced occupational asthma has not been reported. We report a case of occupational asthma and rhinitis in a laboratory worker caused by the inhalation of BSA powder, in which an IgE-mediated response was suggested as the pathogenic mechanism. |
Allergy, asthma & immunology research. 2009 Oct 1;1(1):45-7. | airborne |
| Choudhary S, Commins S, Karim S. | 2022 | Tick salivary gland extract may act as an adjuvant to induce alpha-gal syndrome in alpha-gal deficient mice. Bites from the lone star tick, Amblyomma americanum (Aa), are associated with the development of alpha-gal specific IgE (sIgE) in humans and alpha-gal deficient (AGKO) mice. We have recently reported the presence of alpha-gal in the saliva of Aa and Ixodes scapularis (Is) but not in not in Amblyomma maculatum (Am). Since Am ticks do not contain endogenous alpha-gal, we used this species to test whether feeding Am ticks an alpha-gal-containing blood meal could sensitize AGKO mice and produce alpha-gal syndrome (AGS). |
Journal of Allergy and Clinical Immunology. 2022 Feb 1;149(2):AB52. | pathogenesis; tick salivary gland |
| Choudhary S, Commins SP. | 2018 | Detection of antigen-specific IgE-expressing B cells in food allergy is feasible and inversely associated with dietary antigen exposure. RATIONALE: To understand the regulation of IgE production in the recently described alpha-gal mammalian meat food allergy, we have focused on IgE-expressing (IgE+) B cells. These cells typically circulate in low abundance and are generally difficult to detect. Recent improvements in technical methods have made their analysis more feasible. Once identified, we asked whether circulating alpha-gal-specific IgE+ B cell populations were affected by ongoing dairy consumption as others have shown that B cell receptor (BCR) signaling negatively regulates IgE responses. METHODS: PBMCs were isolated from controls and subjects with alphagal allergy and stained for surface markers CD19, CD38, CD27, CD138, and membrane IgM, IgG, IgD and IgE as well as fluorochrome-labeled alpha-gal. RESULTS: We found that SHIP-1 is phosphorylated at each step of DS, more importantly it is more phosphorylated at early steps, statistically higher at step 3 (P<0.05), at the time when the doses cannot induce bhexosaminidase release. As opposed to Syk and p38 MAPK which are only phosphorylated at activating doses. Of the 11 DS doses, steps 2 and 3 showed significantly higher SHIP-1 phosphorylation when antigen given cumulatively as compared to single doses (P<0.05 and P<0.01, respectively). CONCLUSIONS: DS takes advantage of SHIP-1 at the early steps when low doses cannot induce b-hexosaminidase release to dominate the inhibitory signals over activating molecules as Syk kinase. |
Journal of Allergy and Clinical Immunology. 2018 Feb 1;141(2):AB192. | |
| Choudhary S, Iweala OI, Addison CT, & Commins SP. | 2019 | Tick Salivary Gland Extract Induces Alpha-Gal Allergy in Alpha-Gal Deficient Mice. RATIONALE: Recent retrospective research associated early life acid suppressive medication with food allergies. We sought to prospectively evaluate the association between acid suppressive medication in infancy and development of IgE-mediated food allergy in early childhood. METHODS: The Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) Study is an ongoing prospective observational cohort study of 1003 healthy newborn infants designed to evaluate the development of food allergies in their first 3 years of life. IgE-mediated food allergy was determined by independent agreement of two allergist reviewers based on clinical reactivity and documented IgE sensitivity. RESULTS: Compared to controls, mice treated with TSGE had elevated total IgE and IgG at day 56 (0.6060.12 ng/mL vs 113.2624.77 ng/mL, p<0.0001; 98.07610.32 mg/mL vs 253.4638.93 mg/mL, p<0.0001, respectively). Alpha-gal sIgE was increased in response to TSGE treatment (undetected vs 40.3 pg/mL). Core body temperature decreased following pork challenge with maximal decrease at 30 minutes in the TSGE-treated mice (34.3960.568C) but not in control mice. Interestingly, female mice had higher total IgE responses to TSGE treatment (179.1639.86 vs 56.98617.45 ng/ml) but male mice had larger declines in mean body temperature (-4.9960.6 vs -3.1860.828C). CONCLUSIONS: AGKO mice treated with TSGE recapitulate the delayed allergy to red meat seen in humans and establish the central role of tick bites. In addition, our model serves as a platform for mechanistically studying this new food allergy – already revealing potentially important sex-related differences. |
Journal of Allergy and Clinical Immunology. 2019 Feb 1;143(2):AB252. | pathogenesis; tick salivary gland |
| Choudhary S, Jerath MR, Commins SP. | 2018 | Venom allergy is increased in alpha-gal allergy: shared environmental or immunologic factors? RATIONALE: Expansion of tick populations has been associated with environmental change. We now face a global increasing incidence of mammalian meat food allergy due to alpha-gal sIgE, which has been associated with tick bites. Since patients with alpha-gal allergy frequent the outdoor environment, we sought to determine whether rates of stinging insect venom allergy, another environmentally-influenced condition, are increased in these patients. METHODS: Patients (n5109) presenting to the University of North Carolina allergy clinic with possible alpha-gal allergy were interviewed regarding reactions to stinging insects. Sera were later assayed for sIgE to alpha-gal and mammalian allergens as well as venoms (honey bee, whitefaced hornet, common wasp, paper wasp and fire ant) using Phadia ImmunoCAP platform. Control subjects (n526) were also enrolled for comparison. RESULTS: Subjects with alpha-gal allergy reported a higher rate nonlocal reactions following insect sting and were 5 times more likely to be sensitized (>0.35) to any of five venom allergens compared to controls (Chi-square prob50.0244). Among alpha-gal allergic subjects sensitization to common wasp was most frequent (30.3%), whereas among controls it was fire ant (15.4%). Notably, having alpha-gal allergy was associated with a 3.6-fold increased risk of sensitization to multiple venom sIgE (95% CI 1.02-12.78) compared to controls. Total IgE was not different between the groups. CONCLUSIONS: Development of IgE following ecto-parasitic tick bites and stinging insect envenomations may have a shared immunologic determinant or predisposition, other than just atopy. Given that both conditions are influenced by environmental exposures, ongoing climate change is likely to make these allergic conditions more common |
Journal of Allergy and Clinical Immunology. 2018 Feb 1;141(2):AB199. | |
| Choudhary S. | 2020 | Transcriptional analysis of B cells from patients with alpha-gal allergy. RATIONALE: Patients who develop alpha-gal allergy have tolerated mammalian meat and products for years. Understanding the shift in transcriptional programming of alpha-gal IgE-producing B cells is critical to elucidating the switch from immune tolerance to allergen reactivity. . . METHODS: B cells were enriched from alpha-gal allergic and control subjects by negative selection and sorted for CD27highCD38highIgE+ aGal+ CD138- plasmabast, one cell/well into a 96- well BD precise plate. Target genes were amplified, sequenced and data were analyzed using BD genomic data view software. In conjunction, additional enriched B cell preparations from control and alpha-gal-allergic subjects were analyzed for targeted gene expression using digital barcoded platform. . . RESULTS: We detected AG+ IgE+ plasmablast in the blood of recent tick bitten subject with median percentage of 0.054 (25% Percentile 0.013, 75th percentile 0.105, N513). Further a positive correlation was observed between alpha-gal sIgE and alpha-gal+ IgE+ plasmablast. Projection of data with tSNE plot suggested that genes from subjects with high sIgE annotated together. An increase in gene expression of transcription factors and pseudogenes involved in transcriptional regulation were observed in subjects with high sIgE. Upregulation of TNF gene expression as well as other inflammation-related products was found in alpha-gal allergic subjects without influence of alpha-gal sIgE titer. . . CONCLUSIONS: Subjects with alpha-gal allergy appear to have a strikingly higher percentage of circulating plasmablasts than control subjects. Moreover, these plasmablasts express a distinct transcriptional repertoire consistent with a robust inflammatory stimulus which likely explains the shift from immune tolerance of red meat to clinical food allergy. |
Journal of Allergy and Clinical Immunology. 2020 Feb 1;145(2):AB158. | |
| Choudhary SK, Commins SP. | 2015 | Association of Alpha-gal Red Meat Allergy Severity with Concentration of Antigen in Basophil Activation. RATIONALE: IgE to galactose-alpha-1,3,-galactose has been associatedwith delayed allergic reactions to red meat and appears to developfollowing bites from ecto-parasitic ticks. METHODS: Patients who presented to the University of North Carolinaallergy clinic with histories compatible with delayed reactions to red meat had sera were assayed for IgE antibodies, total IgE and basophil activation titration. RESULTS: IgE was measured to alpha-gal and mammalian allergens aswell as venoms. The presence of IgE antibodies to venom allergens wasincreased in those subjects allergic to alpha-gal. Severity of reactionswas not associated with the titer of IgE antibodies to alpha-gal but waspositive associated with lower antigen concentration leading to basophilactivation. In addition, the ratio of alpha-gal IgE to total IgE nor IgGantibodies to alpha-gal were correlated to titration of basophil activation.The severity of reactions was not related to age of onset or delay beforereactions. CONCLUSIONS: Patients with delayed anaphylaxis to red meat present a novel disease with late onset break in oral tolerance, no immediatesymptoms of food allergy, and a very high incidence of previous exposure to ticks. Atopy was not a predictor of IgE responses or food reactions but basophil activation at low antigen concentration appears to be a predictor of clinical reaction severity. |
Journal of Allergy and Clinical Immunology. 2017 Feb 1;139(2):AB125. | |
| Choudhary SK, Commins SP. | 2017 | Association of Alpha-gal Red Meat Allergy Severity with Concentration of Antigen in Basophil Activation. RATIONALE: IgE to galactose-alpha-1,3,-galactose has been associated with delayed allergic reactions to red meat and appears to develop following bites from ecto-parasitic ticks. METHODS: Patients who presented to the University of North Carolina allergy clinic with histories compatible with delayed reactions to red meat had sera were assayed for IgE antibodies, total IgE and basophil activation titration. RESULTS: IgE was measured to alpha-gal and mammalian allergens as well as venoms. The presence of IgE antibodies to venom allergens was increased in those subjects allergic to alpha-gal. Severity of reactions was not associated with the titer of IgE antibodies to alpha-gal but was positive associated with lower antigen concentration leading to basophil activation. In addition, the ratio of alpha-gal IgE to total IgE nor IgG antibodies to alpha-gal were correlated to titration of basophil activation. The severity of reactions was not related to age of onset or delay before reactions. CONCLUSIONS: Patients with delayed anaphylaxis to red meat present a novel disease with late onset break in oral tolerance, no immediate symptoms of food allergy, and a very high incidence of previous exposure to ticks. Atopy was not a predictor of IgE responses or food reactions but basophil activation at low antigen concentration appears to be a predictor of clinical reaction severity. |
Journal of Allergy and Clinical Immunology. 2017 Feb 1;139(2):AB125. | |
| Chung BY, Cho YS, Kim HO, Park CW. | 2015 | Food Allergy in Korean Patients with Chronic Urticaria. Background: The etiology of chronic urticaria (CU) remains unknown in most patients. Possible causes in some cases include food, but the role of allergy to food antigens in patients with CU remains controversial. Objective: The aim of this study was to evaluate the association between food allergy and CU. Methods: Korean patients with CU were assessed for a previous history of food allergy that caused symptoms of CU. Blood samples were taken from 350 patients to measure food allergen-specific IgE. Based on history and laboratory results, open oral food challenge (OFC) tests were performed. Results: Of 350 participants, 46 (13.1%) claimed to have experienced previous food hypersensitivity. Pork (n=16) was the main food mentioned, followed by beef (n=7), shrimp (n=6), and mackerel (n=6). We found that 73 participants (20.9%) had elevated levels of food-specific IgE, with pork (n=30), wheat (n=25), and beef (n=23) being the most common. However, when the open OFC tests were conducted in 102 participants with self-reported food hypersensitivity or raised levels of food-specific IgE, only four participants showed a positive reaction to pork (n=3) or crab (n=1). Conclusion: Although some participants claimed to have a history of CU related to food intake, when an open OFC test was conducted, few of them had positive results. We therefore conclude that food allergy is an uncommon cause of chronic CU. |
Annals of Dermatology. 2016 Oct 1;28(5):562-8. | Asia; Korea; pork allergy; prevalence |
| Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TAE. | 2008 | *Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. BACKGROUND: Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States. METHODS: We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston. RESULTS: Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain. CONCLUSIONS: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose. |
New England journal of medicine. 2008 Mar 13;358(11):1109-17. | prevalence; medical products; biologic; monoclonal antibody; cetuximab |
| Cocco RR, Ensina LF, Aranda CS, Solé D. | 2016 | Galactose-α-1, 3-Galactose (alphagal) allergy without anaphylaxis: a case report in Brazil. Background: Several studies suggest that tick bites are a cause of IgE antibody responses to alpha-gal in the United States, Europe, Asia and Australia. Delayed-onset reactions, especially anaphylaxis, have beenreported to happen 3 to 6 hours after ingestion of mammalian food products. Hereby we describe the first case of alpha gal allergy in Brazil in a male farmer, who presents with no other symptoms than urticaria. Report: A 55 year-old cattle breeder from North of Brazil (Rondonia) with no previous allergies refer to presenting with a daily scattered and pruritic papules for five years. Symptoms used to show up mostly inthe late afternoon and were closely related to the ingestion of meat (lamb, bovine, pork, chicken) during lunch time. When questioned about tick bites, he clearly described multiple lesions in his body secondaryto his job with animals and farm. Specific serum IgE revealed: bovine meat: 38.80 kU/L; pork meat: 28.60 kU/L; cow’s milk: 9.7 kU/L; serum bovine albumin: 1.51 kU/L; alpha gal: 70.7 kU/L; total IgE 888UI/mL. After orientation to restrict all meats, his symptoms have disappeared. Clinical Relevance: Although most of reports about alpha-gal allergy involve anaphylaxis, this patient presented only with urticaria. The only route of sensitization was through tick bites, since he never hadcontact to cetuximab. Chronic urticaria in farmers or environment with ticks, which can be very often in Brazil, should be investigated for alpha gal allergy. |
Poster presented at 4th Food Allergy and Anaphylaxis Meeting. 2016. | Latin America; Brazil; occupational medicine |
| Coker HB, Jakes ME, Mountcastle EA. | 2013 | Delayed urticaria to beef ingestion. To the Editor: A 50-year-old man presented with a 5-year history of urticaria developing approximately 3 hours after eating ground beef. The eruption cleared with diphenhydramine. In the next 4 years, the patient experienced similar eruptions every time he ate ground beef. Recently, he had awoken with urticaria about 4 hours after consuming a large steak. He reported no problems with chicken, other fowl, or fish ingestion. IgE level to galactose-alpha-1,3-galactose (alpha-gal) was 47 kU/L (normal <0.35 kU/L). The onset of these episodes followed within a few months of a tick bite. The patient could not identify the specific type of tick, but he lived in the southeastern United States where exposure to ticks is common. |
Journal of the American Academy of Dermatology. 2013 Mar 1;68(3):e101. | Alabama |
| Commins S, Choudhary S. | 2022 | Simultaneous measurement of surface proteins and single cell mRNA expression profiling of circulating immune cells in alpha-gal syndrome. |
Journal of Allergy and Clinical Immunology. 2022 Feb 1;149(2):AB93. | Immunological phenotyping; B cells; cell subsets; B cell populations; inflammation; atherosclerosis; Rhapsody; IL-8 |
| Commins SP, Crispell G, Karim S, Choudhary S, Iweala OI, Addison CT, Choudhary S. | 2019 | Red Meat Allergy May Develop Independent of Tick Blood Meal Status. RATIONALE: Alpha-gal syndrome (AGS) is a paradigm-shifting food allergy characterized by delayed reactions to non-primate mammalian meat and derived products. Evidence continues to suggest that AGS develops following tick bites and multiple species have been implicated globally. Tick saliva may contain alpha-gal from prior blood meal or may act as an adjuvant to induce IgE. This study assessed whether tick salivary gland extract (TSGE) could activate alpha-gal-sensitized basophils directly and if IgE reactivity was present in tick saliva. METHODS: PBMCs containing basophils from a non-alpha-gal allergic control subject were stripped of IgE; primed with plasma from subjects with and without alpha-gal allergy; stimulated for 30 minutes with TSGE from 4 species of ticks; and assessed for basophil activation by FACS. IgE reactivity was assessed by immunoassay using TSGE, tick larvae extract and tick saliva. RESULTS: The frequency of CD63+ basophils was 40-fold higher when alpha-gal IgE-sensitized basophils were stimulated with TSGE from Lone Star ticks compared to baseline. Extract from Ixodes scapularis but not the Gulf Coast tick, Amblyomma maculatum, also increased basophil activation. IgE reactivity was found in tick saliva (mean 23.4 IU/mL±1.9) among subjects with AGS but not larval tick or partially fed TSGE. CONCLUSIONS: IgE from subjects with AGS recognizes an antigen present in ticks from some species but not all and this observation can lead to identification of the sensitizing allergen. Interestingly, IgE reactivity appears to be specifically retained in tick saliva, an important distinction that may suggest alpha-gal antigen is present in ticks independent of blood meal status. |
Journal of Allergy and Clinical Immunology. 2019 Feb 1;143(2):AB34. | |
| Commins SP, James H, Tran N, Kelly E, Mullins R, Lieberman P, Platts-Mills TAE. | 2010 | Testing for IgE Antibody to the Carbohydrate galactose-alpha-1,3-galactose (alpha-gal) in Patients with Recurrent, Idiopathic Anaphylaxis: How Many Cases Are We Missing? RATIONALE: Patients with idiopathic anaphylaxis are at increased risk for recurrent episodes if the etiology of anaphylaxis is not established. The carbohydrate, galactose-a-1,3-galactose (alpha-gal), has recently been described as a novel food allergen and patients who have IgE to alpha-gal report delayed anaphylaxis or urticaria occurring 3-6 hours after eating mammalian meat. METHODS: Sera from patients with recurrent, idiopathic anaphylaxis diagnosed in three clinical sites: Tennessee, Virginia and Canberra, Australia were tested for the presence of IgE to alpha-gal. RESULTS: We identified 60 patients diagnosed with idiopathic anaphylaxis. Analysis of sera from patients (n 5 20) in the Tennessee clinic revealed that 5 of 20 (25%) had >1.0 IU/mL of IgE to alpha-gal. Results from the Virginia and Canberra sites showed a higher level of positive responses to alpha-gal (50%). Specifically, 11 of 22 sera from Virginia had >1.0 IU/mL of IgE to alpha-gal, whereas 9 of 18 from Australia were positive. The geometric mean total IgE from sera of patients with recurrent, idiopathic anaphylaxis who tested positive for IgE to alpha-gal from Tennessee, Virginia and Canberra was 325.7, 90.2 and 262.2 IU/mL, respectively. Those patients negative for IgE to alpha-gal had mean total IgE of 80.3, 33.2 and 155.9 IU/mL in Tennessee, Virginia and Canberra. Analysis of other allergens in this population did not reveal a pattern of sIgE to explain the other cases of anaphylaxis. CONCLUSIONS: IgE to galactose-a-1,3-galactose is an important, under-recognized cause of recurrent, ‘‘idiopathic’’ anaphylaxis and should be included in the work-up of patients in the southeastern US and southern Australia. |
Journal of Allergy and Clinical Immunology. 2010 Feb 1;125(2):AB119. | |
| Commins SP, James HR, Kelly LA, Pochan SL, Workman, LJ, Perzanowski MS, Kocan KM, Fahy JV, Nganga LW, Ronmar E, Cooper PJ. | 2011 | The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. BACKGROUND: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. OBJECTIVES: We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur. METHODS: Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP. RESULTS: Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20-fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (χ2=26.8, P<.001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A. americanum (rs=0.75, P<.001). CONCLUSION: The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy. |
Journal of Allergy and Clinical Immunology. 2011 May 1;127(5):1286-93. | ectoparasite; parasite; non-tick vector; helminth |
| Commins SP, James HR, Pochan SL, Workman LJ, Platts-Mills TA. | 2011 | IgE to Alpha-Gal: Clinical and In Vitro Evidence of a Delayed Reaction to Mammalian Meat. RATIONALE: A novel mammalian meat allergy attributed to an IgE abagainst the carbohydrate galactose-a-1,3-galactose (alpha-gal) is nowcommon in central Virginia. Patients who develop these reactions reportonset of urticaria that is consistently delayed by 3-6 hours. However, wehave previously shown that basophils from these patients will activate invitro within 30 minutes. METHODS: Following IRB approval, informed consent was obtainedfrom a subject who reported urticaria 4-5 hours after eating mammalianmeat. After an intravenous catheter was placed and baseline blood workobtained, a food challenge with 35 grams of prosciutto was performed.Hourly blood was obtained to assess for basophil activation and serummarkers of allergic response. RESULTS: Serum analysis revealed a total IgE of 102 IU/mL and IgE toalpha-gal of 22.8 IU/mL. Four hours and fifteen minutes after eating 35grams of prosciutto, pruritus was reported and urticaria appeared. Hivesprogressed over the ensuing 30 minutes until treatment with diphenhydramine. Assessment of basophils showed increased surface expression of theactivation marker CD63 of 12.9 and 11.7% at hours 4 and 5, compared to1.8% at baseline and 2.5, 3.8, and 2.8% at 1, 2 and 3 hours, respectively. CONCLUSIONS: This represents the first, clinically-documented in vivodemonstration of a delayed urticarial reaction to mammalian meat associated with IgE to alpha-gal. Moreover, basophil CD63 expression was increased at 4-5 hours post-challenge, corresponding to the appearance ofhives. The implication is that the form of alpha-gal that causes basophil activation and urticaria takes 4 hours to enter the bloodstream. |
Journal of Allergy and Clinical Immunology. 2011 Feb 1;127(2):AB245. | |
| Commins SP, James HR, Stevens W, Pochan SL, Land MH, King C, Mozzicato S, Platts-Mills TAE. | 2014 | Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose. BACKGROUND: In 2009, we reported a novel form of delayed anaphylaxis to red meat related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Although patients were remarkably consistent in their description of a 3- to 6-hour delay between eating mammalian meat and the appearance of symptoms, this delay has not been demonstrated under observed studies. OBJECTIVES: We sought to formally document the time course of clinical symptoms after the ingestion of mammalian meat in subjects with IgE to alpha-gal and to monitor ex vivo for the appearance of markers of an allergic reaction. METHODS: Open food challenges were performed with mammalian meat in 12 subjects with a history of severe urticarial reactions 3 to 6 hours after eating beef, pork, or lamb, as well as in 13 control subjects. Blood samples were taken hourly during each challenge. RESULTS: Ten of 12 subjects with IgE to alpha-gal had clinical evidence of a reaction during the food challenge (vs none of the control subjects, P < .001). The reactions occurred 3 to 7 hours after the initial ingestion of mammalian meat and ranged from urticaria to anaphylaxis. Tryptase levels were positive in 3 challenges. Basophil activation, as measured by increased expression of CD63, correlated with the appearance of clinical symptoms. CONCLUSION: The results presented provide clear evidence of an IgE-mediated food allergy that occurs several hours after ingestion of the inciting allergen. Moreover, here we report that in vivo basophil activation during a food challenge occurs in the same time frame as clinical symptoms and likely reflects the appearance of the antigen in the bloodstream. |
J Allergy Clin Immunol 2014; 134(1): 108-115. | |
| Commins SP, Jerath MR, Cox K, Erickson LD, Platts-Mills TAE. | 2016 | Delayed anaphylaxis to alpha-gal, an oligosaccharide in mammalian meat. IgE-mediated hypersensitivity refers to immune reactions that can be rapidly progressing and, in the case of anaphylaxis, are occasionally fatal. To that end, identification of the associated allergen is important for facilitating both education and allergen avoidance that are essential to long-term risk reduction. As the number of known exposures associated with anaphylaxis is limited, discovery of novel causative agents is crucial to evaluation and management of patients with idiopathic anaphylaxis. Within the last 10 years several apparently separate observations were recognized to be related, all of which resulted from the development of antibodies to a carbohydrate moiety on proteins. Interestingly, the exposure differed from airborne allergens but was nevertheless capable of producing anaphylactic and hypersensitivity reactions. Our recent work has identified these responses as being due to a novel IgE antibody directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose ("alpha-gal"). This review will present the historical summary of the identification of cetuximab hypersensitivity due to alpha-gal IgE and discuss the non-primate mammalian meat food allergy as well as current goals and directions of our research programs. |
Allergol Int 2016; 65(1): 16-20. | review article |
| Commins SP, Jerath MR, Platts-Mills T. | 2016 | The glycan did it: how the α-gal story rescued carbohydrates for allergists — a US perspective. IgE antibodies to carbohydrate epitopes on allergens are thought to be less common than IgE antibodies to protein epitopes and also of much less clinical significance. Our recent work, however, has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with two distinct forms of anaphylaxis including delayed allergic reactions after eating beef, pork or lamb. IgE antibody responses to alpha-gal have now been found globally. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues. |
Allergo Journal. 2016 Mar 1;25(2):24-8. | |
| Commins SP, Karim S. | 2017 | Development of a novel murine model of alpha-gal meat allergy. Rationale: Specific IgE (sIgE) galactose-alpha-1,3-galactose (alpha-gal) has been associated with delayed reactions to beef, pork or lamb. Development of alpha-gal sIgE and red meat allergy appears to occur following tick bites and alpha-gal has been reported in the gastrointestinal tract of Ixodes ricinusticks. In this study, we examined whether mice treated with tick salivary proteins would develop an alpha-gal IgE response and allergic reaction to red meat. Methods: Wild type (WT) mice were given either Amblyomma americanum (Aa) tick salivary gland extract intradermally (50μg) or saline on days 0, 7 and 21. IgE was assessed on day 28 by ELISA and mice were challenged orally with 10mg pork meat on day 30. Core body temperature was monitored during pork challenge and murine mast cell protease levels (mMCP-1) were assessed. Results: Compared to controls, mice treated with Aa tick extract had elevated alpha-gal sIgE at day 30 (207 IU/mL ± 38.1 vs 3.76 IU/mL ± 1.12, p<0.001). Core body temperature decreased following pork challenge with maximal decrease at 135 minutes in the Aa treated mice (35.6°C ± 2.8), whereas body temperature of control mice did not change. An increase in mMCP-1 was noted in serum of Aa treated mice at the conclusion of pork challenge compared to control mice (1247ng/mL ± 289 vs 15ng/mL ± 5.4). Conclusions: Mice treated with Aa tick extract develop alpha-gal sIgE and exhibit a delayed allergic response to pork meat on oral challenge. This murine model described may provide an important platform for mechanistically studying this new food allergy. |
Journal of Allergy and Clinical Immunology 2017; 139(2, Suppl. S): AB193. | vector; tick; tick saliva; sensitization |
| Commins SP, Kelly LA, Rönmark E, James HR, Pochan SL, Peters EJ, Lundbäck B, Nganga LW, Cooper PJ, Hoskins JM, Eapen SS. | 2012 | Galactose-alpha-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma. RATIONALE: IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract. OBJECTIVES: To evaluate the relationship between IgE antibodies to alpha-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens. METHODS: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131). MEASUREMENTS AND MAIN RESULTS: Patients in Virginia with high-titer IgE antibodies to alpha-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to alpha-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001). CONCLUSIONS: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled. |
American journal of respiratory and critical care medicine. 2012 Apr 1;185(7):723-30. | |
| Commins SP, Lucas S, Hosen J, Satinover SM, Borish L, Platts-Mills TAE. | 2008 | Anaphylaxis and IgE antibodies to galactose-alpha-1,3-galactose (alphaGal): Insight from the identification of novel IgE ab to carbohydrates on mammalian proteins. RATIONALE: Many cases of recurrent anaphylaxis or angioedema lack an obvious cause and are not explained by skin testing. The presence in serum of IgE ab to the xenoantigen galactose-alpha-1,3-galactose (alphaGal) may help in the understanding of these diseases. METHODS: Detailed histories were taken from patients (ages 18-75) presenting to the Allergy Clinic at the University of Virginia with recurrent anaphylaxis or angioedema. Prick tests, intradermal skin tests and serum IgE ab analysis were performed for common indoor, outdoor and food allergens. RESULTS: We identified 10 patients with similar histories and serum IgE ab profiles. These patients had serum IgE ab to beef, pork, lamb, cow’s milk, cat and dog, but were negative for turkey, chicken, and fish, and, in general, to inhaled allergens. Surprisingly, the titer of IgE ab to cat (19.1 IU/ml) and dog (18.2 IU/ml) epithelium were very similar (p 5 0.9) and the correlation between the two was highly significant, r 5 0.98, p < 0.001. In these patients, IgE ab to cat was not explained by sensitivity towards Fel d 1 (r 5 0.58, p 5 0.17). Patients describing a history of anaphylaxis or angioedema four to five hours after the ingestion of red meat reported fewer or no episodes when following an avoidance diet. Direct IgE ab and inhibition assays indicated that the pattern of sensitivity could be explained by IgE ab specific for alphaGal, a carbohydrate commonly expressed on non-primate mammalian proteins. CONCLUSIONS: IgE ab to galactose-alpha-1,3-galactose may be an important cause of recurrent anaphylaxis and angioedema that can be triggered by exposure to beef and pork. Funding: NIH |
Journal of Allergy and Clinical Immunology. 2008 Feb 1;121(2):S25. | |
| Commins SP, Mirakhur B, Platts-Mills TAE. | 2008 | Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose . Reply. |
New England journal of medicine. 2008 Mar 13;358(11):1109-17. | |
| Commins SP, Platts-Mills TAE. | 2009 | Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant. Anaphylaxis is a severe allergic reaction that can rapidly progress and occasionally be fatal. In instances in which the triggering allergen is not obvious, establishing the cause of anaphylaxis is pivotal to long-term management. Assigning cause is limited, however, by the number of known exposures associated with anaphylaxis. Therefore, identification of novel causative agents can provide an important step forward in facilitating new, allergen-specific approaches to management. In contrast to the view that carbohydrate-directed IgE has minimal, if any, clinical significance, recent data suggest that IgE antibodies to carbohydrate epitopes can be an important factor in anaphylaxis that might otherwise appear to be idiopathic. Here we review the evidence relating to carbohydrates in food allergy and anaphylaxis and discuss the implications of a new mammalian cross-reactive carbohydrate determinant. |
Journal of allergy and clinical immunology. 2009 Oct 1;124(4):652-7. | review article |
| Commins SP, Platts-Mills TAE. | 2013 | Delayed Anaphylaxis to Red Meat in Patients with IgE Specific for Galactose alpha-1,3-Galactose (alpha-gal). Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3-6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations. |
Current allergy and asthma reports. 2013 Feb 1;13(1):72-7. | |
| Commins SP, Platts-Mills TAE. | 2013 | Tick bites and red meat allergy. Purpose of review: A novel form of anaphylaxis has been described that is due to IgE antibody (Ab) directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). Ongoing work regarding the cause and distribution of this IgE response is reviewed. Recent findings: Our recent work has identified a novel IgE Ab response that has been associated with two distinct forms of anaphylaxis: immediate-onset anaphylaxis during first exposure to intravenous cetuximab and delayed-onset anaphylaxis 3-6h after ingestion of mammalian food products (e.g. beef and pork). Further studies strongly suggested that tick bites were a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the United States and internationally. Summary: Large numbers of patients with IgE Ab to alpha-gal continue to be identified in the USA and globally. Clinicians should be aware of this IgE response as the reactions often appear to be idiopathic because of the significant delay between eating mammalian meat and the appearance of symptoms. |
Asia Pacific Allergy. 2015 Jan 1;5(1):3-16. | review article |
| Commins SP, Platts-Mills, TAE. | 2010 | Allergenicity of carbohydrates and their role in anaphylactic events. The IgE response to pollen allergens often includes IgE antibodies specific for glycosylation motifs on the pollen proteins. These oligosaccharides are present on many different species and are known as cross-reactive carbohydrate determinants. However, IgE antibodies to plant-derived cross-reactive carbohydrate determinants seem to have only minor clinical significance and have not been related to anaphylaxis. Recently, two novel forms of anaphylaxis have become apparent in the southeastern United States: 1) reactions during the first infusion of the monoclonal antibody cetuximab and 2) adult-onset delayed anaphylaxis to red meat. Detailed investigation of serum antibodies established that in both cases, the patients had IgE antibodies specific for the mammalian oligosaccharide galactose alpha-1, 3-galactose. Identification of these cases is helpful in avoiding infusion reactions to cetuximab or recommending specific avoidance of meat derived from mammals. However, the current evidence does not fully resolve why these IgE antibodies are so common in the Southeast or why the anaphylactic or urticarial reactions to red meat are delayed. |
Current allergy and asthma reports. 2010 Jan 1;10(1):29-33. | |
| Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, Woodfolk JA, Platts-Mills TA. | 2009 | Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose. Background: Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions. Objective: We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb. Methods: Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens. Results: Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow's milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal. Conclusion: We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb. |
Journal of Allergy and Clinical Immunology. 2009 Feb 1;123(2):426-33. | |
| Commins SP, Schuyler AJ, Workman LJ, Matos LA, Eapen SS, Lane CJ, Rispens T, Heymann PW, Platts-Mills TF, Platts-Mills, TA. | 2015 | Delayed Urticarial and Anaphylactic Reactions to Red Meat: Age of Onset, Severity, and Immunology Among 353 Cases and 140 Controls. RATIONALE: Patients with IgE to galactose-alpha-1,3,-galactose report delayed reactions, which vary from itching or gastrointestinal distress to frank anaphylaxis. METHODS: Patients who presented to allergy clinics in Virginia with histories compatible with delayed reactions to red meat (n5353) or with recurrent urticarial or anaphylactic reactions of other types (n5140), many of which appeared to be idiopathic, completed a questionnaire. Sera were assayed for IgE antibodies, total IgE, and alpha-gal specific IgG. RESULTS: IgE was measured to alpha-gal and mammalian allergens, to six inhalant allergens, to five foods, and to two venoms. Results for IgE and IgG to alpha-gal were analyzed in relation to symptoms and related to evidence of preexisting atopy. The presence of IgE antibodies to inhalant allergens was not correlated with sensitization to alpha-gal. Severity of reactions (urticaria, n587 or anaphylaxis, n5249) was not associated with the titer of IgE antibodies to alpha-gal. In addition, neither the ratio of alpha-gal IgE to total IgE nor IgG antibodies to alpha-gal were correlated to reaction severity. Of those with anaphylaxis, 45% reported their first food reaction after age 40, and in 85% of cases the reactions started 2 hours or more after eating meat. The severity of reactions was not related to age of onset or delay before reactions. CONCLUSIONS: Patients with delayed anaphylaxis to red meat present a novel disease with late onset, delayed expression, no immediate symptoms of food allergy, and a very high incidence of previous exposure to ticks. Atopy was not a predictor of IgE responses or food reactions. |
Journal of Allergy and Clinical Immunology. 2015 Feb 1;135(2):AB205. | |
| Commins SP. | 2020 | ‡ Omalizumab reduces food allergy symptoms in patients with alpha-gal syndrome. Rationale: Alpha-gal syndrome (AGS) is a unique food allergy to red meat and products containing mammalian-derived ingredients. Patients can develop AGS after decades of immunologic tolerance of beef, pork, lamb, gelatin and the allergy appears to develop following ectoparasitic tick bites. A subgroup of patients with AGS continue to remain symptomatic despite an appropriate avoidance diet and we assessed whether treatment with omalizumab could improve their symptoms. Methods: Qualifying patients with AGS had urticaria activity score summed over 7 days (UAS7) to assess the itch severity and hive count once daily before, 4 weeks after, and 12 weeks after omalizumab therapy (300 mg every 4 weeks). . Results: Over a 2 year period, fourteen patients with AGS elected to begin omalizumab treatment for chronic urticaria despite an appropriate mammalian avoidance diet. Mean UAS7 scores before treatment were 23.3 (17.8-29.4) and at 4-weeks of treatment the mean UAS7 score declined to 4.2 (1.9-7.5). By 12 weeks of omalizumab therapy, mean UAS7 scores were 0.4 (0-1.1). Patient-reported improvment in symptoms following accidental exposure to mammalian ingredients (e.g., butter, dairy) was noted in 12 of 14 (86%) cases with several noting no symptoms despite intential allergen consumption while on omalizumab. . Conclusions: Omalizumab appears to effectively treat chronic, spontaneous urticaria developing after a new-onset food allergy and may be associated with improved tolerance of accidental exposure to the relevant allergen, alpha-gal. Anti-IgE therapy could offer adjunctive treatment for food allergy when avoidance diet does not sufficiently control symptoms. |
Journal of Allergy and Clinical Immunology. 2020 Feb 1;145(2):AB145. | management |
| Commins SP. | 2020 | **‡ Diagnosis & management of Alpha-gal Syndrome: Lessons from 2,500 patients. Alpha-gal Syndrome (AGS) is a unique allergy to non-primate mammalian meat (and derived-products) that is associated with tick bites and is due to a specific IgE antibody to the oligosaccharide galactose-α-1,3-galactose (alpha-gal). AGS has many novel features that broaden the paradigm of food allergy, including that reactions are delayed 3–6 hours after exposure and patients have frequently tolerated red meat for many years prior to the development of allergic reactions. Due to the ubiquitous inclusion of mammal-derived materials in foods, medications, personal products and stabilizing compounds, full avoidance is difficult to achieve. |
Expert Review of Clinical Immunology. 2020 Jul 9:1-1 | expert opinion; primary care; allergist; symptoms; airborne; fume; GI variant; gastrointestinal; pruritus; joint; cofactor; co-factor; diagnosis; blood test; alpha-gal IgE; skin prick test; intradermal testing; seronegative; food challenge; management; treatment; omalizumab; antihistamine; cromolyn; metformin; food; dairy; mammalian byproduct; food additive; gelatin; carrageenan; chiggers; bees; wasps; drugs; medical product; heparin; biologic; monoclonal antibody; pancreatic enzymes; thyroid; heart valve; antivenom; antivenin; perioperative; anesthesia; surgery; hospitalization; intravenous; parenteral |
| Commins SP. | 2016 | Invited commentary: alpha-gal allergy: tip of the iceberg to a pivotal immune response. The syndrome of delayed allergic reactions to the carbohydrate galactose-alpha-1,3-galactose (“alpha-gal”) has become increasingly recognized in allergy and immunology clinics regionally throughout the southeastern USA. Due to the increasing awareness of this unique food allergy, cases have been identified in the northeastern and central USA as well as in Central and South America, Europe, Asia, Scandinavia, and Australia. Clinically, alpha-gal allergy is characterized by reactions to non-primate mammalian meat (e.g., beef, pork, lamb) that occur 3–6 h following exposure. The IgE response to alpha-gal is thought to develop after tick bites and can result in the loss of tolerance to foods that have been safely consumed for years. Although the initial description of alpha-gal allergy in 2009 was limited to red meat, this epitope is now identified in an expanded number of products, medications and foods—both labeled and unlabeled. Moreover, we are beginning to recognize that alpha-gal food allergy is the tip of the iceberg for this immune response. |
Current allergy and asthma reports. 2016 Sep 1;16(9):61. | dairy vaccine bioprosthetic heart valve atherosclerosis inflammatory bowel disease IBD irritable bowel syndrome IBS gut flora sero-negative seronegative Lyme disease |
| Commins, SP. | 2014 | Carbohydrates as Allergens. Complex carbohydrates are effective inducers of Th2 responses, and carbohydrate antigens can stimulate the production of glycan-specific antibodies. In instances where the antigen exposure occurs through the skin, the resulting antibody production can contain IgE class antibody. The glycan-stimulated IgE may be non-specific but may also be antigen specific. This review focuses on the production of cross-reactive carbohydrate determinants, the recently identified IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), as well as discusses practical implications of carbohydrates in allergy. In addition, the biological effects of carbohydrate antigens are reviewed in setting of receptors and host recognition. |
Current allergy and asthma reports. 2015 Jan 1;15(1):492. | review article |
| Contreras M, Pacheco I, Alberdi P, Díaz-Sánchez S, Artigas-Jerónimo S, Mateos-Hernández L, Villar M, Cabezas-Cruz A, De La Fuente J. | 2020 | Allergic reactions and immunity in response to tick salivary biogenic substances and red meat consumption in the zebrafish model. Ticks are arthropod ectoparasite vectors of pathogens and the cause of allergic reactions affecting human health worldwide. In humans, tick bites can induce high levels of immunoglobulin E antibodies against the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) present in glycoproteins and glycolipids from tick saliva that mediate anaphylactic reactions known as the alpha-Gal syndrome (AGS) or red meat allergy. In this study, a new animal model was developed using zebrafish for the study of allergic reactions and the immune mechanisms in response to tick salivary biogenic substances and red meat consumption. The results showed allergic hemorrhagic anaphylactic-type reactions and abnormal behavior patterns likely in response to tick salivary toxic and anticoagulant biogenic compounds different from α-Gal. However, the results showed that only zebrafish previously exposed to tick saliva developed allergic reactions to red meat consumption with rapid desensitization and tolerance. These allergic reactions were associated with tissue-specific Toll-like receptor-mediated responses in types 1 and 2 T helper cells (TH1 and TH2) with a possible role for basophils in response to tick saliva. These results support previously proposed immune mechanisms triggering the AGS and provided evidence for new mechanisms also potentially involved in the AGS. These results support the use of the zebrafish animal model for the study of the AGS and other tick-borne allergies. |
Frontiers in cellular and infection microbiology. 2020 Mar 10;10:78. | animal model; zebra fish |
| Costa J, Villa C, Verhoeckx K, Cirkovic-Velickovic T, Schrama D, Roncada P, Rodrigues PM, Piras C, Martín-Pedraza L, Monaci L, Molina E. | 2021 | Are Physicochemical Properties Shaping the Allergenic Potency of Animal Allergens?. Key determinants for the development of an allergic response to an otherwise ‘harmless’ food protein involve different factors like the predisposition of the individual, the timing, the dose, the route of exposure, the intrinsic properties of the allergen, the food matrix (e.g. lipids) and the allergen modification by food processing. Various physicochemical parameters can have an impact on the allergenicity of animal proteins. Following our previous review on how physicochemical parameters shape plant protein allergenicity, the same analysis was proceeded here for animal allergens.We found that each parameter can have variable effects, ranging on an axis from allergenicity enhancement to resolution, depending on its nature and the allergen. While glycosylation and phosphorylation are common, both are not universal traits of animal allergens. High molecular structures can favour allergenicity, but structural loss and uncovering hidden epitopes can also have a similar impact. We discovered that there are important knowledge gaps in regard to physicochemical parameters shaping protein allergenicity both from animal and plant origin, mainly because the comparability of the data is poor. Future biomolecular studies of exhaustive, standardised design together with strong validation part in the clinical context, together with data integration model systems will be needed to unravel causal relationships between physicochemical properties and the basis of protein allergenicity. |
Clinical Reviews in Allergy & Immunology.2021 Jan 7;:1-36. | pork-cat syndrome; meat allergy; Animal allergens; Protein families; AllergenicityFood processing; Allergen integrity |
| Côté SD, Rooney TP, Tremblay JP, Dussault C, Waller DM. | 2004 | Ecological impacts of deer overabundance. |
Annu. Rev. Ecol. Evol. Syst.. 2004 Dec 15;35:113-47. | |
| Cox KM, Commins S, Capaldo B, Solga M, McSkimming C, Chew C, Schuyler A, Lannigan J, McNamara C, Erickson L. | 2016 | Using mass cytometry to identify novel B cell subsets in red meat allergy. Previous studies have identified a novel food allergy driven by IgE antibodies specific for galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in red meat. While it is known that B cells play an important role in allergy as the producers of IgE antibodies that drive the allergic response, little is known about the phenotype of these B cells. The number of markers used to identify the major human B cell subsets by flow cytometry has been limited to common B cell proteins and thus precludes high dimensional immune phenotyping of B cell subsets, including unique phenotypes present in allergic individuals. We have addressed this problem by using mass cytometry (CyTOF), which enables the simultaneous analysis of up to 40 markers in a single staining panel. Here we analyzed the expression of 23 cell surface markers in PBMCs from 19 alpha-gal-allergic patients and 20 non-allergic controls by CyTOF. Additionally, we combined our CyTOF data with clinical endpoints to identify markers that may correlate with allergic disease. Our data reveals substantial heterogeneity within major B cells subsets on an individual level. Furthermore, our analysis identifies a number of markers that vary significantly in their expression in allergic versus non-allergic B cells and correlate with serum alpha-gal IgE titers. We hypothesize that B cells with this phenotype play an important role in mediating alpha-gal allergy. These findings demonstrate the power of using CyTOF and analytical tools to extract a hierarchy from high dimensional cytometry data in an unsupervised manner to identify known B cell subsets as well as to find novel B cell populations that differ between alpha-gal allergic and non-allergic individuals. |
J Immunol. 2016; 191-25. | |
| Cox KM, Commins SP, Capaldo BJ, Workman LJ, Platts‐Mills TA, Amir EAD, Lannigan JA, Schuyler AJ, Erickson LD. | 2019 | An integrated framework using high-dimensional mass cytometry and fluorescent flow cytometry identifies discrete B cell subsets in patients with red meat allergy. Summary: Background B cells play a critical role in the development and maintenance of food allergy by producing allergen-specific IgE. Despite the importance of B cells in IgE-mediated food allergy, the identity of sIgE-producing human B cells and how IgE is regulated are poorly understood. Objective: To identify the immunophenotypes of circulating B cells associated with the production of galactose-alpha-1,3-galactose-specific IgE production in patients with red meat allergy. Methods: B cells in PBMC samples obtained from 19 adults with physician-diagnosed red meat allergy and 20 non-meat allergic healthy controls were assessed by mass cytometry along with a bioinformatics analysis pipeline to identify discrete B cell phenotypes that associated with serum sIgE. Fluorescent flow cytometry was then applied to sort purify discrete B cell subsets, and B cells were functionally evaluated on an individual cell level for the production of sIgE by ELISPOT. Results: Discrete B cell phenotypes abundant in meat allergic subjects compared to non-meat allergic controls were found in peripheral blood that do not share typical characteristics of classical isotype-switched memory B cells that express high levels of CD27. These B cell subsets shared higher IgD and lower IgM expression levels coupled with CXCR4, CCR6 and CD25 expression. In vitro polyclonal stimulation of purified B cell subsets from meat allergic subjects demonstrated that these subsets were enriched for cells induced to secrete sIgE. Conclusions and Clinical Relevance: Circulating B cells display increased abundance of discrete B cell subsets in meat allergic subjects. This observation, coupled with the capacity of individual B cell subsets to produce sIgE following activation, implicates these novel B cell phenotypes in promoting IgE in meat allergy. |
Clinical & Experimental Allergy. 2019 May;49(5):615-25. | |
| Cresce ND, Posthumus J, Platts-Mills TAE, Commins SP. | 2012 | Blood Type Does Not Predict the Development of an IgE Response to Galactose-alpha-1,3-Galactose. RATIONALE: Sera from healthy donors of A and O blood types have high levels of IgG antibodies to galactose-alpha-1,3-galactose (alpha-gal), whereas donors of type B or AB blood contain significantly less circulating anti-gal. This is presumably due to the structural similarity of B blood type antigen and alpha-gal. Thus, we hypothesized that blood type B or AB could be protective against the development of IgE to alpha-gal. METHODS: Sera were collected as part of several ongoing studies, each with IRB approval. Individual serum samples (n51047) were ‘‘back’’ typed in the laboratory using standard reagent red blood cells of either A or B type. Agglutination reaction was observed for 5 minutes at 30 C. A logistic regression model was used to assess correlation between blood type and IgE to alpha-gal. A Bonferroni adjustment was used for multiple comparisons in blood types. RESULTS: There was no significant association between blood type and sIgE to alpha-gal (p 5 0.19). Subjects with B/AB blood types constituted 140 of the 1047 samples analyzed (13.4%) and of these, 55 had IgE to alpha-gal (10.1% of positive samples). Within the US, prevalence of blood type B / AB ;15%. No correlation was found for blood type and gender, sIgE to beef, tick exposure or subset of symptoms. CONCLUSIONS: Despite preliminary reports, there does not appear to be an association between blood type and the development of IgE to alpha-gal. Further studies are aimed at assessing the avidity of the IgE response to alpha-gal between subjects of different blood types. |
Journal of Allergy and Clinical Immunology. 2012 Feb 1;129(2):AB80. | |
| Crispell G, Commins SP, Archer-Hartman SA, Choudhary S, Dharmarajan G, Azadi P, Karim S. | 2019 | **Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy. Development of specific IgE antibodies to the oligosaccharide galactose-alpha-1, 3-galactose (alpha-gal) following tick bites has been shown to be the source of red meat allergy. In this study, we investigated the presence of alpha-gal in four tick species: the lone-star tick (Amblyomma americanum), the Gulf-Coast tick (Amblyomma maculatum), the American dog tick (Dermacentor variabilis), and the black-legged tick (Ixodes scapularis) by using a combination of immunoproteomic approach and, carbohydrate analysis. Anti-alpha-gal antibodies identified alpha-gal in the salivary glands of both Am. americanum and Ix. scapularis, while Am. maculatum and De. variabilis appeared to lack the carbohydrate. PNGase F treatment confirmed the deglycosylation of N-linked alpha-gal-containing proteins in tick salivary glands. Immunolocalization of alpha-gal moieties to the salivary secretory vesicles of the salivary acini also confirmed the secretory nature of alpha-gal-containing antigens in ticks. Am. americanum ticks were fed on human blood (lacks alpha-gal) using a silicone membrane system to determine the source of the alpha-gal. N-linked glycan analysis revealed that Am. americanum and Ix. scapularis have alpha-gal in their saliva and salivary glands, but Am. maculatum contains no detectable quantity. Consistent with the glycan analysis, salivary samples from Am. americanum and Ix. scapularis stimulated activation of basophils primed with plasma from alpha-gal allergic subjects. Together, these data support the idea that bites from certain tick species may specifically create a risk for the development of alpha-gal-specific IgE and hypersensitivity reactions in humans. Alpha-Gal syndrome challenges the current food allergy paradigm and broadens opportunities for future research. |
Frontiers in immunology. 2019 May 17;10:1056. | |
| Crispell G. | 2022 | INVESTIGATING THE INVOLVEMENT OF THE TICK VECTOR IN THE INDUCTION OF ALPHA-GALACTOSE HYPERSENSITIVITY (ALPHA-GAL SYNDROME, RED MEAT ALLERGY) IN THE UNITED STATES. Alpha-gal syndrome (AGS or sometimes called red meat allergy) is a result of the development of specific IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (α-gal) after a person has had exposure to tick bites. This dissertation investigates four common tick species found in North America: the lone-star tick (Amblyomma americanum), the Gulf-Coast tick (Amblyomma maculatum), the American dog tick (Dermacentor variabilis), and the black-legged tick (Ixodes scapularis) for the presence of α-gal by utilizing a combination of immunoproteomic approaches and carbohydrate analysis techniques. Anti-α-gal IgM antibodies (M86) were used in immunoblotting to detect α-gal in the saliva and salivary glands of both Am. americanum and Ix. scapularis, while Am. maculatum and De. variabilis were found to lack α-gal. Incubation of Am. americanum partially-fed salivary gland protein extracts with PNGase F confirmed the deglycosylation of N-linked α-gal containing glycans from tick salivary glycoproteins. Immunolocalization of α-gal moieties to the tick salivary secretory vesicles of the salivary acini by confocal microscopy also confirmed the likelihood of a secretory nature of α-gal-containing antigens by ticks. Am. americanum ticks were fed mechanically-defibrinated human blood (lacks α-gal) using a silicone membrane system in an attempt to determine the source of the α-gal. N-linked glycan analysis revealed that Am. americanum and Ix. scapularis contain α-gal in their saliva and salivary glands, but Am. maculatum contains no detectable quantity of α-gal. Consistent with the N-glycan profiling and analysis, salivary samples from Am. americanum and Ix. scapularis stimulated activation of basophils that were primed with plasma from α-gal allergic subjects. Proteomic data generated from these experiments offered multiple potential targets for further investigation and RNAi gene silencing. Together, these data support the theory that bites from only some tick species may specifically create an enhanced risk for the development of α-gal-specific IgE and hypersensitivity reactions in humans. The findings within this research have paved the way for future α-gal research in the tick, however, the exact mechanism by which ticks sensitize a host to α-gal continues to remain unknown. |
Dissertation | Ticks; lone-star tick; Amblyomma americanum; the Gulf-Coast tick ;Amblyomma maculatum; the American dog tick; Dermacentor variabilis; black-legged tick; Ixodes scapularis |
| Croglio MP, Commins SP, McGill SK. | 2021 | Isolated Gastrointestinal Alpha-Gal Meat Allergy Is a Cause for Gastrointestinal Distress without Anaphylaxis. Alpha-gal allergy is characterized by a reaction to beef, pork and othermammalian meat and derived products, typically hours after ingestion, and isdiagnosed by the presence of elevated serum alpha-gal IgE antibodies.1-3 Theallergy appears to develop following the bite of a hard tick and has beendescribed in the United States (particularly the southeastern US), Europe, Africa,Australia, Central and South America and Asia.4-6 Symptoms can includepruritus, rash, diarrhea, abdominal cramping, shock and anaphylaxis, the latter ofwhich is defined by the involvement of two or more systems (skin, GI, cardiac,pulmonary). GI symptoms are caused by IgE-mediated degranulation of mastcells and histamine receptors in the GI tract.Management of the allergy includes counseling on the avoidance ofmammalian meat, and sometimes dairy and other mammalian-derived products. In the case of exposure, short- and long-acting oral anti-histamines such asdiphenhydramine and fexofenadine may be used to ameliorate both GI andallergic symptoms.Allergy and oncology journals have primarily published research on alphagal allergy, and it has not been described previously in the GI literature. Wedescribe patients with the allergy who presented with isolated gastrointestinal(GI) symptoms. |
Gastroenterology. 2021 Jan 29. | Symptoms; GI variant; gastroenterology |
| Crow HM, Samples T, Purser JT. | 2019 | Red Meat Allergy Associated with NSTEMI. Alpha-gal syndrome, also known as mammalian meat allergy, is characterized by a hypersensitivity reaction to galactose-alpha-1,3-galactose. Reactions typically manifest hours after consumption of red meat products such as beef, pork, and lamb. We describe the case of a 64-year-old male resident of rural Oklahoma who presented with anaphylaxis and myocardial infarction. The patient suffered complications that were attributed to porcine-derived heparin in the setting of undiagnosed alpha-gal syndrome. We describe the clinical course of this patient that lead to the diagnosis of alpha-gal syndrome to raise awareness of this disease. |
American Journal of Medical Case Reports. 2019 Jan 23;7(1):13-5. | cardiac; cardiovascular; cardiology; pharmaceutical; heparin |
| Cui Y. | 2014 | When mites attack: domestic mites are not just allergens. Domestic mite species found in indoor environments and in warm or tropical regions are well known for causing allergic disorders. However, little is known about human acariasis, in which mites invade and parasitize the human body in various tissues from the gastrointestinal tract to the lung. Here, we summarize the reported cases of human acariasis of pulmonary, intestinal, oral (anaphylaxis), urinary, otic, and vaginal systems. Because the clinical symptoms of acariasis often overlap with other disease symptoms leading to frequent misdiagnosis, we highlight the need for more attention on these infections. |
Parasites & vectors. 2014 Dec 1;7(1):411. | Arthropod; Acari; mite |
| D'Souza M, Lania M. | 2020 | S3011 Recurring Gastrointestinal Symptoms as a Novel Presentation of Alpha-Gal Allergy. INTRODUCTION: Galactose-alpha-1,3-galactose (alpha-gal) allergy is a delayed allergy after ingestion of mammalian meat such as beef, pork, or lamb. In the literature, symptoms range from urticaria to anaphylaxis with concomitant gastrointestinal manifestations. There are no case reports of adults with abdominal pain as the sole symptom of this allergy. This case delineates a novel presentation of the alpha-gal allergy with a patient with only gastrointestinal symptoms. |
Official journal of the American College of Gastroenterology| ACG. 2020 Oct 1;115:S1587. | gastroenterology; GI symptoms; gastroesophageal reflux disease; abdominal pain; |
| D’Ercole FJ, Dhandha VH, Levi ML | 2019 | Perioperative Challenges in Patients with Alpha-Gal Allergy. Alpha-gal allergy, also known as, mammalian meat allergy (MMA) is well described in the Allergy literature, however, the Anesthesiology literature remains soft in supporting recommendations for perioperative management. The goal of the Centers for Disease Control and Prevention (CDC) is to better understand the pathogenesis, signs and symptoms, and prevention of this delayed anaphylactic reaction compared to the rapid onset of most food allergies, especially immunoglobulin E (IgE) mediated allergy. MMA is not limited to dietary beef, bison, goat, pork, lamb, and venison intake alone but includes some perioperative medication formularies containing inactive ingredients such as gelatin, glycerin or stearate; surgical products such as surgical powder, xenografts, and porcine derived heart valve per the manufacturer's specifications. This report will include the brief of 6 patients with alpha-gal allergy who presented during 2018 for elective surgery at a North Carolina community hospital when no patients prior were identified with MMA. The patients described have demonstrated one or more of the several perioperative challenges unique to alpha-gal allergy outlined in this manuscript. Authors have identified eight challenges representing knowledge gaps impacting safe anesthesia care. |
J Clin Anesth Pain Manag. 2019;3(1):70-8. | hospital; surgery; perioperative; pharmaceutical; pharmacy; anesthesia |
| Dahlgren FS, Paddock CD, Springer YP, Eisen RJ, Behravesh CB. | 2016 | Expanding Range of Amblyomma americanum and Simultaneous Changes in the Epidemiology of Spotted Fever Group Rickettsiosis in the United States. Spotted fever group (SFG) Rickettsia species are etiologic agents of a wide range of human infections from asymptomatic or mild infections to severe, life-threatening disease. In the United States, recent passive surveillance for SFG rickettsiosis shows an increased incidence and decreased severity of reported cases. The reasons for this are not well understood; however, we hypothesize that less pathogenic rickettsiae are causing more human infections, while the incidence of disease caused by more pathogenic rickettsiae, particularly Rickettsia, is relatively stable. During the same period, the range of Amblyomma americanumhas expanded. Amblyomma americanumis frequently infected with CandidatusRickettsia amblyommii”, a SFG Rickettsia of unknown pathogenicity. We tested our hypothesis by modeling incidence rates from 1993 to 2013, hospitalization rates from 1981 to 2013, and case fatality rates from 1981 to 2013 regressed against the presence of A. americanum, the decade of onset of symptoms, and the county of residence. Our results support the hypothesis, and we show that the expanding range of A. americanumis associated with changes in epidemiology reported through passive surveillance. We believe epidemiological and acarological data collected on individual cases from enhanced surveillance may further elucidate the reasons for the changing epidemiology of SFG rickettsiosis. |
The American journal of tropical medicine and hygiene. 2016 Jan 6;94(1):35-42. | |
| Dang Van S, Fouquet O, Jeanneteau A, Leclere JM, Baufreton C. | 2021 | Aortic homograft for aortic valve replacement in patient with Alpha-Gal allergy. Allergy to Galactose-Alpha-1,3-Galactose is an allergy to mammalian proteins, that are present on the surface of standard bioprosthestic valves, and could result in a catastrophic allergic reaction or may cause early deterioration of the bioprostheses. Aortic homograft is an acceptable alternative to standard prosthetic valves (biological and mechanical) to avoid a potential allergic manifestation and the need for definitive oral anticoagulation. We report the implantation of an aortic homograft in a patient with an aortic stenosis who presents a documented AlphaGal allergy. |
General thoracic and cardiovascular surgery. 2021 Jul 19. | cardiac; cardiovascular; xenotransplantation; surgery; perioperative |
| Daripa B, Lucchese S. | 2022 | Novel Case Presentation of Abulia After Lone Star Tick Bite As Evidenced by Raised Titers of Alpha-Gal Specific IgM Immunoglobulin and a Possibility of Alpha-Gal Driven Hypothalamic Dysfunction As the Pathomechanism. Galactose-α-1,3-galactose, an oligosaccharide epitope better acknowledged as α-Gal, is present in non-primate mammal meat, tick bites, microorganisms, and vaccines as a glycoprotein or glycolipid moiety. This can manifest hyperimmune reactions as it enters the human body, known as α-Gal syndrome (AGS). AGS and Guillain-Barré syndrome share cognate immunogenic pathomechanism via conquering immune tolerance further speculating galactose navigated neurological sequel. Unusual symptomatic presentation of abulia in our case, with incidental finding of high titers of α-Gal specific IgE immunoglobulin further supported by temporal resolution of symptoms on abstinence of meat products, raises a high degree of suspicion of neuro-psychiatric manifestation in sensitized α-Gal patients. The pathomechanism is blurry, and an absence of an objective diagnostic tool makes the neurological diagnosis challenging. α-Gal driven immune-related hypothalamic dysfunction could be a possibility that needs further exploration and is a topic of research. |
Cureus. 2022 Apr 28;14(4). | neurology; abulia |
| de la Fuente J, Cabezas-Cruz A, Pacheco I. | 2020 | ‡ Alpha-Gal Syndrome: challenges to understanding sensitization and clinical reactions to alpha-gal. Introduction: The α-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody response against the carbohydrate Galα1-3Galβ1-4GlcNAc-R (α-Gal). Tick bites are recognized as the most important cause of anti-α-Gal IgE antibody increase in humans. Several risk factors have been associated with the development of AGS, but their integration into a standardized disease diagnosis has proven challenging. Areas covered: Herein we discuss the current AGS diagnosis based on anti-α-Gal IgE titers and propose an algorithm that considers all co-factors in the clinical history of α-Gal-sensitized patients to be incorporated into the AGS diagnosis. The need for identification of host-derived gene markers and tick-derived proteins for the diagnosis of the AGS is also discussed. . Expert opinion: The current AGS diagnosis based on anti-α-Gal IgE titers has limitations because not all patients sensitized to α-Gal and with anti-α-Gal IgE antibodies higher than the cut-off (0.35 IU/ml) develop anaphylaxis to mammalian meat and AGS. The basophil activation test proposed to differentiate between patients with AGS and asymptomatic α-Gal sensitization cannot be easily implemented as a generalized clinical test. In coming years, the algorithm proposed here could be used in a mobile application for easier AGS diagnosis in the clinical practice. |
Expert Review of Molecular Diagnostics. 2020 Sep 1. Forthcoming. | diagnosis |
| de la Fuente J, Contreras, M, Estrada-Peña A, Cabezas-Cruz A. | 2017 | Targeting a global health problem: Vaccine design and challenges for the control of tick-borne diseases. It has been over twenty years since the first vaccines for the control of tick infestations became commercially available. These vaccines proved their efficacy and the potential of this approach for the control of tick-borne diseases (TBDs), which represent a growing burden for human and animal health worldwide. In all these years, research in this area has produced new tick-derived and pathogen-derived candidate protective antigens. However, the potential of vaccines for the control of TBDs has been underestimated due to major challenges to reduce tick infestations, pathogen infection, multiplication and transmission, tick attachment and feeding time and/or host pathogen infection. Nevertheless, vaccines constitute the most safe and effective intervention for the control of TBDs in humans, domestic and wild animals. |
Vaccine 2017; 35(38): 5089-5094. | |
| de la Fuente J, Gortázar C, Cabezas‐Cruz A, Contreras M, Villar M, Pacheco I, Arias A, Mas A. | 2021 | Boosting anti‐alpha‐Gal immune response to control COVID‐19. |
Royal Society Open Science Stage1 Registered Report. 2020;20(10.17605). | coronavirus; Covid-19; SARS-Cov-2; virus; pathogen; vaccine |
| de la Fuente J, Pacheco I, Contreras M, Mateos-Hernández L, Villar M, Cabezas-Cruz A. | 2019 | Guillain-Barré and Alpha-gal Syndromes: Saccharides-induced Immune Responses. The molecular interactions between hosts, vectors and pathogens drive the etiology of infectious diseases. At first sight, the Guillain-Barré and Alpha-Gal syndromes have quite different etiologies but, as proposed here, a closer look into the immune response to galactose-containing oligosaccharide structures that characterizes these two diseases reveals striking commonalities. In this Opinion paper, we address the main molecular drivers of two apparently unrelated diseases, and how the characterization of the immune response and immunological tolerance would advance the control and prevention of these diseases. |
Exploratory Research and Hypothesis in Medicine. 2019 Dec 19;4(4):87-9. | |
| de la Fuente J, Pacheco I, Villar M, Cabezas-Cruz A. | 2019 | The alpha-Gal syndrome: new insights into the tick-host conflict and cooperation. This primer focuses on a recently diagnosed tick-borne allergic disease known as the alpha-gal syndrome (AGS). Tick bites induce in humans high levels of IgE antibodies against the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-Gal) present on tick salivary glycoproteins and tissues of non-catarrhine mammals, leading to the AGS in some individuals. This immune response evolved as a conflict and cooperation between ticks and human hosts including their gut microbiota. The conflict is characterized by the AGS that mediate delayed anaphylaxis to red meat consumption and certain drugs such as cetuximab, and immediate anaphylaxis to tick bites. The cooperation is supported by the capacity of anti-alpha-Gal IgM and IgG antibody response to protect against pathogens with alpha-Gal on their surface. Despite the growing diagnosis of AGS in all world continents, many questions remain to be elucidated on the tick proteins and immune mechanisms triggering this syndrome, and the protective response against pathogen infection elicited by anti-alpha-Gal antibodies. The answer to these questions will provide information for the evaluation of risks, diagnosis and prevention of the AGS, and the possibility of using the carbohydrate alpha-Gal to develop vaccines for the control of major infectious diseases. |
Parasites & vectors. 2019 Dec;12(1):1-5. | |
| de la Fuente J, Urra JM, Contreras M, Pacheco I, Ferreras-Colino E, Doncel-Pérez E, de Mera IG, Villar M, Cabrera CM, Hernando CG, Baquero EV | 2020 | A dataset for the analysis of antibody response to glycan alpha-Gal in individuals with immune-mediated disorders Humans evolved by losing the capacity to synthesize the glycan Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal), which resulted in the development of a protective response mediated by anti-α-Gal IgM/IgG/IgA antibodies against pathogens containing this modification on membrane proteins. As an evolutionary trade-off, humans can develop the alpha-Gal syndrome (AGS), a recently diagnosed disease mediated by anti-α-Gal IgE antibodies and associated with allergic reactions to mammalian meat consumption and tick bites. However, the anti-α-Gal antibody response may be associated with other immune-mediated disorders such as those occurring in patients with COVID-19 and Guillain-Barré syndrome (GBS). Here, we provide a dataset (209 entries) on the IgE/IgM/IgG/IgA anti-α-Gal antibody response in healthy individuals and patients diagnosed with AGS, tick-borne allergies, GBS and COVID-19. The data allows correlative analyses of the anti-α-Gal antibody response with factors such as patient and clinical characteristics, record of tick bites, blood group, age and sex. These analyses could provide insights into the role of anti-α-Gal antibody response in disease symptomatology and possible protective mechanisms. |
F1000Research. 2020 Nov 24;9(1366):1366. | anti-gal; immunoglobulin; IgG; IgM; IgE; Guillain-Barre syndrome; Covid-19; coronavirus |
| de la Fuente J. | 2018 | Controlling ticks and tick-borne diseases...looking forward. Tick-borne diseases (TBDs) represent a growing burden for human and animal health worldwide. Several approaches including the use of chemicals with repellency and parasiticidal activity, habitat management, genetic selection of hosts with higher resistance to ticks, and vaccines have been implemented for reducing the risk of TBDs. However, the application of latest gene editing technologies in combination with vaccines likely combining tick and pathogen derived antigens and other control measures should result in the development of effective, safe, and environmentally sound integrated control programs for the prevention and control of TBDs. This paper is not a review of current approaches for the control of ticks and TBDs, but an opinion about future directions in this area. |
Ticks and tick-borne diseases. 2018 Jul 1;9(5):1354-7. | |
| de la Fuente JD, Gortázar C, Cabezas-Cruz A. | 2020 | Immunity to glycan α-Gal and possibilities for the control of COVID-19. |
Immunotherapy.2020 Dec 14. | coronavirus; Covid-19; SARS-Cov-2; virus; pathogen; vaccine |
| de Silva NR, Dasanayake WM, Karunatilake C, Wickramasingha GD, De Silva BD, Malavige GN. | 2018 | Aetiology of anaphylaxis in patients referred to an immunology clinic in Colombo, Sri Lanka. Background: The aetiology of anaphylaxis differs according to types of foods consumed, fauna and foliage and cultural practices. Although the aetiology of anaphylaxis in Western countries are well known, the causes in South Asian countries have not been reported. We sought to determine the causes of anaphylaxis in patients referred to an immunology clinic in Colombo, Sri Lanka. Methods: 238 episodes of anaphylaxis were reviewed in 188 patients who were referred and skin prick tests and in vitro tests (ImmunoCap) were carried out to assess the presence of allergen specific IgE. Clinical features and severity of anaphylaxis was also recorded along with treatment received. Results: Anaphylaxis to food either following direct exposure 90/238 (37.5%) or after exercise in the form of food dependent exercise induced anaphylaxis 29/238 (12.2%) was the predominant cause of anaphylaxis. Allergy to cow’s milk and red meat, after immediate exposure, accounted for 66/238 (27.7%) of instances of all episodes of anaphylaxis and 66/90 (73.33%) of anaphylaxis due to food. Vaccines accounted for 28/238 (11.8%) of instances of anaphylaxis, especially among children. Of those who developed anaphylaxis to the MMR (n = 14), 71.4% of them had specific IgE to cow’s milk and 35.7% of them had specific IgE to beef. Of those who developed anaphylaxis to insect stings, 27/42 of these episodes occurred following stings of ants (family Formicidae). The predominant cause of anaphylaxis changed with the age, with food allergy being the most frequent trigger of anaphylaxis in childhood, while drug allergy and idiopathic anaphylaxis being more frequent after 30 years of age. Conclusions: In this cohort, anaphylaxis to red meat appears to be the predominant cause of food induced anaphylaxis and presence of beef specific IgE and cow’s milk, appears to be a predisposing factor for vaccine induced anaphylaxis. |
Allergy, Asthma & Clinical Immunology. 2018 Dec;14(1):1-9. | Asia; Sri Lanka; prevalence; vaccine |
| de Silva R, Dasanayake WM, Wickramasinhe GD, Karunatilake C, Weerasinghe N, Gunasekera P, Malavige GN. | 2017 | Sensitization to bovine serum albumin as a possible cause of allergic reactions to vaccines. Background: Immediate type hypersensitivity to vaccines containing bovine/porcine excipients, such as the measles, mumps and rubella (MMR) vaccine is probably due to sensitization to bovine/porcine gelatin. Most patients with such reactions in Sri Lanka have cow's milk (CM) or beef allergy. Objectives: We investigated whether those who had beef and CM allergy had a higher incidence of hypersensitivity reactions to vaccines and the possible trigger of such reactions. Material and methods: Twenty patients with immediate type hypersensitivity reactions to vaccines containing bovine/porcine excipients, controls with allergy to beef/pork (n = 11) or CM (n = 11), and 8 non atopic controls were recruited. Total serum IgE, specific IgE to beef, CM, casein, beta lactoglobulin, gelatin and bovine serum albumin (BSA) by Phadia ImmunoCap and IgE to porcine gelatin by Western blot were evaluated. Results: 11/20, 5/20, 2/20, 2/20, 1/20 and 1/20 patients reported allergic reactions to measles containing, JE, rabies primary chick embryo, pentavalent, diphtheria and tetanus, and adult diphtheria and tetanus vaccines, respectively. Only one patient with allergy to vaccines had gelatin specific IgE, whereas IgE to BSA was seen in 73.3%, 90%, 66.6% and 0 of vaccine, beef or CM allergic and non-atopic controls, respectively. The mean IgE to BSA was higher in patients with allergy to vaccines, although not significant. Specific IgE to BSA was present in 54.7% of children with allergy to CM, of whom 11.8% had high levels (>17.5 kUA/L). In contrast, 66.6% of these children did not have specific IgE to β-lactoglobulin, which is one of the major components of whey protein. Conclusion and clinical relevance: Gelatin does not appear to play a major role in Sri Lankan children with allergy to vaccines. In contrast, due to the higher levels of BSA specific IgE, sensitization to BSA is possibly playing a role. |
Vaccine. 2017 Mar 13;35(11):1494-500. | Asia; Sri Lanka; pharmaceutical; medical product; vaccine; bovine serum albumin; BSA; |
| de Silva R, Karunatilake C, Iddagoda J, Dasanayake D. | 2022 | Food allergy in Sri Lanka–A comparative study. Background: The incidence of IgE mediated food allergy (FA) is increasing in the west. Cow's milk (CM), hen's egg, wheat, soy, peanut, tree nut, fish, and shellfish are responsible for 90% of food allergy in the west; however, local dietary habits may result in specific allergies. Data on food allergies in South Asia is scarce. The present study aims to evaluate the foods that cause immediate type hypersensitivity in Sri Lanka, and to compare with Asia and the developed west. Methods: Records of patients referred to an Immunology clinic from 2010–January 2022 were reviewed. The diagnosis of food allergy was based on standard guidelines. Confirmation of the specific food implicated was based on the history and the presence of specific IgE or component resolved diagnostics by in vitro methods (Phadia ImmunoCap) or by skin prick testing with commercial extracts (Alk Abello). Prick to prick testing was performed for fruits and vegetables when commercial extracts were unavailable. Results: Three hundred and forty-six patients were confirmed with food allergy. CM allergy (CMA) was the commonest (31.2%) followed by red meat allergy (27.7%) and food dependent exercise induced anaphylaxis (FDEIA) (17.9%). Allergy to alpha-gal crustaceans, eggs, gelatin, wheat, coconut milk, and mollusks were seen in 2–10% of patients. The onset of CMA was mainly in childhood. However, in 23/108 patients, onset was after 5 years, including 8 patients in adulthood, and in 14 of the 23, it was preceded by red meat allergy. Onset of primary red meat allergy was predominantly in children, but in 33/96 (34.3%) of patients, it was in adults. Most patients with alpha-gal allergy (21/29, 72.4%) had initial symptoms in childhood and adolescence. Anaphylaxis was diagnosed in 213 patients. FDEIA is the commonest cause (24.7%) followed by red meat allergy (23%), CMA (21.5%) and alpha-gal allergy (10.3%). Allergy to peanuts and fruits were rare. Patients with red meat allergy and/or CMA developed allergy, including anaphylaxis, to vaccines containing bovine/porcine products. Conclusion: CM was the most common food allergy in children, but egg allergy was uncommon. Primary red meat allergy was the second most common, and was associated with allergy to vaccines containing bovine products, such as the measles, mumps and rubella (MMR) vaccine. Allergy to peanuts and fruits were rare. Primary red meat allergy may be responsible for late onset CMA. |
World Allergy Organization Journal. 2022 Dec 1;15(12):100723. | Asia; Sri Lanka; red meat allergy; prevalence |
| Dewachter P, Jacquenet S, Beloucif S, Goarin JP, Koskas F, Mouton-Faivre C. | 2019 | Pork-cat syndrome revealed after surgery: Anaphylaxis to bovine serum albumin tissue adhesive. Sensitization to cat serum albumin (SA) cross-reacted to other mammalian SAs and led to anaphylaxis to bovine serum albumin (BSA) tissue adhesive use. In cat-allergic patients, preoperative measurement of the cat SA IgE level could be useful to potentially avoid BSA tissue adhesive if positive. |
The Journal of Allergy and Clinical Immunology: In Practice. 2019 Sep 1;7(7):2450-2. | medical products; adhesive; pork-cat syndrome |
| Dewachter P, Kopac P, Laguna JJ, Mertes PM, Sabato V, Volcheck GW, Cooke PJ. | 2019 | Anesthetic management of patients with pre-existing allergic conditions: a narrative review. This narrative review seeks to distinguish the clinical patterns of pre-existing allergic conditions from other confounding non-allergic clinical entities, and to identify the potential related risks and facilitate their perioperative management. Follow-up investigation should be performed after a perioperative immediate hypersensitivity to establish a diagnosis and provide advice for subsequent anaesthetics, the main risk factor for perioperative immunoglobulin E (IgE)-mediated anaphylaxis being a previous uninvestigated perioperative immediate hypersensitivity reaction. The concept of cross-reactivity between drugs used in the perioperative setting and food is often quoted, but usually not supported by evidence. There is no reason to avoid propofol in egg, soy, or peanut allergy. The allergenic determinants have been characterized for fish, shellfish, and povidone iodine, but remain unknown for iodinated contrast agents. Iodinated drugs may be used in seafood allergy. Evidence supporting the risk for protamine allergy in fish allergy and in neutral protamine Hagedorn insulin use is lacking. Conversely, cross-reactivity to gelatin-based colloid may occur in alpha-gal syndrome. Atopy and allergic asthma along with other non-allergic conditions, such as NSAID-exacerbated respiratory disease, chronic urticaria, mastocytosis, and hereditary or acquired angioedema, are not risk factors for IgE-mediated drug allergy, but there is a perioperative risk associated with the potential for exacerbation of the various conditions. |
British journal of anaesthesia. 2019 Jul 1;123(1):e65-81. | |
| Diaz JH | 2020 | Red Meat Allergies after Lone Star Tick (Amblyomma americanum) Bites. Red meat allergies have followed tick bites on every continent except Antarctica. The sensitizing antigen is galactose-α-1,3-galactose (α-gal), an oligosaccharide constituent of nonprimate blood and meat, acquired by ticks during animal bloodfeeding. Because red meat allergy after tick bites is a worldwide phenomenon, the objectives of this review were to describe the global epidemiology of red meat allergy after tick bites and its immunological mechanisms; to identify the human risk factors for red meat allergy after tick bites; to identify the most common tick vectors of red meat allergy worldwide; to describe the clinical manifestations, diagnostic confirmation, and management of patients with red meat allergy after tick bites; and to recommend strategies for the prevention of tick bites. To meet these objectives, Internet search engines were queried with keywords to select scientific articles for review. The keywords included ticks, tick bites, allergy, anaphylaxis, and meat allergy. The study period was defined as 1980–2019. The major risk factors for red meat allergy after tick bites included male sex, non-B blood type, systemic mastocytosis, a bioprosthetic (bovine or porcine) heart valve, and preexisting allergies to gelatin or animal dander. Following confirmation by challenge testing, patients with red meat allergies should avoid red meats, foods containing gelatin, and intravenous immunotherapy with monoclonal antibodies such as cetuximab and infliximab produced in SP2/0 mouse cell lines. Red meat allergy after tick bites represents an emerging threat from tick bites in addition to infectious diseases. |
Southern Medical Journal. 2020 Jun 1;113(6):267-74. | Review artview artlice |
| Dickel H | 2021 | Exceptional occupational allergies due to food of animal origin. | Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und Verwandte Gebiete. 2021 Apr 20. | Occupational medicine |
| Djagny KB, Wang Z, Xu S. | 2001 | Gelatin: A Valuable Protein for Food and Pharmaceutical Industries: Review |
Critical reviews in food science and nutrition. 2001 Nov 1;41(6):481-92. | |
| Dobrochaeva K, Khasbiullina N, Shilova N, Knirel Y, Obukhova P, Nokel A, Kunetskiy R, Tsygankova S, Bello-Gil D, Costa C, Mañez R. | 2021 | Specificity profile of αGal antibodies in αGalT KO mice as probed with comprehensive printed glycan array: Comparison with human anti-Galili antibodies. Background: The α1,3-galactosyltransferase gene-knockout (GalT KO) mice are able to produce natural anti-αGal antibodies apparently without any specific immunization. GalT KO mice are commonly used as a model immunological system for studying anti-αGal responses to Gal-positive xenografts in human. In this study, we compared the specificity of mouse and human αGal antibodies to realize the adequacy of the murine model. Methods: Using hapten-specific affinity chromatography antibodies against Galα1-3Galβ1-4GlcNAcβ epitope were isolated from both human and GalT KO mice blood sera. Specificity of isolated antibodies was determined using a printed glycan array (PGA) containing 400 mammalian glycans and 200 bacterial polysaccharides. Results: The quantity of isolated specific anti-Galα antibodies corresponds to a content of <0.2% of total Ig, which is an order of magnitude lower than that generally assumed for both human and murine peripheral blood immunoglobulin, with a high predominance of IgM over IgG (95% vs 5%). Analysis using a printed glycan array has demonstrated that (a) antibodies from both species bind not only the Galα1-3Galβ1-4GlcNAcβ epitope, but also unrelated glycans; (b) particularly, for human (but not mouse) antibodies the best binders appear to be bacterial polysaccharides; (c) the profile of mouse antibodies is broader, it is noteworthy that they recognize a variety of human blood group B epitopes and even glycans without the α-galactosyl residue. Conclusions: We believe that the mouse model should be used cautiously in xenotransplantation experiments when the fine epitope specificity of antibodies is critical. |
Xenotransplantation.Jan 12 2020.e12672. doi: 10.1111/xen.12672. Epub ahead of print. PMID: 33432698. | blood group B antigen; glycan; microbiota; natural antibodies; polysaccharides; printed glycan array; αGal antibodies; αGal epitope; αGalT KO |
| Donaldson B, Le MTN. | 2019 | The clinical presentation of alpha-gal allergy among pediatric patients with food allergy in southwest Missouri. Alpha-gal allergy is associated with immunoglobulin E (IgE) antibodies to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in beef, pork, and lamb. First described in the adult population in 2009 by Commins et al, this syndrome is associated with delayed anaphylaxis, angioedema, and urticaria with symptom onset 3 to 6 hours after eating red meat.1-3 Bites from ticks, namely the Lone Star Tick (Amblyomma americanum) in the United States, are associated with production of IgE antibodies to alpha-gal, resulting in an immune system primed to react to foods containing the antigen in patients who previously tolerated meat without symptoms. |
Annals of Allergy, Asthma & Immunology. 2019 Nov 1;123(5):524-5. | |
| Doncel-Pérez E, Contreras M, Gómez Hernando C. | 2020 | What is the impact of the antibody response to glycan alpha-Gal in Guillain-Barré syndrome associated with SARS-CoV-2 infection. There are several reports of the onset of Guillain-Barré syndrome (GBS) symptomsin COVID-19 patients. Previously, we reported that reduction in anti-α-Gal IgE, IgMand IgG antibody titers and alteration of anti-α-Gal antibody isotype compositioncorrelated with COVID-19 severity. In this case study, we aimed to compare the antiα-Gal antibody response in COVID-19 and GBS patients. The levels of anti-α-GalIgE, IgM, IgG and IgA were measured by ELISA in the sera of GBS and COVID-19patients. Patients diagnosed with GBS showed an increase in anti-α-Gal IgM whencompared to healthy individuals and COVID-19 patients. The levels of anti-α-GalIgA were significantly higher in COVID-19 patients. No significant differences wereobserved in the levels of IgE and IgG between GBS and COVID-19 patients. Profileof anti-α-Gal antibody isotypes revealed a higher representation of anti-α-Gal IgMand IgG among GBS and COVID-19 patients, respectively. Remarkably, anti-α-GalIgM was also highly represented in SARS-CoV-2 positive patients suffering GBS.Despite the limited number of cases included in the study, we suggest that anti-α-GalIgM and IgA responses are differentially regulated in GBS and COVID-19 patients,which could reflect the disparate etiologies of these diseases. A possible associationbetween high anti-α-Gal IgA in GBS and COVID-19 severity is proposed. |
Merit Research Journal of Medicine and Medical Sciences (MRJMMS). 2020. | coronavirus; Covid-19; SARS-CoV-2; Guillain-Barré syndrome; glycan; IgG; IgM; IgA |
| Donini R, Haslam SM, Kontoravdi C. | 2021 | Glycoengineering Chinese hamster ovary cells: a short history. Biotherapeutic glycoproteins have revolutionised the field of pharmaceuticals, with new discoveries and continuous improvements underpinning the rapid growth of this industry. N-glycosylation is a critical quality attribute of biotherapeutic glycoproteins that influences the efficacy, half-life and immunogenicity of these drugs. This review will focus on the advances and future directions of remodelling N-glycosylation in Chinese hamster ovary (CHO) cells, which are the workhorse of recombinant biotherapeutic production, with particular emphasis on antibody products, using strategies such as cell line and protein backbone engineering. |
Biochemical Society Transactions. 2021 Apr 30;49(2):915-31. | Chinese Hamster Ovaries; glycosylation; biologics; biotherapeutics; monclonal antibody; mAb; pharmacy; pharmaceutical; drug |
| Drouet M, Boutet S, Lauret MG, Chène J, Bonneau JC, Le Sellin J, Hassoun S, Gay G, Sabbah A. | 1994 | The pork-cat syndrome or crossed allergy between pork meat and cat epithelia (1). This work is a study of the frequency of the association between sensitivity to pork meat and cat epithelia. Comparison with a reference population that was not sensitized to pork meat, shows that this association is highly significant. This suggests therefore the possibility of a crossed allergenicity. If there is a real crossed allergenicity between pork meat and cat epithelia, we suggest that this crossed allergenicity is without doubt much greater and concerns more the meats and epithelia of mammals. |
Allergie et immunologie. 1994 May;26(5):166. | Pork-cat syndrome |
| Drouet M, Sabbah A, Le JS, Bonneau JC, Gay G, Dubois-Gosnet C. | 2001 | Fatal anaphylaxis after eating wild boar meat in a patient with pork-cat syndrome. Crossed allergy between pork and cat epithelia was described by us in 1994. It is due to serum albumin. Nowadays, other bio-chemical observations allow "completion" of the syndrome by extension of the crossed reactivity between other mammal meats and other epithelia of dog and horse. The authors report an observation of the pork-cat syndrome (developing in the form of anaphylaxis, and then ending in the death of the patient), following consumption of wild boar meat. Co-factors, such as effort, taking alcohol or hormonal condition may complicate the picture to make diagnosis more difficult. |
Allergie et immunologie. 2001 Apr;33(4):163-5. | diet; food; boar meat; pork-cat syndrome |
| Drouet M, Sarre ME, Hoppe A, Bonneau JC, Leclere JM, le Sellin J, Beauvillain C, Renier G. | 2016 | Characteristics of a group of 21 patients allergic to meat by sensitization to alpha-Gal allergens. / Caractéristiques d'un groupe de 21 patients allergiques aux viandes par sensibilisation aux allergènes alpha-Gal. Patients allergic to red meat with sensitization to alpha-Gal allergen typically have delayed allergic reactions after eating meats. We present a group of 21 patients allergic to meat with alpha-Gal sensitization and study various characteristics: the existence of tick bites or hymenoptera stings occurring before allergy, the existence of allergic reactions after ingestion of dairy products in particular cheese. Some patients present an associated allergy with dairy products that could lead to suspect an allergy to mammalian milk especially as the IgE sensitization to mammalian milk is common in this syndrome. However, we discuss another possibility: rennet, which is extracted from the stomach of the calf is used to manufacture cheese. This substance derived from offal contains alpha-Gal allergens and could most likely be involved in allergy induced by cheeses. |
Revue Française d'Allergologie 2016; 56(7/8): 533-538. | vector; cross-reactivity; hymenoptera; food; diet; dairy; rennet; cheese |
| Duffy MS, Morris HR, Dell A, Appleton JA, Haslam SM. | 2006 | Protein glycosylation in Parelaphostrongylus tenuis—first description of the Galα1-3Gal sequence in a nematode. The white-tailed deer is the definitive host of the parasitic nematode Parelaphostrongylus tenuis. This parasite also infects a wide variety of domesticated livestock, causing a debilitating neurologic disease. Glycoconjugates are becoming increasingly implicated in nematode strategies to maintain persistent infections in immunologically competent hosts. In this study, we have carried out detailed mass spectrometric analysis together with classical biochemical techniques, including western blotting and immunohistochemical staining with anticarbohydrate monoclonal antibodies and have shown that P. tenuis contains complex-type N-glycans with the antennae capped with Galα1-3Galβ1-4GlcNAc sequence. By mimicking a vertebrate glycan, Galα1-3Gal may aid the parasite in evading immunological detection by the host. This is the first report of the Galα1-3Gal sequence in a nematode. |
Glycobiology. 2006 Sep 1;16(9):854-62. | Nematode; invertebrate |
| Dunkman WJ, Rycek W, Manning MW. | 2019 | † ** What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome. Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-α-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy. |
Anesthesia & Analgesia. 2019 Nov 1;129(5):1242-8. | review article; perioperative care; pharmacy; pharmaceutical; medication; surgery; hospitalization; medical products; drugs; anesthesia |
| Dupont B, Mariotte D, Clarisse B, Galais MP, Bouhier-Leporrier K, Grellard JM, Le Mauff B, Reimund JM, Gervais R. | 2014 | Risk factors associated with hypersensitivity reactions to cetuximab: anti-cetuximab IgE detection as screening test. AIM: To describe the factors associated with a high risk of a hypersensitivity reaction to cetuximab. PATIENTS & METHODS: We retrospectively studied a cohort of patients living in Normandy (France) treated with cetuximab. RESULTS: Among the 229 treated patients, 24 (10.5%) had a hypersensitivity reaction to cetuximab, including 11 grade 3-5 reactions. Detection of anti-cetuximab IgE could be performed in 108 patients. Anti-cetuximab IgE was found in 13 of 17 patients (76.5%) who had a hypersensitivity reaction to cetuximab compared with 17 of 91 control patients (18.7%; adjusted odds ratio: 14.99; 95% CI: 3.59-62.63). No clinical criteria predicted the risk of allergy to cetuximab. CONCLUSION: Anti-cetuximab IgE may help physicians identify patients at risk of a hypersensitivity reaction to cetuximab. |
Future Oncology. 2014 Nov;10(14):2133-40. | |
| Dupont B, Mariotte D, Dugué AE, Clarisse B, Grellard JM, Babin E, Chauffert B, Dakpé S, Moldovan C, Bouhier‐Leporrier K, Reimund, JM. | 2017 | Utility of serum anti-cetuximab immunoglobulin E levels to identify patients at a high risk of severe hypersensitivity reaction to cetuximab. AIM: Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. METHODS: We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels ( RESULTS: Of the 301 assessable patients (mean age: 60.9 +/- 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). CONCLUSIONS: Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs. |
British Journal of Clinical Pharmacology. 2017 Mar;83(3):623-31. | |
| Dupont B, Mariotte D, Moldovan C, Grellard JM, Vergnaud, MC, Laroche D, Gervais R. | 2014 | Case Report About Fatal or Near-Fatal Hypersensitivity Reactions to Cetuximab: Anticetuximab IgE as a Valuable Screening Test. Hypersensitivity reactions are a classic side effect of cetuximab. We report the cases of three patients who developed life-threatening hypersensitivity to cetuximab, which could have been predicted by assessing the concentration of serum anticetuximab immunoglobulin (Ig)E. The anticetuximab IgE concentration could be an interesting test to predict which patients are at risk of experiencing severe hypersensitivity reactions to cetuximab. |
Clinical Medicine Insights: Oncology. 2014 Jan;8:CMO-S13897. | |
| Dupont M, Carlier C, Gower-Rousseau C, Barbier-Lider P, Botsen D, Brasseur M, Burgevin A, Chourbagi C, D’Almeida R, Hautefeuille V, Hentzien M | 2022 | Incidence and associated factors of cetuximab-induced hypersensitivity infusion reactions in 1392 cancer patients treated in four French areas: A possible association with Lyme disease?. |
Published online 2022. https://www.researchsquare.com/article/rs-1210416/latest.pdf | France; pharmaceutical; biologic; monoclonal antibody; cetuximab |
| Eberlein B, Mehlich J, Reidenbach K, Pilz C, Hilger C, Darsow U, Brockow K, Biedermann T. | 2020 | Negative oral provocation test with porcine pancreatic enzyme plus cofactors despite confirmed α-Gal syndrome. This case shows that Kreon, an α-Gal-containing porcine pancreas extract can be tolerated in higher than usual doses and despite cofactors in patients with α-Gal syndrome. This is particularly relevant in cases where the drug is necessary to treat exocrine pancreatic insufficiency. Two similar cases have been described [3], but this is the first case in which cofactors, well-known amplifiers of reactions to α-Gal [4], were also tested with the α-Galcontaining drug. After allergy work-up a hymenoptera allergy could be excluded as cause or co-factor of the anaphylaxis. |
J Investig Allergol Clin Immunol. 2020 Jun 3;30(6):6. | |
| Ebo, D. G., Faber, M., Sabato, V., Leysen, J., Gadisseur, A., Bridts, C. H., & De Clerck, L. S. | 2013 | Sensitization to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal): experience in a Flemish case series. BACKGROUND: Recent observations have disclosed that the galactose-alpha (1,3)-galactose (alpha-gal) moiety of non-primate glycoproteins can constitute a target for meat allergy. OBJECTIVE: To describe adults with allergic reactions to mammalian meat, dairy products and gelatin. To investigate whether patients could demonstrate sensitization to activated recombinant human coagulation factor VII ectapog alpha that is produced in baby hamster kidney cells. METHODS: Ten adults with mammalian meat, dairy products and gelatin allergies were examined using quantification of specific IgE and/or skin prick test for red meat, milk, milk components, gelatin, cetuximab and eptacog alpha. RESULTS: Most patients demonstrate quite typical clinical histories and serological profiles, with anti-alpha-gal titers varying from less than 1% to over 25% of total serum IgE. All patients demonstrate negative sIgE for gelatin, except the patient with a genuine gelatin allergy. All patients also demonstrated a negative sIgE to recombinant milk components casein, lactalbumin and lactoglobulin. Specific IgE to eptacog was positive in 5 out of the 9 patients sensitized to alpha-gal and none of the 10 control individuals. CONCLUSION: This series confirms the importance of the alpha-gal carbohydrate moiety as a potential target for allergy to mammalian meat, dairy products and gelatin (oral, topical or parenteral) in a Flemish population of meat allergic adults. It also confirms in vitro tests to mammalian meat generally to be more reliable than mammalian meat skin tests, but that diagnosis can benefit from skin testing with cetuximab. Specific IgE to gelatin is far too insensitive to diagnose alphaa-gal related gelatin allergy. IgE binding studies indicate a potential risk of alpha-gal-containing human recombinant proteins produced in mammalians. |
Acta clinica Belgica. 2013 Jun 1;68(3):206-9. | |
| Eisen L. | 2022 | Personal protection measures to prevent tick bites in the United States: Knowledge gaps, challenges, and opportunities. Personal protection measures to prevent human tick encounters from resulting in bites are widely recommended as the first line of defense against health impacts associated with ticks. This includes using repellents, wearing untreated or permethrin-treated protective clothing, and conducting tick checks after coming inside, aided by removing outdoor clothing articles and running them in a dryer on high heat (to kill undetected ticks) and taking a shower/bath (to aid in detecting ticks on the skin). These measures have the benefit of incurring no or low cost, but they need to be used consistently to be most effective. In this paper, I review the level of use (acceptability combined with behavior) of the above-mentioned personal protection measures and their effectiveness to prevent tick bites and tick-borne disease. Studies on the level of use of personal protection measures to prevent tick bites have used different recruitment strategies, focused on different types of respondent populations, employed variable phrasings of survey questions relating to a given personal protection measure, and presented results based on variable frequencies of taking action. This complicates the synthesis of the findings, but the studies collectively indicate that members of the public commonly take action to prevent tick bites, most frequently by wearing untreated protective clothing or conducting tick checks (done routinely by 30 to 70% of respondents in most studies of the public), followed by showering/bathing after being outdoors or using repellents on skin/clothing (15 to 40% range), and with permethrin-treated clothing being the least frequently used tick bite prevention method (<5 to 20% range). A suite of experimental studies have shown that applying repellents or permethrin to coveralls or uniform-style clothing can result in decreased numbers of tick bites, but similar studies are lacking for members of the public wearing summer-weight clothing during normal daily activities. Moreover, a set of case-control and cross-sectional studies have explored associations between use of different personal protection measures to prevent tick bites and Lyme disease or other tick-borne infections. The results are mixed for each personal protection measure, with some studies indicating that regular use of the measure is associated with a reduction in tick-borne disease while other studies found no similar protective effect. One possible interpretation is that these personal protection measures can protect against tick-borne infection but the information gathered to date has not been sufficiently detailed to clarify the circumstances under which protection is achieved, especially with regards to frequency of use, parts of the body being protected, and use of combinations of two or more potentially protective measures. In conclusion, personal protection measures to prevent tick bites are used by the public and merit further study to better understand how they need to be used to have the greatest public health impact. |
Ticks and Tick-borne Diseases. 2022 Mar 26:101944. | ticks; tick bite avoidance |
| El Hanache H, Perennec T, Beaumont P, Puillandre E, Schwender D, Donguy L, Froidefond C, Jarlot S, Petit N, Nootens C, Pirson F. | 2023 | Food anaphylaxis in the elderly: Analysis of allergy vigilance network data from 2002 to 2021. Background: Few studies have focused on food allergies in the elderly, even though it may persist or appear de novo. Methods: We reviewed data for all cases of food-induced anaphylaxis in people age ≥ 60 reported to the French "Allergy Vigilance Network" (RAV) between 2002 and 2021. RAV collates data reported by French-speaking allergists regarding cases of anaphylaxis graded II to IV according to the Ring and Messmer classification. Results: In total, 1: 1 cases were reported, with an even sex distribution and mean age was 67.4 years (range 60 to 93). The most frequent allergens were mammalian meat and offal (31 cases, 16.2%), often associated with IgE to α-Gal. Legumes were reported in 26 cases (13.6%), fruits and vegetables in 25 cases (13.1%), shellfish 25 cases (13.1%), nuts 20 cases (10.5%), cereals 18 cases (9.4%), seeds 10 cases (5.2%), fish 8 cases (4.2%) and anisakis 8 cases (4.2%). Severity was grade II in 86 cases (45%), grade III in 98 cases (52%) and grade IV in 6 cases (3%) with one death. Most episodes occurred at home or in a restaurant and in most cases adrenaline was not used to treat the acute episode. Potentially relevant cofactors such as beta-blocker, alcohol or non-steroidal anti-inflammatory drug intake were present in 61% of cases. Chronic cardiomyopathy, present in 11.5% of the population, was associated with greater, grade III or IV reaction severity (OR 3.4; 1.24-10.95). Conclusion: Anaphylaxis in the elderly has different causes to younger people and requires detailed diagnostic testing and individualized care plans. |
Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology. 2023 Feb 22. | Europe; France; prevalence; elderly; senior citizen; age; epidemiology |
| Eller E, Skov PS, Baumann K, Hilger C, Ollert M, Bindslev-Jensen C. | 2021 | Delayed reaction in alpha-gal allergy is reflected in serum levels after ingestion of pork kidney, and absorption is dependent on food processing. Letter to the editor |
Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology. | Kidney; digestion; mechanism of delay |
| Elston DM. Climate change and expansion of tick geography. | 2020 | Climate change and expansion of tick geography. The expanding range of tick-borne diseases is a growing problem worldwide. Climate change plays a preeminent role in the expansion of tick species, especially for southern ticks in the United States such as Amblyomma species, which have introduced new pathogens to northern states.1-5 In addition to well-known tickborne diseases, Amblyomma ticks have been implicated in the spread of emerging severe and potentially fatal viral illnesses, including Bourbon virus and Heartland virus.6 The increasing range of Amblyomma ticks also exposes new populations to tick-induced meat allergy (alpha-gal) syndrome, whereby development of specific IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) following tick bites results in severe allergic responses to consumption of beef, pork, and lamb. |
Cutis. 2020 Apr 1;105(4):161-2. | |
| Enders FB, Elkuch M, Wörner A, Hofmeier KS, Hartmann K. | 2023 | Alpha-gal syndrome initially misdiagnosed as chronic spontaneous urticaria in a pediatric patient: a case report and review of the literature |
Journal of Medical Case Reports. 2023 Dec;17(1):1-3. | Europe; Switzerland; pediatric; gelatin |
| Epelboin L, Roche F, Dueymes M, Guillot G, Duron O, Nacher M, Djossou F, Soria A. | 2021 | Allergy to Mammalian Meat Linked to Alpha-Gal Syndrome Potentially After Tick Bite in the Amazon: A Case Series. The past decade has seen the emergence of a new type of food allergy occurring after ingestion of mammalian meat. This allergy is related to immunoglobulin (Ig)E specific for galactose-alpha-1,3 galactose (α-Gal). Originally described in the United States in 2009, other cases have subsequently been described in Australia and in Europe, but still very few in Latin America. The purpose of this study was to show the existence of this pathology in French Guiana and to describe the historical, clinical, and biological characteristics of these patients. Patients reporting an allergy to mammalian meat were included between September 2017 and August 2019. Eleven patients were included, nine of whom exhibited digestive symptoms; four, urticaria reactions; three, respiratory reactions; and angioedema. The time between ingestion of red meat and reaction varied between 1.5 and 6 hours. The implicated meats were most often beef and pork. All patients had been regularly exposed to tick bites before the appearance of symptoms. All the samples (n = 7) were positive for anti-α-Gal anti-mammalian meats IgE. All the patients were Caucasian French expatriates. This study confirms the presence of this new entity in French Guiana and is the largest reported in Latin America. Our results do not clearly allow us to state that tick bites are the cause of this allergy, but all patients reported being exposed regularly to these arthropods. |
The American journal of tropical medicine and hygiene.:tpmd201630. | South America; French Guiana; Amblyomma cajennense |
| Erickson LD, Chandrasekhar JL, Cox KM. | 2020 | B Cell Responses in the Development of Mammalian Meat Allergy. Studies of meat allergic patients have shown that eating meat poses a serious acute health risk that can induce severe cutaneous, gastrointestinal, and respiratory reactions. Allergic reactions in affected individuals following meat consumption are mediated predominantly by IgE antibodies specific for galactose-α-1,3-galactose (α-gal), a blood group antigen of non-primate mammals and therefore present in dietary meat. α-gal is also found within certain tick species and tick bites are strongly linked to meat allergy. Thus, it is thought that exposure to tick bites promotes cutaneous sensitization to tick antigens such as α-gal, leading to the development of IgE-mediated meat allergy. The underlying immune mechanisms by which skin exposure to ticks leads to the production of α-gal-specific IgE are poorly understood and are key to identifying novel treatments for this disease. In this review, we summarize the evidence of cutaneous exposure to tick bites and the development of mammalian meat allergy. We then provide recent insights into the role of B cells in IgE production in human patients with mammalian meat allergy and in a novel mouse model of meat allergy. Finally, we discuss existing data more generally focused on tick-mediated immunomodulation, and highlight possible mechanisms for how cutaneous exposure to tick bites might affect B cell responses in the skin and gut that contribute to loss of oral tolerance. |
Molecular medical microbiology 2002 Jan 1 (pp. 1089-1116). Academic Press. | review article; vector; tick; tick saliva; sensitization; B cell; tick-mediated immunomodulation |
| Erwin EA, Custis NJ, Satinover SM, Perzanowski MS, Woodfolk JA, Crane J, Wicken, K, Platts-Mills TA. | 2005 | Quantitative measurement of IgE antibodies to purified allergens using streptavidin linked to a high-capacity solid phase. BACKGROUND: Commercially available assays for IgE antibody provide results in international units per milliliter for many allergen extracts, but this is not easily achieved with purified or novel allergens. OBJECTIVE: To develop assays for IgE antibody suitable for purified or novel allergens by using a commercially available immunosorbent. METHODS: Streptavidin coupled to a high-capacity immunosorbent (CAP) was used to bind biotinylated purified allergens from mite (Der p 1 and Der p 2), cat (Fel d 1), and dog (Can f 1). Assays for IgE antibody to these allergens were performed on sera from children (asthma and control) as well as adults with atopic dermatitis. RESULTS: The results were validated by serial dilution of sera with high and low levels of IgE antibody and were quantitated in international units per milliliter by using a standard curve. Values for IgE antibody to Der p 1, Der p 2, and Fel d 1 correlated with values obtained with the allergen extracts (r2 = 0.80, 0.84, and 0.95, respectively; P < .001 in each case). Furthermore, the values for IgE antibody in sera from children with high exposure to mite and cat allergens demonstrated 10-fold higher levels of IgE antibody to Der p 1 and Der p 2 than to Fel d 1 (P < .001). CONCLUSION: The streptavidin immunosorbent technique provides a new method for quantifying IgE antibody to purified proteins. The results provide evidence about the high quantities of IgE antibody to purified inhalant allergens in patients with atopic dermatitis. In addition, the results demonstrate major differences in IgE antibodies specific for mite and cat allergens among children with high exposure to both allergens. |
Journal of allergy and clinical immunology. 2005 May 1;115(5):1029-35. | |
| Ezhuthachan I, Kaplan B. | 2018 | A CASE OF CHRONIC URTICARIA AND ANGIOEDEMA WITH FALSE-POSITIVE ALPHA-GAL IGE. Introduction: Sensitization to galactose-alpha-1,3-galactose (alpha-gal) has been linked with delayed urticaria, angioedema and anaphylaxis to mammalian meat. We report chronic urticaria and angioedema (CUA) in a patient with false-positive alpha-gal and mammalian meat IgE. Case Description: Patient is an 18-year-old male with urticaria and angioedema referred to our clinic for evaluation of positive IgE to alpha-gal and mammalian meat. He first developed urticaria/angioedema at 14 years of age. It was treated with H 1, H 2 blockers and completely resolved in 2 months. After being asymptomatic for 3 years, his symptoms recurred. No triggers were noted, including no dietary changes and worsening in symptoms upon meat or dairy ingestion. Laboratory evaluation was remarkable for positive IgE for alpha-gal (3.76 kU/L), beef (2.01 kU/L), lamb/mutton (0.77 kU/L) and pork (1 kU/L). Treatment with fexofenadine, cetirizine and famotidine was initiated and patient was referred to our clinic for further evaluation. We recommended a 2-week trial of red meat elimination diet, which didn't result in symptom improvement. Hives/angioedema didn't worsen after reintroduction of red meat. Montelukast was added to his medications, resulting in 70% improvement in symptoms. . Discussion: High rate of false-positive IgE to food allergens is well established. To our knowledge this is the first report of false positive alpha-gal IgE in CUA, misdiagnosed as allergy to mammalian meat. This case demonstrates the importance of a comprehensive history in CUA along with careful selection and evaluation of relevant laboratory tests. Note: it's impossible to include this paper in this database without noting that some of us in the alpha-gal community have wondered how the authors came to the conclusion that this was a case of a false positive without eliminating non-meat sources of alpha-gal from the patient's diet that may have been the source of ongoing reactions: dairy, gelatin, etc. |
Annals of Allergy, Asthma & Immunology. 2018 Nov 1;121(5):S115. | |
| Fagerstone KA, Clay WH. | 1997 | Overview of USDA animal damage control efforts to manage overabundant deer. |
Wildlife Society Bulletin (1973-2006). 1997 Jul 1;25(2):413-7. | Lone star tick; host; white-tailed deer |
| Fang ZY, Zhang HT, Lu C, Lu QM, Yu CH, Wang HY. | 2018 | Association between allergic diseases and irritable bowel syndrome: a retrospective study. Background: The relationship between allergic disease and irritable bowel syndrome (IBS) is poorly understood. We aimed to investigate the potential association as well as the underlying immunological mechanisms. Methods: A retrospective case-control study of 108 atopic patients from among outpatients in an allergy clinic (allergic rhinitis [AR], n = 49; chronic urticaria [CU], n = 59) and 74 controls from among ward companions was conducted from November 2016 to March 2017. The detection rates and related gastrointestinal (GI) symptoms of IBS, as well as immunological indices, were calculated. Results: CU patients had a trend of increase in the detection of IBS compared to controls (OR = 4.846; 95% CI 0.967–24.279, p = 0.077). Loose stools (OR = 2.406; 95% CI 1.075–5.386, p < 0.05) and viscous stools (OR = 2.665; 95% CI 1.250–5.682, p < 0.05) were more common in CU patients. Atopic patients positive for serum total immunoglobulin E (IgE) (OR = 3.379; 95% CI 1.088–10.498, p < 0.05) or house dust mite (HDM)-specific IgE (OR = 3.640; 95% CI 1.228–10.790, p < 0.05) were more likely to have abdominal bloating. Besides, a positive association between levels of total IgE and severity of abdominal bloating was observed (p < 0.05). An HDM-specific IgE-positive reaction was independently associated with abdominal bloating in atopic patients (p < 0.05). Conclusions: Allergic disease has a clear clinical association with IBS with more frequent and severe symptoms of IBS. CU patients have a tendency to suffer from IBS, usually with diarrhea. Serum total IgE and HDM-specific IgE are positively correlated with GI symptoms in atopic patients. |
International archives of allergy and immunology. 2018;177(2):153-9. | gastrointestinal disease; GI; irritable bowel syndrome; IBS |
| Farooque S, Kenny M, Marshall SD. | 2019 | Anaphylaxis to intravenous gelatin-based solutions: a case series examining clinical features and severity. Summary: The proportion of patients receiving intravenous gelatin-based colloids has increased in the last decade due to safety concerns about starch-based products. Recent research suggests hypersensitivity reactions to intravenous gelatin-based solutions occur at similar rates per administration as non-depolarising neuromuscular blocking agents such as rocuronium (6.2/100,000 administrations). There are scant published data on clinical features, diagnosis and time course of these reactions. We undertook a review of cases reported and tested at one of the UK's largest drug allergy clinics. All patients seen in the drug allergy clinic at Imperial College Healthcare NHS Trust (London, UK) with a confirmed diagnosis of anaphylaxis to gelatin-based solutions between May 2013 and May 2018 were included. We retrospectively reviewed clinical histories, skin test results and severity of reactions in this cohort of patients. Twelve patients with anaphylaxis to gelatin-based solutions were identified (eight women, mean (SD) age 58 (17) years). Eleven reactions were severe or life-threatening with three progressing to cardiac arrest. Presentation was commonly delayed; only three patients suffered reactions within 5 min of the solution being administered with a further six presenting 10–70 min later. Where measured, tryptase was elevated in all patients (median (IQR [range]) 14.7 (8.2–23.8 [6.5–83.4]) ng.ml−1). Reactions to gelatin-based solutions are usually severe and can present with latency uncommon with other intravenous anaesthetic triggers. The use of gelatin-based solutions in the peri-operative setting should be re-assessed given the risk of severe allergy. |
Anaesthesia. 2019 Feb;74(2):174-9. | medical products; gelatin; plasma volume expander; colloid; hospital; perioperative |
| Faruque MO, Mohiuddin AK, Mahmud S. | 2020 | Prevalence, severity and risk factors of food allergy and food addiction among the people of Tangail district, Bangladesh. Food allergy is an abnormal response of some particular foods triggered by the body’s immune system. Food addiction which generally shares a similar neurobiological and behavioral framework with substance addiction like foods. The aim of this study was to evaluate common food items responsible for food allergy along with food addiction among Bangladeshi people. Methods: A cross-sectional study among 699 participants in the Tangail district of Bangladesh was done to record the presence of food allergy and food addiction patterns. Chi-square tests and logistic regression analysis were performed to assess the association between different factors with food allergy and food addiction. Results: It was found that brinjal was the most frequent food item responsible for 28.3% of people’s food allergy. The main symptoms due to the food allergy were about 28.5% itching and 22.7% rash on the skin. According to this study, 50.4% of allergic patients took medicine and most of the allergic patients didn’t seek medical advice. A maximum of 72.8% of allergic patients also had an addiction to food. Street foods like jhalmuri, fried foods were the general food addicted items covering 34.9%. Food-addicted participants with food allergies reported significantly more problems with foods, where obesity and heart disease are recognized as clinical effects due to having higher amounts of fat and sugar to these foods. Conclusions: The study revealed some important determinants of food allergic and food addiction that will help to increase our knowledge for the greater interest of our health and further research. |
International Journal of Community Medicine and Public Health. 2020 Oct;7(10):3810. | Asia; Bangaldesh; prevalence; beef allergy |
| Fernando DD, Fischer K. | 2020 | Proteases and Pseudoproteases in Parasitic Arthropods of Clinical Importance. rasitic arthropods feed on blood or skin tissue and share comparable repertoires of proteases involved in haematophagy, digestion, egg development and immunity. While proteolytically active proteases of multiple classes dominate, an increasing number of pseudoproteases have been discovered that have no proteolytic function but are pharmacologically active biomolecules,evolved to carry out alternative functions as regulatory, anti-haemostatic, anti-inflammatory or immunomodulatory compounds. In this review, we provide an overview of proteases and pseudoproteases from clinically important arthropod parasites. Many of these act in central biological pathways of parasite survival and host–parasite interaction and may be potential targets for therapeutic interventions. |
The FEBS Journal. | |
| Fiocchi A, Restani P, Riva E, Mirri GP, Santini I, Bernardo L, Galli CL. | 1998 | Heat treatment modifies the allergenicity of beef and bovine serum albumin. The effect of heat on the allergenicity of beef and bovine serum albumin was investigated among 10 toddlers skin prick test (SPT)‐positive to raw and cooked beef. The meat‐allergy diagnosis was confirmed during double‐blind, placebo‐controlled food challenge (DBPCFC) with 180 g of beef cooked for 5 min at 100°C. SPT with homogenized and freeze‐dried beef, and heated and unheated bovine serum albumin were performed. Both heated and unheated bovine serum albumin, homogenized beef, and freeze‐dried beef were used in trial DBPCFC. All children were SPT‐positive to unheated bovine serum albumin. Seven were positive to heated bovine serum albumin, one to freeze‐dried beef, and none to homogenized beef. DBPCFCs were negative for homogenized beef and freeze‐dried beef, positive for unheated bovine serum albumin in five patients, and positive for heated albumin in four children. We conclude that heating reduces sensitization to beef and bovine serum albumin but does not abolish reactivity to albumin under home conditions. However, industrially heat‐treated and sterilized homogenized beef and freeze‐dried beef may be suitable substitutes in beef‐allergic children's diets. |
Allergy. 1998 Aug;53(8):798-802. | skin prick test SPT dairy cow's milk allergy |
| Fiocchi A, Restani P, Riva E. | 2000 | Beef allergy in children. Beef allergy was poorly known before the ’90s. Since then, a number of papers appeared elucidating the nature, epidemiology, and symptoms of beef allergy in children allergic to cow’s milk and children suffering from atopic dermatitis. It is now clear that beef allergy is not an infrequent occurrence, with an incidence between 3.28% and 6.52% among children with atopic dermatitis, its incidence may be as much as 0.3% in the general population. A diagnosis of beef allergy must be supported by skin prick tests, RASTs, and challenges. The specificity and sensitivity according to type of test and the type of extract, however, remains to be evaluated. Despite the fact that other allergens can be sensitizing, the major beef allergen is bovine serum albumin (BSA). Beef-sensitive children are also sensitized to ovine serum albumin, as well as to other serum albumins; therefore, the use of alternative meats in beef-allergic children must be carefully evaluated on an individual basis. Because industrial heat processing is more efficient than domestic cooking in reducing reactivity in beef-sensitive children, freeze-drying and homogenization may support the introduction of processed beef into the diet of beef-allergic children. |
Nutrition. 2000 Jun 1;16(6):454-7. | Europe; Italy; beef allergy; prevalence; BSA |
| Fischer J, Biedermann T. | 2016 | Delayed immediate-type hypersensitivity to red meat and innards: current insights into a novel disease entity./Verzögerte Soforttyp-Allergie gegen rotes Fleisch und Innereien: aktueller Wissensstand zu einem neuen Krankheitsbild. The development of component-resolved diagnostics instead of whole extracts has brought about major advances in recent years. Particularly remarkable has been the identification of new disease entities based on the detection of IgE antibodies against specific individual components. In this context, delayed immediate-type hypersensitivity to red meat and innards plays a key role. This disorder is more common in German-speaking countries and likely still underdiagnosed. Affected individuals exhibit delayed type I reactions following the consumption of red meat or innards (responses to the latter are more rapid). All patients have IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose - alpha-gal. Those affected also have to avoid-alpha-gal-containing drugs such as cetuximab or gelatin-containing colloidal solutions. Also referred to as alpha-gal syndrome, this condition is unique in that it is characterized by type I hypersensitivity to a sugar instead of a protein. Given that many patients have a history of recurrent episodes of acute urticaria or angioedema, dermatologists should be familiar with the alpha-gal syndrome. |
Journal der Deutschen Dermatologischen Gesellschaft. 2016 Jan;14(1):38-43. | |
| Fischer J, Eberlein B, Hilger C, Eyer F, Eyerich S, Ollert M, Biedermann T. | 2017 | Alpha-gal is a possible target of IgE-mediated reactivity to antivenom. BACKGROUND: Antivenoms are mammalian immunoglobulins with the ability to neutralize snake venom components and to mitigate the progression of toxic effects. Immediate hypersensitivity to antivenoms often occurs during the first administration of these heterologous antibodies. A comparable clinical situation occurred after introduction of cetuximab, a chimeric mouse-human antibody, for cancer treatment. The carbohydrate epitope galactose-alpha-1,3-galactose, located on the Fab region of cetuximab, was identified as the target responsible for IgE reactivity. OBJECTIVE: To investigate whether serum IgE antibodies directed to the -gal epitope are associated with hypersensitivity to equine antivenoms. METHODS: Antivenoms were screened for -gal epitopes via immunoblot and in comparison with cetuximab and pork kidney by IgE reactivity assays. Basophil activation tests were used to investigate reactivity to antivenoms in samples from 20 patients with specific IgE antibodies to -gal and 10 controls. Additional IgE detection, IgE inhibition, ImmunoCAP inhibition, and skin prick tests were performed using samples from selected patients. RESULTS: Both antivenoms and cetuximab induced positive skin prick test results in patients with sIgE to -gal. Alpha-gal epitopes were detected by immunoblotting on antivenoms. Measurements of IgE reactivity and ImmunoCAP inhibition indicated that the antivenoms contained lower -gal contents than cetuximab. Deglycosylation assays and IgE inhibition tests confirmed that IgE-mediated reactivity to antivenom is associated with -gal. Antivenoms, pork kidney, and cetuximab activated basophils from patients with IgE to -gal. CONCLUSION: Alpha-gal is a potential target of IgE-mediated reactivity to equine antivenom and a possible cause of the high incidence of hypersensitivity reactions during the first application of equine antivenom. |
Allergy. 2017 May;72(5):764-71. | |
| Fischer J, Hebsaker J, Caponetto P, Platts-Mills TA, Biedermann T. | 2014 | * Galactose-alpha-1,3-galactose sensitization is a prerequisite for pork-kidney allergy and cofactor-related mammalian meat anaphylaxis. Delayed type I reactions to red meat are typical for patients sensitized to galactose-alpha-1,3-galactose (α-Gal), and increasing numbers of patients are being recognized worldwide. Interestingly, allergic reactions to pork kidney are mainly observed in Europe and are a good example of how regional differences in meat consumption can influence the clinical presentation of this specific variant of type I allergy. The aim of this study was to outline how an understanding of allergy to pork kidney can be helpful for the understanding of red meat allergy in general. |
Journal of allergy and clinical immunology. 2014 Sep 1;134(3):755-9. | co-factor; cofactor, ACE inhibitor/β-agonist; exercise; alcohol; non-steroidal anti-inflammatory drug; NSAID |
| Fischer J, Hilger C. | 2017 | Alpha-Gal Syndrome: Clinical Presentation, New Concepts, and Unmet Needs. For decades, carbohydrate determinants were seen as cross-reactive structures without clinical impact. The discovery of specific IgE to the carbohydrate galactose-α-1,3-galactose, called α-gal, changed our perspective on the allergenic potential of carbohydrate determinants. α-Gal is present in tissues of non-primate mammals and, upon ingestion, can provoke a delayed form of allergic reaction in sensitized patients. We are faced with a new and unique entity of allergy with high clinical relevance in food allergy and anaphylaxis to drugs derived from mammalian products. Tick bites are assumed to constitute the primary sensitization source to α-gal. To address the complexity of this disease, the term α-gal syndrome has been suggested. |
Current Treatment Options in Allergy. 2017 Sep 1;4(3):303-11. | |
| Fischer J, Huynh HN, Hebsaker J, Forchhammer S, Yazdi AS. | 2020 | **Prevalence and Impact of Type I Sensitization to Alpha-Gal in Patients Consulting an Allergy Unit. Background: Alpha-gal syndrome is a complex allergy with high clinical relevance regarding mammalian-derived food and drugs and is characterized by the presence of IgE antibodies directed at the carbohydrate galactose-α-1,3-galactose. As not all alpha-gal sIgE-positive individuals present clinical symptoms upon consumption of mammalian meat, the diagnostic value of alpha-gal sIgE has yet to be clarified. Objective: To investigate the prevalence of alpha-gal-sIgE positivity among allergy patients, examine the impact of tick bites as associated risk factors and determine the diagnostic value of alpha-gal-sIgE positivity. Methods: A retrospective cross-sectional study evaluating patients in the Allergy Unit was performed. Alpha-gal-sIgE levels were assessed by ImmunoCAP assay. Exposure to tick bites was assessed by a questionnaire. A receiver operating characteristics (ROC) curve analysis was performed to determine the diagnostic value of alpha-gal sIgE for the diagnosis of alpha-gal syndrome. Results: In the study population (n = 1369), the overall prevalence of alpha-gal-sIgE-positive (≥0.10 kUA/L) individuals was 19.9%, and the highest prevalence (30.2%) was found in patients with insect venom allergies. A reported tick bite within the 12 months prior to blood sampling significantly increased the risk of alpha-gal-sIgE positivity (OR 2.084). The ROC curve analysis indicated alpha-gal sIgE ≥0.54 kUA/L as the optimal cutoff point for assessing the diagnostic value of alpha-gal syndrome in allergy patients. Conclusions: In allergy care settings, alpha-gal-sIgE positivity is a common finding. Alpha-gal sIgE is a sensitive marker in the diagnosis of alpha-gal syndrome but has limited predictive value for the characteristics or severity of this allergy. |
International Archives of Allergy and Immunology. 2020;181(2):119-27. | prevalence |
| Fischer J, Lupberger E, Hebsaker J, Blumenstock G, Aichinger E, Yazdi AS, Reick D, Oehme R, Biedermann T. | 2017 | ** Prevalence of type I sensitization to alpha-gal in forest service employees and hunters. BACKGROUND: The production of IgE molecules specific to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal) is known to induce delayed anaphylaxis against mammalian meat. Tick bites constitute the primary sensitization source, as ticks transfer alpha-gal in their saliva to a host during a bite. The reported prevalence of alpha-gal-specific IgE (alpha-gal-sIgE) positivity varies between different populations from diverse geographic regions. OBJECTIVE: To investigate the prevalence of alpha-gal-sIgE positivity in a population of forest service employees who are highly exposed to ticks in comparison with a residential population and a historic sample. METHODS: A cross-sectional study evaluating 300 forest service employees and hunters from southwest Germany was performed. Alpha-gal-sIgE levels were assessed by ImmunoCAP assay. The prevalence of alpha-gal-sIgE-positive individuals was compared with a matched cohort composed of a residential population and blood samples from forest service employees collected 15 years ago. RESULTS: In the study population, the prevalence of alpha-gal-sIgE-positive (>/=0.10 kUA /L) individuals was 35.0%, whereas the prevalence of individuals with alpha-gal-sIgE levels >/=0.35 kUA /L was 19.3%. Alpha-gal-sIgE positivity was associated with total IgE levels and recent tick bites. Mammalian meat-induced delayed anaphylaxis was found in 8.6% of the participants with alpha-gal-sIgE levels >/=0.35 kUA /L. For forest service employees and hunters, the odds ratio for alpha-gal-sIgE positivity was 2.48 compared to the residential population. The prevalence of alpha-gal-sIgE positivity in the current and historic cohort was comparable. CONCLUSION: Forest service employees and hunters compose a population with a high prevalence of alpha-gal-sIgE positivity and carry a considerable risk of red meat allergy. |
Allergy. 2017 Oct;72(10):1540-7. | prevalence |
| Fischer J, Riel S, Fehrenbacher B, Frank A, Schaller M, Biedermann T, Hilger C, Mackenstedt U. | 2020 | Spatial distribution of alpha-gal in Ixodes ricinus-a histological study. Alpha-gal syndrome is a complex allergic disease in humans that is caused by specific IgE (sIgE) against the carbohydrate galactose-α-1,3-galactose (alpha-gal). Tick saliva contains alpha-gal, and tick bites are considered a major cause of the induction of alpha-gal-sIgE. The origin of alpha-gal in tick saliva remains unclarified. The presence of alpha-gal in tick tissue was visualized in this study to provide an overview of the spatial distribution of alpha-gal and to further elucidate the origin of alpha-gal in tick saliva. Fed and unfed Ixodes ricinus females were examined by histology, immunohistochemistry, immunofluorescence, transmission electron microscopy and immunoelectron microscopy using the alpha-gal-specific monoclonal antibody M86 and Marasmius oreades agglutinin (MOA) lectin. Alpha-gal epitopes were detected in the midgut, hemolymph and salivary glands, and the immunofluorescence analysis revealed signs of the endocytosis of alpha-gal-containing constituents during the process of hematophagy. Alpha-gal epitopes in endosomes of the digestive gut cells of the ticks were observed via immunoelectron microscopy. Alpha-gal epitopes were detected in dried droplets of hemolymph from unfed ticks. Intense staining of alpha-gal epitopes was found in type II granular acini of the salivary glands of fed and unfed ticks. Our data suggest that alpha-gal is not ubiquitously expressed in tick tissue but is present in both fed and unfed ticks. The findings also indicate that both the metabolic incorporation of constituents from a mammalian blood meal and endogenous production contribute to the presence of alpha-gal epitopes in ticks. |
Ticks and Tick-borne Diseases. 2020 Jul 2:101506. | ticks; vector of sensitization |
| Fischer J, Yazdi AS, Biedermann T. | 2016 | Clinical spectrum of alpha-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat. The term alpha-Gal syndrome describes a novel IgE-mediated immediate-type allergy to the disaccharide galactose-alpha-1,3-galactose (alpha-Gal). Its classification as a syndrome is proposed on the basis of its clinical relevance in three different fields of allergy: food, drugs, and tick bites. The main focus of the present article is on alpha-Gal as an eliciting allergen in food allergy. It was recently shown that immediate-type allergies to pork kidney and other mammalian innards belong to the spectrum of alpha-Gal syndrome. These allergic reactions manifest as classic immediate-type allergies with a typical latency of under 1 h. The phenomenon of a delayed-onset immediate-type allergy with a latency of 3-6 h following ingestion of mammalian meat is considered pathognomonic for alpha-Gal syndrome. This clinically distinct type of presentation can be explained using the concept of food-dependent exercise-induced anaphylaxis (FDEIA). However, clinical observations and challenge testing in this constellation reveal that individual sensitivity in alpha-Gal patients is highly variable and which broadens our basic understanding of alpha-Gal syndrome. |
Allergo journal international. 2016 Mar 1;25(2):55-62. | |
| Fischer J. | 2015 | Food Allergy through Tick Bites a new Health Risk? No abstract available |
Allergologie. 2015;38:194-195. | |
| Fisher EJ, Mo J, Lucky AW. | 2006 | Multiple pruritic papules from lone star tick larvae bites. Background: Ticks are the second most common vectors of human infectious diseases in the world. In addition to their role as vectors, ticks and their larvae can also produce primary skin manifestations. Infestation by the larvae of ticks is not commonly recognized, with only 3 cases reported in the literature. The presence of multiple lesions and partially burrowed 6-legged tick larvae can present a diagnostic challenge for clinicians. Observation: We describe a 51-year-old healthy woman who presented to our clinic with multiple erythematous papules and partially burrowed organisms 5 days after exposure to a wooded area in southern Kentucky. She was treated with permethrin cream and the lesions resolved over the following 3 weeks without sequelae. The organism was later identified as the larva of Amblyomma species, the lone star tick. Conclusions: Multiple pruritic papules can pose a diagnostic challenge. The patient described herein had an unusually large number of pruritic papules as well as tick larvae present on her skin. Recognition of lone star tick larvae as a cause of multiple bites may be helpful in similar cases. |
Archives of dermatology. 2006 Apr 1;142(4):491-4. | vector; tick vs chigger |
| Flaherty MG, Kaplan SJ, Jerath MR. | 2017 | *Diagnosis of Life-Threatening Alpha-Gal Food Allergy Appears to Be Patient Driven. Objective: Patients exhibiting life-threatening symptoms associated with the alpha-gal food allergy (delayed urticaria or anaphylaxis due to mammalian meat) are frequently undiagnosed, causing unnecessary emergency department (ED) and health care visits, and extensive pain and suffering. This study aimed to determine the path to diagnosis experienced by alpha-gal patients. Methods: Semistructured interviews were conducted from March to June 2016 with a chronological systematic sample of approximately 10% of patients diagnosed with alpha-gal and treated by the University of North Carolina Allergy and Immunology Clinic (n = 28). Main outcome measures included average length of time between first symptoms’ appearance and diagnosis, number and type of health care encounters en route to diagnosis, and typical symptom severity. Results: Six interviewees (21%) were diagnosed within a year of experiencing symptoms, of the remaining 22, mean time to diagnosis was 7.1 years. In over 100 medical encounters (including 28 ED visits and 2 urgent care) the correct diagnosis or effective diagnosing referral occurred less than 10% of the time. Seventy-one percent (20/28) described their first symptoms as severe. More patients found the allergist specializing in this condition on their own (n = 12; 43%) than those who were formally diagnosed or received referrals (n = 10; 36%) through the health care system. Conclusions: The medical community is challenged to stay abreast of emerging and newly uncovered illnesses through traditional medical literature communication channels. Presently, patients more often discover a diagnosis of alpha-gal allergy by using information resources on their own than by presenting to the ED with anaphylaxis. |
Journal of primary care & community health. 2017 Oct;8(4):345-8. | |
| Flaherty MG, Threats M, Kaplan SJ. | 2018 | Patients’ Health Information Practices and Perceptions of Provider Knowledge in the Case of the Newly Discovered Alpha-gal Food Allergy. Background:Alpha-gal food allergy is a life-threatening, newly discovered condition with limited presence in authoritative information sources. Sufferers seeking diagnosis are likely to encounter clinicians unfamiliar with the condition. Objective: To understand information practices of individuals diagnosed with alpha-gal allergy, how they obtained diagnosis, and their perceptions of health-care providers’ awareness of the condition. Methods: Semistructured interviews with open- and closed-ended questions were completed with a chronological systematic sample of 28 adults (11% of alpha-gal clinic patients at the time) diagnosed with alpha-gal allergy and treated at University of North Carolina Allergy and Immunology Clinic. Results: The majority of patients determined they had alpha-gal allergy through nontraditional health information channels. Three-quarters of patients rated their primary care provider as having little to no knowledge. In 25 specialists’ encounters, 23 were rated as having little to no knowledge. Conclusion: With new conditions, information is often available through informal networks before appearing in the vetted medical literature. In this study, social connections were the primary pathway to successful diagnosis. Health practitioners need to develop mechanisms to understand that process. |
Journal of Patient Experience. 2020 Feb;7(1):132-9. | patient perceptions; clinician–patient relationship; health literacy |
| Flaherty MG, Threats M, Kaplan SJ. | 2020 | * Patients’ Health Information Practices and Perceptions of Provider Knowledge in the Case of the Newly Discovered Alpha-gal Food Allergy. Background: Alpha-gal food allergy is a life-threatening, newly discovered condition with limited presence in authoritative information sources. Sufferers seeking diagnosis are likely to encounter clinicians unfamiliar with the condition. . Objective: To understand information practices of individuals diagnosed with alpha-gal allergy, how they obtained diagnosis, and their perceptions of health-care providers’ awareness of the condition. Methods: Semistructured interviews with openand closed-ended questions were completed with a chronological systematic sample of 28 adults (11% of alpha-gal clinic patients at the time) diagnosed with alpha-gal allergy and treated at University of North Carolina Allergy and Immunology Clinic. . Results: The majority of patients determined they had alpha-gal allergy through nontraditional health information channels. Three-quarters of patients rated their primary care provider as having little to no knowledge. In 25 specialists’ encounters, 23 were rated as having little to no knowledge. . Conclusion: With new conditions, information is often available through informal networks before appearing in the vetted medical literature. In this study, social connections were the primary pathway to successful diagnosis. Health practitioners need to develop mechanisms to understand that process |
Journal of Patient Experience. 2020 Feb;7(1):132-9. | patient perceptions; clinician–patient relationship; health literacy |
| Flebbe-Rehwaldt L, Altrich ML. | 2014 | Cross Reactivity Of Alpha Gal Allergy With An Extended Red Meat Panel. RATIONALE: Galactose-alpha-1,3-galactose (alpha-gal), is a carbohydrate moiety found in red meats such as beef, pork and lamb and associated with a delayed IgE response, leading to urticaria and/oranaphylaxis. Alpha Gal specific IgE is believed to be responsible for cross reactive allergies to beef, pork and lamb, but little data exists showing the cross reactivity of Alpha Gal and other non-primate mammalian meats such as rabbit and veal. METHODS: De-identified serum samples from Alpha Gal positive(n515) and negative (n515) patients were tested for IgE reactivity withbeef, pork, lamb, rabbit, veal, and chicken (as a negative control). Data was compiled into groups based on a cutoff of 0.1 kU/L as a positive test. RESULTS: Thirteen percent of Alpha Gal negative samples contained IgE antibodies against at least one red meat. In the alpha gal positive subset, 13 percent of samples were negative to veal, and 20 percent were negative to rabbit. However none were negative for beef, pork, or lamb. Twelve percent of beef IgE positive samples were negative for IgE to veal. CONCLUSIONS: Analysis of results testing for red meat and Alpha Galreactive IgE revealed that a large portion of samples contained antibodies to both red meats and Alpha Gal, supporting the inter-related nature of these allergies and the need for complete testing to identify source(s). Interestingly, there was not complete agreement between veal and beef positivity indicating there may be different allergens present in the various meat preparations. |
Journal of Allergy and Clinical Immunology. 2014 Feb 1;133(2):AB112. | diagnosis; testing |
| Flebbe-Rehwaldt L, Wells H, Hester J, Altrich M. | 2013 | ALPHA GAL ALLERGY AND CROSS-REACTIVE RED MEAT ALLERGY: ANALYSIS OF CLINICAL DATA. Introduction: Galactose-alpha-1,3-galactose (alpha-gal), is a cross-reactive carbohydrate moiety found in red meats such as beef, pork and lamb and is associated with a delayed IgE response, leading to urticaria and/or anaphylaxis. Methods: A retrospective review of national laboratory data was performed over eighteen months of the testing for IgE to Beef, Pork, Lamb, and Alpha Gal utilizing data with de-identified patient health information. Data was compiled into groups based on a cutoff of 0.1 kU/L as a positive test. Results: Thirty two percent of samples contained IgE antibodies against all 4 allergens, while 53 percent contained no detectable antibodies to any of the 4 allergens. Seven percent of samples were positive for at least one red meat (beef, pork, and/or lamb) but were negative for Alpha Gal. An additional 2 percent of samples were positive for IgE recognizing all three red meats but were negative for IgE to Alpha Gal. Interestingly, 4 percent of samples were positive for low levels (<1kU/L) of Alpha Gal IgE, but negative for IgE recognizing any of the three meats. Conclusions: Analysis of results testing for red meat and Alpha Gal reactive IgE revealed that a large portion of samples contained antibodies to both red meats and alpha gal, supporting the inter-related nature of these allergies. Surprisingly, 4 percent of samples were positive for Alpha Gal (albeit low levels) and negative to all three red meats. This suggests that the level of alpha gal contained in commercial products testing for red meat IgE are not sufficient to detect Alpha Gal IgE when present in low levels. Additionally a small portion of samples were negative for Alpha Gal reactive IgE, but positive for IgE recognizing some or all of the red meats. This indicates there are IgE antibodies that bind meat proteins and not the Alpha Gal carbohydrate, thus testing to red meat and Alpha Gal is important to gain a complete clinical picture. Further analysis may reveal if certain demographics (age or sex) contribute to this population of samples. |
Annals of Allergy, Asthma & Immunology. 2013; 111(5): A99-A99. | |
| Flebbe-Rehwaldt L, Wells H, Roberts S, Walters P, Ling M, Brockus C, Halsey JF, James H, Commins S, Platts-Mills T, Altrich M. | 2011 | An Immunoassay to Measure IgE to Galactose alpha 1,3 Galactose Associated with Red Meat Allergies. RATIONALE: IgE antibodies specific for the galactose-a-1,3 galactose (Alpha-Gal) carbohydrate found on non-primate mammalian proteins have recently been linked to delayed hypersensitivity reactions following the consumption of these proteins. IgE-mediated hypersensitivity to Alpha-Gal typically develops in adults who have had no previous sensitivity to meat. METHODS: This assay is a solid phase immunoassay that measures the concentration of IgE specific for Alpha-Gal in human serum. Specimens analyzed were de-identified discard sera from an immunology laboratory. RESULTS: The assay for Alpha-Gal specific IgE proved to be highly reproducible and specific. The useful analytical range is 0.1kU/L to 100kU/L and the reference range is <0.35kU/L. The coefficients of variation for intra- and inter-assay precision were < 2.5% and 8.5%, respectively. Among adult serum samples randomly selected from specimens positive for IgE specific for beef, pork and/or lamb, 50% tested positive for Alpha-Gal specific IgE. In contrast, no sera from patients under the age of 10 years with IgE specific for beef, pork and/or lamb tested positive for Alpha-Gal specific IgE. CONCLUSIONS: IgE antibodies specific for Alpha-Gal can be detected and accurately quantified by this immunoassay. Since the assay has been released approximately two thirds of the samples submitted for clinical testing have been positive for Alpha-Gal specific IgE. This test will more specifically identify the etiology of allergic responses to meat allergens in patients, information that may be critical for effective clinical management of a patient. |
Journal of Allergy and Clinical Immunology. 2011 Feb 1;127(2):AB185. | |
| Fong A, Schuyler AJ, Platts-Mills TA, Becker A. | 2015 | Rapid Onset Anaphylaxis to Red Meat in Three Siblings from Uganda. RATIONALE: IgE to galactose-a1,3-galactose(‘‘alpha-gal’’) is associated with delayed onset anaphylaxis and has been measured in sub-Saharan Africa, but without reports of anaphylaxis. We present three siblings with rapid onset anaphylaxis to red meat while in a Uganda refugee camp. METHODS: Commercial extracts, raw and cooked meats were used for SPT. Allergen specific IgE (sIgE) was measured to foods, alpha-gal, cat, Fel d 1, Fel d 2 and parasites. Alpha-gal was then absorbed with beef thyroglobulin conjugated to sepharose beads. RESULTS: The siblings developed anaphylaxis within an hour of consuming goat, beef or pork. SPT for all siblings was positive to commercial beef, pork; raw beef, goat; cooked beef, and cat. Sibling 3 SPT was also positive to cooked goat. sIgE for all siblings was positive to alpha-gal (5.62; 8.38; 6.70 KU/L), beef (4.82; 6.72; 7.00 KU/L), pork (4.60; 5.86; 6.46 KU/L), cow’s milk (3.02; 4.38; 5.26 KU/L), cat (1.62; 2.58; 3.92 KU/L) and echinococcus (2.02; 3.26; 5.04 KU/L). Pork albumin, Fel d 1, Fel d 2, ascaris, and anisakis sIgE were negative. Goat sIgE was not available. After depletion of alpha-gal from the sera, beef, pork, cow’s milk, cat and echinococcus sIgE were negative. The siblings consume chicken, fish and cow’s milk. There is no clear history of tick bites. CONCLUSIONS: To the best of our knowledge, these are the first reported cases of red meat anaphylaxis from Africa. The early onset of their symptoms may indicate another sp |
Journal of Allergy and Clinical Immunology. 2015 Feb 1;135(2):AB206. | Africa; Uganda; prevalence |
| Fournier PE, Thuny F, Grisoli D, Lepidi H, Vitte J, Casalta JP, Weiller PJ, Habib G, Raoult D | 2011 | A deadly aversion to pork. On August 3, 2006, a 53-year-old man with penicillin allergy presented with afebrile blood-culture-negative endocarditis (BCNE). He lived in an urban area near Marseille and had never travelled abroad. He did not report any specific food allergies. 4 months earlier, he had had a mitral valve replacement with a bioprosthetic valve (porcine Hancok II, Medtronic, Minneapolis, USA). Transoesophageal echocardiography identified vegetation on the bioprosthesis. Although blood cultures and serological test results were negative, empirical anti-staphylococcal therapy was started. The vegetation increased in size and caused valvular obstruction, necessitating a replacement with the same type of Hancok II valve. Our patient experienced two further relapses of afebrile BCNE necessitating mitral valve replacements, with Hancok II bioprostheses, in October and December, 2006. In June, 2007, he had a third relapse and died. Each removed valve showed inflammatory infiltrates and a vegetation, which led to diagnoses of endocarditis. At each episode, we tested blood samples and the removed valves using a comprehensive diagnostic procedure previously reported to identify the aetiology of BCNE. 1 In each episode, all test results were negative. |
The Lancet. 2011 Apr 30;377(9776):1542. | cardiology; cardiac surgery; bioprosthetic heart valve |
| Fowler PD, Nguyentran S, Quatroche L, Porter ML, Kobbekaduwa V, Tippin S, Miller G, Dinh E, Foster E, Tsao JI. | 2022 | Northward Expansion of Amblyomma americanum (Acari: Ixodidae) into Southern Michigan. Amblyomma americanum (Linnaeus) (Acari: Ixodidae) (lone star tick) is an aggressive, generalist parasite that vectors numerous important human and animal pathogens. In recent decades its geographic range has been expanding northwards from endemic regions in the southeastern and southcentral US. In 2019 five questing A. americanum comprising two life stages were detected at one site in Berrien County, in southwestern Michigan, satisfying one CDC criterium for an established population for the first time in the state. To better characterize the northern extent of emerging A. americanum, we conducted active surveillance (i.e., drag sampling) in summer 2020 throughout Michigan’s southern counties and detected one adult A. americanum from each of six widespread sites, including where they had been detected in 2019. A larger established population was identified at another site in Berrien County, which yielded 691 A. americanum comprising three life stages. Questing tick phenologies at this site were similar to that reported for other regions. Statewide surveillance in 2021 revealed no A. americanum outside of Berrien County, but establishment criteria were met again at the two sites where established populations were first detected respectively in 2019 and 2020. These observations may represent the initial successful invasion of A. americanum into Michigan. Data from passive (1999-2020) and active surveillance (2004-2021) efforts, including a domestic animal sentinel program (2015-2018), are reported to provide context for this nascent invasion. Continued active surveillance is needed to help inform the public, medical professionals, and public health officials of the health risks associated with this vector. |
bioRxiv. 2022 Jan 1:2021-12. | vector; tick; Amblyomma americanum; lone star tick; tick distribution; geography; range |
| Foy AB, Giannini C, Raffel C. | 2008 | Allergic reaction to a bovine dural substitute following spinal cord untethering: Case report. Bovine tissues are now routinely used for dural closure in cranial and spinal surgery. The authors report the case of an 18-year-old woman with a history of myelomeningocele who had symptoms of tethered cord syndrome and presented to a regional hospital. At that hospital she underwent a cord untethering procedure. The spinal dura was closed with Durepair, a dural substitute derived from fetal bovine skin. Her postoperative course was complicated by a cerebrospinal fluid leak that was surgically repaired. Following this, she developed erythroderma, intermittent fevers, eosinophilia, and marked elevation in serum immunoglobulin E. She was then transferred to the authors' institution. A skin antigen test to beef was administered, which revealed a positive reaction. A radioallergosorbent test to beef also yielded positive results. She was taken to the operating room for removal of the bovine graft due to concern for an allergic reaction to the graft. The graft material showed evidence of eosinophilic infiltration. Her clinical symptoms and laboratory values all improved after surgery. To the authors' knowledge this is the first reported case of an allergic reaction to bovine-based dural substitutes. |
Journal of Neurosurgery: Pediatrics. 2008 Feb 1;1(2):167-9. | Pharmacy; perioperative; surgery; neurosurgery; bovine tissue; Durepair |
| Franks MD AM, Murphy BS M, Griffis MD M, Franks BA, CWR R, Franks CM, Petty MD G | 2021 | Alpha-Gal Allergy: a new threat to Appalachia. Alpha-gal allergy, or mammalian meat allergy, is described as the development of IgE antibodies to the oligosaccharide galactose-a-1,3-galactose following a bite from the tick species Amblyomma americanum (Lone Star tick) or Dermacentor variabilis (Wood tick). Dermatologic or gastrointestinal symptoms are usually delayed by four to six hours after exposure, making the diagnosis difficult. Due to the use of mammalian proteins in many common medications, surgical equipment, and prosthesis, unexpected reactions can occur. In the United States, this pathology is predominately seen in the southeast but has been associated with other tick species on every continent except Antarctica. As the habitat for Amblyomma and Dermacentor continues to move further north due to changing patterns in deer population and weather, the incidence of alpha-gal syndrome has increased in the states outside its normal southeastern locale, especially in people with occupations and hobbies that require time outdoors in wooded areas. |
Marshall Journal of Medicine. 2021;7(4):2. | Appalachia; West Virginia |
| Fuertes LV, Bustamante MP, Fernandez AB, Pino AG, De La Losa FP. | 2013 | A case of eosinophilic esophagitis, with sensitization to BSA (meat allergy) and rhinoconjunctivitis due to dog epithelium. Background: Patients with eosinophilic esophagitis (EEo) have a prior history of atopy. Skin prick test(SPT) is able to identify the allergens involved, allowing a correct dietary approach, in order to achieve the remission of sympthoms and discontinue swallowed costicostheroids. Allergy to bovine meat and especially to Bovine serum albumin (BSA) is exceptional in adult life, but can be a cause of EEo. Methods: We present one 26-year-old patient with EEo diagnosed six months before, who presented characteristic sympthoms after eating mamal´s meat (well cooked beef and pork), and legumes (chickpea), as food impactation. She had history of rhinitis, related to sensitization to dog epithelium. The patient underwent SPT, specific IgE detection and SDS-PAGE immunoblotting studies. Results: The SPT with food allergens showed negative responses to pork, cow, rabbit, lamb, chicken meat, milk, egg, legumes (including chickpea), nuts, fruits and vegetables, fish, seafood, cereals. It showed positive result to BSA. The SPT with aeroallergens showed negative responses to all we studied, but dog epithelium that was positive. The determination of specific IgE were negative to beef and pig meat,milk,egg, legumes, nuts, cereals. The result was positive to dog epithelium (17.1 ku/l CAP), dog BSA (8.03 ku/l), cow BSA (0.51 ku/l). Total IgE 214UI/l.IgE-Immunoblotting indicates recognition bands of 60-70 kDa components (molecular weight compatible with BSA) in dog epithelium extract, and less intensity response in meat extracts. Two allergens with a molecular weight close to 15-20 kDa were recognized. We found reactivity to 40-45 KDa allergens in meat extract also. Conclusion: We report a case of EEo, who had sensitization to BSA and dog epithelium. The patient suffered previous rhinoconjunctivitis related to her dog, but we could not demonstrate cross-reactivity. It is suggested a potential inciting role for aeroallergens in patient with EEo, and the subsequent food allergy. BSA is an approximately 67 KDa protein involved both in milk (especially in children) and beef allergy. It explains cross-reactivity among different meats and epitheliums and different mammal´s meat. In our case, the patient´s serum recognized a protein with a molecular weight of 17 kDa, that could correspond to myoglobin, a heat-resistant protein that explains why some patients do not tolerate undercooked or even cooked meat. Thank our study, the patient could discontinue swallowed corticosteroids and avoidance diet, but meats. |
Clinical and Translational Allergy. 2013 Jul 1;3(S3):P166. | eosinophilic easaphagitis; BSA |
| Fujiwara M, Arak T. | 2019 | Immediate anaphylaxis due to beef intestine following tick bites. Letter to the Editor: Red meat allergy induces delayed anaphylaxis 3e6 h after ingestion of mammalian meat. Such delayed anaphylaxis is associated with immunoglobulin E (IgE) antibodies to galactose-alpha-1,3-galactose (a-Gal), a carbohydrate epitope contained in both mammalian meat and tick saliva. In addition, it has been reported that Japanese patients with red meat allergy often experience an allergic reaction after ingesting flounder roe. By contrast, an immediate reaction to mammalian organ meat in patients with red meat allergy is not well-reported in the literature. Here we report a case of red meat allergy in which the individual received tick bites followed by episodes of immediate anaphylaxis that developed after ingesting beef intestine and flounder roe. |
Allergology International. 2019;68(1):127-9. | Asia; Japan; diet; foods; organ meats; intestine; fish eggs; flounder eggs |
| Fukunaga T, Tanaka N, Furumoto T, Nakakita S, Ohashi T, Higuchi Y, Maekawa H, Takegawa K. | 2021 | Substrate specificities of α1, 2-and α1, 3-galactosyltransferases and characterization of Gmh1p and Otg1p in Schizosaccharomyces pombe. In the fission yeast Schizosaccharomyces pombe, α1,2- and α1,3-linked D-galactose (Gal) residues are transferred to N- and O-linked oligosaccharides of glycoproteins by galactosyltransferases. Although the galactomannans are important for cell–cell communication in S. pombe (e.g., in nonsexual aggregation), the mechanisms underlying galactosylation in cells remain unclear. Schizosaccharomyces pombe has 10 galactosyltransferase-related genes: seven belonging to glycosyltransferase (GT) family 34 and three belonging GT family 8. Disruption of all 10 α-galactosyltransferases (strain Δ10GalT) has been shown to result in a complete lack of α-Gal residues. Here, we have investigated the function and substrate specificities of galactosyltransferases in S pombe by using strains expressing single α-galactosyltransferases in the Δ10GalT background. High-performance liquid chromatography (HPLC) analysis of pyridylaminated O-linked oligosaccharides showed that two GT family 34 α1,2-galactosyltransferases (Gma12p and Gmh6p) and two GT family 8 α1,3-galactosyltransferases (Otg2p and Otg3p) are involved in galactosylation of O-linked oligosaccharide. Moreover, 1H-NMR of N-glycans revealed that three GT family 34 α1,2-galactosyltransferases (Gmh1p, Gmh2p and Gmh3p) are required for the galactosylation of N-linked oligosaccharides. Furthermore, HPLC and lectin-blot analysis revealed that Otg1p showed α1,3-galactosyltransferase activity under conditions of co-expression with Gmh6p, indicating that α-1,2-linked galactose is required for the galactosylation activity of Otg1p in S. pombe. In conclusion, eight galactosyltransferases have been shown to have activity in S. pombe with different substrate specificities. These findings will be useful for genetically tailoring the galactosylation of both N- and O-glycans in fission yeast. |
Glycobiology. 2021 Apr 28. | Fungus; yeast; Schizosaccharomyces; brewing; traditional beer; alcohol |
| Gaines DN, Operario DJ, Stroup S, Stromdahl E, Wright C, Gaff H, Broyhill J, Smith J, Norris DE, Henning T, Lucas A. | 2014 | Ehrlichia and spotted fever group Rickettsiae surveillance in Amblyomma americanum in Virginia through use of a novel six-plex real-time PCR assay. The population of the lone star tick Amblyomma americanum has expanded in North America over the last several decades. It is known to be an aggressive and nondiscriminatory biter and is by far the most common human-biting tick encountered in Virginia. Few studies of human pathogen prevalence in ticks have been conducted in our state since the mid-twentieth century. We developed a six-plex real-time PCR assay to detect three Ehrlichia species (E. chaffeensis, E. ewingii, and Panola Mountain Ehrlichia) and three spotted fever group Rickettsiae (SFGR; R. amblyommii, R. parkeri, and R. rickettsii) and used it to test A. americanum from around the state. Our studies revealed a presence of all three Ehrlichia species (0–24.5%) and a high prevalence (50–80%) of R. amblyommii, a presumptively nonpathogenic SFGR, in all regions surveyed. R. parkeri, previously only detected in Virginia's Amblyomma maculatum ticks, was found in A. americanum in several surveyed areas within two regions having established A. maculatum populations. R. rickettsii was not found in any sample tested. Our study provides the first state-wide screening of A. americanum ticks in recent history and indicates that human exposure to R. amblyommii and to Ehrlichiae may be common. The high prevalence of R. amblyommii, serological cross-reactivity of all SFGR members, and the apparent rarity of R. rickettsii in human biting ticks across the eastern United States suggest that clinical cases of tick-borne disease, including ehrlichiosis, may be commonly misdiagnosed as Rocky Mountain spotted fever, and that suspicion of other SFGR as well as Ehrlichia should be increased. These data may be of relevance to other regions where A. americanum is prevalent. |
Vector-Borne and Zoonotic Diseases. 2014 May 1;14(5):307-16. | Tick-borne disease; ehrichia; rickettsiae; lone star tick; amblyomma |
| Galili U | 2021 | Biosynthesis of α-Gal Epitopes (Galα1-3Galβ1-4GlcNAc-R) and Their Unique Potential in Future α-Gal Therapies The α-gal epitope is a carbohydrate antigen which appeared early in mammalian evolution and is synthesized in large amounts by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) in non-primate mammals, lemurs, and New-World monkeys. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent complete extinction 20–30 million years ago, and their mutated progeny lacking α-gal epitopes survived. Humans, apes, and Old-World monkeys which evolved from the surviving progeny lack α-gal epitopes and produce the natural anti-Gal antibody which binds specifically to α-gal epitopes. Because of this reciprocal distribution of the α-gal epitope and anti-Gal in mammals, transplantation of organs from non-primate mammals (e.g., pig xenografts) into Old-World monkeys or humans results in hyperacute rejection following anti-Gal binding to α-gal epitopes on xenograft cells. The in vivo immunocomplexing between anti-Gal and α-gal epitopes on molecules, pathogens, cells, or nanoparticles may be harnessed for development of novel immunotherapies (referred to as “α-gal therapies”) in various clinical settings because such immune complexes induce several beneficial immune processes. These immune processes include localized activation of the complement system which can destroy pathogens and generate chemotactic peptides that recruit antigen-presenting cells (APCs) such as macrophages and dendritic cells, targeting of antigens presenting α-gal epitopes for extensive uptake by APCs, and activation of recruited macrophages into pro-reparative macrophages. Some of the suggested α-gal therapies associated with these immune processes are as follows: 1. Increasing efficacy of enveloped-virus vaccines by synthesizing α-gal epitopes on vaccinating inactivated viruses, thereby targeting them for extensive uptake by APCs. 2. Conversion of autologous tumors into antitumor vaccines by expression of α-gal epitopes on tumor cell membranes. 3. Accelerating healing of external and internal injuries by α-gal nanoparticles which decrease the healing time and diminish scar formation. 4. Increasing anti-Gal–mediated protection against zoonotic viruses presenting α-gal epitopes and against protozoa, such as Trypanosoma, Leishmania, and Plasmodium, by vaccination for elevating production of the anti-Gal antibody. The efficacy and safety of these therapies were demonstrated in transgenic mice and pigs lacking α-gal epitopes and producing anti-Gal, raising the possibility that these α-gal therapies may be considered for further evaluation in clinical trials. |
Front. Mol. Biosci. 2021 Nov 4; 8:746-83. | Anti-gal |
| Galili U, Anaraki F, Thall A, Hill-Black C, Radic M. | 2011 | One percent of human B lymphocytes are capable of producing the natural anti-Gal antibody. The natural anti-Gal antibody constitutes 1% of circulating IgG in humans and interacts specifically with the carbohydrate epitope Gal alpha 1-3Gal beta 1-4GlcNAc-R (the alpha-galactosyl epitope). In view of the unusually large amounts of this antibody in the serum, it was of interest to determine the proportion of circulating B lymphocytes capable of synthesizing anti-Gal. For this purpose, blood B lymphocytes were incubated with Epstein-Barr virus (EBV) and plated in microtiter wells. Proliferation of the EBV transformed B lymphocytes was readily visible after 3 weeks of incubation. The supernatants from wells containing proliferating B-lymphoid clones were assayed for anti-Gal by an agglutination assay with rabbit red blood cells and the specificity of the agglutinating antibodies was further confirmed by their interaction with synthetic oligosaccharides and by enzyme-linked immunosorbent assay with glycoproteins. Approximately 5% of the wells contained anti-Gal antibodies. Limiting dilution studies and IgH gene rearrangement patterns suggested that each well contained an average of five proliferating B-lymphoid clones. Thus, it is concluded that approximately 1% of circulating B lymphocytes are capable of producing anti-Gal. The proportion of anti-Gal--producing lymphoid clones exceeds by fourfold that of clones producing anti-blood group A or anti-blood group B antibodies. Individual anti-Gal clones display fine variations in their combining site, as indicated by their differential interaction with alpha-galactosyl epitopes on glycolipids and on N-linked carbohydrate chains of glycoproteins. The high frequency of precursor B lymphocytes capable of producing anti-Gal, found in every individual and the restricted specificity of this antibody to alpha-galactosyl epitopes, potentially makes anti-Gal--producing lymphocytes an effective system for studying human Ig genes involved in the natural immune response to structurally defined haptens. |
Blood. 2011 Jul 14. | |
| Galili U, Avila JL, editors. | 2012 | α–Gal and Anti–Gal: α1, 3–Galactosyltransferase, α–Gal Epitopes, and the Natural Anti–Gal Antibody Subcellular Biochemistry (Subcellular Chemistry Vol. 32) [BOOK] From Amazon.com: This is an interdisciplinary book which for the first time assembles the wide spectrum of information on the basic and clinical aspects of the natural anti-Gal antibody, the alpha-gal epitope and the enzyme producing it, alpha-1,3-galactosyltransferase. Anti-Gal is the most abundant antibody in humans, apes and Old World monkeys (monkeys of Asia and Africa). It binds specifically to the alpha-gal epitope (Galalpha1-3Galbeta1-4GlcNAc-R) on glycoproteins and glycolipids. Humans, apes and Old World monkeys lack alpha-gal epitopes. In contrast, the alpha-gal epitope is produced in large amounts on cells of nonprimate mammals prosimians and New World monkeys (monkeys of South America), by the glycosylation enzyme alpha-1,3-galactosyltransferase. This differential distribution of the alpha-gal epitope and anti-Gal in mammals is the result of an evolutionary selective process which led to the inactivation of alpha-1,3-galactosyltransferase in ancestral Old World primates. A direct outcome of this event is the present rejection of xenografts such as pig organs in humans and monkeys because of the binding of human anti-Gal to alpha-gal epitopes on pig cells. The various chapters in this book were contributed by researchers studying basic and clinically related aspects of this area. The book aims to provide comprehensive and updated information on this antigen/antibody system, which at present is the major obstacle in xenotransplantation, and on some of the genetic engineering approaches developed for overcoming this obstacle. In addition, this book describes the significance of anti-Gal and alpha-gal epitopes in some parasitic, bacterial and viral infections, as well as in the pathogenesis of autoimmune diseases such as Graves' disease. Finally, this book describes novel approaches for exploiting the natural anti-Gal antibody for increasing immunogenicity of cancer and viral vaccines in humans. This book is edited and partly written by Dr. Uri Galili who originally discovered anti-Gal and the unique evolution of &agr;-1,3-galactosyltransferase, and by Dr. Jose-Luis Avila who has been studying anti-Gal significance in Chagas' disease and in Leishmania infections. This book covers the main areas of research on &agr;-1,3galactosyltransferase, its product the &agr;-gal epitope (Gal&agr;1-3Gal&bgr;1-4GlcNAc-R) and the natural anti-Gal antibody that interacts with this epitope. The book includes chapters on: The evolution of &agr;-1,3 galactosyltransferase in mammals; the structure of the &agr;-1,3galactosyltransferase gene; the structure function relationship of the &agr; 1,3galactosyltransferase enzyme; the molecular characteristics of &agr;-gal epitopes on glycolipids and glycoproteins and methods for its detection; the natural anti-Gal antibody and its significance in xenotransplantation; attempts to prevent xenograft rejection by elimination of &agr;-1,3galactosyltransferase gene, and by modulating &agr;-gal epitope expression and anti-Gal activity; significance of anti-Gal and &agr;-gal epitopes in viral, bacterial and protozoal infections; and the possible clinical exploitation of anti-Gal for the enhancement of cancer and viral vaccine immunogenicity. |
Springer Science & Business Media; 2012 Dec 6. | |
| Galili U, Clark MR, Shohet SB, Buehler J, Macher BA. | 1987 | Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1----3Gal epitope in primates. Anti-Gal is a natural antibody, which constitutes as much as 1% of circulating IgG in humans and displays a distinct specificity for the structure Gal alpha 1----3Gal. This glycosidic structure has been found on various tissues of many nonprimate mammals. A comparative study of the occurrence of anti-Gal versus the expression of the Gal alpha 1----3Gal epitope was performed in primates, and a distinct evolutionary pattern was observed. Whereas anti-Gal was found to be present in Old World monkeys and apes in titers comparable to those in humans, its corresponding antigenic epitope is abundantly expressed on erythrocytes of New World monkeys. Immunostaining with anti-Gal of glycolipids from New World monkey erythrocytes indicated that the molecules to which anti-Gal binds are similar to those found in rabbit and bovine erythrocytes. These findings indicate that there is an evolutionary reciprocity between New World and Old World primates in the production of the Gal alpha 1----3Gal structure and the antibody that recognizes it. The expression of the Gal alpha 1----3Gal epitope was evolutionarily conserved in New World monkeys, but it was suppressed in ancestral lineages of Old World primates. The suppression of this epitope was accompanied by the production of anti-Gal. The observed in vivo binding of anti-Gal to human normal senescent and some pathologic erythrocytes implies that the Gal alpha 1----3Gal epitope is present in man in a cryptic form. |
Proceedings of the National Academy of Sciences. 1987 Mar 1;84(5):1369-73. | |
| Galili U, Ishida H, Tanabe K, Toma H. | 2002 | Anti-gal A/B, a novel anti-blood group antibody identified in recipients of abo-incompatible kidney allografts1. Background: The most prevalent anticarbohydrate antibodies in human serum are anti-Gal interacting specifically with the α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) and anti-blood group antibodies interacting with blood group A and B antigens. The α-gal epitope, although absent in humans, comprises part of the core of carbohydrate chain in A and B antigens. Therefore, it was of interest to determine whether immunoglobulin (Ig) G antibodies, elicited in patients rejecting ABO-incompatible kidney allografts, can interact with the α-gal epitope. Methods: Anti-A and anti-B antibodies were determined by enzyme-linked immunosorbent assay (ELISA) with blood group A or B human red cell membranes, as solid phase antigens. Anti-Gal was determined by ELISA with α-gal–bovine serum albumin as solid-phase antigen. Specific removal of anti-Gal was performed by adsorption on fixed rabbit red cells. Results: Blood group O patients who underwent transplantation with either A or B kidney produced an antibody that bound to all three carbohydrate antigens. This multispecific antibody, designated anti-Gal A/B, is specific to the core α-gal epitope within A and B antigens. Recipients of allograft expressing incompatible blood group B also produce anti-Gal B antibody, which binds to the core α-gal epitope only in the B antigen. Anti-Gal A/B and anti-Gal B constitute most of the elicited anti-blood group antibody response. Allograft recipients also produced pure anti-A, or pure anti-B, which require the complete blood group structure for binding. Conclusions: The findings in this study imply that much of the immune response elicited by incompatible A or B antigens on kidney allografts results in activation of anti-Gal B-cell clones producing antibodies to the core α-gal epitope in these blood group antigens. Only less than 25% of the elicited antibodies interact with the complete A or B antigens (i.e., pure anti-A or pure anti-B). These findings suggest that prevention of the anti-Gal response may decrease the immune rejection of ABO-incompatible allografts. |
Transplantation. 2002 Dec 15;74(11):1574-80. | |
| Galili U, Shohet SB, Kobrin E, Stults CL, Macher BA. | 1988 | Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. The study of the expression of alpha-galactosyl epitopes on various mammalian cells is of particular interest, since as much as 1% of circulating IgG antibodies in humans interact with this carbohydrate residue. This natural antibody, designated "anti-Gal," was previously found to bind to terminal Gal alpha 1----3Gal beta 1----4GlcNAc-R on biochemically defined glycolipids (Galili, U., Macher, B. A., Buehler, J., and Shohet, S. B. (1985) J. Exp. Med. 162, 573-582; Galili, U., Buehler, J., Shohet, S. B., and Macher, B. A. (1987) J. Exp. Med. 165, 693-704). The expression of anti-Gal binding epitopes on nucleated cells from various mammalian species was studied by immunostaining with this antibody. The binding of anti-Gal to various cells was correlated with the binding of the lectin Bandeiraea (Griffonia) simplicifolia IB4 (BS lectin). The BS lectin also interacts with alpha-galactosyl residues and particularly with high affinity with Gal alpha 1----3Gal beta 1----4GlcNAc residues. We observed a striking evolutionary pattern in the expression of these epitopes on mammalian nucleated cells. Fibroblasts, epithelial cells, endothelial cells, smooth muscle cells, and lymphoid cells of nonprimate mammals, prosimians, and New World monkeys readily bound both anti-Gal and BS lectin. However, no such binding was detectable on cells of Old World monkeys, apes, and humans. Measurment of the binding of radiolabeled BS lectin to the various nucleated cells suggests that cells binding anti-Gal express 10(6) to 3.5 x 10(7) alpha-galactosyl epitopes, most of which, based on the anti-Gal specificity, seem to have the structure of Gal alpha 1----3Gal beta 1----4GlcNAc-R. The absence of these epitopes from human cells results from diminished activity of the enzyme alpha 1----3 galactosyltransferase, which catalyzes the following reaction. Gal beta 1----4GlcNAc-R + UDP-Gal(alpha 1----3-galactosyltransferase)----Gal alpha 1----3Gal beta 1----4GlcNAc-R + UDP This enzyme, which participates in the glycosylation of cell membrane glycoconjugates in nonprimate mammals, prosimians, and New World monkeys, appears to have been suppressed in Old World primates as a result of evolutionary events which occurred 20-30 million years ago. It is argued that an anomalous activity of this enzyme in man may result in initiation of autoimmune diseases because of the de novo expression of Gal alpha 1----3Gal beta 1----4GlcNAc-R epitopes recognized by anti-Gal. |
Journal of Biological Chemistry. 1988 Nov 25;263(33):17755-62. | |
| Galili U, Shohet SB, Kobrin E, Stults CL, Macher BA. | 1988 | Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. The study of the expression of alpha-galactosyl epitopes on various mammalian cells is of particular interest, since as much as 1% of circulating IgG antibodies in humans interact with this carbohydrate residue. This natural antibody, designated "anti-Gal," was previously found to bind to terminal Gal alpha 1----3Gal beta 1----4GlcNAc-R on biochemically defined glycolipids (Galili, U., Macher, B. A., Buehler, J., and Shohet, S. B. (1985) J. Exp. Med. 162, 573-582; Galili, U., Buehler, J., Shohet, S. B., and Macher, B. A. (1987) J. Exp. Med. 165, 693-704). The expression of anti-Gal binding epitopes on nucleated cells from various mammalian species was studied by immunostaining with this antibody. The binding of anti-Gal to various cells was correlated with the binding of the lectin Bandeiraea (Griffonia) simplicifolia IB4 (BS lectin). The BS lectin also interacts with alpha-galactosyl residues and particularly with high affinity with Gal alpha 1----3Gal beta 1----4GlcNAc residues. We observed a striking evolutionary pattern in the expression of these epitopes on mammalian nucleated cells. Fibroblasts, epithelial cells, endothelial cells, smooth muscle cells, and lymphoid cells of nonprimate mammals, prosimians, and New World monkeys readily bound both anti-Gal and BS lectin. However, no such binding was detectable on cells of Old World monkeys, apes, and humans. Measurment of the binding of radiolabeled BS lectin to the various nucleated cells suggests that cells binding anti-Gal express 10(6) to 3.5 x 10(7) alpha-galactosyl epitopes, most of which, based on the anti-Gal specificity, seem to have the structure of Gal alpha 1----3Gal beta 1----4GlcNAc-R. The absence of these epitopes from human cells results from diminished activity of the enzyme alpha 1----3 galactosyltransferase, which catalyzes the following reaction. Gal beta 1----4GlcNAc-R + UDP-Gal(alpha 1----3-galactosyltransferase)----Gal alpha 1----3Gal beta 1----4GlcNAc-R + UDP This enzyme, which participates in the glycosylation of cell membrane glycoconjugates in nonprimate mammals, prosimians, and New World monkeys, appears to have been suppressed in Old World primates as a result of evolutionary events which occurred 20-30 million years ago. It is argued that an anomalous activity of this enzyme in man may result in initiation of autoimmune diseases because of the de novo expression of Gal alpha 1----3Gal beta 1----4GlcNAc-R epitopes recognized by anti-Gal. |
Journal of Biological Chemistry. 1988 Nov 25;263(33):17755-62. | |
| Galili U. | 2018 | Why Do We Produce Anti-Gal: Evolutionary Appearance of Anti-Gal in Old World Primates. The natural anti-Gal antibody is one of the multiple natural anti-carbohydrate antibodies produced in humans against a wide range of carbohydrate antigens on GI bacteria. The antibody is unique to humans, apes, and Old World monkeys, and it binds specifically to a mammalian carbohydrate antigen called the α-gal epitope that is synthesized in nonprimate mammals, lemurs (prosimians) and New World monkeys by the glycosylation enzyme α1,3GT. The α1,3GT gene (GGTA1) appeared in mammals >100 million years ago, prior to the split between marsupial and placental mammals. This gene has been conserved in its active form, in all mammals, except for Old World monkeys, apes, and humans. Inactivation of the α1,3GT gene in ancestral Old World primates occurred 20–30 million years ago and could have been associated with epidemics of enveloped viruses in the Eurasia-Africa continent. It is suggested that prior to such epidemics, few ancestral Old World primates acquired deletion point mutations that inactivated the α1,3GT gene and eliminated α-gal epitopes. This resulted in loss of immune tolerance to the α-gal epitope and thus, in production of the anti-Gal antibody against antigens on bacteria colonizing the GI tract. This accidental inactivation of the α1,3GT gene in very small populations is analogous to the highly rare blood type “Bombay” individuals who do not synthesize blood group H (O antigen) because of inactivation of the α1,2-fucosyltransferase gene. The loss of immune tolerance to blood group H antigen has resulted in production of natural anti-blood group H antibodies in the blood group Bombay individuals. It is suggested that anti-Gal protected against infections by enveloped viruses presenting α-gal epitopes, which were lethal to the parental primate populations that conserved active α1,3GT and thus, synthesized α-gal epitopes. Alternative causes for the elimination of Old World primates synthesizing α-gal epitopes could be bacteria or protozoa parasites presenting α-gal or α-gal-like epitopes, and bacterial toxins, or detrimental viruses that used α-gal epitopes in these primates as “docking receptors.” Ultimately, any of these proposed selective processes could result in extinction of Old World primates synthesizing α-gal epitopes on their cells. These ancestral primates were replaced by offspring populations lacking α-gal epitopes and producing the anti-Gal antibody, which continues to be produced by Old World monkeys, apes, and humans. New World monkeys and lemurs were protected from pathogens of the Old World by oceanic barriers, thus they continue to synthesize α-gal epitopes and lack the ability to produce the anti-Gal antibody. This scenario of few individuals in a large population having a mutation(s) that inactivates a glycosyltransferase gene thus, resulting in production of evolutionary advantageous natural antibodies against the eliminated carbohydrate antigen, may reflect one of the mechanisms inducing changes in the carbohydrate profile of various mammalian populations. |
The Natural Anti-Gal Antibody As Foe Turned Friend In Medicine. 2018:23. | anti-gal; evolution |
| Galili U. | 2018 | Evolution in primates by “Catastrophic‐selection” interplay between enveloped virus epidemics, mutated genes of enzymes synthesizing carbohydrate antigens, and natural anti‐carbohydrate antibodies. “Catastrophic‐selection” is an evolutionary mechanism, by which entire parental‐populations are eliminated but very few mutated offspring survive and replace extinct parental‐populations. The human natural anti‐carbohydrate antibodies, anti‐Gal and anti‐Neu5Gc suggest the occurrence of catastrophic‐selection events in primate evolution. Parental‐populations synthesizing corresponding carbohydrate‐antigens underwent extinction in viral epidemics, and few offspring survived. These offspring carried accidental mutations that inactivated carbohydrate‐antigen synthesis and produced natural‐antibody against the lost antigen. Such natural anti‐carbohydrate antibody was produced against environmental carbohydrate‐antigens (e.g., gastrointestinal bacteria). The carbohydrate‐antigen in infected parental‐populations was also synthesized on viruses by the host glycosylation‐machinery. The natural‐antibody in the offspring bound to the carbohydrate‐antigen on infecting viruses produced in parental‐populations, destroyed the viruses and protected these offspring from extinction. This process occurred in ancestral Old‐World monkeys and apes synthesizing α‐gal epitopes, which were replaced 20–30 million‐years‐ago by offspring lacking α‐gal epitopes and producing natural anti‐Gal antibody against this antigen, and later in hominins synthesizing the sialic‐acid antigen Neu5Gc, which were replaced by offspring lacking Neu5Gc and producing anti‐Neu5Gc antibody. A present‐day example for accidental mutations in very few humans that lost a common carbohydrate‐antigen and produce a natural antibody against it is the rare blood‐group “Bombay” individuals. These individuals lack the H‐antigen (blood‐group O) which is synthesized in all other humans, and produce the natural anti‐H antibody against blood‐group O. Overall, it is suggested that natural anti‐carbohydrate antibodies played a critical role in preventing complete extinction of mammalian species in epidemics of highly virulent viruses and may have similar role in future events. |
American Journal of Physical Anthropology. 2019 Feb;168(2):352-63. | evolution; |
| Galili U. | 1989 | Abnormal expression of α-galactosyl epitopes in man: a trigger for autoimmune processes?. 1% of circulating IgG in man is anti-Gal antibody, which interacts specifically with the carbohydrate structure Gal alpha 1----3Gal beta 1----4GlcNAc-R on mammalian glycoconjugates (described throughout as the alpha-galactosyl epitope). This epitope is abundant on cell surface glycoconjugates of non-primate mammals, prosimians, and New World monkeys. It is not found on cells of Old World monkeys, apes, and man because of diminished alpha 1----3 galactosyltransferase enzyme activity. However, the alpha 1----3 galactosyltransferase gene seems to be present within the human genome. A mechanism that increases alpha 1----3 galactosyltransferase activity in human cells could trigger an autoimmune process mediated by anti-Gal binding to the newly synthesised alpha-galactosyl epitopes. |
The Lancet. 1989 Aug 12;334(8659):358-61. | autoimmune disease |
| Galili U. | 1993 | Evolution and pathophysiology of the human natural anti-α-galactosyl IgG (anti-Gal) antibody Anti-Gal is a human natural antibody which interacts specifically with the mammalian carbohydrate structure Galα1-3Galβ1-4GlcNAc-R, termed, the α-galactosyl epitope. This antibody constitutes approximately 1% of circulating IgG in human serum and is produced, upon stimulation, by 1% of circulating B lymphocytes. Anti-Gal is also present as IgA antibodies in body secretions such as saliva, milk and colostrum. The antigenic source for the constant production of anti-Gal seems to be the α-galactosyl-like epitopes found on many bacteria of the gastrointestinal flora. Whereas anti-Gal is abundant in humans, apes and Old World monkeys, it is absent from New World monkeys, prosimians and nonprimate mammals. The latter group of species produces, however, large amounts of α-galactosyl epitopes (> 106 epitopes per cell). It is estimated that anti-Gal appeared in ancestral Old World primates less than 28 million years ago, possibly as a result of an evolutionary event which exerted a selective pressure for the suppression of α-galactosyl epitopes expression by inactivation of the gene for the enzyme α1,3 galactosyltransferase. This also resulted in the loss of immune tolerance to the α-galactosyl epitope and the production of anti-Gal. The physiologic role of this antibody is not clear as yet. It may participate in the protection against gastrointestinal bacteria. In addition it seems to contribute to the removal of normal and pathologically senescent red cells by interacting with the few hundred cryptic α-galactosyl epitopes which are exposed de novo in the course of red cell aging, thereby opsonizing these cells for phagocytosis by reticuloendothelial macrophages. The α-galactosyl epitope has been found to be aberrantly expressed on human cells and the interaction of anti-Gal with such epitopes may result in autoimmune disease. Preliminary data suggest such a mechanism in Graves' disease. Anti-Gal has been found to interact with therapeutic recombinant proteins expressing α-galactosyl epitopes, but so far there is no indication that it affects the half-life in the circulation and the biologic activity. Detection of anti-Gal in the seminal fluid and in the cerebrospinal fluid may serve as a simple means for assessment of damage to the blood-genital tract barrier or the blood-brain barrier. Studies on the interaction of anti-Gal with aberrantly expressed α-galactosyl epitopes on human cells may elucidate the possible role of anti-Gal in human autoimmune diseases. |
Springer seminars in immunopathology. 1993 Sep 1; 15(2-3): 155-171. | evolution; autoimmune disease; Graves; thyroid; semen |
| Galili U. | 2020 | Human Natural Antibodies to Mammalian Carbohydrate Antigens as Unsung Heroes Protecting against Past, Present, and Future Viral Infections. Human natural antibodies to mammalian carbohydrate antigens (MCA) bind to carbohydrate-antigens synthesized in other mammalian species and protect against zoonotic virus infections. Three such anti-MCA antibodies are: (1) anti-Gal, also produced in Old-World monkeys and apes, binds to α-gal epitopes synthesized in non-primate mammals, lemurs, and New-World monkeys; (2) anti-Neu5Gc binds to Neu5Gc (N-glycolyl-neuraminic acid) synthesized in apes, Old-World monkeys, and many non-primate mammals; and (3) anti-Forssman binds to Forssman-antigen synthesized in various mammals. Anti-viral protection by anti-MCA antibodies is feasible because carbohydrate chains of virus envelopes are synthesized by host glycosylation machinery and thus are similar to those of their mammalian hosts. Analysis of MCA glycosyltransferase genes suggests that anti-Gal appeared in ancestral Old-World primates following catastrophic selection processes in which parental populations synthesizing α-gal epitopes were eliminated in enveloped virus epidemics. However, few mutated offspring in which the α1,3galactosyltransferase gene was accidentally inactivated produced natural anti-Gal that destroyed viruses presenting α-gal epitopes, thereby preventing extinction of mutated offspring. Similarly, few mutated hominin offspring that ceased to synthesize Neu5Gc produced anti-Neu5Gc, which destroyed viruses presenting Neu5Gc synthesized in parental hominin populations. A present-day example for few humans having mutations that prevent synthesis of a common carbohydrate antigen (produced in >99.99% of humans) is blood-group Bombay individuals with mutations inactivating H-transferase; thus, they cannot synthesize blood-group O (H-antigen) but produce anti-H antibody. Anti-MCA antibodies prevented past extinctions mediated by enveloped virus epidemics, presently protect against zoonotic-viruses, and may protect in future epidemics. Travelers to regions with endemic zoonotic viruses may benefit from vaccinations elevating protective anti-MCA antibody titers. |
Antibodies. 2020 Jun;9(2):25. | evolution; virus; mammalian carbohydrate antigens |
| Galili U. | 2013 | Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits. Anti-Gal is the most abundant natural antibody in humans, constituting ~ 1% of immunoglobulins. Anti-Gal is naturally produced also in apes and Old World monkeys. The ligand of anti-Gal is a carbohydrate antigen called the 'alpha-gal epitope' with the structure Galalpha1-3Galbeta1-4GlcNAc-R. The alpha-gal epitope is present as a major carbohydrate antigen in non-primate mammals, prosimians and New World monkeys. Anti-Gal can contributes to several immunological pathogeneses. Anti-Gal IgE produced in some individuals causes allergies to meat and to the therapeutic monoclonal antibody cetuximab, all presenting alpha-gal epitopes. Aberrant expression of the alpha-gal epitope or of antigens mimicking it in humans may result in autoimmune processes, as in Graves' disease. alpha-Gal epitopes produced by Trypanosoma cruzi interact with anti-Gal and induce 'autoimmune like' inflammatory reactions in Chagas' disease. Anti-Gal IgM and IgG further mediate rejection of xenografts expressing alpha-gal epitopes. Because of its abundance, anti-Gal may be exploited for various clinical uses. It increases immunogenicity of microbial vaccines (e.g. influenza vaccine) presenting alpha-gal epitopes by targeting them for effective uptake by antigen-presenting cells. Tumour lesions are converted into vaccines against autologous tumour-associated antigens by intra-tumoral injection of alpha-gal glycolipids, which insert into tumour cell membranes. Anti-Gal binding to alpha-gal epitopes on tumour cells targets them for uptake by antigen-presenting cells. Accelerated wound healing is achieved by application of alpha-gal nanoparticles, which bind anti-Gal, activate complement, and recruit and activate macrophages that induce tissue regeneration. This therapy may be of further significance in regeneration of internally injured tissues such as ischaemic myocardium and injured nerves. |
Immunology. 2013 Sep;140(1):1-1. | |
| Galili U. | 2018 | The natural anti-gal antibody as foe turned friend in medicine. Chapter 7: Anti-Gal IgE Mediates Allergies to Red Meat. [BOOK] Immunoglobulin class (isotype) switch to anti-Gal IgE was first observed in cancer patients receiving an immunotherapy treatment by infusion of the monoclonal antibody cetuximab (anti-epidermal growth factor receptor antibody). When produced in a hybridoma, this antibody carries the α-gal epitope, which binds anti-Gal IgE antibody in these patients, inducing allergic and anaphylactic reactions. Studies on the production of anti-Gal IgE indicated that it is rare in Northern regions of the United States (<1%) but is frequently found Southern regions (>20%). The production of anti-Gal IgE was further found to correlate with allergies to red meat (beef, pork, and lamb). One of the reasons for class switch from anti-Gal IgM or IgG1 to IgE was found to be “lone star” (Amblyomma americanum) tick bites. Bites of the ticks Ixodes ricinus in Europe, Haemaphysalis longicornis in Asia and Ixodes holocyclus in Australia were found to cause similar seroconversion to anti-Gal IgE and appearance of allergic reactions to red meat. Such allergies also are found with pork kidneys because they contain very large amounts of α-gal epitopes. The substances in tick saliva which stimulate the class switch in anti-Gal B cells into IgE producing cells have not been identified yet. Prevention of allergic reactions to α-gal epitopes may be achieved by identifying patients producing anti-Gal IgE, either by the use of a lab test or by a skin test with natural or synthetic α-gal epitopes linked to lipids or to other molecules. Use of therapeutic natural or recombinant glycoproteins and monoclonal antibodies lacking α-gal epitopes will also prevent anti-Gal IgE-mediated allergic reactions. This may be achieved by enzymatic destruction of α-gal epitopes with recombinant α-galactosidase or by using eukaryotic expression systems confirmed not to include the biosynthetic pathway for synthesis of α-gal epitopes. Because such biosynthetic pathways are also present in mammary glands of nonprimate mammals, recombinant therapeutic glycoproteins produced in mammary glands and secreted in milk of transgenic farm animals should be evaluated for presence of α-gal epitopes. If present, the α-gal epitopes may be destroyed enzymatically with α-galactosidase. Alternatively, the milk may be produced in knockout mammals for the α1,3GT gene, i.e., mammals that lack the ability to synthesize the α-gal epitope. Lastly, it would be of interest to determine whether red meat from cows, pigs, or lambs engineered to lack α-gal epitopes by disruption of the α1,3GT (GGTA1) gene, can be consumed by individuals producing anti-Gal IgE without having allergic reactions to this food. |
The natural anti-Gal antibody as foe turned friend in medicine. Academic Press; 2017 Sep 5. | |
| Galili U. | 2019 | Evolution in primates by “Catastrophic‐selection” interplay between enveloped virus epidemics, mutated genes of enzymes synthesizing carbohydrate antigens, and natural anti‐carbohydrate antibodies “Catastrophic‐selection” is an evolutionary mechanism, by which entire parental‐populations are eliminated but very few mutated offspring survive and replace extinct parental‐populations. The human natural anti‐carbohydrate antibodies, anti‐Gal and anti‐Neu5Gc suggest the occurrence of catastrophic‐selection events in primate evolution. Parental‐populations synthesizing corresponding carbohydrate‐antigens underwent extinction in viral epidemics, and few offspring survived. These offspring carried accidental mutations that inactivated carbohydrate‐antigen synthesis and produced natural‐antibody against the lost antigen. Such natural anti‐carbohydrate antibody was produced against environmental carbohydrate‐antigens (e.g., gastrointestinal bacteria). The carbohydrate‐antigen in infected parental‐populations was also synthesized on viruses by the host glycosylation‐machinery. The natural‐antibody in the offspring bound to the carbohydrate‐antigen on infecting viruses produced in parental‐populations, destroyed the viruses and protected these offspring from extinction. This process occurred in ancestral Old‐World monkeys and apes synthesizing α‐gal epitopes, which were replaced 20–30 million‐years‐ago by offspring lacking α‐gal epitopes and producing natural anti‐Gal antibody against this antigen, and later in hominins synthesizing the sialic‐acid antigen Neu5Gc, which were replaced by offspring lacking Neu5Gc and producing anti‐Neu5Gc antibody. A present‐day example for accidental mutations in very few humans that lost a common carbohydrate‐antigen and produce a natural antibody against it is the rare blood‐group “Bombay” individuals. These individuals lack the H‐antigen (blood‐group O) which is synthesized in all other humans, and produce the natural anti‐H antibody against blood‐group O. Overall, it is suggested that natural anti‐carbohydrate antibodies played a critical role in preventing complete extinction of mammalian species in epidemics of highly virulent viruses and may have similar role in future events. |
American Journal of Physical Anthropology. 2019 Feb;168(2):352-63. | |
| Galili U. | 2016 | Natural anti-carbohydrate antibodies contributing to evolutionary survival of primates in viral epidemics?. Humans produce multiple natural antibodies against carbohydrate antigens on gastrointestinal bacteria. Two such antibodies appeared in primates in recent geological times. Anti-Gal, abundant in humans, apes and Old-World monkeys, appeared 20–30 million years ago (mya) following inactivation of the α1,3GT gene (GGTA1). This gene encodes in other mammals the enzyme α1,3galactosyltransferase (α1,3GT) that synthesizes α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) which bind anti-Gal. Anti-Neu5Gc, found only in humans, appeared in hominins <6 mya, following elimination of N-glycolylneuraminic-acid (Neu5Gc) because of inactivation of CMAH, the gene encoding hydroxylase that converts N-acetylneuraminic-acid (Neu5Ac) into Neu5Gc. These antibodies, were initially produced in few individuals that acquired random mutations inactivating the corresponding genes and eliminating α-gal epitopes or Neu5Gc, which became nonself antigens. It is suggested that these evolutionary selection events were induced by epidemics of enveloped viruses, lethal to ancestral Old World primates or hominins. Such viruses presented α-gal epitopes or Neu5Gc, synthesized in primates that conserved active GGTA1 or CMAH, respectively, and were lethal to their hosts. The natural anti-Gal or anti-Neu5Gc antibodies, produced in offspring lacking the corresponding carbohydrate antigens, neutralized and destroyed viruses presenting α-gal epitopes or Neu5Gc. These antibodies further induced rapid, effective immune responses against virus antigens, thus preventing infections from reaching lethal stages. These epidemics ultimately resulted in extinction of primate populations synthesizing these carbohydrate antigens and their replacement with offspring populations lacking the antigens and producing protective antibodies against them. Similar events could mediate the elimination of various carbohydrate antigens |
Glycobiology. 2016 Nov 14;26(11):1140-50. | |
| Galliker N, Vallelian F, Petrausch U, Ballmer-Weber B, Schmid-Grendelmeier P. | 2013 | Perioperative anaphylaxis due to Physiogel-and allergy to beef and gelatine. No abstract available |
ALLERGOLOGIE. 2013 Sep 1;36(9):410-2. | perioperative care; surgery; gelatine; gelatin; Physiogel; personal care prodcut |
| Galvao VR, Castells MC. | 2015 | Hypersensitivity to biological agents-updated diagnosis, management, and treatment. Biological agents are used in the treatment of neoplastic, autoimmune, and inflammatory diseases and their clinical applications are becoming broader. Following their increased utilization, hypersensitivity reactions linked to these drugs have become more frequent, sometimes preventing the use of first-line therapies. The clinical presentation of hypersensitivity reactions to biological agents ranges from mild cutaneous manifestations to life-threatening reactions. In this scenario, rapid desensitization is a groundbreaking procedure that enables selected patients to receive the full treatment dose in a safe way, in spite of their immediate hypersensitivity reaction to the drug, and protects them against anaphylaxis. The aim of this review is to update and discuss some of the main biological agents used in clinical practice (rituximab, trastuzumab, cetuximab, ofatumumab, tocilizumab, brentuximab, omalizumab, and tumor necrosis factor alpha inhibitor agents) and their associated hypersensitivity reactions, including clinical presentations, diagnosis, and treatment in the acute setting. In addition, novel management options with rapid desensitization are presented. |
The Journal of Allergy and Clinical Immunology: In Practice. 2015 Mar 1;3(2):175-85. | medical product; pharmacy; pharmaceutical; biologic |
| Ganiko L, Silva LS, Puccia R, Freymüller-Haapalainen E, Matsuo AL, Almeida IC, Miranda K, Medeiros LC, Sinigaglia-Coimbra R, Vallejo MC. | 2011 | The Pathogenic Fungus Paracoccidioides brasiliensis Exports Extracellular Vesicles Containing Highly Immunogenic α-Galactosyl Epitopes. Exosome-like vesicles containing virulence factors, enzymes, and antigens have recently been characterized in fungal pathogens, such as Cryptococcus neoformans and Histoplasma capsulatum. Here, we describe extracellular vesicles carrying highly immunogenic α-linked galactopyranosyl (α-Gal) epitopes in Paracoccidioides brasiliensis. P. brasiliensis is a dimorphic fungus that causes human paracoccidioidomycosis (PCM). For vesicle preparations, cell-free supernatant fluids from yeast cells cultivated in Ham's defined medium-glucose were concentrated in an Amicon ultrafiltration system and ultracentrifuged at 100,000 × g. P. brasiliensis antigens were present in preparations from phylogenetically distinct isolates Pb18 and Pb3, as observed in immunoblots revealed with sera from PCM patients. In an enzyme-linked immunosorbent assay (ELISA), vesicle components containing α-Gal epitopes reacted strongly with anti-α-Gal antibodies isolated from both Chagas' disease and PCM patients, with Marasmius oreades agglutinin (MOA) (a lectin that recognizes terminal α-Gal), but only faintly with natural anti-α-Gal. Reactivity was inhibited after treatment with α-galactosidase. Vesicle preparations analyzed by electron microscopy showed vesicular structures of 20 to 200 nm that were labeled both on the surface and in the lumen with MOA. In P. brasiliensis cells, components carrying α-Gal epitopes were found distributed on the cell wall, following a punctuated confocal pattern, and inside large intracellular vacuoles. Lipid-free vesicle fractions reacted with anti-α-Gal in ELISA only when not digested with α-galactosidase, while reactivity with glycoproteins was reduced after β-elimination, which is indicative of partial O-linked chain localization. Our findings open new areas to explore in terms of host-parasite relationships in PCM and the role played in vivo by vesicle components and α-galactosyl epitopes. |
Eukaryot. Cell. 2011;10:343-51. | fungus; ascomycetes; ascomycota; Paracoccidioides |
| Gao B, Long C, Lee W, Zhang Z, Gao X, Landsittel D, Ezzelarab M, Ayares D, Huang Y, Cooper DK, Wang Y. | 2017 | Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans. Our group previously investigated the levels of anti-Gal and anti-nonGal IgM and IgG in a cohort of 75 healthy humans of various backgrounds, and found some significant differences related to factors such as age, gender, ABO blood group, diet, vaccination history, and geographic location during childhood. We have now expanded our cohort (n = 84) to investigate the levels of anti-Neu5Gc and anti-nonGal/nonNeu5Gc antibodies in healthy humans. Anti-nonGal and anti-nonGal/nonNeu5Gc human IgM and IgG binding to pRBCs and pAECs from GTKO/CD46 and GTKO/CD46/Neu5GcKO pigs were measured by flow cytometry. Anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. In summary, (i) the great majority (almost 100%) of humans had anti-Neu5Gc IgM and IgG antibodies that bound to pAECs and approximately 50% had anti-Neu5Gc antibodies that bound to pRBCs, (ii) there was significantly less human antibody binding to pig cells that did not express either Gal or Neu5Gc compared with those that did not express Gal alone, (iii) the levels of both IgM and IgG binding to GTKO/CD46/Neu5GcKO pRBCs and pAECs were low, (iv) the level of anti-Neu5Gc IgG was higher in men than women, (v) the level did not change with age or diet, and there was some variability associated with (vi) previous vaccination history and (vii) the geographic region in which the individual spent his or her childhood. Our study confirms that human antibody binding to RBCs and AECs from GTKO/CD46/Neu5GcKO pigs is greatly reduced compared to binding to GTKO/CD46 cells. However, all humans appear to have a low level of antibody that binds to pAECs that is not directed to either Gal or Neu5Gc. Our findings require consideration in planning clinical trials of xenotransplantation. |
PLoS One. 2017 Jul 17;12(7):e0180768. | xenoglycan; glycan antigen; glycan antibody; Neu5Gc; carbohydrate; sialic acid |
| Garcia MB, Gomez-Samper AF, Garcia E, Peñaranda A. | 2020 | Delayed urticaria or anaphylaxis after consumption of red meat with evidence of alpha-gal sensitisation |
BMJ Case Reports CP. 2020 Dec 1;13(12):e236923. | |
| García-Menaya JM, Cordobés-Durán C, Gómez-Ulla J, Zambonino MA, Mahech, AC, Chiarella GM, Giangrande N, Bobadilla-González P. | 2016 | Successful Desensitization to Cetuximab in a Patient With a Positive Skin Test to Cetuximab and Specific IgE to Alpha-gal. Cetuximab (Erbitux, Merck KGaA) is an IgG1 chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). It is approved for the treatment of RAS wild-type metastatic colorectal cancer as well as head and neck cancer. Severe reactions tend to occur during the first administration [1]. In 2008, severe anaphylactic reactions after the first infusion of cetuximab were reported for the first time, and the authors demonstrated that pre-existing specific IgE (sIgE) antibodies to galactose-alpha-1,3-galactose (alpha-gal) were responsible for the reactions [2]. Alpha-gal is present on the Fab portion of the cetuximab heavy chain. Very few cases of desensitization to cetuximab have been described since these first reports of severe reactions [3-5]. Moreover, in recent years, severe hypersensitivity reactions to red meat with a delay of several hours have been reported in patients with IgE to alpha-gal [6]. Here, we present the case of a 50-year-old man without a previous history of atopy or drug allergy who was diagnosed with pyriform sinus squamous cell cancer in 2014. The cancer was treated by surgery followed by chemotherapy and radiation therapy. The disease progressed, however, and a year later the patient was diagnosed with lung metastases. |
Journal of investigational allergology & clinical immunology. 2016;26(2):132. | Garcia-Menaya Bobadilla-Gonzalez |
| Gaspar A, Santos N, Faria E, Câmara R, Rodrigues-Alves R, Carrapatoso I, Gomes E, Pereira AM, Carneiro-Leão L, Morais-Almeida M, Delgado L, Pedro E, Branco-Ferreira M. | 2020 | Anaphylaxis: a decade of a nationwide allergy society registry Background: Anaphylaxis is an acute, life-threatening, multi-organ hypersensitivity reaction. Objective: The aim of this study was to identify the causes of anaphylaxis in Portugal, contributing to a better knowledge of the anaphylaxis epidemiology and management. Methods: During a 10-year period a nationwide notification system for anaphylaxis. was implemented, with voluntary reporting by allergists. Data on 1783 patients with anaphylaxis were included. Detailed characterization of etiopathogenesis, manifestations and clinical management was obtainedfrom pediatric and adult ages. Results: The mean age was 32.720.3 years, 30% under 18 years of age; 58% were female. The mean age at the first anaphylaxis episode was 27.520.4 years (ranging from 1-month-old to 88years). The main culprits of anaphylaxis were foods (48%), drugs (37%) (main trigger in adults, 48%) and hymenoptera-venoms (7%). The main culprit foods were shellfish (27%), fresh fruits (17%), cow’s milk (16%), treenuts (15%), fish (8%), egg (7%) and peanut (7%). The main drugs were nonsteroidal antiinflammatory drugs(43%), antibiotics (39%) and anaesthetic agents (6%). Other causes were exercise (3%), latex (2%), cold-induced (2%) and idiopathic anaphylaxis (2%). Most patients (80%) were admitted to the emergency department; only 43% received adrenaline treatment. Recurrence of anaphylaxis occurred in 41% of patients (21% with ≥3 anaphylactic episodes); 7% used an adrenaline autoinjector device. Conclusions: Food has been the leading cause of anaphylaxis in Portugal, while drugs were the main elicitors in adults. We highlight the undertreatment with adrenaline and recurrent episodes, pointing for the need to improve diagnostic and therapeutic approaches of anaphylaxis. Note: alpha-gal syndrome was not found to be a major cause of anaphylaxis. |
Journal of investigational allergology & clinical immunology.:0. | Europe; Portugal; prevalence; anaphylaxis |
| Gelatin Manufacturers Institute of America | 2012 | Gelatin Handbook |
Gelatin Manufacturers Institute of America | |
| Ghahramani GK, Temprano J. | 2015 | Tick bite-related meat allergy as a cause of chronic urticaria, angioedema, and anaphylaxis in endemic areas. | International Journal of Dermatology. 2015 Jan 23;2(54):e64-5. | chronic spontaneous urticaria CSU chronic idiopathic urticaria CIU cross-contamination; venison; dermatology; west virginia; routine screening |
| Gleim ER, Conner LM, Berghaus RD, Levin ML, Zemtsova GE, Yabsley MJ. | 2014 | The phenology of ticks and the effects of long-term prescribed burning on tick population dynamics in southwestern Georgia and northwestern Florida Some tick populations have increased dramatically in the past several decades leading to an increase in the incidence and emergence of tick-borne diseases. Management strategies that can effectively reduce tick populations while better understanding regional tick phenology is needed. One promising management strategy is prescribed burning. However, the efficacy of prescribed burning as a mechanism for tick control is unclear because past studies have provided conflicting data, likely due to a failure of some studies to simulate operational management scenarios and/or account for other predictors of tick abundance. Therefore, our study was conducted to increase knowledge of tick population dynamics relative to long-term prescribed fire management. Furthermore, we targeted a region, southwestern Georgia and northwestern Florida (USA), in which little is known regarding tick dynamics so that basic phenology could be determined. Twenty-one plots with varying burn regimes (burned surrounded by burned [BB], burned surrounded by unburned [BUB], unburned surrounded by burned [UBB], and unburned surrounded by unburned [UBUB]) were sampled monthly for two years while simultaneously collecting data on variables that can affect tick abundance (e.g., host abundance, vegetation structure, and micro- and macro-climatic conditions). In total, 47,185 ticks were collected, of which, 99% were Amblyomma americanum, 0.7% were Ixodes scapularis, and fewer numbers of Amblyomma maculatum, Ixodes brunneus, and Dermacentor variabilis. Monthly seasonality trends were similar between 2010 and 2011. Long-term prescribed burning consistently and significantly reduced tick counts (overall and specifically for A. americanum and I. scapularis) regardless of the burn regimes and variables evaluated. Tick species composition varied according to burn regime with A. americanum dominating at UBUB, A. maculatum at BB, I. scapularis at UBB, and a more even composition at BUB. These data indicate that regular prescribed burning is an effective tool for reducing tick populations and ultimately may reduce risk of tick-borne disease. |
PLoS One. 2014 Nov 6;9(11):e112174. | tick; tick management; lone star tick |
| Gonzales-González VA, Díaz AM, Fernández K, Rivera MF. | 2018 | Prevalence of food allergens sensitization and food allergies in a group of allergic Honduran children. Background: Food allergy is a public health problem that has increased in the last decade. Despite the increasing rates in children, quality data on the burden of these diseases is lacking particularly in developing countries. Honduras has no studies in pediatric patients. Objectives: The objective of this research was to identify the most common sensitization patterns to food through epicutaneous skin testing and food allergy rates in children and their correlation with common allergic diseases in a group of patients from Hospital of Pediatrics Maria. . Methods: Cross-sectional retrospective, descriptive study in which records and database of all allergic patients in the immunology outpatient clinic from Hospital of Pediatrics Maria were reviewed between the periods of January 2015 through June 2016. . Results: A total of 365 children were analyzed, the age of participants were in the range from 1 to 18 years, with an average of 9.8 years. Sensitization to food allergens were found in 23, and 58.3% were poly-sensitized. The most common food allergens that patients were sensitized to: milk 9.0%, eggs 6.9%, peanut 4.9% and pork meat 4.4%. Food allergy was confirmed via oral food challenged in 9.3% of the patients. The most frequent food allergies found were: cow’s milk allergy 6%, hen’s egg allergy 5.2% and wheat allergy 1.9%.. Conclusions: Milk and egg were the most common a food allergens found in the population studied. Most of the patients were found to be poly-sensitized. The frequent food allergies confirmed via oral food challenge were cow’s milk allergy, hen’s egg allergy and wheat allergy. |
Allergy, Asthma & Clinical Immunology. 2018 Dec 1;14(1):23. | Latin America; Honduras; prevalence |
| Gonzalez‐Quintela A, Dam Laursen AS, Vidal C, Skaaby T, Gude F, Linneberg A. | 2014 | IgE antibodies to alpha-gal in the general adult population: relationships with tick bites, atopy, and cat ownership. Letter to the editor: Background: The carbohydrate alpha-gal epitope is present in many animal proteins, including those of red meat and animal immunoglobulins, such as cat IgA. Systemic anaphylaxis to the alpha-gal epitope has recently been described. Objective: To investigate and compare the prevalence of alpha-gal-specific (s)IgE and its associated factors in the general adult population from two separated (Northern and Southern) European regions (Denmark and Spain, respectively). Methods: Cross-sectional study of 2297 and 444 randomly selected adults from 11 municipalities in Denmark and one in Spain. Alpha-gal sIgE was assessed by ImmunoCAP to bovine thyroglobulin. Additional assessments included a panel of skin prick test (SPT) to common aeroallergens and epidemiological factors, including the history of tick bites in the Danish series. Results: The prevalence of positive (>= 0.1 kU(A)/L) sIgE to alpha-gal was 5.5% and 8.1% in the Danish and Spanish series, respectively. The prevalence of sIgE >= 0.35 kU(A)/L was 1.8% and 2.2% in Denmark and Spain, respectively. Alpha-gal sIgE positivity was associated with pet ownership in both series and, particularly, cat ownership (data available in the Danish series). Alpha-gal sIgE positivity was associated with atopy (SPT positivity) in both series, although it was not associated with SPT positivity to cat or dog dander. Alpha-gal sIgE positivity was strongly associated with a history of tick bites. Conclusions and Clinical Relevance: The prevalence of alpha-gal sIgE antibodies in these general adult European populations is similarly low. The presence of alpha-gal sIgE antibodies is associated with a history of tick bites, atopy, and cat ownership. |
Clinical & Experimental Allergy. 2014 Aug;44(8):1061-8. | Europe; Spain; Denmark; prevalence |
| Gosnell H, Stein A, Acosta DE. | 2022 | Postoperative fever secondary to enoxaparin usage with pork allergy. Postoperative fevers are common in hospitalised patients and warrant workup beyond the early post-op period. A 50-year-old man was admitted after sustaining a tibial plateau fracture. Fevers began 3 days after external fixation and persisted through a second surgery despite initial negative workup. Careful review of medications revealed enoxaparin as the instigating agent of a febrile drug reaction, and the fevers resolved after discontinuing the drug. On further questioning, it was discovered the patient had an allergy to pork, from which the main components of enoxaparin are typically derived. To our knowledge, this is the first reported enoxaparin-induced fever in the setting of a pork allergy. Enoxaparin-induced fevers should be considered in patients with unexplained post-op fever. Our case demonstrates the importance of analysing newly administered medications. Simple detailed history may significantly reduce patient morbidity and help to broaden differentials during investigation. |
BMJ Case Reports CP. 2022 Jan 1;15(1):e246904. | Perioperative; surgery; blood thinner; medical products; porcine; enoxaparin; febrile; fever; post-operative fever |
| Gowda DC, Glushka J, Halbeek HV, Thotakura RN, Bredehorst R, Vogel CW. | 2001 | N-linked oligosaccharides of cobra venom factor contain novel α (1-3) galactosylated Lex structures. Cobra venom factor (CVF), a nontoxic, complement-activating glycoprotein in cobra venom, is a functional analog of mammalian complement component C3b. The carbohydrate moiety of CVF consists exclusively of N-linked oligosaccharides with terminal α1-3-linked galactosyl residues, which are antigenic in human. CVF has potential for several medical applications, including targeted cell killing and complement depletion. Here, we report a detailed structural analysis of the oligosaccharides of CVF. The structures of the oligosaccharides were determined by lectin affinity chromatography, antibody affinity blotting, compositional and methylation analyses, and high-resolution 1H-NMR spectroscopy. Approximately 80% of the oligosaccharides are diantennary complex-type, ∼12% are tri- and tetra-antennary complex-type, and ∼8% are oligomannose type structures. The majority of the complex-type oligosaccharides terminate in Galα1-3Galβ1-4(Fucα1-3)GlcNAcβ1, a unique carbohydrate structural feature abundantly present in the glycoproteins of cobra venom. |
Glycobiology. 2001 Mar 1;11(3):195-208. | |
| Gray CL, Van Zyl A, Strauss L. | 2016 | Midnight anaphylaxis: to red meat in patients with alpha-gal sensitisation : a recent discovery in the food allergy world and a case report from South Africa : guest review. A syndrome of delayed anaphylaxis to red meat, occurring in geographical clusters; initially identified in the United States, was first described in 2009. A few years later, this enigmatic anaphylactic reaction was ascribed to IgE antibodies to galactose-alpha-1,3-galactose (alphagal), an oligosaccharide, which is a major blood group substance in non-primate mammals. It appears that the predominant source of sensitisation to alpha-gal is bites from certain ticks. Since 2009, several hundreds to thousands of cases of delayed red-meat allergy have been described worldwide, but very few reports have come out of Africa. This case series describes 2 cases of an acquired form of delayed anaphylaxis to beef and mutton in patients who were subsequently found to be highly sensitised to alpha-gal, residing in the same region. |
Current Allergy & Clinical Immunology. 2016 Jun 1;29(2):102-4. | Africa; South Africa; non-tick vectors; helminth; scabies; |
| Greenhawt M, Oppenheimer J, Shaker M. | 2019 | Fearing the Bark That Has No Bite Parsing Practical From Theoretical Risk Editorial repy to: Mawhirt S.L. Banta E. Successful intravenous heparin administration during coronary revascularization surgery in a patient with alpha-gal anaphylaxis history [published online May 28, 2019]. Ann Allergy Asthma Immunol. 2019; |
Annals of Allergy, Asthma & Immunology. 2019 Oct 1;123(4):327-8. | Pharmacy; pharmaceutical; medication; heparin; perioperative |
| Grönlund H, Adédoyin J, Commins SP, Platts-Mills TA, van Hage M. | 2009 | The carbohydrate galactose-alpha-1,3-galactose is a major IgE binding epitope on cat IgA. Letter to the editor: Cross-reactive carbohydrate determinants are widely occurring IgE epitopes. Glycan-related IgE reactivity has been demonstrated in most allergen sources, especially in the plant kingdom. The clinical effect of these cross-reactive carbohydrate determinants is debated. We were recently able to show that IgE Abs to the cat IgA, present in cat-sensitized patients, are mainly directed to a glycan moiety localized on the α-chain. In addition, we have reported that these carbohydrates are present on IgM Abs from cat, as well as on IgM from many different mammalian species, but not human immunoglobulins. Interestingly, IgE antibodies to cat IgM and cat IgA show a complete cross-reactivity, whereas cat IgG does not, suggesting an identical oligosaccharide on the two former immunoglobulin classes. Because this is the first mammalian carbohydrate IgE epitope found, it is of major interest to identify the carbohydrate structure responsible for the broad cross-reactivity. |
Journal of allergy and clinical immunology. 2009 May 1;123(5):1189-91. | Europe; Sweden; cat |
| Guillier A, Fauconneau A, De Barruel F, Guez S, Doutre MS. | 2015 | Allergic hypersensitivity to red meat induced by tick bites: a French case report. An increasing number of cases of delayed anaphylactic reactions after the consumption of red meat have been reported in the United States but few similar cases have been reported in Europe. We report herein a French observation. A 54-year-old man first developed generalized urticaria, tachycardia, abdominal pain, nausea and vomiting 4 hours after eating beef kidneys. He subsequently had several similar episodes after eating beef, lamb and pork meat. He ate chicken and fish without problems. He did not drink alcohol nor exercise during these episodes. The patient reported a tick bite a few months before the onset of symptoms. The patient lived in the Southeast of France where exposure to Ixodes ricinus is common. He had no atopy, previous food or respiratory allergy. Allergological investigations showed positive specific IgE to pork (6.15 kU/l, N< 0.10 kU/L), beef (5.10 kU/L, N<0.10 kU/L) and Galactose-alpha-1,3-galactose (alpha-gal) IgE (77 kU/L, N<0.10 kU/L). Specific IgE to chicken (0.10 kU/L) and turkey (0.10 kU/L) were negative. After the withdrawal of red meat, he has remained free from urticaria and digestive symptoms |
European Journal of Dermatology. 2015 Jun 30;25(3):277. | Europe; France |
| Gulbin K, Keskin Ö, Asilsoy S, Zeyrek D, Kilic M, Altintas D, Kucukosmanoglu E, Yilmaz M, Kendirli S. | 2012 | Food allergy profile in tertiary clinics in southeast part of Turkey:‘a multi center study: 1336. No abstract available |
Journal of Allergy and Clinical Immunology. 2012 Nov; 67. | Asia; Europe; Turkey; prevalence |
| Gülsen A, Wedi B, Jappe U. | 2020 | Hypersensitivity reactions to biologics (part II): classifications and current diagnostic and treatment approaches. |
Allergo Journal International. 2020 Jun 19:1-6. | Gulsen; biologics |
| Guo RR, Lageveen-Kammeijer GS, Wang W, Dalebout H, Zhang W, Wuhrer M, Liu L, Heijs B, Voglmeir J. | 2023 | Analysis of Immunogenic Galactose-α-1, 3-galactose-Containing N-Glycans in Beef, Mutton, and Pork Tenderloin by Combining Matrix-Assisted Laser Desorption/Ionization-Mass Spectroscopy and Capillary Electrophoresis Hyphenated with Mass Spectrometry via Electrospray Ionization. Severe allergic reactions to certain types of meat following tick bites have been reported in geographic regions which are endemic with ticks. This immune response is directed to a carbohydrate antigen (galactose-α-1,3-galactose or α-Gal), which is present in glycoproteins of mammalian meats. At the moment, asparagine-linked complex carbohydrates (N-glycans) with α-Gal motifs in meat glycoproteins and in which cell types or tissue morphologies these α-Gal moieties are present in mammalian meats are still unclear. In this study, we analyzed α-Gal-containing N-glycans in beef, mutton, and pork tenderloin and provided for the first time the spatial distribution of these types of N-glycans in various meat samples. Terminal α-Gal-modified N-glycans were found to be highly abundant in all analyzed samples (55, 45, and 36% of N-glycome in beef, mutton, and pork, respectively). Visualizations of the N-glycans with α-Gal modification revealed that this motif was mainly present in the fibroconnective tissue. To conclude, this study contributes to a better understanding of the glycosylation biology of meat samples and provides guidance for processed meat products, in which only meat fibers are required as an ingredient (i.e., sausages or canned meat). |
Journal of Agricultural and Food Chemistry. 2023 Feb 21. | Connective tissue; bioprosthetic valves; surgical implants; medical products |
| Gupta M, Schuyler A, Workman L, Commins S, Platts-Mills T, Wilson J. | 2018 | Galactose-A-1,3-Galactose Sensitization and the A-Gal Syndrome: Characteristics of Subjects Seeking Emergency Care. Introduction: Galactose -α-1,3- galactose (α-Gal) is an oligosaccharide of non-primate mammals and the culprit allergen in a syndrome of delayed anaphylaxis to mammalian meat (ie, α-Gal syndrome). We sought to describe the clinical presentations of a large cohort of subjects from Central Virginia, with or without IgE to α-Gal, who presented for emergent care for allergic reactions. Methods: A detailed questionnaire regarding clinical reactions was completed by patients who received care at a Virginia allergy clinic and who reported a history of anaphylaxis or urticaria. Many, but not all, related their reactions to mammalian meat. Serum was obtained and total IgE and α-Gal specific IgE (sIgE) were measured by ImmunoCAP. Results: Of 408 patients who completed the survey, 224 had sought urgent care (195 of which were in the emergency department) for allergic reactions. Of these, 191 were α-Gal sIgE positive, of whom 82% perceived an association between consumption of mammalian meat and allergic symptoms. When compared to non-sensitized subjects, α-Gal sensitized subjects were more commonly male (45% vs. 18%, p2 hours after a perceived trigger (82% vs. 25%, p Conclusions: The α-Gal syndrome is commonly adult-onset, has a characteristic delay of onset >2 hours following mammalian meat ingestion, and frequently results in presentation for emergent medical care. |
Annals of Allergy, Asthma & Immunology. 2018 Nov 1;121(5):S11. | ER emergency care |
| Gupta M, Workman L, Schuyler AJ, Commins SP, Platts-Mills TA, Wilson JM. | 2019 | Description of Subjects Reporting Reactions to Mammalian Meat Who Test Negative for IgE to Galactose-alpha-1,3-galactose (alpha-Gal). RATIONALE: The oligosaccharide a-Gal has recently emerged as a regionally important cause of a syndrome of IgE-mediated delayed anaphylaxis to mammalian meat; however, other allergens can also contribute to meat allergy. We sought to describe subjects who were evaluated for suspicion of mammalian meat allergy but who tested negative for IgE to a-Gal. METHODS: As part of an IRB-approved observational study, 254 patients with histories of suspected allergic reactions (urticaria and anaphylaxis) to mammalian meat were enrolled from central Virginia. Serum was obtained and subjects completed detailed questionnaires. Assays were conducted for total IgE, as well as specific IgE (sIgE) to aGal, cat, beef, pork, gelatin, cat serum albumin, bovine serum albumin and pork serum albumin using standard ImmunoCAP assays. RESULTS: Using a cut-off of 0.35 IU/mL, sIgE to a-Gal was detected in 238 of the 254 subjects. Of the 16 remaining subjects, 10 (63%) described onset of symptoms occurring >_ 2 hrs after mammalian meat ingestion. Specific IgE testing supported a diagnosis of pork-cat syndrome in 3 subjects (sIgE detected to cat, pork and cat serum albumin >_ 0.1 IU/mL), 5 were found to have low-titer a-Gal sIgE (ie, 0.1-0.34 IU/mL) and 3 had detectable sIgE to beef (>_ 0.1 IU/mL) suggestive of primary beef allergy. CONCLUSIONS: In central Virginia sIgE to a-Gal is a common cause of anaphylaxis to mammalian meat, however other causes such as pork-cat syndrome, primary beef allergy, and gelatin allergy should also be considered. |
Journal of Allergy and Clinical Immunology. 2019 Feb 1;143(2):AB256. | pork-cat syndrome primary meat allergy gelatin gelatine |
| Gupta S, Rabinovitch N. | 2019 | M059 CHOLINERGIC URTICARIA WITH ANAPHYLAXIS IN A PATIENT DIAGNOSED WITH ALPHA-GAL ALLERGY. Introduction: Cholinergic urticaria is a form of inducible urticaria triggered by passive elevation of core body temperature or by strong emotion. This form of physical urticaria may range from isolated cutaneous involvement to anaphylaxis. Diagnosis should be considered in young women who present with cutaneous, upper airway, lower airway, and/or GI symptoms. Case Description: A 16-year-old girl presented with a history of sudden onset episodes of abdominal pain, vomiting, hives, and difficulty breathing without identifiable trigger. Due to demonstration of alpha-gal sensitization, the patient was strictly avoiding all mammalian meat products with significant impact on quality of life and persistent symptoms. Examination showed dermatographism after scratching and urticaria on pressured areas suggestive of physical urticaria. Sweat chloride testing resulted in a well demarcated localized wheel. Free run exercise challenge resulted in immediate development of skin changes, difficulty breathing with audible stridor, and nausea. Spirometry demonstrated a 13% drop in FEV1. Vitals remained stable. Serum tryptase performed prior to and after challenge remained unchanged. Symptoms resolved within 30 minutes of cooling down and with Zyrtec. She was started on Zyrtec 10mg twice daily. Two days later, free run exercise challenge was repeated with nebulized beta agonist and anticholinergic pretreatment. She remained asymptomatic throughout with stable exam and spirometry. Later, beef was reintroduced into the diet after passing oral food challenge. Discussion: Our case demonstrates the importance of considering cholinergic urticaria with anaphylaxis in patients presenting with idiopathic anaphylaxis as the prevention and treatment can vary dramatically depending on etiology. |
Annals of Allergy, Asthma & Immunology. 2019 Nov 1;123(5):S80. | Dermatology ??? |
| Haji-Ghassemi O, Müller-Loennies S, Saldova R, Muniyappa M, Brade L, Rudd PM, Harvey DJ, Kosma P, Brade H, Evans SV. | 2014 | Groove-type recognition of chlamydiaceae-specific lipopolysaccharide antigen by a family of antibodies possessing an unusual variable heavy chain N-linked glycan. The structure of the antigen binding fragment of mAb S25-26, determined to 1.95 A resolution in complex with the Chlamydiaceae family-specific trisaccharide antigen Kdo(2-->8)Kdo(2-->4)Kdo (Kdo = 3-deoxy-alpha-d-manno-oct-2-ulopyranosonic acid), displays a germ-line-coded paratope that differs significantly from previously characterized Chlamydiaceae-specific mAbs despite being raised against the identical immunogen. Unlike the terminal Kdo recognition pocket that promotes cross-reactivity in S25-2-type antibodies, S25-26 and the closely related S25-23 utilize a groove composed of germ-line residues to recognize the entire trisaccharide antigen and so confer strict specificity. Interest in S25-23 was sparked by its rare high mum affinity and strict specificity for the family-specific trisaccharide antigen; however, only the related antibody S25-26 proved amenable to crystallization. The structures of three unliganded forms of S25-26 have a labile complementary-determining region H3 adjacent to significant glycosylation of the variable heavy chain on asparagine 85 in Framework Region 3. Analysis of the glycan reveals a heterogeneous mixture with a common root structure that contains an unusually high number of terminal alphaGal-Gal moieties. One of the few reported structures of glycosylated mAbs containing these epitopes is the therapeutic antibody Cetuximab; however, unlike Cetuximab, one of the unliganded structures in S25-26 shows significant order in the glycan with appropriate electron density for nine residues. The elucidation of the three-dimensional structure of an alphaGal-containing N-linked glycan on a mAb variable heavy chain has potential clinical interest, as it has been implicated in allergic response in patients receiving therapeutic antibodies. |
Journal of Biological Chemistry. 2014 Jun 13;289(24):16644-61. | |
| Hamsten C, Starkhammar M, Tran TA, Johansson M, Bengtsson U, Ahlen G, Sällberg M, Grönlund H, van Hage M. | 2013 | Identification of galactose-alpha-1,3-galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy. Patients with IgE antibodies against the carbohydrate epitope galactose-alpha-1,3-galactose (alpha-Gal) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between IgE to alpha-Gal and tick bites. We provide the first direct evidence that alpha-Gal is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to alpha-Gal, with development of red meat allergy as a secondary phenomena. Serum from Swedish patients with delayed severe reactions to red meat was included in the study. A dose-dependent inhibition of IgE responses to alpha-Gal by the tick Ixodes ricinus is demonstrated. Furthermore, using cryostat-cut sections of I. ricinus, we show that both a monoclonal and a polyclonal antibody against alpha-Gal stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to alpha-Gal. These results confirm that the alpha-Gal epitope is present in I. ricinus and imply host exposure to alpha-Gal during a tick bite. This provides further evidence that tick bites are associated with IgE responses to alpha-Gal and red meat allergy. |
Allergy. 2013 Apr;68(4):549-52. | Europe; Sweden; vector; tick; Ixodes ricinus |
| Hamsten C, Tran TA, Starkhammar M, Brauner A, Commins SP, Platts-Mills TA, van Hage M. | 2013 | Red meat allergy in Sweden: Association with tick sensitization and B-negative blood groups. Letter to the Editor: ... |
Journal of allergy and clinical immunology. 2013 Dec 1;132(6):1431-4. | Europe; Sweden; vector; tick; Ixodes ricinus |
| Hansson GK, Hermansson A. | 2011 | The immune system in atherosclerosis Cardiovascular disease, a leading cause of mortality worldwide, is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Lesions of atherosclerosis contain macrophages, T cells and other cells of the immune response, together with cholesterol that infiltrates from the blood. Targeted deletion of genes encoding costimulatory factors and proinflammatory cytokines results in less disease in mouse models, whereas interference with regulatory immunity accelerates it. Innate as well as adaptive immune responses have been identified in atherosclerosis, with components of cholesterol-carrying low-density lipoprotein triggering inflammation, T cell activation and antibody production during the course of disease. Studies are now under way to develop new therapies based on these concepts of the involvement of the immune system in atherosclerosis. |
Cellular and Molecular Life Sciences. 2013 Oct 1;70(20):3847-69. | Atherosclerosis |
| Harper V, Wagner A, Sowa P, Rutkowski K | 2019 | Allergy in frequent travelers: the alpha-gal story and the first UK case series. Galactose-α-(1,3)-galactose (alpha-gal) is found in most nonprimate mammalian cell membranes. 1 Humans, apes, and Old World monkeys lack alpha-1,3 galactosyltransferase required for the synthesis of this carbohydrate. 2 It is therefore highly immunogenic to humans and implicated in alpha-gal syndrome/allergy—the first noninfectious tickborne disease in humans. 3 Alpha-gal moiety has been found in tick salivary proteins, and primary immunoglobulin E (IgE) sensitization to alpha-gal is thought to occur through inoculation of saliva during a tick bite. 2 , 4 Recurrent tick bites induce high levels of anti-alpha-gal IgE antibodies, which in some individuals results in hypersensitivity reactions on consumption of red meat, innards, dairy, and gelatin. 2 Different tick species seem responsible: lone star tick ( Amblyomma americanum) (United States), Ixodes ricinus (Europe), and Ixodes holocyclus and I australianises (Australia), Amblyomma variegatum (Africa—Ivory coast), Haemaphysalis longicornis (Korea), H longicornis and Amblyomma testudinarium (Japan), Amblyomma cajennense (Panama, Costa Rica), Amblyomma sculptum (Brazil). 2 , 5 , 6 In the United Kingdom, a culprit tick species is yet to be identified, but I ricinus is likely given its distribution in Europe. 6 Hypersensitivity reactions of varying severity. They can present with cutaneous (pruritus, urticaria, angioedema), gastrointestinal, and systemic symptoms, including anaphylaxis, and are often delayed (3-8 hours post food). 1 Alpha-gal also might be responsible for hypersensitivity reactions to cetuximab, snake anti-venom, and Varicella zoster vaccine. 2 , 7 |
Annals of Allergy, Asthma & Immunology. 2019 Dec 1;123(6):616-8. | United Kingdom UK |
| Hashizume H, Fujiyama T, Umayahara T, Kageyama R, Walls AF, Satoh T. | 2018 | Repeated Amblyomma testudinarium tick bites are associated with increased galactose-a-1,3-galactose carbohydrate IgE antibody levels: a retrospective cohort study in a single institution. Background: Alpha-gal syndrome is a hypersensitivity reaction to red meat mediated by IgE antibody specific to galactose-α-1,3-galactose carbohydrate (alpha-gal). Amblyomma tick bites are associated with this condition, but the pathophysiology is not understood. Objective: To clarify the mechanism of development of alpha-gal syndrome after tick bites. Methods: We compared alpha-gal antibody levels between patients with and without a history of tick bites and examined histologic stainings of tick bite lesions between patients with and without detectable alpha-gal IgE antibody. Results: Patients who had ≥2 tick bites had higher levels of alpha-gal IgE antibody compared with those with only 1 tick bite or healthy individuals. On histologic investigation, greater numbers of basophils and eosinophils, but not mast cells, were observed infiltrating lesions of patients with ≥2 tick bites compared with those with 1 tick bite. Type 2 cytokine-producing T-cell infiltration was predominantly observed in such patients. Limitations: The study was conducted at a single institution in Japan. Conclusion: In Amblyomma tick bite lesions, basophils; eosinophils; and type 2, cytokine-producing T cells infiltrate the skin and alpha-gal IgE antibodies are produced. These findings provide a potential mechanistic connection between Amblyomma bites and red meat hypersensitivity. |
Journal of the American Academy of Dermatology. 2018 Jun 1;78(6):1135-41. | Vector; Amblyomma testudarium; tick bites; multiple tick bites; increases in alpha-gal Ige; mechanism of induction |
| Hawkins RB, Frischtak HL, Kron IL, Ghanta RK. | 2016 | Premature Bioprosthetic Aortic Valve Degeneration Associated with Allergy to Galactose-Alpha-1,3-Galactose. We present the cases of two patients with bioprosthetic aortic valves who developed an allergy to alpha-gal. Each had premature degeneration of their bioprosthesis and demonstrated rapidly increasing transvalvular gradients after development of their allergy. Each underwent successful replacement with a mechanical aortic valve within 1-2 years of symptom onset. ...Although there is little evidence that device companies are aggressively developing solutions for carbohydrate antigens, the process for bringing these advances to market is long; the Food and Drug Administration regulates not only the new valve but also the genetically modified animal. With 3 potential solutions to alleviate α-gal–related bioprosthetic valve degeneration, we hope that the academic and biotechnology communities can come together to find the best option and bring this to market rapidly. We must work together to continue improving the care of our patients. |
Journal of cardiac surgery. 2016 Jul;31(7):446-8. | cardiac; cardiovascular; cardiology; atherosclerosis; CAD coronary artery disease; medical products; bioprosthetic heart valve; pharmacy; pharmaceutical |
| Hawkins RB, Ghanta RK. | 2017 | Mammalian Meat Allergy and Advances in Bioprosthetic Valve Technology Reply. Letters to the Editor. We read with interest the letter to the editor by Ankersmit and colleagues. ‘‘When Meat Allergy Meets Cardiac Surgery: A Driver for Humanized Bioprosthesis.’’ The University of Virginia has led the epidemiologic characterization of the mammalian meat allergy to galactose-a-1,3-galactose (a-gal). |
The Journal of thoracic and cardiovascular surgery. 2017 Oct;154(4):1327. | bioprosthetic heart valve; cardiac; cardiothoracic surgery; cardiac; cardiovascular; cardiology; atherosclerosis; CAD coronary artery disease; medical products; bioprosthetic heart valve; pharmacy; pharmaceutical |
| Hawkins RB, Wilson JM, Mehaffey JH, Platts-Mills TA, Ailawadi G. | 2020 | Safety of Intravenous Heparin for Cardiac Surgery in Patients with Alpha-Gal Syndrome. Background:Alpha-gal syndrome is a tick-acquired disease caused by IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), causing allergic reactions to meat and products sourced from non-primate mammals. As heparin is porcine-derived, we hypothesized that patients with alpha-gal syndrome who received high-dose heparin for cardiac surgery would have increased risk of anaphylaxis. MethodsAll cardiac surgery patients at an academic medical center from 2007-2019 were cross-referenced with research and clinical databases for the alpha-gal IgE blood test. Clinical data was obtained through the institutional Society of Thoracic Surgeons Adult Cardiac Database and chart review. Patients were stratified by development of an allergic reaction for univariate statistical analysis. ResultsOf the 8,819 patients, 17 (0.19%) had a positive alpha-gal test prior to cardiac surgery. Of these 17 patients, 4 (24%) had a severe allergic reaction. The median alpha-gal titer was significantly higher in patients with a reaction (75 [61-96] vs 8 [3-18] IU/mL, p=0.006). There were no differences in median heparin loading dose, total dose, or maximum activated clotting time (all p>0.05). In a subgroup of 8 patients with recent alpha-gal IgE level, 4 (50%) developed an allergic reaction. ConclusionsAlthough alpha-gal is rare in patients undergoing cardiac surgery, there is up to a 50% risk of serious allergic reaction to heparin for cardiopulmonary bypass. Higher preoperative alpha-gal titers may confer a higher risk of severe allergic reaction. For patients with a clinical suspicion of alpha-gal syndrome, we recommend pre-screening with IgE levels and pre-medicating prior to receiving high doses of intravenous heparin. |
The Annals of Thoracic Surgery. 2020 Oct 5. | Cardiac surgery; cardiothoracic; cardiology; heart; pharmaceutical; pharmacy; medical prroducts; heparin, perioperative; anesthesia |
| Heffes-Doon A, McGintee E, Akerman M, Banta E. | 2022 | Abstract only A017 ALPHA-GAL SYNDROME ON EASTERN LONG ISLAND: IGE RATIOS MORE GENERALIZABLE THAN ALPHA-GAL SIGE ALONE. Conclusion This represents the first study describing AGS on Long Island; AGS should be on the differential for cases of idiopathic anaphylaxis. The difference between alpha-gal sIgE levels for males and females suggests isolated use of these levels should be replaced by ratios or percentages. Weight may be one of many contributors explaining the difference in alpha-gal sIgE between males and females. |
Annals of Allergy, Asthma & Immunology. 2022 Nov 1;129(5):S6. | New York; Long Island; diagnosis; ratio |
| Hennings L, Artaud C, Jousheghany F, Monzavi-Karbassi B, Pashov A, Kieber-Emmons T. | 2011 | Carbohydrate mimetic peptides augment carbohydrate-reactive immune responses in the absence of immune pathology. Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses. |
Cancers. 2011 Dec;3(4):4151-69. | peptide mimetics |
| Herman-Giddens ME, Herman-Giddens DM. | 2017 | Retrospective Case Reports of Two Central North Carolina Residents: Frequency of Tick Bites and Associated Illnesses, 2001-2014. BACKGROUND: Tick bites are a source of illness and disease agents that may lead to morbidity and occasional fatalities in North Carolina. Public health interest in tick-borne illness and disease has increased due to continuing discoveries of tick-borne diseases and their increasing geographic spread and disease incidence. There are no data published on lay individuals with cumulative tick bites and associated illnesses over a period of years. METHODS: We learned of a married couple living on a central North Carolina property who had used reasonable bite prevention methods, kept attached ticks after removal, and recorded dates and related illness records from 2001–2014. We obtained permission to analyze their records. Ticks were identified by an entomologist. RESULTS: The male subject had a total of 219 bites from identifiable ticks comprising 213 Amblyomma americanum, 4 Dermacentor variabilis, and 2 Ixodes scapularis. He was treated for possible Rocky Mountain spotted fever once and presumed Southern Tick Associated Rash Illness once. The female subject had 193 bites comprising 168 A. americanum, 23 D. variabilis, and 2 I. scapularis. She was treated for 4 episodes of presumed Southern Tick Associated Rash Illness and one possible case of a tick-borne infection. Several years of data were missing for both subjects. LIMITATIONS: This retrospective report relied on the subjects' own records for much of the data. The experience of these individuals cannot be generalized. Diagnoses of these tick-related illnesses are inexact due to lack of tests for the Southern Tick Associated Rash Illness and cross-reactivity in tests for spotted fever rickettsiosis. CONCLUSIONS: This report demonstrates that tick-associated illnesses, including episodes fitting the Center for Disease Control and Prevention's definition of the Southern Tick Associated Rash Illness, may be more common than realized. Use of personal tick protection measures for tick bite illness and disease prevention may not be sufficiently protective. Further subject-based research on tick and disease burden on selected populations would be informative, and could aid in planning appropriate actions to mitigate the effects of tick-borne disease in North Carolina. |
North Carolina Medical Journal. 2017 May 1;78(3):156-63. | |
| Hess S, O'Leary D. | 2015 | ALPHA GAL ALLERGY DIAGNOSIS MADE BY LISTENING TO PATIENT'S FAMILY: A CASE REPORT. |
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY. 2015 Nov 1; 115( 5): A68-A69. | |
| Higuita NI, Franco-Paredes C, Henao-Martínez AF. | 2021 | The expanding spectrum of disease caused by the Lone Star Tick, Amblyomma americanum. Ticks are remarkable vectors of a diverse and growing list of infectious agents of importance to both medical and veterinary disciplines. The tick Amblyomma americanum is one of the most frequently identified ticks in the United States with an expanding spectrum of human disease given its vast geographic range. The recently described Bourbon and Heartland viruses are likely transmitted by the Lone Star tick and are just two of the several novel tick-borne pathogens discovered in recent decades. The review will focus on these two viruses that can cause illness with similar characteristics to other diseases transmitted by the Lone Star tick. Healthcare professionals should consider these viruses in patients presenting with an ailment suggestive of a tick-born rickettsial disease that fails to improve with treatment with doxycycline. Additionally, some individuals may develop life-threatening allergic reactions triggered by the bite of the Lone Star tick. |
life.;11:12. | lone star tick; tick borne disease; tickborne disease; heartland virus; bourbon virus; differential |
| Hilger C, Clark E, Swiontek K, Chiriac AM, Caimmi DP, Demoly P, Bourrain JL. | 2020 | Anaphylaxis to bovine serum albumin tissue adhesive in a patient without meat allergy No abstract available |
J Investig Allergol Clin Immunol. 2020;30(5). | Pharmacy; pharmaceutical; bovine serum albumin; bioglue; cyolife; pork-cat syndrome; cat allergy |
| Hilger C, Fischer J, Swiontek K, Hentges F, Lehners C, Eberlein B, Morisset M, Biedermann T, Ollert M. | 2016 | * Two galactose-alpha-1,3-galactose carrying peptidases from pork kidney mediate anaphylactogenic responses in delayed meat allergy. Background: Serum IgE antibodies directed at galactose-alpha-1,3-galactose (alpha-Gal) are associated with a novel form of delayed anaphylaxis occurring upon consumption of red meat or innards. Pork kidney is known as the most potent trigger of this syndrome, but the culprit allergens have not yet been identified. The aim of this study was the identification and characterization of pork kidney proteins mediating delayed anaphylactic reactions through specific IgE to alpha-Gal. Methods: A cohort of 59 patients with specific IgE to alpha-Gal was screened by immunoblot for IgE-reactive proteins in pork kidney. Proteins were identified by peptide mass fingerprinting. Isolated proteins were assayed in ELISA and ELISA inhibition, basophil activation and skin prick test. Results: Several IgE-binding proteins of high molecular weight (100- >200 kDa) were detected in pork kidney extracts by immunoblot using patient sera and an anti-alpha-Gal antibody. Two major IgE-binding proteins were identified as porcine angiotensin-I-converting enzyme (ACE I) and aminopeptidase N (AP-N). Reactivity of patient sera and anti-alpha Gal antibody to both proteins was abolished by carbohydrate oxidation. The alpha-Gal IgE epitopes were resistant to heat denaturation. Pork kidney extract, isolated ACE I, and AP-N were able to activate patient basophils and elicit positive responses in skin prick tests. Conclusion: Two cell-membrane proteins carrying alpha-Gal epitopes were identified in pork kidney. For the first time, isolated meat proteins were shown to induce basophil activation in patients with delayed anaphylaxis to red meat providing further confirmation for the clinical relevance of these alpha-Gal-carrying proteins. |
Allergy. 2016 May;71(5):711-9. | Alpha-gal carrying proteins; organs; kidney; lungs; intestines; heat stability; thermal stability |
| Hilger C, Fischer J, Wölbing F, Biedermann T. | 2019 | Role and mechanism of galactose-alpha-1,3-galactose in the elicitation of delayed anaphylactic reactions to red meat. Purpose of Review: The alpha-Gal (α-Gal) syndrome is characterized by the presence of IgE antibodies directed at the carbohydrate galactose-alpha-1,3-galactose (α-Gal). In this article, we review the presence of α-Gal in food and non-food sources; we discuss the evolutionary context of the antibody response to α-Gal and highlight immune responses to α-Gal and other carbohydrates. Recent findings: IgE antibodies have been associated with delayed allergy to red meat. In addition to food, drugs, and other products of animal origin are increasingly perceived as a risk for patients sensitized to α-Gal. The link between tick bites and anti-α-Gal IgE-antibody production that has been established first by epidemiological studies has now been confirmed in mouse models. Summary: The anti-α-Gal immune response is complex and characterized by a unique feature. IgM and IgG antibodies have been found to confer protection against pathogens whereas the IgE-response to α-Gal is detrimental and causes severe reactions upon exposure to mammalian meat and other products. |
Current allergy and asthma reports. 2019 Jan 1;19(1):3. | Wolbing; review article |
| Hilger C, Kohnen M, Grigioni F, Lehners C, Hentges F. | 1997 | Allergic cross‐reactions between cat and pig serum albumin: Study at the protein and DNA levels. After observing a patient allergic to cat dander and pork but devoid of other allergies, we prospectively screened patients known to be allergic to cat for a second sensitization to pork. After collecting the sera of 10 young patients found to contain specific IgE to cat dander and pork, we undertook this study to detect the possible cross‐reactive allergen, define its molecular characteristics, and evaluate its clinical relevance. Through immunoblotting techniques, cat and porcine serum albumin were found to be jointly recognized molecules. These findings were further analyzed by specific anti‐albumin IgE titrations and cross‐inhibition experiments. Cat serum albumin cDNA was obtained from cat liver, and the corresponding amino acid sequence was deduced and compared to the known porcine and human serum albumin sequences. Inhibition experiments showed that the spectrum of IgE reactivity to cat serum albumin completely contained IgE reactivity to porcine serum albumin, suggesting that sensitization to cat was the primary event. In two cohorts of cat‐allergic persons, the frequency of sensitization to cat serum albumin was found to lie between 14% and 23%. Sensitization to porcine albumin was found to lie between 3% and 10%. About 1/3 of these persons are likely to experience allergic symptoms in relation to pork consumption. Sensitization to cat serum albumin should be considered a useful marker of possible cross‐sensitization not only to porcine serum albumin but also to other mammalian serum albumins. |
Allergy. 1997 Feb;52(2):179-87. | |
| Hilger C, Swiontek K, Codreanu-Morel F, Morisset M. | 2018 | Alpha-Gal beyond meat. | Journal of general internal medicine. 2013 Feb 1;28(2):322-5. | |
| Hils M, Wölbing F, Hilger C, Fischer J, Hoffard N, Biedermann T. | 2020 | The history of carbohydrates in type I allergy. Although first described decades ago, the relevance of carbohydrate specific antibodies as mediators of type I allergy had not been recognized until recently. Previously, allergen specific IgE antibodies binding to carbohydrate epitopes were considered to demonstrate a clinically irrelevant cross-reactivity. However, this changed following the discovery of type I allergies specifically mediated by oligosaccharide structures. Especially the emerging understanding of red meat allergy characterized by IgE directed to the oligosaccharide alpha-gal showed that carbohydrate-mediated reactions can result in life threatening systemic anaphylaxis which in contrast to former assumptions proves a high clinical relevance of some carbohydrate allergens. Within the scope of this review article, we illustrate the historical development of carbohydrate-allergen-research, reaching from only diagnostically relevant crossreactive-carbohydrate-determinants to clinically important antigens mediating type I allergy. Focusing on clinical and immunological features of the alpha-gal syndrome, we highlight the discovery of oligosaccharides as potentially highly immunogenic antigens and mediators of type I allergy, report what is known about the route of sensitization and the immunological mechanisms involved in sensitization and elicitation phase of allergic responses as well as currently available diagnostic and therapeutic tools. Finally, we briefly report on carbohydrates being involved in type I allergies different from alpha-gal. |
Frontiers in Immunology. 2020;11:2493. | carbohydrate allergy |
| Hinterholzer A, Moises J, Regl C, Schwap S, Rapp E, Huber CG, Schubert M. | 2022 | Unambiguous identification of α-Gal epitopes in intact monoclonal antibodies by NMR spectroscopy. The α-Gal epitope consisting of the terminal trisaccharide Galα1,3Galβ1,4GlcNAc exposed on cell or protein surfaces can cause severe immune reactions, such as hypersensitivity reactions, in humans. This epitope is also called the xenotransplantation epitope because it is one of the main reasons for the rejection of non-human organ transplants by the human innate immune response. Recombinant therapeutic proteins expressed in murine cell lines may contain α-Gal epitopes, and therefore their absence or presence needs to be tightly monitored to minimize any undesired adverse effects. The analytical identification of α-Gal epitopes in glycoproteins using the common standard techniques based on liquid chromatography and mass spectrometry is challenging, mainly due to the isobaricity of hexose stereoisomers. Here, we present a straightforward NMR approach to detect the presence of α-Gal in biotherapeutics based on a quick screen with sensitive 1H-1H TOCSY spectra followed by a confirmation using 1H-13C HSQC spectra. |
InmAbs 2022 Dec 31 (Vol. 14, No. 1, p. 2132977). Taylor & Francis. | pharmacy; pharmaceutical; biologic; monoclonal antibodies; chemical detection; NMR |
| Hodgeman N, Horn CL, Paredes A. | 2019 | An Unusual Mimicker of Irritable Bowel Disease: 1855. INTRODUCTION: Delayed anaphylactic reaction to red meat is a rare phenomenon that was first recognized during clinical trials for cetuximab. Through careful retrospective study of the patients afflicted, it was discovered there was a geographic overlap with the Amblyomma americanum tick, also known as the lone star tick. These patients were also found to have IgE antibodies to the peptide galactose-alpha-1,3-galactose (α-gal), commonly found in non-primate mammalian meat. Since the trials with cetuximab, allergic reactions to red meat has been documented in patients who have not been exposed to cetuximab, believed to be caused by the bite of the lone star tick. We present the case of a 46-year-old male who was evaluated for 6 months of progressive gastrointestinal symptoms and was ultimately found to have elevated α-gal IgE levels. CASE DESCRIPTION/METHODS: A 46-year-old male was evaluated for 6 months of progressive abdominal distress following consumption of red meat. He reported severe nausea, vomiting and diarrhea that persisted for hours after consumption of red meat. He had not experienced anaphylaxis, but had a 40 pound weight loss since symptom onset. He had recently moved to Texas from Maryland and denied any outdoor recreation, to include camping, hiking, or known tick bites. Initial work up was unrevealing for infectious or inflammatory cause of his symptoms, and cross-sectional imaging was noncontributory. EGD and colonoscopy were notable only for mild esophagitis and duodenitis. Due to concern for α-gal syndrome and at the prompting of the patient and his wife, total serum IgE and α-gal IgE were drawn, both noted to be elevated at 6215 IU/mL and 0.2 kU/L (ULN < 0.10 kU/L) respectively. A presumptive diagnosis of α-Gal syndrome was made and he was referred to nutrition for dietary counseling. Following removal of red meat from his diet, he reported his gastrointestinal symptoms had markedly improved. DISCUSSION: This case demonstrates the unique and uncommon condition known as α-gal syndrome. Our presentation’s presentation was not as dramatic as other documented cases, which likely led to a delay in his initial diagnosis. Diagnosis is made by first noting an elevated serum IgE. Specific α-gal IgE levels can then be drawn, which if elevated has high sensitivity and specificity for this syndrome. Improvement on a red meat restricted diet is ultimately diagnostic. As was seen in this case, improvement |
American Journal of Gastroenterology. 2019 Oct 1;114(2019 ACG Annual Meeting Abstracts):S1039. | diagnosis; differential; gastroenterology; IBD; symptoms; GI |
| Hodžić A, de la Fuente J, Cabezas-Cruz A. | 2020 | COVID-19 in the Developing World: Is the Immune Response to α-Gal an Overlooked Factor Mitigating the Severity of Infection? Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has affected millions of people worldwide. Considerably lower prevalence and fatality rates resulting from COVID-19 are reported in Africa and Asia than in the industrialized world. In this Viewpoint, we discuss the possibility that this intriguing phenomenon could be, among other factors, due to protective immunity of the oligosaccharide galactose-α-1,3-galactose (α-Gal). The α-Gal immunity induced by gut microbiota that express the same glycan modification may prevent COVID-19 through the activation of different mechanisms involved in SARS-CoV-2 neutralization and the downregulation of the inflammatory response in the lungs of infected patients. |
ACS Infectious Diseases. 2020 Nov 12. | Hodzic; virus; coronavirus; Covid-19 |
| Hodžić A, Mateos-Hernández L, de la Fuente J, Cabezas-Cruz A. | 2019 | Delayed hypersensitivity reaction to mammalian galactose-alpha-1,3-galactose (alpha-gal) after repeated tick bites in a patient from France. The alpha-Gal syndrome is a tick-associated and emerging IgE-mediated hypersensitivity reaction directed against the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-Gal) epitope after red meat intake. Herein, we describe a clinical case of a 44-year-old French patient who suffered from recurrent anaphylactic reactions after mammalian meat consumption for five years before the final diagnosis of the alpha-Gal syndrome was established in 2018. The patient also reported multiple tick bites prior to symptom onset. This unique type of allergy has increasingly been reported across the world, but it is still unknown in many European countries. Therefore, the present clinical case should increase awareness among primary care practitioners and further improve the early diagnosis of the alpha-Gal syndrome in affected individuals. |
Ticks and tick-borne diseases. 2019 Aug 1;10(5):1057-9. | Hodzic Mateos-Hernandez |
| Hodžić A, Mateos-Hernández L, Fréalle E, Román-Carrasco P, Alberdi P, Pichavant M, Risco-Castillo V, Le Roux D, Vicogne J, Hemmer W, Auer H. | 2020 | Infection with Toxocara canis Inhibits the Production of IgE Antibodies to α-Gal in Humans: Towards a Conceptual Framework of the Hygiene Hypothesis?. α-Gal syndrome (AGS) is a type of anaphylactic reaction to mammalian meat characterized by an immunoglobulin (Ig)E immune response to the oligosaccharide α-Gal (Galα1-3Galβ1-4GlcNAc-R). Tick bites seems to be a prerequisite for the onset of the allergic disease in humans, but the implication of non-tick parasites in α-Gal sensitization has also been deliberated. In the present study, we therefore evaluated the capacity of helminths (Toxocara canis, Ascaris suum, Schistosoma mansoni), protozoa (Toxoplasma gondii), and parasitic fungi (Aspergillus fumigatus) to induce an immune response to α-Gal. For this, different developmental stages of the infectious agents were tested for the presence of α-Gal. Next, the potential correlation between immune responses to α-Gal and the parasite infections was investigated by testing sera collected from patients with AGS and those infected with the parasites. Our results showed that S. mansoni and A. fumigatus produce the terminal α-Gal moieties, but they were not able to induce the production of specific antibodies. By contrast, T. canis, A. suum and T. gondii lack the α-Gal epitope. Furthermore, the patients with T. canis infection had significantly decreased anti-α-Gal IgE levels when compared to the healthy controls, suggesting the potential role of this nematode parasite in suppressing the allergic response to the glycan molecule. This rather intriguing observation is discussed in the context of the 'hygiene hypothesis'. Taken together, our study provides new insights into the relationships between immune responses to α-Gal and parasitic infections. However, further investigations should be undertaken to identify T. canis components with potent immunomodulatory properties and to assess their potential to be used in immunotherapy and control of AGS. |
Vaccines. 2020 Jun;8(2):167. | Hodzic A; Mateos-Hernandez L; Frealle E; ectoparasites; endoparasites; |
| Hodžić A, Mateos-Hernández L, Leschnik M, Alberdi P, Rego RO, Contreras M, Villar M, De La Fuente J, Cabezas-Cruz A, Duscher GG | 2019 | Tick bites induce anti-α-Gal antibodies in dogs. Due to the functional inactivation of the gene encoding for the enzyme that is involved in the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal) synthesis, humans and Old-World primates are able to produce a large amount of antibodies against the glycan epitope. Apart from being involved in the hyperacute organ rejection in humans, anti-alpha-Gal antibodies have shown a protective effect against some pathogenic agents and an implication in the recently recognized tick-induced mammalian meat allergy. Conversely, non-primate mammals, including dogs, have the ability to synthetize alpha-Gal and, thus, their immune system is not expected to naturally generate the antibodies toward this self-antigen molecule. However, in the current study, we detected specific IgG, IgM, and IgE antibodies to alpha-Gal in sera of clinically healthy dogs by an indirect enzyme-linked immunosorbent assay (ELISA) for the first time. Furthermore, in a tick infestation experiment, we showed that bites of Ixodes ricinus induce the immune response to alpha-Gal in dogs and that the resulting antibodies (IgM) might be protective against Anaplasma phagocytophilum. These findings may help lead to a better understanding of the underlying mechanisms involved in mammalian meat allergy and tick-host-pathogen interactions, but they also open up the question about the possibility that dogs could develop an allergy to mammalian meat after tick bites, similar to that in humans. |
Vaccines. 2019 Sep;7(3):114. | Hodzic Mateos-Hernandez dogs |
| Holbert SE, Patel D, Rizk T, Dimitri NG, Jones M. | 2020 | Intraoperative Anaphylaxis in Response to Hemostatic Agents With Protein Derivatives. Topical hemostatic agents are commonly used in a wide variety of surgical procedures to assist in hemostasis. However, the use of these agents is not without risk as many contain biologically active agents derived from human and animal products that have the potential to cause adverse reactions. This case report covers a 44-year-old man with a history of alpha-gal syndrome who was scheduled for an open reduction and internal fixation of a left distal radius fracture. Alpha-gal syndrome is characterized by an IgE-mediated type 1 hypersensitivity reaction to a mammalian oligosaccharide epitope. Patients with this condition have a history of a past tick bite and subsequent development of an allergic reaction to mammalian protein products, most notably red meat. The patient had concerns about products used during surgery and potential reactions based on his allergy. The intent of this case report is to promote physician awareness of the widespread use of mammalian products in surgical hemostatic agents and potential immunogenic reactions. By increasing awareness of the alpha-gal syndrome, the goal is that medical device companies will actively disclose product components that could potentiate these adverse reactions and continue to develop alternative agents. |
Cureus. 2020 Aug;12(8). | Pharmaceutical; medical product; hemostatic agent; surgifoam; recothrom |
| Hollander DH. | 1995 | Beef allergy and the persian gulf syndrome. It is suggested that the Persian Gulf Syndrome (PGS) is caused by beef allergy. In the first symptomless phase, as a result of an energetic US Army immunizing program, using sera with adjuvants to produce detectable antibody levels, the subjects not only developed immunity to the targeted substances, but also became sensitized to one or more of the other substances in the immunizing sera, and specifically to beef protein. The subjects remained healthy while in the war zone on a restricted diet essentially free from beef, but developed PGS after they came home, and were again able to obtain steaks and hamburgers. |
Medical hypotheses. 1995 Sep 1;45(3):221-2. | Gulf War Syndrome Persian Gulf Syndrome PGS vaccine |
| Homann A, Schramm G, Jappe U. | 2017 | Glycans and glycan-specific IgE in clinical and molecular allergology: Sensitization, diagnostics, and clinical symptoms. Glycan-specific IgE antibodies cross-react with highly similar or even identical carbohydrate structures on a variety of different natural allergens, the so-called cross-reactive carbohydrate determinants (CCDs). In clinical practice CCDs often interfere with the specificity of in vitro allergy diagnostics, thus impairing allergy therapy decisions for individual patients. Strikingly, these IgE antibodies directed against CCDs often do not cause clinically relevant allergy symptoms. On the other hand, the IgE-binding glycan allergen galactose-alpha-(1,3)-galactose (alpha-Gal) is associated with IgE-mediated delayed anaphylaxis in meat allergy. The reason for this discrepancy is not known. The discovery of alpha-Gal stimulated new discussions and investigations regarding the relevance of anti-glycan IgE for allergic diseases. In this review the effect of glycans and glycan-specific IgE on sensitization to allergens and allergy diagnosis is described. Because parasite infections elicit a similar immunologic environment as allergic diseases, the association of glycan-specific antibodies against parasite glycoproteins with glycan structures on allergens is discussed. |
Journal of Allergy and Clinical Immunology. 2017 Aug 1;140(2):356-68. | review article |
| Hon KL, Chan IH, Chow CM, Wang SS, Lam CW, Ng PC, Leung TF. | 2011 | Specific IgE of common foods in Chinese children with eczema. Food atopy is important but inadequately studied among children with atopic dermatitis (AD). We evaluated whether any association existed between AD severity, quality of life, total IgE, eosinophil counts, and the number of food items sensitized. Specific IgE of ten common food items was measured for a group of consecutive AD patients (n = 85) enrolled during a randomized trial and correlated the findings with eczema severity. Twenty‐four patients (28%) were negative for any of the ten common food items. The most commonly sensitized foods were shrimp (54%), egg white (43%), wheat (42%), and peanut (41%). Atopy to beef as a protein and orange as a fruit were least common among the food items studied, even among patients positive for 8–9 IgE items. Patients with severe AD (objective SCORAD > 40) were more likely to be positive for at least one of the food items (Yates corrected p = 0.024 for ≥1 food‐specific IgE in severe vs. moderate AD, OR 3.42 and 95% CI 1.15–10.32); and for at least seven of the food items (p = 0.001 for ≥7 food‐specific IgE vs. nil with OR 11.67 and 95% CI 2.29–67.77), respectively. The Spearman coefficients between the number of positive food‐specific IgE and total SCORAD, objective SCORAD, area of AD involvement, Children’s Dermatology Life Quality Index (CDLQI), total IgE levels, and eosinophil counts were 0.42 (p < 0.001), 0.45 (p < 0.001), 0.50 (p < 0.001), 0.17 (p = 0.116), 0.80 (p < 0.001), and 0.22 (p = 0.043), respectively. Specific IgE levels for beef correlated with all the other food‐specific IgE levels, including cow’s milk (ρ = 0.061, p < 0.001) and soy (ρ = 0.70, p < 0.001). The number of common food items sensitized correlated with disease severity, extent, and total IgE levels. IgE sensitization to beef protein is unlikely in the majority of children with AD, but its serum IgE level is associated with disease severity and risk of sensitization to other foods. |
Pediatric allergy and immunology. 2011 Feb;22(1‐Part‐I):50-3. | Asia; China; pediatric; prevalence; dermatology; eczema |
| Honda Y, Yamamoto M, Nakajima K, Chinuki Y, Sano S. | 2015 | Delayed Anaphylaxis after Eating Beef Likely Due to IgE Antibody Specific for Galactose-a-1,3-galactose. A 67-year-old Japanese man experienced 4 episodes of delayed anaphylaxis between March, 2012 and October, 2013. Delayed anaphylactic attacks occurred several hours after eating egg-bearing flatfish or beef. The skin prick allergen test was positive for beef, pork, and cow's milk. Moreover, CAP-RAST testing revealed the presence of IgE antibodies specific to beef, pork, cow's milk, and dandruff of cat and dog. Western blotting analysis using the patient's sera showed a putative IgE with high affinity for the 50-kDa protein of the mouse chimeric antibody, cetuximab, which contains the oligosaccharide galactose-α-1, 3-galactose (α-gal), a common epitope for the delayed anaphylaxis response to beef meat. Since the patient lived in an area where Japanese spotted fever, for which a tick bites are a cause, is endemic, he might have a history of unnoticed tick bites that sensitized him to α-gal. Furthermore, we speculate that some medicines including aspirin might lower the threshold for exposure to this allergen above which anaphylactic symptoms occur. |
本田由美, 山本真有子, 中島喜美子, 千貫祐子, 佐野栄紀. 牛肉による遅発型アナフィラキシー. 西日本皮膚科. 2015 Oct 1;77(5):453-5. | Japan; fish; roe; flounder |
| Hong DI, Bankova L, Cahill KN, Kyin T, Castells MC, Maggi, Peck, Garai, Castells, Hanauer, Cheifetz. | 2012 | Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies. Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion. While the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who otherwise would not be able to tolerate their monoclonal antibody therapy owing to drug-induced anaphylaxis. This article reviews the current literature on desensitization and other readministration protocols to monoclonal antibodies with an emphasis on four agents: rituximab, infliximab, cetuximab and trastuzumab. |
Expert review of clinical immunology. 2012 Jan 1;8(1):43-54. | mAb; monoclonal antibody; biologic; biological agent |
| Hopps S, Medina P, Pant S, Webb R, Moorman M, Borders E. | 2013 | Cetuximab hypersensitivity infusion reactions: Incidence and risk factors. INTRODUCTION: Cetuximab is a chimeric mouse-human (30:70) IgG1 monoclonal antibody that competitively inhibits the binding of epidermal growth factor. Cetuximab is generally well tolerated; however, hypersensitivity infusion reactions have been reported. The incidence at the University of Oklahoma was currently unknown, though anecdotally high. The purpose of this study was to determine the incidence of severe HIRs and secondarily to determine risk factors for cetuximab-induced hypersensitivity infusion reactions. METHODS AND RESULTS: A retrospective chart review was conducted and included all patients that received cetuximab from 2005 to 2010 at the outpatient clinics of the Oklahoma University Health Sciences Center. A total of 153 patients were included in the analysis. The overall incidence proportion of severe hypersensitivity infusion reactions was 12.4%. Male patients had an increased incidence of severe hypersensitivity infusion reactions compared to female patients (20.6% vs. 5%, p = 0.0036). Current smokers had an increased incidence of severe hypersensitivity infusion reactions of 23.6% when compared to never smokers or former smokers, p = 0.0012. Cervical cancer had a significantly decreased risk of severe hypersensitivity infusion reactions when compared to other tumor types (5.3% vs. 16.7%, p = 0.0387). Multivariate analysis identified risk factors associated with severe HIRs to be: male gender, RR = 3.9, p = 0.01 and current smokers, RR = 3.98, p = 0.0048. . CONCLUSION: Patients at the University of Oklahoma had an increased incidence of severe hypersensitivity infusion reactions when compared to the national average. Male patients and current smokers were found to be at increased risk for severe hypersensitivity infusion reactions in our study. Further investigation is warranted. |
Journal of Oncology Pharmacy Practice. 2013 Sep;19(3):222-7. | |
| Hosen J, Perzanowski M, Carter MC, Odhiambo J, Ngari P, Satinover S, Platts-Mills TA. | 2008 | IgE antibodies to helminths and the cross-reactive oligosaccharide galactose-alpha-1,3-galactose (alphaGal) among children in a village in Africa. Rationale: Recent reports have identified IgE antibodies to alphaGal as a cause of anaphylactic reactions to the mAb cetuximab. These IgE antibodies cross-react with proteins from cat, dog, beef and pork. Previous reports showed that children in Africa had IgE ab to cat allergens despite negative skin tests and no exposure to cats. We report here the connection between IgE ab to alphaGal, cat proteins and helminth parasites. Methods: Sera from children (age 9-11) in rural (Kabati) and urban (Thika) Kenya and Atlanta, GA were assayed for IgE ab to alphaGal, cat, mite, Ascaris and Echinococcus, using ImmunoCAP or the modified assay with biotinylated antigens bound to Streptavidin CAP. . Results: Of 130 sera tested from Kabati 100 were positive for alphaGal IgE (GM: 3.96 IU/mL). In Thika 36 out of 123 were positive, in Atlanta 0 out of 52 were. In Kabati 95 of 130 sera were positive for Ascaris and 75 were positive for Echinococcus. The correlation with IgE to alphaGal was much stronger for Echinococcus (r = 0.84; p < 0.001) than for Ascaris (r = 0.19; p = 0.05). There was a close correlation between IgE ab to cat and IgE to alphaGal (r = 0.86; p < 0.001). . Conclusions: IgE ab to alphaGal is widespread among children in an African village, less common in a small town and virtually non-existent among African American children in Atlanta. While the cause of sensitization is unclear, the correlation with Echinococcus suggests a tapeworm could be responsible. The correlation with IgE ab to alphaGal explains the previously enigmatic IgE ab to cat found in African sera. |
Journal of Allergy and Clinical Immunology. 2008 Feb 1;121(2):S140. | Africa; Kenya; helminths |
| Houchens N, Hartley S, Commins SP, Claar D, Saint S. | 2021 | Hunting for a Diagnosis A 47-year-old man presented to a Michigan emergency department in January with a 1-day history of presyncope, swelling of the eyelids, and a diffuse pruritic rash. He also reported a 3-week history of postprandial watery bowel movements, without blood. Beginning 5 days before presentation, he had noted diffuse crampy abdominal pain and nausea with occasional nonbloody emesis. |
New England Journal of Medicine. 2021 Feb 4;384(5):462-7. | diagnosis; GI variant |
| Howanietz H, Lubec G. | 1985 | Idiopathic nephrotic syndrome, treated with steroids for five years, found to be allergic reaction to pork. No abstract available. |
The Lancet. 1985 Aug 24;326(8452):450. | Nephrology; nephrotic syndrome; kidney |
| Hsieh YH, Ofori JA. | 2011 | Blood-derived products for human consumption. Blood, the first by-product obtained after the slaughter of an animal, has long been used in European and Asian countries as an ingredient in traditional foods such as blood sausages, puddings, blood soups, breads and crackers (Mandal, Rao, Kowale, & Pal, 1999). For many years US slaughter houses used to discard blood as an unwanted by-product (Halliday, 1973) but its high nutritional value, coupled with serious disposal issues, has fueled recent research and industrial efforts to incorporate blood proteins into a wide range of food products. Commercial blood products, either from plasma or the cellular fraction of blood including whole blood, serve particular functions in different products. Although they are mainly used in meat products, primarily to increase protein levels and enhance water binding and emulsifying capacity (Mandal, et al., 1999), advances in food technology mean that blood derived products are beginning to be found as ingredients in non-meat processed food and dietary supplements. Consumers are often unaware that some of these products are now being used in sectors of the food industry that hitherto did not use blood ingredients, with these often being declared on the label merely by their brand name or the name of the protein. This is a serious issue for Jews and Muslims, who are forbidden to eat anything derived from blood as a result of the dietary restrictions imposed by their religions, as well as others who avoid blood-tainted food or any product of animal origin due to ethical, cultural, or health reasons, or simple personal preference. Regulatory guidance in the proper labeling of these products is now crucial to protect consumers and the development of effective analytical methods for the detection of hidden ingredients derived from blood in food products is thus urgently needed. |
Revelation and Science. 2011;1(01). | Food; byproduct; ingredient; blood |
| Huai G, Qi P, Yang H, Wang Y. | 2016 | Characteristics of a-Gal epitope, anti-Gal antibody, a1,3 galactosyltransferase and its clinical exploitation (Review). The α-Gal epitope (Galα1,3Galα1,4GlcNAc‑R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti‑Gal antibody with the α‑Gal epitope, humans have a distinct anti‑α‑gal reactivity, which is responsible for hyperacute rejection of organs transplanted from α‑gal donors. In addition, the α1,3 galactosyltransferases (α1,3GT) can catalyze the synthesis of the α‑Gal epitope. Therefore, the α1,3GT gene, which encodes the α1,3GT, is developed profoundly. The distributions of the α‑Gal epitope and anti‑Gal antibody, and the activation of α1,3GT, reveal that the enzyme of α1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human α1,3‑GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the α1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the α‑Gal epitope and anti‑Gal antibody, they can be applied to clinical exploitation. Knocking out the α1,3GT gene will eliminate the xenoantigen, Gal(α1,3)Gal, so that the transplantation of α1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the α‑Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti‑Gal‑mediated autologous tumor vaccines, which express α‑Gal epitope to antigen‑presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, α‑Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues. |
International Journal of Molecular Medicine. 2016 Jan 1;37(1):11-20. | |
| Huang Z, Zhu H, Lin R, Wu L, An N, Zheng P, Sun B. | 2021 | Serum Albumin as a Cross-Reactive Component in Furry Animals May Be Related to the Allergic Symptoms of Patients with Rhinitis. Background: The prevalence of allergies has increased significantly in the past decade. Further research on allergic diseases caused by furry animals is of great importance for the clinical prevention, diagnosis and treatment of allergies. Objective: To identify the sensitization profile and clinical association of various furry animal crude extracts and components based on component resolved diagnosis (CRD). Methods: A total of 211 patients with allergic rhinitis with sensitivities to cats and/or dogs were recruited, and the specific immunoglobulin E (sIgE) against various furry animals (such as dog/cat extracts and their components, pigeon, parrot, duck, chicken, sheep, rat, mouse, goose, cow and horse extracts) were measured to analyze the sensitization profiles, crossreactivity and clinical relevance with regards to allergies. Results: A total of 91.67% of cat-sensitized patients were sensitive to Fel d 1, while only 16.03% of cat-sensitized patients responded to Fel d 2. Can f 1 and Can f 5 were the major components of dogs, and the positive rates were 23.53% and 16.18%, respectively. Twenty percent of patients were sensitized to 10 other furry animals, and the positive rate was between 0% and 19.12%. There was a significant correlation between components (Can f 1–5 and Fel d 2) and 5 furry animals (mouse, sheep, Horse, rat, cow), especially between serum albumin (SA) (Can f 3, Fel d 2) and furry animals. Most of the animal crude extracts and components sensitization rates in patients who were SA-positive were significantly higher than that of patients who were SA-negative. In particular, for sensitization to mice, sheep, horses, rats and cows, more than 10-fold higher in patients who were SA-positive than in patients who were SA-negative. The VAS of symptoms and life of quality (LoQ) in the SA-sensitized patients was higher than that in unsensitized patients, and the patients with lipocalin sensitivities had a worse LoQ. Conclusion: Serum albumin Fel d 2 and Can f 3, as minor allergens in cats and dogs, but not lipocalin or prostatic kallikrein, is associated with other furry animals presumably due to serum albumin cross-reactivity. Patients sensitized with serum albumin had a significantly higher risk of sensitization to other animals and had a higher rhinitis VAS score. |
Journal of Asthma and Allergy. 2021;14:1231. | |
| Huvier AD, Tetart F, Bauvin, O, Martinet J, Joly P. | 2018 | Recurring acute urticaria and abdominal pain: Consider a diagnosis of alpha-galactose anaphylaxis. BACKGROUND: Food urticaria is common and generally benign, and it may be of viral or idiopathic aetiology. A food origin of the allergy is frequently sought but rarely found. Mammalian meat anaphylaxis, or alpha-galactose (alpha-gal) anaphylaxis, is a rare and recently discovered entity. PATIENTS AND METHODS: Herein, we report a case of alpha-galactose (alpha-gal) anaphylaxis in a 60-year-old woman presenting four episodes of acute urticaria with signs of anaphylaxis occurring a few hours after meals containing mammalian meat (beef meat, pork meat and offal). The diagnosis was confirmed by a positive gelatine prick-test and the presence of alpha-gal IgE. DISCUSSION: In the event of acute urticaria associated with systemic symptoms, in particular gastrointestinal signs, allergy to alpha-galactose should be considered. |
Annales de Dermatologie et de Vénéréologie. 2018 Nov 1; 145(11): 690-693. | Recurrent urticaria; dermatology |
| Iglesia EG, Stone C, Commins SP. | 2019 | Regional and Temporal Patterns of Alpha-Gal Allergy Using Google Trends. RATIONALE: An increasing number of cases of alpha-gal allergy (AGA) have been reported in the U.S. and in several parts of the world over the past decade. In the U.S., cases of AGA are most often reported in the southeastern region, overlapping with the distribution of the Lone Star tick. However, epidemiological and time trend studies on AGA are lacking. METHODS: Using Google Trends (GT), a web-based surveillance tool that captures data on search engine terms, time and geographic trends were explored from January 2004 - August 2018 for the following queries: alpha-gal allergy (topic), alpha gal (search term), alpha-gal (search term), red meat allergy (search term), and meat allergy (search term). For each query, search interest over time and search interest by country and subregion of the U.S. were quantified according to relative search volume (RSV). RESULTS: Search interest for all AGA queries have increased since 2012. There is interest in alpha-gal allergy (topic) in 47 out of 50 U.S. states, with the highest RSV in Arkansas, Kentucky, Tennessee, North Carolina, and Virginia. There is also interest in AGA on 6 continents, with Sweden, the U.S., Australia, Canada, and South Africa having the highest RSV among countries. CONCLUSIONS: By GTanalysis, there is widespread awareness of AGA in the U.S. and search interest in AGA continues to increase. The countries and subregions with the highest GT RSV coincide with the highest reported rates of AGA. |
Journal of Allergy and Clinical Immunology. 2019 Feb 1;143(2):AB161. | |
| Inam M, Shafique RH, Roohi N, Irfan M, Abbas S, Ismail M. | 2016 | Prevalence of sensitization to food allergens and challenge proven food allergy in patients visiting allergy centers in Rawalpindi and Islamabad, Pakistan. In this study, we estimated the prevalence of food allergy in the adult allergic patients of Rawalpindi and Islamabad , Pakistan, based on self-report, skin prick test (SPT) and oral food challenge test (OFC). SPT was used for the estimation of sensitization to wheat, egg, milk, beef, chicken, mutton, fish, corn, lentils, rice, soya, peanut and banana. Among 689 patients, 39.19 % showed sensitivity to one or more foods, where, sensitization to wheat (156; 22.6 %) was highest, followed by egg (148; 21.48 %) and milk (138; 20.03 %). Sensitization to various proteins ranged between 15.53–15.97 %, while lentils, corn, rice, soya and peanut sensitization was 15.4, 16, 12.5, 12 and 11.5 % respectively. Only 7.1 % patients were SPT positive for banana allergen. SPT was performed in patients with self-reported food allergy (341/689) and also with no self-reported history of food allergy (348/689). SPT results were positive in 69.8 % of the self-report group, whereas, in the patients with no self-reported food allergy 9.2 % were found sensitized to one or more tested food allergens. 101 patients were recruited for OFC, 61 % of these were confirmed of food allergy. The prevalence of food allergy in the study population was 9 %. Food specific OFC results show that wheat allergy is affecting 1.6 % (95 % CI 0.9–2.84 %) of the total allergy patients, followed by egg allergy 1.31 % (95 % CI 0.70–2.47 %). Furthermore, corn allergy, rice allergy and peanut allergy were 1.02, 0.87 and 0.73 %, respectively. In conclusion, wheat allergy is the most prevalent, followed by egg, chicken, beef and fish allergy, respectively. |
SpringerPlus. 2016 Dec 1;5(1):1330. | |
| Ionova Y, Wilson L. | 2020 | Biologic excipients: Importance of clinical awareness of inactive ingredients Due to the complexity and fragility of biological drug products, several challenges exist in their formulation development. Excipients are added to increase product stability, maintain tonicity, and facilitate drug delivery. The potential implications of these additive substances merit clinical consideration. We assessed the safety risk of excipients on the basis of their type and variability through an assessment framework, which quantifies excipient complexity in 230 biological formulations, and identifies excipient-related adverse events through published case reports. A biologic on average contained 4.45 excipients, half of that found in oral medications. The frequency distribution was heavily skewed towards the most commonly occurring excipients: water (40.4%), sodium chloride (38.3%), polysorbate 80 (28.7%), sucrose (24.4%), and mannitol (20.9%), with 44.4% of formulations not listing the concentration of the most commonly occurring inactive ingredients. A literature search revealed only 17 case reports of excipient-related adverse events, suggesting the need for more clarity for clinicians on the safety of chemical additives. These cases included injection site reactions, anaphylaxis, hyperglycemia, and acute renal failure. With the expansion of the biopharmaceutical market, it is important to consider the safety data of biologic excipients, so that therapy can be tailored appropriately for a specific patient. |
PloS one. 2020 Jun 25;15(6):e0235076. | biologics; mAb; monoclonal antibody; biological agent; inactive ingredients; gelatin |
| Iwamoto T, Okamoto A, Ishinaga H, Shimizu K, Gayle AA, Arai N, Takeuchi K, Okuda M. | 2016 | A novel approach to predict cetuximab-induced hypersensitivity reaction: detection of drug-specific IgE on basophils. Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab-specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab-induced HR. Twelve head and neck cancer patients were enrolled in this single-institution study: four with a history of cetuximab-induced HR and eight with no such history. Cetuximab-specific and galactose-alpha-1,3-galactose (alpha-gal) specific IgEs in serum were measured in vitro using an enzyme-linked immunosorbent assay (ELISA). IgE-cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcepsilonRI. The positive predictive value associated with the presence of cetuximab- or alpha-gal-specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P < 0.05). However, this was not the case in patients who did not develop HR. In conclusion, our results strongly imply that the IgE-cetuximab interaction on basophils may be key to developing improved methods for predicting severe cetuximab-induced HR. |
Cancer medicine. 2016 Jun;5(6):1004-12. | |
| Iweala O, Brennan PJ, Commins SP. | 2017 | Serum IgE Specific for Alpha-Gal Sugar Moiety Can Bind Glycolipid. RATIONALE: Alpha-gal meat allergy, characterized by anaphylaxis to mammalian meats like beef, pork or lamb three or more hours after consumption, has been associated with specific IgE (sIgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal) lining the surface of non-primate mammalian tissues. Meat fat content appears to impact reaction severity in alpha-gal-allergic patients. Because antigenic lipids are presented in complex with CD1 antigen-presenting molecules, we hypothesized that delayed anaphylaxis in alpha-gal allergy may be explained by alpha-gal sIgE binding to glycolipids complexed with CD1, since CD1-based presentation of glycolipids requires additional time for assembly and loading. Because CD1d presents the canonical invariant NK T cell glycolipid agonist alpha-galactosylceramide, a molecule structurally similar to alpha-gal, we measured sIgE-binding to this isoform. METHODS: Sera from alpha-gal allergic subjects containing alpha-gal sIgE (n55) were incubated with biotinylated human CD1d monomers unloaded or loaded with either alpha-gal containing glycosphingolipid isogloboside 3 (iGb3) or galactose-alpha-1,4-containing globotriaosylceramide (GB3) coupled with streptavidin attached to the solid phase of a sandwich immunoassay. . RESULTS: CD1d monomers loaded with alpha-gal containing iGB3 bound IgE (2.6 6 0.7 IU/mL) whereas unloaded CD1d did not. Less IgE binding (0.49 6 0.2 IU/mL) was present in GB3 loaded monomers. In contrast, serum from a subject without alpha-gal sIgE was negative for iGB3 and GB3 binding. . CONCLUSIONS: Alpha-gal sIgE from mammalian meat-allergic subjects binds glycolipid complexed with human CD1d and does so with increased specificity to glycolipids containing the alpha-1,3 linkage. Thus, antigen presentation of dietary lipid through CD1 molecules may represent a mechanism of delayed food allergy. |
Journal of Allergy and Clinical Immunology. 2017 Feb 1;139(2):AB88. | |
| Iweala O, Fereydouni M, Motaghed M, Choudhary S, Kapita C, Commins S, Kepley C. | 2020 | Alpha-gal Induced Mediator Release by Human Mast Cells. RATIONALE: Alpha-gal syndrome, typically characterized by delayed allergic reactions to mammalian meat, is associated with IgE to galactosealpha-1,3-galactose (alpha-gal), a carbohydrate moiety found in nonprimate mammals. Greater than 90% of alpha-gal allergic patients report urticaria following ingestion of alpha-gal. However, no one has demonstrated that alpha-gal-containing compounds can activate human mast cells sensitized with alpha-gal-specific IgE. METHODS: Primary human skin and lung mast cells were sensitized overnight with human plasma containing alpha-gal-specific IgE ranging from 0.1 to 58 IU/ml. The next day, cells were washed and challenged with anti-FcEpsilonRI antibodies, beef thyroglobulin (BTG), or cetuximab for 30 minutes. Mast cell mediators released into cell culture supernatants were measured. . RESULTS: Alpha-gal-containing compounds, including BTG and cetuximab, induced mediator release from skin, but not lung, mast cells. The extent of skin mast cell degranulation and cytokine production correlated with plasma alpha-gal-specific IgE levels. . CONCLUSIONS: Alpha-gal-containing compounds activate primary skin-derived human mast cells sensitized with plasma from alpha-gal allergic subjects, resulting in mast cell degranulation and cytokine production. Notably, lung-derived human mast cells sensitized with alpha-gal allergic plasma do not respond to challenge with the doses of |
Journal of Allergy and Clinical Immunology. 2020 Feb 1;145(2):AB187. | |
| Iweala OI, Burks AW. | 2016 | Food Allergy: Our Evolving Understanding of Its Pathogenesis, Prevention, and Treatment. Food allergy is defined as an IgE-mediated hypersensitivity response to ingested food with allergic symptoms ranging from urticaria to life-threatening anaphylaxis. Food allergy is thought to develop because of (1) failed induction of tolerance upon initial exposure to food antigen or (2) breakdown of established tolerance to food antigen. We review current understanding of the pathogenesis, epidemiology, and natural history of food allergy, including the unconventional IgE-mediated food allergy to mammalian meat known as alpha-gal food allergy. We highlight emerging data on food allergy treatment and prevention, emphasizing the growing appeal of manipulating the gut microenvironment using probiotics and helminth products to blunt systemic allergic responses to food. |
Current allergy and asthma reports. 2016 May 1;16(5):37. | |
| Iweala OI, Choudhary SK, Addison CT, Batty CJ, Kapita CM, Amelio C, Schuyler AJ, Deng S, Bachelder EM, Ainslie KM, Savage PB | 2020 | Glycolipid-mediated basophil activation in alpha-gal allergy. Letter to the editor: ...Allergic reactions to alpha-gal may not occur with every allergen exposure. This variability depends on the amount of allergen ingested and the biologic macromolecules within the alpha-gal–containing food. During food challenges, we found that lipid-rich mammalian meats were associated with more consistent, severe reactions.2 Thus, we hypothesized that glycolipid could activate allergic effector cells in alpha-gal allergy. A role for lipids in enhancing allergenic potency has been described in peach3 and cow’s milk allergies.4 We now demonstrate that alpha-gal sIgE binds mammalian glycolipids and that alpha-gal–containing glycolipids can activate basophils sensitized with alpha-gal sIgE, highlighting a potential role for glycolipid in alpha-gal meat allergy. ...To our knowledge, this is the first demonstration that mammalian glycolipid can activate allergic effector cells via surface-bound sIgE. Given the delayed onset of a reaction after ingestion of mammalian meat in individuals with alpha-gal allergy, perhaps failure of the antigen to appear rapidly in the circulation or packaging of immunogenic lipids with plasma proteins or CD1d glycolipid antigen-presenting molecules delays allergic effector cell activation, which possibly explains the delay in allergic symptoms. These results suggest a unique role for glycolipid that has been rarely described in IgE-mediated food allergy. |
Journal of Allergy and Clinical Immunology. 2020 Feb 20. | |
| Iweala OI, Choudhary SK, Addison CT, Commins SP | 2021 | T and B Lymphocyte Transcriptional States Differentiate between Sensitized and Unsensitized Individuals in Alpha-Gal Syndrome. The mechanisms of pathogenesis driving alpha-gal syndrome (AGS) are not fully understood. Differences in immune gene expression between AGS individuals and non-allergic controls may illuminate molecular pathways and targets critical for AGS development. We performed immune expression profiling with RNA from the peripheral blood mononuclear cells (PBMCs) of seven controls, 15 AGS participants, and two participants sensitized but not allergic to alpha-gal using the NanoString nCounter PanCancer immune profiling panel, which includes 770 genes from 14 different cell types. The top differentially expressed genes (DEG) between AGS subjects and controls included transcription factors regulating immune gene expression, such as the NFκB pathway (NFKBIA, NFKB2, REL), antigen presentation molecules, type 2/allergic immune responses, itch, and allergic dermatitis. The differential expression of genes linked to T and B cell function was also identified, including transcription factor BCL-6, markers of antigen experience (CD44) and memory (CD27), chemokine receptors (CXCR3, CXCR6), and regulators of B-cell proliferation, cell cycle entry and immunoglobulin production (CD70). The PBMCs from AGS subjects also had increased TNF and IFN-gamma mRNA expression compared to controls. AGS is associated with a distinct gene expression profile in circulating PBMCs. DEGs related to antigen presentation, antigen-experienced T-cells, and type 2 immune responses may promote the development of alpha-gal specific IgE and the maintenance of AGS |
International journal of molecular sciences. 2021 Jan;22(6):3185. | Pathogenesis; genetics; T cell; B cell |
| Iweala OI, Hardy LC, Choudhary S, Hsing-Hui W, Addison CT, Milind N, Orgel KA, Kulis MD, Urban JF, Nagler CR, Burks AW. | 2019 | Epigenetic Dysfunction in T cells is Associated with Enhanced Type-2 and Blunted Regulatory Immunity. RATIONALE: Epigenetic alterations partly mediated by histone H3 lysine 27 (H3K27) demethylase UTX are critical for humoral and cellular immunity against chronic viral infections. Whether UTX-modulated epigenetic changes impact type 2 immunity in allergic sensitization and type 2/regulatory immunity associated with chronic helminth infection is unclear. METHODS: We used mice with UTX-deficient T cells (UTX-TCD) to assess whether T cell-specific UTX expression affects 1) IgE production following subcutaneous sensitization to galactose-alpha-1,3-galactose (alpha-gal) and 2) the immunosuppressive effects of preexisting intestinal helminth infection on antibody responses to intramuscular vaccination. We sensitized wildtype (WT) C57Bl/6J or UTX-TCD mice 3 times at 1 to 2- week intervals with 50 micrograms of lone star tick (Amblyomma americanum)-derived salivary gland extract (TSGE). We examined polyclonal and antigen-specific IgE and CD4+ T cell responses 2 weeks after the last subcutaneous injection. In separate experiments, WT and UTX-TCD mice were infected or not with the mouse intestinal parasitic nematode Heligmosomoides polygyrus bakeri and vaccinated intramuscularly twice at 1-week intervals with chicken-egg ovalbumin adsorbed to alum (OVA-alum). Polyclonal and antigen-specific IgE and IgG1 responses were assessed. . RESULTS: Without UTX expression in T cells, TSGE injection enhanced polyclonal IgE production and CD4+ IL4+ Th2 cell frequency despite reduced CD4+ T cell frequency. Polyclonal IgE production was preserved during chronic intestinal helminth infection, but Th2-skewed OVA-specific IgG1 responses to OVA-alum vaccination were not significantly reduced. . CONCLUSIONS: Our results suggest that epigenetic factors like UTX in T cells may regulate cellular and humoral immunity associated with type 2 and immunoregulatory responses during allergic sensitization and helminth infection |
Journal of Allergy and Clinical Immunology. 2019 Feb 1;143(2):AB205. | |
| Iweala OI, Savage PB, Commins SP. | 2018 | A Role for CD1d-restricted Invariant Natural Killer T Cells and Glycolipids in Alpha-Gal Allergy. RATIONALE: Alpha-gal meat allergy is associated with IgE-mediated sensitization to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate moiety found in non-primate mammals. Lipid content of consumed meat drives reaction severity, suggesting that mammalian meat-derived glycolipids containing alpha-gal may act as immunogens. Immunogenic lipids complexed to CD1d antigen-presenting molecules activate iNKT cells. We have shown that alpha-gal-specific IgE binds mammalian glycosphingolipids complexed with CD1d. Thus, we hypothesized that iNKT cells and CD1d-mediated presentation of glycolipid are involved in the pathogenesis of alpha-gal allergy. METHODS: PBMCs from alpha-gal allergic subjects and controls were stained with fluorochrome-labeled human CD1d tetramers bound to PBS57 (analog of canonical iNKT cell immunogen alpha-galactosylceramide) and antibodies against CD3 and the activation marker CD69. In separate experiments, basophils from a control subject were stripped of IgE; primed with plasma from subjects with and without alpha-gal allergy; stimulated with glycolipids PBS-112 (contains galactose-alpha-1,4-galactose) or PBS-113 (contains alpha-gal); and stained with fluorochrome-labeled antibodies against basophil marker CD123 and activation markers CD63 and CD203c. RESULTS: PBMCs from subjects with alpha-gal allergy (n58) contained double the frequency of activated CD69+ iNKT cells than control PBMCs (n55). The frequency of activated CD203c+CD63+ basophils among PBMCs stimulated with IL-3 and PBS-113 increased 9-fold when PBMCs were sensitized with plasma from alpha-gal-allergic versus control subjects. CONCLUSIONS: Alpha-gal-containing glycolipids robustly activated basophils sensitized with alpha-gal sIgE compared to glycolipid without alpha-gal. Circulating activated CD1d-restricted iNKT cells were present at higher frequencies in alpha-gal allergic subjects than controls, suggesting unique roles for iNKT cells and glycolipid rarely described in IgEmediated food allergy. |
Journal of Allergy and Clinical Immunology. 2018 Feb 1;141(2):AB288. | |
| Jackson WL. | 2018 | Mammalian meat allergy following a tick bite: a case report. The alpha-gal allergy is an emerging IgE-mediated reaction against the galactose-alpha-1,3-galactose carbohydrate found in mammalian meats. Patients with this condition will develop anaphylactic symptoms 3-6 h after the ingestion of mammalian meat food products such as beef, pork or lamb. The prevalence of this allergy is drastically increasing and severe reactions including anaphylactic shock have been reported, yet many patients experience symptoms for years before a diagnosis is made. We describe the presentation, diagnosis and management of a patient with the alpha-gal allergy in attempt to improve early recognition and management of patients with this condition. |
Oxford medical case reports. 2018 Feb;2018(2):omx098. | |
| Jacquenet S, Moneret-Vautrin DA, Bihain BE. | 2009 | Mammalian meat-induced anaphylaxis: clinical relevance of anti-galactose-alpha-1,3-galactose IgE confirmed by means of skin tests to cetuximab. Letter to the Editor. Severe anaphylaxis is often associated with food allergy. Classically, the diagnosis of food allergy is established through a careful evaluation of a patient’s allergy history, including skin tests and in vitro tests. If the specific trigger cannot be established, then the patient might be diagnosed with idiopathic anaphylaxis, which is a major concern for both the patient and the physician. Some of these cases are due to rare food allergies.1 Recently, a new specific IgE to galactose-a-1,3-galactose (a-gal) was shown to be linked with anaphylaxis or angioedema reactions to mammalian meats.2,3 The present study reports on 2 cases of anaphylaxis to mammalian meats, which were evaluated by using an in-house a-gal IgE immunoassay4 and novel intradermal tests (IDTs) to cetuximab. Cetuximab is an mAb presenting the a-gal oligosaccharide in the Fab portion of the heavy chain. |
Journal of Allergy and Clinical Immunology. 2009 Sep 1;124(3):603. | |
| Jacquenet S. | 2016 | Alpha-gal, from invertebrate to vertebrate. No abstract available |
Frontiers in Immunology. 2019;10:1996. | |
| Jaison PL, Kannan VM, Geetha M, Appukuttan PS. | 1993 | Epitopes recognized by serum anti-α-galactoside antibody are present on brain glycoproteins in man. |
Journal of biosciences. 1993 Jun;18(2):187-93. | Brain |
| James H, Commins S, Hosen J, Cooper P, Kocan K, Platts-Mills T. | 2010 | Tick Bites From Amblyomma Americanum As A Major Cause Of Ige Antibodies Specific To Galactose-alpha-1,3-galactose. RATIONALE: The high prevalence of IgE to galactose-a-1,3-galactose (alpha-gal) in Virginia, North Carolina, Tennessee, Arkansas, Oklahoma, and Missouri correlates with an area where tick bites are common. METHODS: Using a modified ImmunoCAP assay, we measured IgE to biotinylated proteins from two tick species, A. americanum and D. variabilis. Sera were obtained from three subjects who had experienced extensive tick bites, 100 subjects who presented with delayed anaphylaxis to red meat and were found to have IgE to alpha-gal, and from 60 children living in rural Ecuador. Ticks for extracts were obtained from OSU Tick Rearing Facility. . RESULTS: Two of the three subjects who developed IgE to alpha-gal also developed IgE to A. americanum, the species responsible for the bites. Among the 100 alpha-gal positive subjects, 93% reported a recent episode of tick bites and 60% had detectable IgE to A. americanum. Only 15% had detectable IgE to D. variabilis. In Virginia, serum titers of tick IgE have been observed up to 11 IU/ml. In a cohort of children from rural Ecuador, higher titer IgE to tick has been observed (38.5 IU/ml). Although the presence of IgE to tick correlates closely with IgE to alpha-gal, there was only a weak quantitative correlation (r 5 0.234, p 5 0.014). Absorption experiments confirmed that the IgE to tick antigens cannot be explained by IgE to alpha-gal. . CONCLUSION: The evidence strongly suggests that ticks, primarily A. americanum, are an important cause of IgE antibodies to alpha-gal and can also induce IgE to tick protein. |
Journal of Allergy and Clinical Immunology. 2010 Feb 1;125(2):AB28. | |
| James H, Commins S, Hosen J, Cooper P, Kocan K, Platts-Mills T. | 2018 | Meat allergy associated with galactosyl‐α‐(1,3)‐galactose (α‐Gal)—Closing diagnostic gaps by anti‐α‐Gal IgE immune profiling Background: Glycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl--(1,3)-galactose (-Gal). It is known that -Gal is immunogenic in humans and causes glycan-specific IgG and also IgE responses with clinical relevance. -Gal is part of the IgE-reactive monoclonal therapeutic antibody cetuximab (CTX) and is associated with delayed anaphylaxis to red meat. In this study, different -Gal-containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against -Gal. Methods: Three serum groups, -Gal-associated meat allergy (MA) patients, idiopathic anaphylaxis (IA) patients with suspected MA, and non-meat-allergic healthy control individuals (HC), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for -Gal-containing analytes CTX, bovine thyroglobulin (Bos d TG), and human serum albumin (HSA)-conjugated -Gal. Results: Singleplex allergy diagnostics using the -Gal analytes CTX and Bos d TG confirms the history of MA patients in 91% and 88% of the cases, respectively. A novel dot blot-based assay system for the detection of IgE against -Gal reveals individual IgE sensitization profiles for -Gal-containing analytes. An -Gal-associated IgE cross-reactivity profile (IgE against CTX, Bos d TG, and HSA--Gal) was identified, which is associated with MA. Conclusions: Detection of individual sensitization patterns with different -Gal-containing analytes provides the basis for an individual allergy diagnosis for -Gal-sensitized patients. Higher amounts of -Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity. |
Allergy. 2018 Jan;73(1):93-105. | idiopathic anaphylaxis; testing; immunoblot |
| James H, Kennedy JL, Platts-Mills T, Stallings AP, Workman LJ, Tripathi A, Pochan S, Lane C, Matos LA, Eapen SS, McBride DC. | 2013 | Pediatric Alpha-Gal: IgE Antibodies to Galactose-Alpha-1,3-Galactose in Children Presenting with Delayed Urticaria or Anaphylaxis. RATIONALE: Chronic urticaria, recurrent acute urticaria, and idiopathic anaphylaxis in children commonly present without a cause. Recent research established IgE to galactose-alpha-1,3-galactose (alpha-gal) as an important cause of delayed urticaria and anaphylaxis in adults living in the southeastern United States. We posited that a similar disease could be present in children with delayed urticaria and anaphylaxis in a similar geographical distribution. METHODS: Children with a history of delayed urticaria or anaphylaxis after consuming mammalian meat were enrolled at the University of Virginia and two private practice clinics in Lynchburg, Virginia. Serum was assayed for total IgE and specific IgE to alpha-gal, beef, pork, lamb, milk, dog, cat dander, Fel d 1, and cat albumin. RESULTS: Forty-five children with IgE antibodies specific for alpha-gal and history of recurrent idiopathic urticaria or anaphylaxis were identified. All subjects reported tick bites and 39/45 had experienced persistent pruritis and erythema at the site of the bite. Titers of IgE to cat, dog, pork, beef, and milk were positive in most subjects and were significantly correlated with IgE to alpha-gal (p<0.001). Additionally, although 32/45 children had IgE specific for both cat and dog, only 9/32 reported rhinitis symptoms upon exposure to these animals. Although a majority reported urticaria (92%), many subjects also reported anaphylaxis (44%). CONCLUSIONS: Delayed anaphylaxis or urticaria following consumption of mammalian meat has been found in children with IgE antibodies specific for alpha-gal. Diagnosis by skin testing is difficult, but alpha-gal should be considered in children with recurrent idiopathic urticaria living in the southeastern United States |
Journal of Allergy and Clinical Immunology. 2013 Feb 1;131(2):AB217. | |
| James HR, Commins SP, Kelly LA, Pochan SL, Workman LJ, Mullins RJ, Platts-Mills TA. | 2011 | Further Evidence For Tick Bites As A Cause Of The IgE Responses To Alpha-gal That Underlie A Major Increased In Delayed Anaphylaxis To Meat. RATIONALE: Delayed onset of urticaria or anaphylaxis after eating meat in patients who have IgE to alpha-gal is now a common presenting cause of food allergy in Virginia. The evidence that ticks are related to this IgE response comes from histories of bites, absence of this ab in areas where tick bites are rare, and from following IgE responses after tick bites. METHODS: Detailed histories and assays for IgE were compared in a population of anaphylaxis, asthma, and clinic controls. RESULTS: Among those with full histories (n5100), a report of prolonged or severe reactions to tick bites correlated with titer of IgE to alpha-gal (Chi-square 5 17.6, p<0.001). The IgE responses following tick bites have distinctive features: a) they can increase to high level (i.e., greater than 50 IU/ml within a month), b) IgE to cat and dog epithelium and beef increase in parallel with IgE to alpha-gal, while IgE to other allergens remain negative or unchanged, and c) absorption experiments confirm that these IgE responses to alpha-gal explain up to 50% of total serum IgE. In keeping with this, titers of total IgE and IgE to alpha-gal correlate closely (r50.7, p<0.001). CONCLUSION: Some of the patients have had episodes of delayed anaphylaxis for over 15 years; however, the bulk of these cases are of recent onset. At present, the best explanation for increasing incidence of this syndrome is a major increase in tick bites related to the massive increase in the population of their primary host, the white-tailed deer. |
Journal of Allergy and Clinical Immunology. 2011 Feb 1;127(2):AB243. | |
| James HR, Kelly LA, Pochan SL, Commins SP, Workman LJ, Nganga LW, Cooper P, Platts-Mills TA. | 2012 | Parasite-related IgE Antibodies, Including IgE to Galactose-alpha-1,3-galactose, in Sera from Virginia and Ecuador. RATIONALE: IgE antibodies to galactose-alpha-1,3-galactose (alphagal) have become increasingly prevalent in the southeastern United States. These antibodies have recently been linked to bites from the tick Amblyomma americanum, but the possibility of a role for other parasites remains. . METHODS: Assays for IgE were performed on patients with delayed urticaria or anaphylaxis to meat and controls in Virginia (n5125), as well as a cohort from Esmeraldas Province, Ecuador (n5295) where Echinococcus is not endemic. . RESULTS: The significant association between IgE antibodies to alphagal and IgE to Echinococcus was strongest in Virginia (r50.74 vs r50.62 for Ecuador, both p<0.001). Further, only 3/37 Echinococcus IgE-positive subjects in Virginia were not positive for IgE to alpha-gal. In Ecuador, 118/ 223 Ascaris-positive sera were negative for IgE to alpha-gal; by contrast, in Virginia 52/79 alpha-gal positive sera were negative for Ascaris and only one sera was Ascaris-positive and alpha-gal negative. Virginia sera with IgE to Echinococcus (class 2 and 3) were absorbed with alpha-gal linked to Sepharose beads, which removed all detectable IgE to Echinococcus. . CONCLUSIONS: We think that the limited number of positive assays for Echinococcus and Ascaris in Virginia can be explained by cross-reactivity with alpha-gal, which may also be relevant for Echinococcus in Esmeraldas. By contrast, many sera in Ecuador had high titer IgE to Ascaris with negative responses to alpha-gal. None of these IgE antibodies were significantly associated with asthma in the United States, while IgE to Ascaris was significantly associated with asthma in Ecuador. |
Journal of Allergy and Clinical Immunology. 2012;129(2):AB82. | Latin America; Ecuador; platyhelminthes; endoparasites |
| Jappe U, Kuehn A. | 2016 | Diagnostically relevant single allergens from plant and animal source foods - an update. Over the past years, considerable progress has been made in the field of molecular allergology. Some new single allergens have been isolated from various sources of food allergens, and some of these single allergens are already available for routine allergy diagnosis, which results in a higher sensitivity and specificity of IgE determination. Furthermore, the underlying cause of a new disease entity delayed-type anaphylaxis has been found: galactose alpha-1,3-galactose, a disaccharide of mammalian meat. Now, meat allergy can be confirmed more frequently and does not have to be classified as idiopathic anaphylaxis so often. In addition, completely new allergens could be isolated: hydrophobic and lipophilic peanut allergens, the defensins and oleosins. With this, it might be possible to close a diagnostic gap, i.e., the allergens of the lipid fractions of oilseeds. |
ALLERGOLOGIE. 2016 Sep 1;39(9):425-38. | |
| Jappe U, Minge S, Kreft B, Ludwig A, Przybilla B, Walker A, Varga R, Seidel P, Biedermann T, Anemüller W, Kromminga A. | 2018 | Meat allergy associated with galactosyl‐α‐(1, 3)‐galactose (α‐Gal)—Closing diagnostic gaps by anti‐α‐Gal IgE immune profiling. BackgroundGlycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl‐α‐(1,3)‐galactose (α‐Gal). It is known that α‐Gal is immunogenic in humans and causes glycan‐specific IgG and also IgE responses with clinical relevance. α‐Gal is part of the IgE‐reactive monoclonal therapeutic antibody cetuximab (CTX) and is associated with delayed anaphylaxis to red meat. In this study, different α‐Gal‐containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against α‐Gal.MethodsThree serum groups, α‐Gal‐associated meat allergy (MA ) patients, idiopathic anaphylaxis (IA ) patients with suspected MA, and non‐meat‐allergic healthy control individuals (HC ), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for α‐Gal‐containing analytes CTX, bovine thyroglobulin (Bos d TG), and human serum albumin ( HSA )‐conjugated α‐Gal.ResultsSingleplex allergy diagnostics using the α‐Gal analytes CTX and Bos d TG confirms the history of MA patients in 91% and 88% of the cases, respectively. A novel dot blot‐based assay system for the detection of IgE against α‐Gal reveals individual IgE sensitization profiles for α‐Gal‐containing analytes. An α‐Gal‐associated IgE cross‐reactivity profile (IgE against CTX, Bos d TG, and HSA ‐α‐Gal) was identified, which is associated with MA.ConclusionsDetection of individual sensitization patterns with different α‐Gal‐containing analytes provides the basis for an individual allergy diagnosis for α‐Gal‐sensitized patients. Higher amounts of α‐Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity. |
Allergy. 2018 Jan;73(1):93-105. | diagnosis; intestine |
| Jappe U. | 2014 | Anaphylaxis caused by hidden food allergens: the alpha-Gal syndrome. Hidden allergens may be defined as allergen deliberately added to food but unlabeled in the ingredient list or present due to unintentional cross contact during food manufacturing itself and, therefore, not recognizable for the consumer. An allergen present in food may also be considered as "hidden" if causing reactions in a patient because of so far unknown cross-reactivity. A novel food allergen is one that has been introduced to human diet for the first time, e.g., kiwi at the beginning of the 1980s, and to which patients develop sensitivity after exposure. A new allergen also can be an IgE-binding molecule that has never been described and identified before in a particular species as allergen source, a-Gal is an ubiquitous glycan moiety expressed on cells and tissue of nonprimate mammals, but not in humans, which is the reason for its strong immunogenicity for the latter. a-Gal is located on the Fab portion of the monoclonal treatment antibody Cetuximab. In 2008, it has been identified as being responsible for severe, sometimes fatal anaphylactic reactions to Cetuximab. Anti-alpha-Gal-IgE also seem to be responsible for severe allergy to red meat, innards and to gelatine, however, fatal reactions have not been reported so far. Anti-a-Gal-IgE are associated with a novel food allergy, a delayed anaphylaxis (more than 3 hours) following the ingestion of red meat and innards, a phenomenon which is still to be elucidated. An additional characteristic feature is that for most of these patients conventional skin prick tests with commercial reagents proved insufficient for diagnosis. Anti-a-Gal-IgE were first detected in sera from patients in an area of the southeastern U.S. and bound to a wide range of mammalian allergens. The geographic distribution prompted investigations of sensitization routes apart from the ingestion of red meat, like tick bites und parasitic infections. |
Allergologie. 2014 Jul 1;37(7):265-74. | |
| Jappe U. | 2012 | Update on meat allergy. alpha-Gal: a new epitope, a new entity? The association between the carbohydrate galactose-[alpha]-1,3-galactose (alpha-Gal) and anaphylaxis was first documented after severe hypersensitivity reactions to cetuximab, a chimeric mouse-human IgG1 monoclonal antibody approved for targeted therapy of carcinomas of colon, as well as of the head and neck region. alpha-Gal is a ubiquitous glycan moiety expressed on cells and tissue of non-primate mammals. Since this epitope is not expressed in humans, it is very immunogenic for them. alpha-Gal is located on the Fab portion of cetuximab and thus on the murine part of the chimera. The anaphylactic reactions to the antibody were mediated by IgE specific for alpha-Gal. Anti-alpha-Gal-IgE were first detected in sera of patients from the southeastern U.S. and reacted with a wide range of mammalian allergens. The geographic distribution prompted investigations of sensitization routes apart from the ingestion of red meat, such as tick bites und parasitic infections. Anti-alpha-Gal-IgE seems to be of clinical relevance for allergy to red meat and for the pork-cat syndrome. It is also associated with a novel form of delayed anaphylaxis, which appears more than 3 hours following the ingestion of red meat (beef, pork and lamb), a phenomenon which is still to be elucidated. For most of these patients conventional skin prick tests with commercial reagents proved insufficient for diagnosis. |
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2012 Apr;63(4):299. | |
| Jayanth SH, Chandra YP, Singh YK. | 2014 | Fatal Anaphylaxis to Pork: A Case Report. Food allergy is a common cause of anaphylaxis, which affects up to 10% of young children and 2–3% of adults, and its prevalence appears to be increasing constantly; however the precise incidence of food-induced fatal anaphylaxis among people is unknown. In the case of anaphylactic shock death is likely to occur rapidly and without any warning in seemingly healthy subjects. The lack of reliable laboratory biomarkers and common standard definitions of signs and symptoms makes it difficult for clinicians to diagnose a suspected anaphylactic event. Furthermore at autopsy the findings might hint at the allergic reaction, but classic manifestations may not be appreciated thereby making postmortem diagnosis of anaphylaxis difficult. Here we report one such case of death due to anaphylaxis in a young women with childhood history of allergy to pork. |
Journal of Allergy and Clinical Immunology. 1999 May 1;103(5):717-28. | Asia; India; anaphylaxis; mortality |
| Jeong BY, Kim DY, Fan JP, Chung HC, Han GD. | 2009 | Studies on the Prevalence of Meat Allergy and Potential Beef Allergens The prevalence of food allergies was investigated using questionnaires with 300 subjects whose ages ranged from 19 to 24 years old and the causative food allergens was analyzed using immunological analysis with serum of the subjects who answered that they have/had food allergy. The questionnaire showed that 11.33Uo of subjects have/had experience of food hypersensitivity, where the main causative foods were fish, beef, chicken, milk, egg, and pork in order. The meat allergy shared 4.659o f2.337c for beef, 1.669c for chicken, 0.669n for pork) in the prevalence of food allergies. The causative beef allergens were investigated with the serum of 6 subjects who have had beef allergy. Western blots were carried ‹but with the serum of P6 subject who showed a positive reaction to beef extract in ELISA. The two specific bands were detected in beef extract on the PVDF membrane, and no band was detected in extracts of pork and chicken. A calculation of the distance of migration by SDS-PAGE enabled the molecular masses of the two bands to be estimated as 67 kDa and 31 kDa, respectively. The 67 kDa was revealed as bovine serum albumin (BSA) which is one of the important beef allergens as reported previ- ously though an analysis of the N-terminal amino acid sequence. However we could not identify the sequence of 31 kDa, probably because they comprised several subunits and were modified proteins such as glycoprotein that were unlikely to be easily degraded by the Edman method. The 31 kDa band were dyed with the PAS tperiodic acid-schiff reagent), suggesting that it might be a glycoprotein. These results suggested that the 31 kDa might be considered as a novel potential beef aller- gen which is not reported previously, although further studies are needed. |
Food Science of Animal Resources. 2009;29(2):151-6. | Asia; Korea; prevalence |
| Jerath MR, Sheikh SZ. | 2013 | Characteristics of Patients with Delayed Allergic Reactions to Mammalian Meat Presenting to a Tertiary Care Academic Medical Center in North Carolina. Rationale: This study aims to describe the characteristics of patients who were diagnosed at our institution with an allergy to galactose-a1,3-galactose (‘alpha-gal’), mediating a delayed reaction to mammalian meat. Little is known about the epidemiology and clinical features of this condition. Methods: We performed a retrospective chart review to collect demographic, clinical, and laboratory data on 100 adult patients diagnosed with this condition. Results: In our sample, 52% of patients were male and the mean age was 49. The mean time to reaction was 5 hours. Urticaria was reported by 86% and anaphylaxis by 30%. Epinephrine was used to treat 21% of reactions. Ninety-six percent of individuals reported a history of tick/chigger bite, with 85% of patients reporting one in the past year. Eighty-five percent denied any reactions to cow’s milk and 83% reported no reactions after avoidance of mammalian meat. Hypertension (25%), hyperlipidemia (19%), hypothyroidism (10%), and diabetes mellitus (10%) were the main associated co-morbidities. Venom hypersensitivity was seen in 6% of the patients. The mean alpha-gal IgE was 20 IU/ml, mean total IgE was 323 kU/L, and mean IgE receptor antibody was 9.5%. The concurrent rate of other atopic disease was 46%, significantly higher than that of the general population (25%), p<.0001. Conclusions: We report a large cohort of patients diagnosed with ‘alpha-gal’ allergy in North Carolina, with similar demographic characteristics as previously reported from the University of Virginia. As our database grows, we hope to determine risk factors for developing this condition and identify predictors of severity. |
Journal of Allergy and Clinical Immunology. 2013 Feb 1;131(2):AB217. | North Carolina; prevalence; symptom prevalence |
| Jiang X, Rao Q, Mittl K, Hsieh YH. | 2019 | Monoclonal antibody-based sandwich ELISA for the detection of mammalian meats. In order to (1) reduce the risk of intentional or unintentional contamination of foods, (2) better comply with food regulations, and (3) decrease economic loss to the food industry caused by recall, it is necessary to develop reliable methods for the detection of different food adulterants/contaminants. This study was conducted to characterize two mammalian skeletal troponin (sTn) specific monoclonal antibodies (mAbs 6G1 and 8F10), and use them to develop a mAb-based sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of mammalian meats. From our results, both mAbs were positive to porcine sTnI and sTnC but negative to sTnT. The extractability and antigenicity of target analytes in pork were enhanced by the addition of urea and β-mercaptoethanol into the extraction buffer. The optimized sandwich ELISA was specific to heated mammalian meats and was adequate to analyze samples subject to the most severe heat treatment (132 °C/2 bar/120 min). Mammalian fat (10–30%, g/g) did not significantly affect the assay signal. The optimized assay could detect as low as 1% (g/g) of heated mammalian meats adulterated in poultry meats. Overall, this assay has the potential to fight food fraud, comply with food regulations, and decrease food recalls, which may open up new diagnostic methods for the food industry and the food regulatory authorities. "Around 10% of the foods produced in the U.S. were adulterated and 7% contain fraudulent ingredients (Layton, 2010). From 1980 to 2013, (1) the leading reported type of fraudulent foods was animal products including meat and meat products (7%); (2) 65% of the total incidents were due to substitution or dilution; and (3) in about 30% of the total incidents, the involved food products were produced in the U.S. (National Center for food Protection and Defense, 2015)" |
International journal of environmental research and public health. 2013 Apr;10(4):1598-608. | Food safety; food adulteration; meat adulteration |
| Jiang Y, Yuan IH, Dutille EK, Bailey R, Shaker MS. | 2019 | Preventing iatrogenic gelatin anaphylaxis. Objective:To assess the iatrogenic risks of gelatin allergy and identify resources for patient management. Data Sources:A literature review was performed using PubMed and public databases provided by the National Library of Medicine. Study Selections:Reports of iatrogenic gelatin allergy associated with vaccines, hemostatic agents, intravenous colloids, medicinal capsules, and intraoperative surgical supplies. Results:Gelatin ingredients may not be identified by electronic medical record safeguards, and an exhaustive listing of potential iatrogenic exposures is elusive. The National Library of Medicine AccessGUDID (https://accessgudid.nlm.nih.gov/) can be a useful resource in evaluating medical devices for gelatin content. Unexpected sources of iatrogenic gelatin exposure include hemostatic agents, vascular grafts, intravascular cannulas, bone replacement implants, and emergency resuscitation fluids. Conclusion:Vigilance is important within medical systems to avoid inadvertent gelatin exposure when caring for patients with gelatin allergy. Additional safeguards are needed to remove latent health care system errors that fail to prevent gelatin administration in this at-risk population. |
Annals of Allergy, Asthma & Immunology. 2019 Oct 1;123(4):366-74. | pharmacy; pharmaceutical; perioperative; gelatin |
| Jin HJ, Nam YH, Hwang EK, Shin YS, Ye YM, Park HS. | 2011 | Immunologic evaluation of delayed hypersensitivity to meat in adults Background: Mammalian meat allergy is not common in adults, but increasing in recent years. Although the pathogenic mechanisms are not understood, various immunological and non-immunologic mechanisms were suggested. The aim of this study was to evaluate clinical and immunological characteristics of the patients with delayed hypersensitivity developed after consumption of meat. Methods: Thirty patients with delayed hypersensitivity to beef and/or pork (developed 2 hrs later) were enrolled from Ajou University Hospital. Skin prick tests were performed with commercial beef and pork extracts (Bencard, Bradford, UK) and considered positive if they produced a wheal with a diameter ≥ 3 mm. Serum specific IgE antibodies to beef, pork and galactose- α-1,3- galactose (α-gal) were measured by immunoCAP (Phadia, Sweden). Serum specific IgG1 and G4 antibodies to beef and pork were measured by ELISA. Results: Twenty (66.7%) were female and 25 (83%) were atopics. The most common symptoms were urticaria/angioedema (83.3%) followed by anaphylaxis (16.7%) and gastrointestinal symptoms (13.3%). The skin prick test to beef and pork extracts showed negative results in all, while serum specific IgE to beef and pork was found in 16.7% and 10% of them. The specific IgE to α-gal was found in 3(10%) patients. High serum specific IgG1 to beef and pork was detected in 2(6.7%) and 3 patients (10%), while serum specific IgG4 was detected in 3(10%) and 1 patient (3.3%). Conclusion: We suggested that IgE mediated response to α-gal as well as IgE and IgG responses to beef and pork may induce delayed hypersensitivity to meat. Future investigations will be needed on cellular immune mechanisms. This study was supported by a grant from the Korea Science and Engineering Foundation (KOSEF) funded by the Korean government (MEST, 2009-0078646). |
대한내과학회 추계학술발표논문집. 2011;2011(1):307-. | Asia; Korea |
| Jin R, Greenwald A, Peterson MD, Waddell TK. | 2006 | Human monocytes recognize porcine endothelium via the interaction of galectin 3 and α-GAL. Monocytes are one of the key inflammatory cells recruited to xenografts and play an important role in delayed xenograft rejection. Previous studies have demonstrated the ability of monocytes to bind to the major xenoantigen Gal-α(1,3)Gal-β(1,4)GlcNAc-R; however, the receptor that mediates this interaction has yet to be identified. We provide evidence that it is Galectin-3, a ∼30-kDa lectin that recognizes β-galactosides (Gal-β(1–3/4)GlcNAc) and plays diverse roles in many physiological and pathological events. Human monocyte binding is strikingly increased on porcine aortic endothelial cells (PAEC), which express high levels of Gal-α(1,3)Gal-β(1,4)GlcNAc-R, compared with human aortic endothelial cells. Human monocytes obtained from healthy donors bind to Gal-α(1,3)Gal-β(1,4)GlcNAc-R at variable intensities. This variation of binding intensity was consistent and reproducible in individual donors. Galectin-3 is mainly expressed in human monocytes, not lymphocytes. Purified Galectin-3 is able to bind directly to Gal-α(1,3)Gal-β(1,4)GlcNAc-R. Galectin-3 can also be affinity isolated from monocytes (and not lymphocytes) using an Gal-α(1,3)Gal-β(1,4)GlcNAc-R-biotin/streptavidin-bead pull-down system. Soluble Galectin-3 binds preferentially to PAEC vs human aortic endothelial cells, and this binding can be inhibited by lactose, indicating dependence on the carbohydrate recognition domain of Galectin-3. Gal-α(1,3)Gal-β(1,4)GlcNAc-R is at least partly responsible for this phenomenon, as binding decreased after digestion of PAEC with α-galactosidase. Furthermore, monocytes pretreated with a blocking anti-Galectin-3 Ab show decreased adhesion to PAEC when compared with isotype control in a parallel plate flow chamber perfusion assay. Thus, we conclude that Galectin-3 expressed in human monocytes is a receptor for the major xenoantigen (Gal-α(1,3)Gal-β(1,4)GlcNAc-R), expressed on porcine endothelial cells. |
The journal of Immunology. 2006 Jul 15;177(2):1289-95. | xenotransplantation |
| Johansen KL, Rasmussen K. | 2014 | IgE-induced anaphylactic reaction after eating lamb meat. This article presents the case of a 54-year-old male, who was admitted to hospital after suffering a severe anaphylactic reaction after tasting a spoonful of chili con carne and four months later after eating lamb meat. Galactose-alpha-1,3-galactose allergy was suspected and the subsequent blood test showed highly elevated specific IgE levels. Delayed allergy to meat is a relatively new type of allergy and the delayed onset of allergic symptoms poses a diagnostic challenge to the physician. This type of allergy should be considered when there has been no obvious allergen exposition prior to the allergic reaction. |
Ugeskrift for laeger. 2014 Aug 1;176(35). | Europe; Denmark; lamb |
| Joral A, Azketa N, Sanchez P, Vélez-del-Burgo A, Aranzabal-Soto MA, Lizarza S, Martínez J, Postigo I. | 2022 | The Quantification of IgG Specific to α-Gal Could Be Used as a Risk Marker for Suffering Mammalian Meat Allergy. The alpha‐Gal Syndrome is a delayed meat allergy characterized by the presence of sIgEagainst α‐Gal epitope. It is known that the α‐Gal present in tick saliva induces the sensitization to this epitope ending in the production of sIgG and sIgE to α‐Gal. It could be considered that the more times a person is bitten by tick species, the higher the probability of making the switch from sIgG to sIgE to α‐Gal and developing allergy, but it is no clear when the switch occurs. To determine the likelihood that a subject bitten by ticks but without AGS be at risk of developing this allergy, we quantified the levels of sIgG to α‐Gal by an automated system (ImmunoCap). To stablish a cut‐off value for sIgG to α‐Gal, a receiving operating curve (ROC) was constructed. The statistical analysis demonstrated that the risk of suffering AGS in individuals bitten by ticks was 35% when the sIgG to α‐Gal was greater than or equal to 40 μg/mL. Our data indicate that the sIgG values against α‐Gal could be used as a prognostic marker for developing mammalian meat allergy. |
Foods. 2022 Jan;11(3):466. | IgG; markers; anti-gal; pathogenesis |
| Josko D. | 2019 | Anaphylactic Reaction After Beef Consumption Due to the Development of IgE Antibodies Against the Carbohydrate Galactose-Alpha-1,3-Galactose. A 52-year old female was seen in the emergency department with symptoms of anaphylaxis. History revealed that shortly after eating dinner she developed hives, which quickly evolved into wheezing, throat tightness, and difficulty breathing. Her symptoms intensified even after taking Benadryl. Once in the emergency department she was treated with epinephrine as well as 125 mg of Solu-Medrol. She was later admitted for observation. The patient stated she had several visits to the emergency department in the past few years with hives possibly due to food allergies but not this severe. Subsequent laboratory testing revealed elevated levels of IgE specific antibodies to the beef allergen. An alpha-gal panel was performed for beef, lamb/mutton, and pork IgE levels which were all elevated. The patient was advised to avoid eating these types of meats in the future. Individuals with IgE antibodies to galactose-alpha-1,3galactose (alpha-gal) are at risk for delayed anaphylaxis, angioedema, or urticaria following consumption of these products. The patient lives in a rural area in New Jersey and has been bitten numerous times by ticks. Recently, several cases in Virginia have been reported of hives and difficulty breathing in 45 children aged 4–17 after ingesting red meat. All described being bitten by a tick within the past year. It is believed the Lone Star tick, which is endemic in the southern and eastern United States, carries the carbohydrate alpha-gal in its saliva and once bitten, the patient develops antibodies against this sugar, which can result in life-threatening anaphylaxis. Although there is currently no treatment, individuals who experience symptoms such as hives and difficulty breathing after ingesting meat should be tested for alpha-gal sensitivity and if positive, should avoid consumption of mammalian meat in the future. |
American Journal of Clinical Pathology. 2014 Oct 1;142(suppl 1):A027. | |
| Jungewelter S, Airaksinen L, Pesonen M. | 2019 | Occupational rhinitis, asthma, and contact urticaria from IgE‐mediated allergy to pork. We describe four cases of slaughterhouse workers with occupational immediate allergy to raw pork allergens, confirmed by positive skin prick testing and specific immunoglobulin E (IgE) antibodies. Our first patient was diagnosed with occupational asthma from raw pork allergens. Two patients were diagnosed with occupational rhinitis caused by raw pork allergens, which was confirmed by a nasal provocation test. One of these also had occupational contact urticaria caused by raw pork meat. We were unable to diagnose an occupational respiratory or skin disease in the fourth patient, despite signs of immediate sensitization to raw pork meat from occupational exposure. Based on proper diagnoses, measures to prevent allergen exposure were taken, which led to the improvement of symptoms in these four patients. The present patient cases highlight the importance of recognition of early signs of occupational allergy and identification of causative allergens in order to allow avoidance of allergens, with the aim of preventing persistence and worsening of symptoms. |
American journal of industrial medicine. 2019 Jan;62(1):80-4. | airborne reactions; occupational medicine |
| Kageyama R, Fujiyama T, Satoh T, Keneko Y, Kitano S, Tokura Y, Hashizume H. | 2019 | The contribution made by skin-infiltrating basophils to the development of alpha-gal syndrome. No abstract available |
Allergy. 2019 Sep;74(9):1805-7. | |
| Kaloga M, Kourouma S, Kouassi YI, Ecra EJ, Gbery IP, Allou AS, Diabate A, Djeha D, Sangaré A, Yoboue YP. | 2016 | Allergy to Red Meat: A Diagnosis Made by the Patient and Confirmed by an Assay for IgE Antibodies Specific for Alpha-1,3-Galactose. We report the first case of allergy to red meat observed in Ivory Coast. A 49-year-old male presented with pruritus. The diagnosis of allergy to red meat was confirmed by an assay for IgE antibodies specific for alpha-1,3 galactose. Interestingly, the disease was considered a spell to the patient who was suspected of being a sorcerer by the community. |
Case reports in dermatology. 2016;8(1):10-3. | Sangare; Africa; Ivory Coast; Côte d'Ivoire; self-diagnosis; dermatology; pruritus; vector; insect |
| Kaman K, Robertson D. | 2018 | ALPHA-GAL ALLERGY; MORE THAN MEAT? Introduction: Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate moiety found on non-primate mammalian cell membranes. Over the last 10 years, delayed allergic reactions caused by IgE to alpha-gal has drastically changed the way we think about food allergy. Patients with alpha gal allergy classically present with delayed allergic reactions, including anaphylaxis, hours after consuming mammalian meats. Alpha-gal has also been found to be present in other mammalian products via immunoblot, primarily in dairy that contains higher fat content, but the vast majority of patients tolerate other mammalian byproducts (e.g. milk) with no issue. We present a case of delayed urticaria in a patient with known alpha-gal allergy associated with whey consumption. Case Description: A 37 y/o M presented with delayed urticaria x3 after consuming hamburgers. He was employed as a camp counselor with positive tick exposures. Negative skin prick and specific IgE testing to beef, but positive to Galactose-alpha-1,3-galactose. He subsequently developed delayed urticaria after consuming high doses of whey protein concentrate. Specific IgE testing was negative to whey and other milk proteins. Discussion: Delayed allergic reactions to alpha-gal caused by meat ingestion is well established. We present a case of delayed reaction to alpha-gal in the from of ingested whey, which has not been well documented in the literature. We hypothesize that the bovine-gamma-globulin component in both mammalian meat and whey contains the alpha-gal moiety. Additionally, the form in which bovine-gamma-globulin is consumed or processed may affect reactivity to the alpha component. |
Frontiers in Immunology. 2020;11. | dairy; dairy byproducts; mammalian byproducts; whey |
| Kaplan AC, Carson MP. | 2018 | Diagnosing Meat Allergy After Tick Bite Without Delay. ...Here, we present a case of delayed urticarial angioedema due to a mammalian meat allergy caused by alpha-gal immunoglobulin E acquired after tick exposures, and the knowledge and patient education required to prevent recurrences. It is estimated that approximately 0.5% to 1.0% of the general population will experience an episode of angioedema in their lifetime, and this case demonstrates why clinicians in areas that are inhabited by ticks, particularly the Lone Star species, should include this cause in their differential. |
The Journal of the American Board of Family Medicine. 2018 Jul 1;31(4):650-2. | |
| Kappler K, Hennet T. | 2020 | Emergence and significance of carbohydrate-specific antibodies. Carbohydrate-specific antibodies are widespread among all classes of immunoglobulins. Despite their broad occurrence, little is known about their formation and biological significance. Carbohydrate-specific antibodies are often classified as natural antibodies under the assumption that they arise without prior exposure to exogenous antigens. On the other hand, various carbohydrate-specific antibodies, including antibodies to ABO blood group antigens, emerge after the contact of immune cells with the intestinal microbiota, which expresses a vast diversity of carbohydrate antigens. Here we explore the development of carbohydrate-specific antibodies in humans, addressing the definition of natural antibodies and the production of carbohydrate-specific antibodies upon antigen stimulation. We focus on the significance of the intestinal microbiota in shaping carbohydrate-specific antibodies not just in the gut, but also in the blood circulation. The structural similarity between bacterial carbohydrate antigens and surface glycoconjugates of protists, fungi and animals leads to the production of carbohydrate-specific antibodies protective against a broad range of pathogens. Mimicry between bacterial and human glycoconjugates, however, can also lead to the generation of carbohydrate-specific antibodies that cross-react with human antigens, thereby contributing to the development of autoimmune disorders. |
Brain. 2002 Dec 1;125(12):2591-625. | |
| Karasuyama H, Tabakawa Y, Ohta T, Wada T, Yoshikawa S. | 2018 | Crucial role for basophils in acquired protective immunity to tick infestation. |
Frontiers in Physiology. 2018 Dec 7;9:1769. | Arthropod; Acari; tick; acquired tick immunity; evolution |
| Karim S, Ribeiro JM. | 2015 | An insight into the sialome of the lone star tick, Amblyomma americanum, with a glimpse on its time dependent gene expression. Hard ticks feed for several days or weeks on their hosts. Blood feeding is assisted by tick saliva, which is injected in the host skin regularly, alternating with blood ingestion. Tick saliva contains hundreds or thousands of different peptides and other bioactive compounds that assist feeding by inhibiting their hosts’ blood clotting, platelet aggregation, vasoconstriction, as well as pain and itching. Immunomodulatory and antimicrobial peptides are also found in tick saliva. Molecular characterization of tick salivary compounds, or its sialome (from the Greek sialos = saliva), helps identification of possible antigens that might confer anti-tick immunity, as well as identifying novel pharmacologically active compounds. Amblyomma americanum is a major nuisance tick in Eastern and Southern US, being a vector of Theileria and Ehrlichia bacteria to animals and humans. Presently we report an RNAseq study concerning the salivary glands of adult female A. americanum ticks, which involved sequencing of four libraries collected at different times of feeding. A total of 5,792 coding sequences were deduced from the transcriptome assembly, 3,139 of which were publicly deposited, expanding from the previously available 146 salivary sequences found in GenBank. A remarkable time-dependent transcript expression was found, mostly related to secretory products, supporting the idea that ticks may have several “sialomes” that are expressed at different times during feeding. The molecular nature of this sialome switching remains unknown. The hyperlinked spreadsheet containing the deduced coding sequences can be found at http://exon.niaid.nih.gov/transcriptome/Amb_americanum/Ambame-web.xlsx. |
PLoS One. 2015 Jul 1;10(7):e0131292. | |
| Kato T, Yoshizawa A, Manabe S, Takanashi S, Kawamura A, Yoshizawa S, Kuwaki K. | 2021 | Xenoimmune Response Can Elicit Postoperative Bioprosthetic Valve Degeneration. |
The Journal of Heart and Lung Transplantation. 2021 Apr 1;40(4):S299. | Pharmacy; pharmaceutical; medical products; cardiac surgery; cardiovascular; bioprosthetic heart valve |
| Kazimírová M, Stibraniova I. | 2013 | Tick salivary compounds: their role in modulation of host defences and pathogen transmission Ticks require blood meal to complete development and reproduction. Multifunctional tick salivary glands play a pivotal role in tick feeding and transmission of pathogens. Tick salivary molecules injected into the host modulate host defence responses to the benefit of the feeding ticks. To colonize tick organs, tick-borne microorganisms must overcome several barriers, i.e., tick gut membrane, tick immunity, and moulting. Tick-borne pathogens co-evolved with their vectors and hosts and developed molecular adaptations to avoid adverse effects of tick and host defences. Large gaps exist in the knowledge of survival strategies of tick-borne microorganisms and on the molecular mechanisms of tick-host-pathogen interactions. Prior to transmission to a host, the microorganisms penetrate and multiply in tick salivary glands. As soon as the tick is attached to a host, gene expression and production of salivary molecules is upregulated, primarily to facilitate feeding and avoid tick rejection by the host. Pathogens exploit tick salivary molecules for their survival and multiplication in the vector and transmission to and establishment in the hosts. Promotion of pathogen transmission by bioactive molecules in tick saliva was described as saliva-assisted transmission (SAT). SAT candidates comprise compounds with anti-haemostatic, anti-inflammatory and immunomodulatory functions, but the molecular mechanisms by which they mediate pathogen transmission are largely unknown. To date only a few tick salivary molecules associated with specific pathogen transmission have been identified and their functions partially elucidated. Advanced molecular techniques are applied in studying tick-host-pathogen interactions and provide information on expression of vector and pathogen genes during pathogen acquisition, establishment and transmission. Understanding the molecular events on the tick-host-pathogen interface may lead to development of new strategies to control tick-borne diseases. |
Frontiers in cellular and infection microbiology. 2013 Aug 20;3:43. | vector; tick; tick saliva |
| Keating K, Walko C, Stephenson B, O’Neil BH, Weiss J. | 2014 | Incidence of cetuximab-related infusion reactions in oncology patients treated at the University of North Carolina Cancer Hospital. Purpose: The primary purpose of this study was to determine the rate of infusion reactions to cetuximab in oncology patients treated at the University of North Carolina Cancer Hospital. Secondarily, we sought to evaluate predictors of grade 3–4 hypersensitivity, including geography. Methods: Data were collected by retrospective chart review for patients treated with cetuximab at the University of North Carolina Cancer Hospital between 15 November 2006 and 31 December 2010. Data were analyzed for occurrence of hypersensitivity reaction in 125 patients with various cancer types. Results: Of the 125 subjects, 31 (24.8%) experienced an infusion reaction of any grade. Of 125, 18 (14.4%) experienced a grade 3 or 4 reaction. The odds ratio for patients with an allergy history having a grade 3 or 4 reaction was 2.57 (95% CI 0.93 to 7.09, p = 0.07). Pretreatment with steroids was associated with absence of grade 3 or 4 reaction with an odds ratio of 0.21 (95% CI 0.05 to 0.83, p = 0.04). Mapping of reaction rates by county revealed higher rates in some of the more rural counties of North Carolina, however, statistical power was lacking. Conclusions: Rates of hypersensitivity reaction at UNC are similar to rates seen in other areas of the southeastern United States and higher than in other regions of the United States and Europe. Rates of both hypersensitivity reactions and grade 3 to 4 hypersensitivity reactions have not substantially changed over time. Geography, allergy history, and perhaps smoking or cancer type may help predict who will react to cetuximab. Steroids should be strongly considered as premedication in addition to diphenhydramine. |
Journal of Oncology Pharmacy Practice. 2014 Dec;20(6):409-16. | prevalence; biologic; biological agent; monoclonal antibody; mAb, cetuximab |
| Keleş Ş, Gündüz M. | 2019 | Alpha gal specific IgE positivity due to tick bites and red meat allergy: the first case report in Turkey. Galactose-alpha-1,3-galactose is a carbohydrate moiety found in the cell membranes of many organisms, commonly known as alpha-gal (alpha-Gal). This oligosaccharide is not found in the group of primates in which humans are involved. It has been found that alpha-Gal plays a key role in delayed IgE-mediated red meat allergy and this allergen is triggered by tick bites. Here we present a 7-year-old boy with alpha-gal allergy from Turkey. |
Turk J Pediatr. 2019;61(4):615-617. | Keles; GunduzAsia; Europe; Turkey; |
| Kelly EA, Pochan SL, James HR, Workman LJ, Heymann PW, Commins SP, Platts-Mills TA. | 2011 | IgE Antibodies To The Oligosaccharide Galactose-Alpha-1,3-Galactose (Alpha-Gal) Cross-React With Cat Allergens But Are Not Associated With Asthma. RATIONALE: In contrast to most food allergic patients, relatively few patients with delayed anaphylaxis after ingestion of mammalian meat and IgE specific for galactose-alpha-1,3-galactose (a-gal) suffer from atopic diseases. While these individuals frequently have IgE to cat, only a minority report symptoms of asthma. METHODS: Sera from 97 subjects with mammalian meat allergy, 42 asthmatics, and 52 controls were assayed for total serum IgE and IgE to a-gal and several inhalant allergens. Spirometry and eNO were performed as markers of asthma. RESULTS: The prevalence of asthma amongst these meat allergic subjects was 17%, surprisingly low given that 86% of these subjects have IgE to cat epithelium. The mean FEV1/FVC amongst meat allergic subjects was 0.78, not significantly different from controls at 0.82 (p5NS), compared to 0.72 in asthmatics (p50.02). Likewise, the mean eNO of meat allergic subjects was 22 ppb (16 ppb in controls, p5NS), significantly lower than that of asthmatics at 56 ppb (p50.001). While most had IgE to cat epithelium, only 22% had IgE to Fel d 1, the difference attributed to a-gal moieties present in cat epithelium. Separating out those subjects with IgE to both a-gal and cat epithelium, but not Fel d 1, who were living with a cat in the home, we found the prevalence of asthma dropped to 9%, mean FEV1 of 101%, FEV1/FVC 0.81, and eNO 18 ppb. . CONCLUSIONS: Despite a history of food-related urticaria, angioedema, and anaphylaxis, elevated total IgE, and IgE to cat, patients with mammalian food allergy do not have increased risk for asthma. |
Curr Allergy Asthma Rep. 2017 Jan; 17(1): 8. | cat; asthma |
| Kelly LA, Pochan SL, James HR, Workman LJ, Heymann PW, Commins SP, Platts-Mills TA. | 2012 | Ectoparasite Induced Elevations of alpha-gal Specific IgE are Associated with Increased Total Serum IgE and Cat Sensitization but not with Asthma. PURPOSE OF REVIEW: The objective is to discuss recent progress in our understanding of the role of the indoor environment in asthma, focusing on the special role of cat allergens. RECENT FINDINGS: Sensitization to Fel d 1 is the dominant event in inhalant responses to cat; however, there are also IgE responses to the lipocalin (Fel d 4), to cat albumin (Fel d 2), and to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) on cat IgA (Fel d 5w) and other molecules. The dose response and routes of sensitization for these allergens are now thought to be diverse. It is important to remember that exposure outside a house with a cat is sufficient to cause sensitization. Furthermore, the only solid evidence about a role in asthma relates to Fel d 1. Recently, it has been shown that tolerance associated with early exposure to cats can persist to age 18 and that IgE to alpha-gal (on cat IgA) is not related to asthma. In addition, a recent study of anti-IgE reinforces the evidence that IgE antibodies to indoor allergens make a major contribution to asthma severity. SUMMARY: Exposure to Fel d 1 in a home with a cat is far higher than the levels necessary to induce an allergic (IgE antibody) response. In keeping with that, children may develop tolerance, which can be long-lived. In addition, there is increasing evidence that IgE antibodies to an inhalant allergen, such as Fel d1, dust mite, or cockroach, are causally related to lung inflammation and asthma. |
Journal of Allergy and Clinical Immunology. 2012 Feb 1;129(2):AB7. | cat; asthma |
| Kelly LA, Pochan SL, James HR, Workman LJ, Heymann PW, Commins SP, Platts-Mills TA. | 2011 | Delayed Anaphylactic Reactions to Mammalian Meat are not Associated with an Increased Prevalence of Asthma. RATIONALE: In contrast to most food allergic patients, relatively few patients with delayed anaphylaxis after ingestion of mammalian meat and IgE specific for galactose-alpha-1,3-galactose (a-gal) suffer from atopic diseases. While these individuals frequently have IgE to cat, only a minority report symptoms of asthma. METHODS: Sera from 97 subjects with mammalian meat allergy, 42 asthmatics, and 52 controls were assayed for total serum IgE and IgE to a-gal and several inhalant allergens. Spirometry and eNO were performed as markers of asthma. . RESULTS: The prevalence of asthma amongst these meat allergic subjects was 17%, surprisingly low given that 86% of these subjects have IgE to cat epithelium. The mean FEV1/FVC amongst meat allergic subjects was 0.78, not significantly different from controls at 0.82 (p5NS), compared to 0.72 in asthmatics (p50.02). Likewise, the mean eNO of meat allergic subjects was 22 ppb (16 ppb in controls, p5NS), significantly lower than that of asthmatics at 56 ppb (p50.001). While most had IgE to cat epithelium, only 22% had IgE to Fel d 1, the difference attributed to a-gal moieties present in cat epithelium. Separating out those subjects with IgE to both a-gal and cat epithelium, but not Fel d 1, who were living with a cat in the home, we found the prevalence of asthma dropped to 9%, mean FEV1 of 101%, FEV1/FVC 0.81, and eNO 18 ppb. . CONCLUSIONS: Despite a history of food-related urticaria, angioedema, and anaphylaxis, elevated total IgE, and IgE to cat, patients with mammalian food allergy do not have increased risk for asthma. |
Journal of Allergy and Clinical Immunology. 2011 Feb 1;127(2):AB4. | cat; asthma |
| Kelso JM. | 2022 | The adverse reactions to vaccines practice parameter 10 years on-what have we learned?. Objective: To provide updated information on the evaluation and management of adverse reactions to vaccines. Data Sources: PubMed (MEDLINE) search since publication of a practice parameter in 2012. Study Selections: Original articles and guidelines on adverse reactions to vaccines, including vaccines against severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19). Results: Current guidelines conclude that patients with egg allergy are not at increased risk for reaction to egg-based influenza vaccines. Except for gelatin, most patients with allergy to vaccine constituents tolerate vaccines containing them. Most patients who have immediate reactions after receiving COVID-19 vaccines go on to receive a subsequent dose uneventfully. Conclusion: The risk of reactions to vaccination should be weighed against the risk of having a vaccine-preventable disease if the vaccine is withheld. There is no need to ask about egg allergy before the administration of influenza vaccines, including on screening forms. In most cases, an allergy to a vaccine constituent is not a contraindication to the vaccine containing it. Patients who have had possible anaphylactic reactions to vaccines should be evaluated by an allergist rather than simply being labeled allergic, because most can go on to receive subsequent doses. Most immediate reactions to COVID-19 vaccines are not allergic, and care should be taken to not label such reactions as anaphylactic. The role, if any, of polyethylene glycol in these reactions has yet to be revealed. |
Annals of Allergy, Asthma & Immunology. 2022 Jan 31. | medical products; vaccines; vaccination; gelatin; graded dosing; vaccination protocol |
| Kennedy JL, Stallings AP, Platts-Mills TA, Oliveira WM, Workman L, James HR, Tripathi A, Lane CJ, Matos L, Heymann PW, Commins SP. | 2013 | Galactose-alpha-1,3-galactose and Delayed Anaphylaxis, Angioedema, and Urticaria in Children. BACKGROUND AND OBJECTIVE: Despite a thorough history and comprehensive testing, many children who present with recurrent symptoms consistent with allergic reactions elude diagnosis. Recent research has identified a novel cause for "idiopathic" allergic reactions; immunoglobulin E (IgE) antibody specific for the carbohydrate galactose-alpha-1,3-galactose (alpha-Gal) has been associated with delayed urticaria and anaphylaxis that occurs 3 to 6 hours after eating beef, pork, or lamb. We sought to determine whether IgE antibody to alpha-Gal was present in sera of pediatric patients who reported idiopathic anaphylaxis or urticaria. METHODS: Patients aged 4 to 17 were enrolled in an institutional review board-approved protocol at the University of Virginia and private practice allergy offices in Lynchburg, VA. Sera was obtained and analyzed by ImmunoCAP for total IgE and specific IgE to alpha-Gal, beef, pork, cat epithelium and dander, Fel d 1, dog dander, and milk. RESULTS: Forty-five pediatric patients were identified who had both clinical histories supporting delayed anaphylaxis or urticaria to mammalian meat and IgE antibody specific for alpha-Gal. In addition, most of these cases had a history of tick bites within the past year, which itched and persisted. . CONCLUSIONS: A novel form of anaphylaxis and urticaria that occurs 3 to 6 hours after eating mammalian meat is not uncommon among children in our area. Identification of these cases may not be straightforward and diagnosis is best confirmed by specific testing, which should certainly be considered for children living in the area where the Lone Star tick is common. |
Pediatrics. 2013 May 1;131(5):e1545-52. | pediatrics |
| Kersh GJ, Salzer J, Jones ES, Binder AM, Armstrong PA, Choudhary SK, Commins GK, Amelio CL, Kato CY, Singleton J, Biggerstaff BJ | 2022 | Tick bite as a risk factor for alpha-gal specific IgE antibodies and development of alpha-gal syndrome. Background: The disaccharide galactose-α-1,3-galactose (alpha-gal) is expressed in mammals other than humans, apes, and old-world monkeys. In humans, elevated immunoglobulin-E (IgE) antibodies specific for alpha-gal can result in allergic hypersensitivity known as alpha-gal syndrome (AGS). Case reports and series suggest that tick bites can induce alpha-gal specific IgE antibodies. Objective: Evaluate tick exposure as a risk factor for AGS and elevated alpha-gal specific IgE (sIgE). Methods: We conducted a case-control study comparing AGS patients from a North Carolina allergy clinic with controls who were patients at a nearby internal medicine clinic. Cases and controls were administered a questionnaire to obtain information about demographics, home environment, outdoor activities, and recollection of tick bite. Serum samples taken at the time of enrollment were tested for total IgE, alpha-gal sIgE, and antibodies to other tickborne pathogens. Results: AGS patients were more likely to recall finding a tick on themselves (OR=11.20, 95% CI 4.97-25.15), live near wooded forest (OR=2.27, 95% CI 0.92-5.55), and spend 17 or more hours per week outdoors in wooded areas (OR=5.58, 95% CI 2.56-12.19). AGS patients were also more likely to report 4 or more tick bites (OR=33.05, 95% CI 9.92-155.12) and reactions at the site of tick bites (OR=7.93, 95% CI 3.74-16.80). Elevated alpha-gal sIgE was also observed in 33% of controls and was also associated with tick exposure in the controls (OR=4.25, 95% CI 2.21-8.18). Conclusion: The results define tick bite as a risk factor for AGS and elevated alpha-gal sIgE. |
Annals of Allergy, Asthma & Immunology. 2022 Nov 26. | Ticks; risk factors; etiology |
| Khoury JK, Khoury NC, Schaefer D, Chitnis A, Hassen GW. | 2018 | A tick-acquired red meat allergy. Allergic reaction is a common clinical picture in the Emergency Department (ED). Most allergic reactions are from food or drugs. A detailed history is an integral aspect of determining the causative agent of an allergy. Galactose-alpha-1,3-galactose (alpha-gal) allergy is a tick-acquired red meat allergy that causes delayed-onset allergic reaction or anaphylaxis due to molecular mimicry. Alpha-gal allergy may not be widely known as a cause of allergic reactions. Lack of universal awareness of this phenomenon in the ED and Urgent Care setting could lead to misdiagnosis, or delayed diagnosis. Subsequently, lack of proper instruction to avoid red meat could put patients at risk for future attacks with morbidity or mortality. We report three cases of allergic reaction presumed from red meat consumption secondary to alpha-gal allergy. |
The American Journal of Emergency Medicine. 2018 Feb 1;36(2):341-e1. | Emergency medicine; first responders; ER; urgent care |
| Kieber‐Emmons A, Monzavi‐Karbassi B, Kieber‐Emmons T. | 2020 | Antigens: Carbohydrates II. eLS.:1-29. Glycosylation is critical for a wide range of biological processes across both normal and disease states. Carbohydrate antigens, for example, are polymeric chains of diverse monomeric sugar molecules that play a fundamental role in the pathogenicity and virulence of many organisms. Moreover, these pathogen‐associated glycan structures can also be found in association with other types of cells, including tumours. These types of glycan commonalities have helped generate critical discoveries in terms of glycan structure, allowing for the development of working hypotheses for their functions, in addition to the development of agents that target or mediate their expression levels. Therefore, through discussion of glycans as antigens, new insights of key molecular and cellular interactions between them and immune cells can be discerned, and the implication of these interactions in health and disease is enhanced. Numerous reviews and even this ELS series have described the structure of carbohydrates and glycans in general. |
Antigens: Carbohydrates II. 2020; eLS 1-29 | glycan antigen; carbohydrate; glycomics |
| Kiewiet MB, Apostolovic D, Grundstrom J, Starkhammar M, Hamsten C, van Hage M. | 2019 | Clinical and serological characterization of a large cohort of red meat allergic patients from Sweden. Background: Red meat allergy is a novel form of food allergy recognized worldwide. The patients experience severe allergic reactions several hours after meat consumption and have IgE antibodies directed against the carbohydrate galactose‐α1,3‐galactose (α‐Gal), which is present in mammalian meat. The onset of the disease is associated with tick bites. Here, we characterize a cohort of red meat allergic patients from Sweden on a clinical and serological level. Method: A total of 137 patients were enrolled in the study by a physician experienced in allergic disease, after they were diagnosed with red meat allergy. All had answered to a detailed questionnaire regarding symptoms related to meat intake and tick exposure. The patient sera were analysed for IgE reactivity against protein extract from the European tick Ixodes ricinus (streptavidin ImmunoCAP) and birch and timothy pollen using the ImmunoCAP System (Thermofisher Scientific, Uppsala, Sweden). The limit of detection was set at 0.1 kUA/L. . Results: All patients were IgE positive to α‐Gal and the median α‐Gal IgE level of the cohort was 17.4 kUA/L (range 0.26‐144 kUA/L). Sensitization to pork and beef was observed in 98% and 98.5% of the patients, respectively. They all suffered from the “classical” α‐Gal‐syndrome with delayed severe symptoms after mammalian meat consumption. Nearly half (47%) reported anaphylaxis. The majority reported urticaria (91%) and gastrointestinal symptoms (75%) and more than half (60%) experienced angioedema. Neither the anti‐α‐Gal IgE/total IgE ratio nor the anti‐α‐Gal levels were associated with symptom severity. The median age of the patients at time of inclusion was 49 years and men and women were in equal numbers. All but three belonged to the B‐negative blood groups (A/O). All patients but one reported that they had been tick bitten and 77% were IgE positive to Ixodes ricinus. Also, 44% of the patients were clinically diagnosed with airborne allergies, and sensitization to birch and timothy was observed in 72% and 63% of these subjects respectively. . Conclusion: The awareness of the α‐Gal syndrome is increasing in Sweden. In this large cohort of patients almost half experienced anaphylactic shock pointing to the severity of the disease. All but one patient had been tick bitten underlining the strong relationship with tick bites. Pollen sensitization and the traditional atopic phenotype with airborne allergy was found to be common among these patients. |
Allergy 2019 Aug 1; 74:877-877. | Europe; Sweden; |
| Kiewiet MB, Apostolovic D, Starkhammar M, Grundström J, Hamsten C, van Hage M. | 2020 | Clinical and serological characterization of the α-Gal syndrome-importance of atopy for symptom severity in a European cohort. Background: The galactose-α1,3-galactose (α-Gal) syndrome (AGS) is a novel form of food allergy. Patients experience delayed severe allergic reactions after mammalian meat consumption due to IgE antibodies directed against the carbohydrate α-Gal present in mammalian meat. The onset of the disease is associated with tick bites. Objective: To characterize a cohort of patients with AGS from Sweden on a clinical and serological level, and identify risk factors for disease severity. . Methods: A total of 128 patients with symptoms after mammalian meat intake and IgE to α-Gal were included. Medical examination and diagnosis were made by an allergologist and questionnaires were filled in regarding onset of symptoms, tick exposure, and airborne allergies. Serum IgE reactivity against multiple food and airborne allergens, as well as protein extract from the tick Ixodes ricinus, was measured using ImmunoCAP. . Results: The majority of patients were middle aged, with equal gender distribution. Nearly all reported symptoms more than 2 hours after meat consumption. Urticaria (90%) and gastrointestinal symptoms (74%) were most common. Almost half of the patients suffered from anaphylaxis, and α-Gal IgE levels were significantly higher among these patients compared with those without anaphylaxis. Nearly all patients had been tick bitten and 75% had IgE against I. ricinus. More than half of the patients with AGS were atopic, and atopy increased the risk of anaphylaxis with pulmonary manifestations. Only 2 patients belonged to blood group B/AB. . Conclusion: AGS is an upcoming food allergy where patients report severe symptoms and tick bites. Atopy was found to affect the manifestation of the disease in Swedish patients. . |
J Allergy Clin Immunol Pract. 2020 Mar 3;8(6):2027-34.e2. | Europe; Sweden; atopy gastrointestinal symptoms; GI; Ixodes ricinus; blood type; airborne allergy |
| Kiewiet MB, Grundström J, Apostolovic D, Andersson M, Borres MP, Hamsten C, Starkhammar M, van Hage M. | 2020 | Elucidating the α‐Gal syndrome at the molecular allergen level. |
Allergy. 2020 Nov 18. | Molecular; lactoferrin; pet dander; anaphylaxis; diagnosis; Europe; Sweden; |
| Kiewiet MB, Perusko M, Grundström J, Hamsten C, Starkhammar M, Apostolovic D, van Hage M. | 2022 | Cross-reactivity between tick and wasp venom can contribute to frequent wasp sensitization in patients with the α-Gal syndrome Background: α-Gal syndrome (AGS) is a food allergy with severe delayed allergic reactions, mediated by IgE-reactivity to galactose-α1,3-galactose (α-Gal). AGS is strongly associated with tick bites. An increased incidence of venom sensitization has been found in AGS patients. Here, we evaluated the frequency of wasp sensitization in Swedish AGS patients and the possible cross-reactivity between wasp venom and tick proteins. Methods: Sera from 136 Swedish AGS patients and 29 wasp-positive non-AGS control sera were analyzed for IgE-reactivity against wasp venom (Vespula spp.), the European tick Ixodes ricinus (Streptavidin ImmunoCAP), α-Gal and total IgE by ImmunoCAP. The presence of α-Gal on wasp venom proteins (Vespula vulgaris) was investigated by western blot (WB), and possible cross-reactivity between wasp venom and tick proteins by enzyme-linked immunosorbent assay and WB. Involvement of cross-reactive carbohydrate domains (CCDs) was also assessed. Results: Wasp sensitization was present in 54% of AGS patients, although the IgE levels were low. Wasp sensitized patients had higher IgE levels to α-Gal and total IgE levels compared to non-wasp sensitized AGS patients. α-Gal was not detected in wasp venom, but cross-reactivity between wasp and tick proteins was demonstrated which was not dependent on CCDs. The same cross-reactivity was also observed in the control sera. Furthermore, 17 putative cross-reactive peptides were identified using an in silico approach. Conclusions: For the first time, cross-reactivity between wasp venom and tick proteins has been described. This may be a reason why the majority of Swedish AGS patients, who have all been tick bitten, are also sensitized against wasp. |
Clinical and Translational Allergy. 2022 Jan;12(1):e12113. | vector; hymenoptera; wasp; cross-reactivity; Europe; Sweden; |
| Kim HO, Cho SI, Kim JH, Chung BY, Cho HJ, Park CW, Lee CH. | 2013 | Food hypersensitivity in patients with childhood atopic dermatitis in Korea. Background: It is well known that atopic dermatitis (AD) is related to food hypersensitivity, although its prevalence varies among several studies according to age group, severity, country, survey time, and test method. Objective: To examine the prevalence and status of food hypersensitivity among childhood AD patients in Korea. Methods: A total of 95 patients were enrolled in the study. The history of food hypersensitivity was collected by interviews. The severity of AD was evaluated by eczema area and severity index (EASI). We took blood samples to measure serum total and food-specific immunoglobulin E (IgE) levels. Based on the histories and serum IgE levels, open oral food challenge (OFC) testing was performed to confirm food hypersensitivity. Results: Forty-two (44.2%) of the 95 AD patients had histories of food hypersensitivity. They reported that the most common suspicious foods were egg (n=13, 13.7%), pork (n=9, 9.5%) and cow milk (n=8, 8.4%). The mean EASI score was 16.05±9.76. Thirty-nine (41.1%) of the 95 patients showed elevated serum food-specific IgE levels. The specific IgE levels were elevated for egg (n=17, 17.9%), milk (n=12, 12.6%), peanut (n=10, 10.5%) and wheat (n=8, 8.4%). Fifty-one (53.8%) of 95 patients underwent open OFC, and only 7 (13.7%) of these patients showed positive reactions. Conclusion: The overall prevalence of food hypersensitivity in patients with childhood AD in Korea was 8.3% (7/84). The most common foods causing food hypersensitivity were egg and milk. Among the foods causing hypersensitivity, AD patients in Korea often underestimated peanut, while they overestimated pork. |
Annals of dermatology. 2013 May 1;25(2):196-202. | Asia; Korea; prevalence; pork allergy; atopic dermatitis; dermatology |
| Kim J, Kwon J, Noh G, Lee SS. | 2013 | The effects of elimination diet on nutritional status in subjects with atopic dermatitis. A food allergy is an adverse health effect arising from a specific immune response that occurs reproducibly upon exposure to a given food. In those with food allergies that are thought to cause aggravation of eczema, food avoidance is important. The objective of this study was to research the nutritional status of patients with food allergies. A total of 225 subjects diagnosed with atopic dermatitis underwent a skin prick test as well as measurement of serum immunoglobulin E. Food challenge tests were conducted using seven food items: milk, eggs, wheat, soybeans, beef, pork, and chicken. At post-food challenge visits to the test clinic, participants completed a three-day dietary record, which included two week days and one weekend day, in order to evaluate energy intake and diet quality during the challenge. We analyzed nutrient intake based on differential food allergens. Subjects with a food allergy to milk showed lower intake of Ca, Zn, and vitamin B2, and subjects with a food allergy to egg showed lower intake of vitamin A, B1, B2, niacin, and cholesterol. Subjects with a food allergy to wheat and soybean showed lower intake of Ca, P, Fe, K, Zn, vitamin B2, vitamin B6, and niacin; and subjects with a food allergy to beef, pork, and chicken showed lower intake of Fe and higher intake of K, vitamin A, B2. Subjects with atopic dermatitis were lacking in several nutrients, including vitamin A and vitamin C. A greater number of food allergies showed an association with a greater number of nutrient intake deficiencies. Allergen avoidance is the basic treatment for atopic dermatitis. However, when the allergen is food, excessive restriction can lead to nutrition deficiency. Findings of this study suggest the necessity for enhanced nutritional education in order to provide substitute foods for patients with food allergies who practice food restriction. |
Nutrition Research and Practice. 2013 Dec 1;7(6):488-94. | |
| Kim JH, An S, Kim JE, Choi GS, Ye YM, Park HS. | 2010 | Beef-induced anaphylaxis confirmed by the basophil activation test. Beef allergies are relatively rare, especially in adults. However, clinical manifestations can vary from urticaria, angioedema, anaphylaxis to gastrointestinal symptoms. Currently available tests, such as skin testing or in vitro determination of beef-specific immunoglobulin E (IgE), do not provide an accurate diagnosis of beef allergy. The recent development of the basophil activation test (BAT) presents a new opportunity for the diagnosis of food allergies. Here, we report a 37-year-old woman with a history of recurrent generalised urticaria, nausea, vomiting and hypotension after ingestion of beef, suggesting a beef allergy. Although the skin prick test and serum specific IgE to beef, pork and milk allergens showed negative results using commercial kits, the BAT showed significant upregulation of CD203c in a dose-dependent manner compared to both non-atopic and atopic controls. To our knowledge, this is the first case study of beef allergy consisting of a non-IgE-mediated reaction. The detection of food allergies using direct basophil activation is suggested to complement conventional diagnostic tests. |
Allergy, asthma & immunology research. 2010 Jul 1;2(3):206-8. | Asia; Korea; beef allergy; basophil activation test; CD203c |
| Kim MS, Straesser MD, Keshavarz B, Workman L, McGowan EC, Platts-Mills TA, Wilson JM. | 2019 | * IgE to galactose-alpha-1,3-galactose wanes over time in patients who avoid tick bites. Galactose-a-1,3-galactose (a-Gal) is an oligosaccharide of nonprimate mammals and the target of IgE antibodies in the syndrome of delayed anaphylaxis to mammalian meat. The connection between IgE sensitization to a-Gal and tick bites is now well established, and in North America, the a-Gal syndrome has consistently been associated with Amblyomma americanum. Case reports and clinical experience suggest that levels of IgE to a-Gal can decrease over time in some patients, particularly those who avoid additional tick exposures, but the natural history of IgE to a-Gal has not been systematically examined. Here we report results of a retrospective investigation into the trend and rate of changes in a-Gal specific IgE (sIgE) and total IgE in relation to tick exposure in subjects with established a-Gal syndrome. Clinical Implications • IgE specific to galactose-α-1,3-galactose (α-Gal) and total IgE decrease over time in patients with α-Gal syndrome who avoid further tick bites. These findings provide further support for the connection between tick bites and the pathogenesis of the syndrome. |
The Journal of Allergy and Clinical Immunology: In Practice. 2020 Jan 1;8(1):364-7. | |
| Kim TK, Tirloni L, Pinto AF, Diedrich JK, Moresco JJ, Yates III JR, da Silva Vaz Jr I, Mulenga A. | 2020 | Time-resolved proteomic profile of Amblyomma americanum tick saliva during feeding. PLoS neglected tropical diseases. Amblyomma americanum ticks transmit more than a third of human tick-borne disease (TBD) agents in the United States. Tick saliva proteins are critical to success of ticks as vectors of TBD agents, and thus might serve as targets in tick antigen-based vaccines to prevent TBD infections. We describe a systems biology approach to identify, by LC-MS/MS, saliva proteins (tick = 1182, rabbit = 335) that A. americanum ticks likely inject into the host every 24 h during the first 8 days of feeding, and towards the end of feeding. Searching against entries in GenBank grouped tick and rabbit proteins into 27 and 25 functional categories. Aside from housekeeping-like proteins, majority of tick saliva proteins belong to the tick-specific (no homology to non-tick organisms: 32%), protease inhibitors (13%), proteases (8%), glycine-rich proteins (6%) and lipocalins (4%) categories. Global secretion dynamics analysis suggests that majority (74%) of proteins in this study are associated with regulating initial tick feeding functions and transmission of pathogens as they are secreted within 24–48 h of tick attachment. Comparative analysis of the A. americanum tick saliva proteome to five other tick saliva proteomes identified 284 conserved tick saliva proteins: we speculate that these regulate critical tick feeding functions and might serve as tick vaccine antigens. We discuss our findings in the context of understanding A. americanum tick feeding physiology as a means through which we can find effective targets for a vaccine against tick feeding. |
PLoS neglected tropical diseases. 2020 Feb 12;14(2):e0007758. | |
| Kim YG, Gil GC, Harvey DJ, Kim BG. | 2008 | Structural analysis of α‐Gal and new non‐Gal carbohydrate epitopes from specific pathogen‐free miniature pig kidney. The major barrier in transplantation of pig organs into humans is the presence of surface carbohydrate antigens (e.g., the Galα1‐3Galβ1‐4GlcNAc‐R (α‐Gal) epitope) expressed on pig endothelial cells. In this study, total N‐glycans from membrane glycoproteins derived from specific pathogen‐free miniature pig kidney are identified by MALDI‐TOF, negative ion ESI MS/MS and normal‐phase HPLC (NP‐HPLC) combined with exoglycosidase digestion. Over 100 N‐glycans, including sialylated and neutral types, were identified. As well as the known α‐Gal antigens, some of these glycans contained novel non‐Gal carbohydrate antigens such as (Neu5Gc‐Gal‐GlcNAc) and Galα1‐3Lewisx (Gal‐Gal‐(Fuc)GlcNAc) which have not been reported before in N‐glycans from pig organs. The ability of MALDI, ESI, and HPLC to measure the relative proportions of the glycans was evaluated. The HPLC resolution was insufficient for accurate work and some minor differences were noted in the ionization efficiencies of different glycan groups when measured by the two mass spectrometric techniques. However, the results indicated that the relative quantity of α‐Gal epitope was in the region of 50% of the complex glycans. High‐mannose type glycans were also abundant (35–43%) but appeared to be ionized more efficiently than the complex glycans by ESI than by MALDI. |
Proteomics. 2008 Jul;8(13):2596-610. | |
| Kimpel D, Wilson J, Lewis J. | 2019 | *SERO-REACTIVITY TO GALACTOSE-ALPHA-1,3-GALACTOSE AND CLINICAL PRESENTATIONS OF PATIENTS SEEN IN A RHEUMATOLOGY OUTPATIENT PRACTICE. Background: Analphylactic reactions to cetuximab, a monoclonal antibody used in cancer therapy, were recognized in 2007 as a regional complication related to recognition of a protein epitope by IgE. This protein epitope was defined as galactose-alpha-1,3-galactose (alpha-gal), which is found in non-primate mammalian tissue. Reactivity to this epitope was also found to occur after meat consumption with manifestations including anaphylaxis, urticaria, or angioedema. Further study showed that reactivity was induced by tick bites from the Lone Star tick. Similar cases of reaction to red meat have been described in Australia in 2006, and more recently in Japan and various European countries. In our Rheumatology practices where patients often raise concerns about possible tick-borne illnesses, we have observed patients presenting with symptoms related to consumption of mammalian meat, but generally less severe, and with IgE reactivity to alpha-gal. Objectives: We have characterized the range of presenting symptoms in our alpha-gal positive patients, and their response to dietary modification. . Methods: Patients referred to this Rheumatology practice who had known exposure or risk factors for tick exposure were tested for IgE antibodies against galactose-alpha-1,3-galactose (alpha-gal) using a standardized test administered by Viacor-IBT, and also tested for typical Rheumatologic markers, as indicated by their symptoms. Alph-gal IgE levels varied from 0.38 to >100 kU/L (normal <0.35 kU/L). . Results: 147 patients were identified as positive for alpha-gal, and were recommended to avoid mammalian meat. Followup testing and evaluation was achieved in 38 patients, along with documentation of symptoms for improvement or persistence. Clinical manifestations, laboratory findings, and reasons for referral in symptomatic alpha-gal positive patients were diverse. Dermatologic manifestations occurred in 9 including urticarial vasculitis, serpiginous urticarial rash, purpuric rash, psoriasiform rash, nummular eczema, and subcutaneous nodules. Arthritic manifestations varied and included monoarthritis (one patient, with negative Lyme PCR of fluid), oligoarthritis in 2 patients, inflammatory polyarthritis in 10 who did not meet criteria for a diagnosis of RA, and polyarthralgia in 22. 15 patients were diagnosed with Rheumatoid Arthritis, and 13 with Spondyloarthritis. 28 patients were referred with positive ANA tests. 25 were felt to be false positive ANAs who did not meet criteria for any connective tissue disease. Anticardiolipin antibodies were present in 4 patients. Surprisingly only 11 patients had a history of severe reaction to mammalian meat, and only one had been previously diagnosed with mammalian meat allergy Of the 38 patients seen in followup, 10 reported symptom improvement with mammalian meat restriction. . Conclusion: Alpha-gal reactivity from tick bites is more common than Lyme disease or other tick-borne disease in our catchment area. The patients rarely recall distinct exposure to a Lone Start tick. Manifestations are protean, and do not correlate with alpha-gal IgE level. Some patients are shown to improve with restriction of dietary mammalian meat. Somewhat surprisingly, other patients prefer to tolerate intermittent mild symptoms to maintain current dietary patterns. In areas where Lone Star ticks are present, and in patients with risk factors for tick exposure, alpha gal IgE reactivity should be considered and tested for as part of a “tick panel” in patients who present with symptoms of potential rheumatologic diseases. |
Annals of the Rheumatic Diseases 78(Suppl. 2): 1317-1318. | atypical symptom; rheumatology; arthritis |
| Kinoshita M, Newton S. | 2019 | Alpha-gal Allergy in a 6-Year-Old Male: A Case Report. Alpha-gal allergy is a reaction where the immunoglobulin E antibody elicits a response to galactosealpha-1,3-galactose (alpha-gal) which is a mammalian oligosaccharide epitope found in nonprimate mammalian. After being exposed to a tick bite, particularly the Lone Star tick (Amblyomma americanum), an individual has been known to develop an alpha-gal allergy. Our patient presented with symptoms of delayed-onset allergy 3-8 hours after consuming mammalian meat products including beef and pork. These symptoms can include, but not limited to, the following: urticaria, angioedema, anaphylaxis, nausea, diarrhea, indigestion. Since symptoms do not present immediately, a delay in diagnosis can occur. Our patient highlights one of the few reported childhood cases with an alpha-gal allergy. We recommend a careful history, in particular, asking if the patient has a past history of tick bites and the appearance of allergy symptoms following beef or pork consumption. |
JNMA; Journal of the Nepal Medical Association. 2019 Sep 1;57(219):379-81. | Asia; Nepal; pediatric |
| Kitajima K, Inoue S, Inoue Y. | 1989 | Isolation and characterization of a novel type of sialoglycoproteins (hyosophorin) from the eggs of medaka, Oryzias latipes: Nonapeptide with a large N-linked glycan chain as a tandem repeat unit We found a novel type of sialoglycoprotein (SGP) with apparent molecular mass ranging from 15,000 to 100,000 Da in the unfertilized eggs of the medaka fish, Oryzias latipes. From fertilized eggs we isolated the corresponding sialoglycopeptides of apparent molecular weight 7000. The amino acid and carbohydrate compositions of these glycoproteins and glycopeptides are very similar, if not identical, and they contain 90%, by weight, of carbohydrate, the predominant sugars being Gal, GlcNAc, and NeuAc. The chemical and physical data indicate that 15- to 100-kDa SGPs are made up of tandem repeat structures whose repeating unit is 7-kDa sialoglycopeptide, and, upon fertilization, higher molecular weight SGPs undergo proteolytic depolymerization to the least structural unit, 7-kDa sialoglycopeptide. As is the case with polysialoglycoproteins (PSGP) found in salmonid fish eggs, a novel family of sialoglycoproteins has been proven to be a major component of cortical alveoli of medaka eggs, namely, hyosophorin. However, we found that they differ markedly from PSGPs (salmonid fish egg hyosophorins) in terms of the carbohydrate composition. The chemical composition and the results of Smith degradation indicate that SGP contains one large N-linked glycan chain per repeat unit. We have determined the amino acid sequence of 7-kDa sialoglycopeptide: Asp-Ala-Ala-Ser-Asn∗-Gln-Thr-Val-Ser, where ∗ indicates the asparagine residue to which a large glycan chain consisting of Fuc2Man3Gal15GlcNAc9NeuAc6 is attached. The direct experimental evidence for the presence of a polyprotein structure suggests that the covalent nature of the higher molecular weight SGPs should be expressed as [Asp-Ala-Ala-Ser-Asn∗-Gln-Thr-Val-Ser]N, where N = 2 to 14 but for the major fraction N = 12. |
Developmental biology. 1989 Apr 1;132(2):544-53. | Fish; fish roe; hyosophorin |
| Kleiman AM, Littlewood KE, Groves DS. | 2017 | †Delayed Anaphylaxis to Mammalian Meat Following Tick Exposure and Its Impact on Anesthetic Management for Cardiac Surgery: A Case Report. Hypersensitivity reactions to mammalian meat following tick exposure are increasing in prevalence and provide a unique challenge to anesthesiologists. The reactions, including anaphylaxis, are delayed and therefore may not be easily recognized and treated. The risk is especially high in cardiac surgery, where several potential triggers, including biological valves as well as heparin, are used frequently. In the presence of such hypersensitivity, prophylactic measures including preoperative testing and pharmacologic prophylaxis may be useful in modulating the immune response such that triggering agents may be used relatively safely. We present 3 patients with previous sensitization to meat protein following a tick bite with known allergic reactions to mammalian meat who presented for cardiac surgery involving exposure to potential allergens and discuss the perioperative management including possible prevention. |
Case Reports 8(7): 175-177. | perioperative care; anesthesiology; anesthesia; cardiac surgery; heparin; pharmaceutical; pharmacy; cardiac; cardiovascular; cardiology; atherosclerosis; CAD coronary artery disease; medical products; bioprosthetic heart valve; pharmacy; pharmaceutical |
| Knight ME, Wyatt K, James HC. | 2015 | Exercise-induced anaphylaxis after consumption of red meat in a patient with IgE antibodies specific for galactose-alpha-1,3-galactose. Letter to the editor Clinical implications: Testing for alpha-gal antibodies in patients with exercise-induced anaphylaxis should be considered even if the patient has not exhibited symptoms at times not associated with exercise. |
J Allergy Clin Immunol Pract 3(5): 801-802. | cofactors; co-factors; augmentation factors; exercise; anaphylaxis |
| Knoedler A, Gupta M, Eschenbacher W, Keshavarz B, Platts-Mills T, Wilson J. | 2020 | The UVA experience with α-Gal testing: a retrospective investigation of 2456 subjects tested for α-Gal. Rationale: In 2009 our group reported that IgE to galactose-α-1,3-galactose (α-Gal) was associated with episodes of delayed anaphylaxis to mammalian meat. Since that time there has been increased recognition of “the α-Gal syndrome”, however, most studies to date have involved case series or small cohorts. Methods: In 2010 a test for serum IgE to α-Gal was introduced at the University of Virginia (UVA) clinical lab. Here we conducted a retrospective analysis of patients who had α-Gal specific IgE testing between January 1st, 2010-July 1st, 2017. We reviewed baseline characteristics, ICD codes to accompanying allergic diseases, total IgE, eosinophil counts and tryptase. . Results: There were 2456 patients with α-Gal-specific IgE testing. Using a cut-off of 0.35 IU/mL, 971 were positive (39.5%) and of these: 459 were male (47.0%), 858 were Caucasian (88.4%), the age range was 2-86 (median 52 years) and the median level of α-Gal specific-IgE was 5.7 IU/mL (IQR 1.4-18.3). Compared to the α-Gal negative group these patients were more commonly male (p <0.001), Caucasian (p<0.001) and older (p<0.001). Anaphylaxis was coded in 43.2% of the α-Gal sensitized compared to 26.9% of the non-sensitized (p<0.001). Tryptase and eosinophil counts were similar, however total IgE was greater in the α-Gal positive group (157 vs 69 IU/mL, p<0.001). . Conclusions: Between 2010 and 2017 there were almost 1000 subjects identified with positive α-Gal specific-IgE titers. Consistent with prior reports and likely related to the fact that sensitization occurs via tick bites, positive subjects were more often of older age, male and had higher total IgE levels. . |
Journal of Allergy and Clinical Immunology. 2020 Feb 1;145(2):AB145. | |
| Koike C, Uddin M, Wildman DE, Gray EA, Trucco M, Starzl TE, Goodman M. | 2007 | Functionally important glycosyltransferase gain and loss during catarrhine primate emergence. A glycosyltransferase, α1,3galactosyltransferase, catalyzes the terminal step in biosynthesis of Galα1,3Galβ1–4GlcNAc-R (αGal), an oligosaccharide cell surface epitope. This epitope or antigenically similar epitopes are widely distributed among the different forms of life. Although abundant in most mammals, αGal is not normally found in catarrhine primates (Old World monkeys and apes, including humans), all of which produce anti-αGal antibodies from infancy onward. Natural selection favoring enhanced resistance to αGal-positive pathogens has been the primary reason offered to account for the loss of αGal in catarrhines. Here, we question the primacy of this immune defense hypothesis with results that elucidate the evolutionary history of GGTA1 gene and pseudogene loci. One such locus, GGTA1P, a processed (intronless) pseudogene (PPG), is present in platyrrhines, i.e., New World monkeys, and catarrhines but not in prosimians. PPG arose in an early ancestor of anthropoids (catarrhines and platyrrhines), and GGTA1 itself became an unprocessed pseudogene in the late catarrhine stem lineage. Strong purifying selection, denoted by low nonsynonymous substitutions per nonsynonymous site/synonymous substitutions per synonymous site values, preserved GGTA1 in noncatarrhine mammals, indicating that the functional gene product is subjected to considerable physiological constraint. Thus, we propose that a pattern of alternative and/or more beneficial glycosyltransferase activity had to first evolve in the stem catarrhines before GGTA1 inactivation could occur. Enhanced defense against αGal-positive pathogens could then have accelerated the replacement of αGal-positive catarrhines by αGal-negative catarrhines. However, we emphasize that positively selected regulatory changes in sugar chain metabolism might well have contributed in a major way to catarrhine origins. |
Proceedings of the National Academy of Sciences. 2007 Jan 9;104(2):559-64. | primate evolution; galactosyltransferase; glycosyltransferase |
| Kollmann D, Nagl B, Ebner C, Emminger W, Wöhrl S, Kitzmüller C, Vrtala S, Mangold A, Ankersmit HJ, Bohle B. | 2017 | The quantity and quality of alpha-gal-specific antibodies differ in individuals with and without delayed red meat allergy. Background: IgG to galactose-alpha-1,3-galactose (alpha-gal) are highly abundant natural antibodies (Ab) in humans. alpha-Gal-specific IgE Ab cause a special form of meat allergy characterized by severe systemic reactions 3-7 h after consumption of red meat. We investigated 20 patients who experienced such reactions and characterized their alpha-gal-specific IgE and IgG responses in more detail. . Methods: alpha-Gal-specific IgE was determined by ImmunoCAP. IgE reactivity to meat extract and bovine gamma globulin (BGG) was assessed by immunoblotting and ELISA, respectively. In some experiments, sera were pre-incubated with alpha-gal or protein G to deplete IgG Ab. alpha-Gal-specific IgG(1-4) Ab in individuals with and without meat allergy were assessed by ELISA. . Results: In immunoblots, BGG was the most frequently recognized meat protein. Binding of IgE and IgG to BGG was confirmed by ELISA and completely abolished after pre-incubation with alpha-gal. Neither the depletion of autologous alpha-gal-specific IgG Ab nor the addition of alpha-gal-specific IgG Ab from nonallergic individuals changed the IgE recognition of BGG of meat-allergic patients. Meat-allergic patients showed significantly higher alpha-gal-specific IgG1 and IgG3 Ab than nonallergic individuals, whereas the latter showed significantly higher levels of alpha-gal-specific IgG4 Ab. . Conclusion: Patients with delayed meat allergy display IgE and IgG Ab that selectively recognize the alpha-gal epitope on BGG. Their enhanced alpha-gal-specific IgE levels are accompanied by high levels of alpha-gal-specific IgG1 devoid of IgE-blocking activity. This subclass distribution is atypical for food allergies and distinct from natural alpha-gal IgG responses in nonallergic individuals. |
Allergy. 2017 Feb;72(2):266-73. | immunoglobulin g; IgG |
| Konakci KZ, Bohle B, Blumer R, Hoetzenecker W, Roth G, Moser B, Boltz‐Nitulescu G, Gorlitzer M, Klepetko W, Wolner E, Ankersmit HJ. | 2005 | Alpha‐Gal on bioprostheses: xenograft immune response in cardiac surgery. Background: The α-Gal (Galα1,3-Galβ1–4GlcNAc-R) epitope is the major xenoantigen causing hyperacute rejection of pig organs transplanted into primates. Porcine bioprostheses are utilized in cardiac surgery. However, premature degeneration of bioprostheses has limited utilization in younger patients and the immune response remains elusive. We sought to investigate whether a specific α-Gal immune response may play a role in this clinical scenario. Materials and methods: We investigated the presence of α-Gal-epitope on native and fixed porcine valves by means of confocal laser scanning microscope (CLSM). ELISA was utilized to evidence whether implantation of bioprostheses elicits augmentation of pre-existing cytotoxic anti α-Gal IgM antibodies within 10 days of surgery. Patients who underwent coronary artery bypass grafting (CABG) or mechanical valve replacement served as controls (each group, n = 12). To corroborate the clinical relevance of the α-Gal immune response in vivo, we studied serum obtained before and after implantation of bioprostheses and its potency to lyse porcine α-Gal-bearing PK15 cells. Results: We found the immunogenic α-Gal-epitope on fibrocytes interspersed in the connective tissue of porcine valves as determined by vimentin/IB4 lectin binding. Moreover, patients who were provided with a bioprostheses had developed a significant increase of naturally occurring cytotoxic IgM antibodies directed towards α-Gal after surgical intervention as compared with control patients (P < 0·0001, respectively). Sera obtained from the patients after the implantation of bioprostheses demonstrated an increased cytotoxicity against α-Gal-bearing PK-15 cells as compared with preoperative sera (P < 0·001). The specificity of the cytotoxic effects was proven as soluble Galα1–3Galβ1–4GlcNAc markedly inhibited cell death of α-Gal-bearing PK15 cells (P < 0·001). Conclusion: Our data suggest that implantation of bioprostheses in cardiac surgery induces a xenograft-specific immune response. Procedures diminishing the presence of α-Gal on bioprostheses, such as utilization of genetically manipulated α-Gal-deficient xenograft or pretreatment with α-Galactosidase, might diminuate the immune response against bioprostheses and extend durability. |
European journal of clinical investigation. 2005 Jan;35(1):17-23. | Cardiac surgery; cardiology; medical products; bioprosthetic heart valve; |
| Kondo M, Matsushima Y, Iida S, Umaoka A, Nakanishi T, Habe K, Yamanaka K. | 2021 | A Case of α-Gal-Unrelated Red Meat-Induced Urticaria Treated by Omalizumab. A 70-year-old healthy woman was referred to our hospital for chronic urticaria. She did not have a history of allergy, asthma, and rhinitis. She was initially diagnosed with α-gal-related urticaria based on an episode of delayed-type urticaria after eating red meat. The results of the intracutaneous allergen test for beef and pork were negative. Fluorenzyme immunoassays specific for IgE against α-gal, beef, and pork were also negative. She was diagnosed with an α-gal-unrelated red meat allergy following the reproduction of urticaria by a food challenge test. The patient was unresponsive to several drugs, including antihistamines or immunosuppressants. However, omalizumab administration suppressed her symptoms. Key Clinical Message: The diagnosis of red meat allergy may require a repeatability test by consuming red meat even though serum α-gal IgE antibody might be negative. The α-gal-unrelated red meat urticaria may be responsive to omalizumab. |
Case Reports in Dermatology. 2021;13:437-40. | Asia; Japan; management; treatment; omalizumab |
| Kondo M, Nakagawa T, Yamanaka K, Mizutani H. | 2017 | Case with acute urticaria by red meat after Haemaphysalis longicornis bite. Letter to the editor. No abstract available. |
The Journal of Dermatology. 2017 Jul;44(7):e168-9. | Haemaphysalis longicornis; Asian longhorned tick; tick species; Japan |
| Kondo M, Yamanaka K, Mizutani H, Isoda K, Nakamura T, Yoshida K, Mizutani H, Sekiya A, Kono M, Tsujiuchi H, Akiyama M. | 2017 | 575 Rapid changes in the red meat and alpha-Gal specific IgE-RAST level profile in the clinical course of a case with red meat allergy and Haemaphysalis longicornis bite. A case with stroke was referred to our hospital with two ticks attached on her right arm. Five days after admission, she started slurry food including red meat, and developed generalized urticarial rash. Then, she was diagnosed having urticarial allergic reaction to red meat, and red meat was eliminated from her hospital diet. The eruption disappeared within 3 days without systemic corticosteroid therapy. Her rash didn’t recur during 4 months hospitalization. High prevalence of urticarial type red meat allergy was reported in the endemic area of Japanese spotted fever, which is mediated by Haemaphysalis longicornis (H. longicornis). Then, we investigated immunological background of the present case. We performed PCR analysis of the removed tick, and confirmed it asH. longicornis after sequence analysis of the PCR product. By skin prick test with beef antigen, positive reaction was observed at the beef tested skin after 30 minutes. Then, we investigated changes in the serum red meat specific IgE levels and serum anti-galactose-alpha-1.3-galactose (α-Gal) antibody, because α-Gal is a shared epitope in red meat and saliva of H. longicornis. Her red meat specific IgE level was 11.30 Ua/ml at admission. Two days after allergic episode, it increased to 15.5 Ua/ml. At 4 days after elimination of the red meat food, it decreased to 9.23Ua/ml. The simultaneously serially measured α-Gal specific IgE-RAST levels were more than the highest detection limit through the clinical course. The present results indicate she was already sensitized to α-Gal by repeated H. longicornis bite before hospitalization. α-Gal is a shared epitope between the red meat and H. longicornis salivary antigen, and rapid changes in red meat specific IgE levels but not α-Gal specific IgE levels indicated clinical effect of elimination of red meat food in red meat allergy due to shortness of its serum half-life of IgE. |
Journal of Investigative Dermatology. 2017 May 1;137(5):S99. | Haemaphysalis longicornis; Asian longhorned tick; tick species; Japan |
| Koo G, Plager J, Fahrenholz JM, Phillips E, Stone CA. | 2022 | Reactivity to Heparin in Alpha-Gal Allergic Patients: A Potential Role for Skin Testing?. Galactose-alpha-1,3-galactose (alpha-gal) syndrome is an immunoglobulin (Ig)E-mediated allergy syndrome to an oligosaccharide found in nonprimate mammalian meat and mammalian-derived products.1 Oral consumption reactions are characteristically delayed, but are immediate with parenteral administration.1 Since the discovery of alpha-gal IgE antibodies while investigating hypersensitivity reactions to cetuximab, much attention has been paid to both theoretical risks and reported cases of hypersensitivity reactions to various medications and medical devices derived from nonprimate mammals.1,2 The true extent of this risk is still largely unknown.3 One medication of interest is heparin; both unfractionated heparin and low-molecular weight heparin, enoxaparin, are derived from porcine intestinal tissue. In a case of immediate hypersensitivity to heparin in a patient with a high concentration of alpha-gal–specific IgE (sIgE), we would like to draw attention to positive skin testing result to heparin products. |
Annals of Allergy, Asthma & Immunology. 2022 Jul 21. | medical products; drugs; surgery; pharmacology; blood thinner; diagnosis; testing; heparin |
| Kopsco HL, Duhaime RJ, Mather TN. | 2021 | Crowdsourced Tick Image-Informed Updates to US County Records of Three Medically Important Tick Species. Burgeoning cases of tick-borne disease present a significant public health problem in the United States. Passive tick surveillance gained traction as an effective way to collect epidemiologic data, and in particular, photograph-based tick surveillance can complement in-hand tick specimen identification to amass distribution data and related encounter demographics. We compared the Federal Information Processing Standards (FIPS) code of tick photos submitted to a free public identification service (TickSpotters) from 2014 to 2019 to published nationwide county reports for three tick species of medical concern: Ixodes scapularis Say (Ixodida: Ixodidae), Ixodes pacificus Cooley and Kohls (Ixodida: Ixodidae), and Amblyomma americanum Linneaus (Ixodida: Ixodidae). We tallied the number of TickSpotters submissions for each tick species according to “Reported” or “Established” criteria per county, and found that TickSpotters submissions represented more than half of the reported counties of documented occurrence, and potentially identified hundreds of new counties with the occurrence of these species. We detected the largest number of new county reports of I. scapularis presence in Michigan, North Carolina, and Texas. Tick image submissions revealed potentially nine new counties of occurrence for I. pacificus, and we documented the largest increase in new county reports of A. americanum in Kentucky, Illinois, Indiana, and Ohio. These findings demonstrate the utility of crowdsourced photograph-based tick surveillance as a complement to other tick surveillance strategies in documenting tick distributions on a nationwide scale, its potential for identifying new foci, and its ability to highlight at-risk localities that might benefit from tick-bite prevention education. |
Journal of Medical Entomology. 2021 May 11. | North America; United States; vector; tick; lone star tick; geography; distribution |
| Krishna N, Krishna S, Krishna R. | 2017 | P112 Correlation between clinical findings and laboratory tests for alpha gal sensitivity. Rationale: Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate moiety present on cells of non-primate mammalian species. After sensitization to alpha-gal, most often due to tick bites, patients reported delayed anaphylactic symptoms to red meats. Methods: The charts of 40 patients with positive symptoms and high clinical suspicion for red meat sensitivity were analyzed (18 pediatric, 22 adult). Of these, 25 tested positive to red meats by skin prick test or serum IgE assay (ImmunoCAP). Of the forty, 10 underwent alpha-gal testing at a commercial lab. The remaining 30 were untested for alpha-gal due to various reasons such as young age, or voluntarily forgoing testing. . Results: For all the 12 patients whose serums were tested, the alpha-gal lab test results were negative. We have been unable to confirm our positive clinical features with current alpha-gal lab tests, and we found 100% negative correlation between suspected alpha-gal sensitivity and the lab result. . Conclusion: Clinicians must be aware of poor cross-correlation between clinical history, skin test results and laboratory data in patients with red meat sensitivity. Clinicians should remain vigilant in cases with delayed allergic reactions following meat ingestion, relying more on their clinical acumen for further management, rather than the laboratory test for alpha-gal. Until the FDA approves an alpha-gal test with better sensitivity and specificity, it would be prudent to be skeptical of negative alpha-gal results. Reproducibility is crucial to any lab test, and the current state of alpha-gal testing needs improvement. |
Annals of Allergy, Asthma & Immunology. 2017 Nov 1;119(5):S37. | diagnostic testing; diagnosis |
| Krstić Ristivojević M. | 2020 | Monitoring of in vitro Bioavailability and Uptake of Glycosylated Food Allergens Using Cell-Based Models. |
(Doctoral dissertation, Univerzitet u Beogradu-Hemijski fakultet). | delayed reaction; glycoproteins |
| Krstić-Ristivojević M, Apostolović D, Grundström J, Tran TT, Ćirković-Veličković T, Hamsten C, van Hage M. | 2016 | alpha-Gal epitope on protein surface decreases transcytosis through Caco-2 monolayer. Background: Transepithelial transport of proteins is the first step in the cascade of events during an immune response to food allergens. Red meat allergy is characterized by an IgE response against the carbohydrate galactose-a-1,3-galactose (a-Gal) and severe allergic reactions several hours after red meat consumption. The aim of this study was to reveal if the presence of aGal epitopes on the protein surface influenced transcytosis through a Caco-2 monolayer (an in-vitro cell-based system that faithfully mimics gut transportation offood allergens). Method: Human serum albumin (HSA) and HSA conjugated a-Gal (HSA-a-Gal) were labeled with fluorescein isothiocyanate(FITC). Caco-2 cells were seeded at 6 9 104 cells/cm2 on polycarbonate membrane inserts and cultured for 21 days. Cell monolayers with a transepithelial electrical resistance (TEER) above 400 O were used andthe transport of 80 lg or 40 lg of FITClabeled proteins in the cMEM culture medium was evaluated. Fluorescence of passed protein was measured at various time points (0.5, 1, 2, 4, 6 h) and calculated from standard curves of the corresponding protein using a spectrofluorimeter. Results: A constant increase of transported protein over time was noted. The amount of transported HSA-a-Gal when 80 lg was applied on monolayer was in the range from 17.7 0.2 ng after 0.5 h of transcytosis up to 89 9 ng of protein after 6 h of transcytosis. When HSA was administrated in the same amount, levels were in the range of 55 2 ng up to 382 36 ng for 0.5 and 6 h of transcytosis, respectively. This was an approximately 3 times higher amount in comparison with transcytosis for HSA-a-Gal. No statistically significant difference in the rate of transcytosis between 80 lg and 40 lg of appliedproteins was found. After 6 h of transcytosis no change in TEER values were noted, which suggests that monolayers stayed intact. Conclusion: We showed that transcytosis of proteins was a well-defined process dependent on the bioavailability of the protein and not on the applied concentration. The prolonged transepithelial transport of HSA-a-Gal may contribute to the delayed symptoms after red meat consumption in patients allergic to red meat. |
Allergy. 2016;71:402. | Europe; Sweden; |
| Kuehn BM. | 2018 | Tick bite linked to red meat allergy. Rare cases of recurrent life-threatening allergic reactions to red meat have been linked to tick bites, according to researchers from the National Institute of Allergy and Infectious Diseases (NIAID). Lone Star ticks range from the Southeast through the Eastern United States and bites from the arachnids are known to cause a rare allergy to galactose-α-1,3-galactose (α-gal), a type of sugar found in beef, pork, lamb, and other red meats. Now, researchers from NIAID have found antibodies to α-gal in the blood of 6 of 70 individuals treated for recurrent, unexplained anaphylaxis. All 6 individuals had a history of tick bites and lived in states where Lone Star ticks are common. Adopting red meat-free diets allowed them to avoid further anaphylaxis for the duration of follow-up, which ranged from 18 months to 3 years. |
Journal of Allergy and Clinical Immunology. 2014 Nov 1;134(5):1016-25. | idiopathic anaphylaxis |
| Kugler C, Biedermann T. | 2016 | Delayed anaphylaxis to mammalian meat (Alpha-Gal) - oral challenge. / Orale Provokationstestung bei verzögerter Soforttypallergie auf Sägetierfleisch (Alpha-Gal). No abstract available |
Rev Fr Allergol. 2016; 497-501. | diagnosis |
| Kuhlen JL, Virkud YV. | 2015 | Pathogenesis, newly recognized etiologies, and management of idiopathic anaphylaxis. Idiopathic anaphylaxis (IA) is a life-threatening allergic disease and the most common diagnosis given to patients following an anaphylactic event. The inability of the healthcare provider and the patient to identify the trigger for anaphylaxis makes standard allergen avoidance measures ineffectual. IA is diagnosed after other causes of anaphylaxis have been excluded. Mast cell activation syndromes (MCAS), mastocytosis, IgE to galactose-alpha-1,3-galactose (alpha-gal), and certain medications have recently been recognized as causes of anaphylaxis that were previously labeled idiopathic. This review will describe the epidemiology and proposed theories of pathogenesis for IA, its diagnostic approach, its clinical management, and examine newly recognized disorders that were previously labeled as idiopathic anaphylaxis. |
Discovery medicine. 2015 Feb;19(103):137. | idiopathic anaphylaxis |
| Kular H, Dean J, Cook V. | 2018 | A CASE OF CARRAGEENAN ALLERGY IN A PEDIATRIC PATIENT Carrageenan is a common food additive obtained from Eucheuma, Chrondrus, and Gigartina species of seaweed. It is used in dairy, processed meat, sauces, pharmaceuticals and other food products as a thickener and stabilizer. It's soluble fiber properties are used to alter the consistency, appearance, and nutritional properties of food. Although it has been reported to cause adverse gastrointestinal effects, reports of IgE-mediated allergy appear limited to a case of anaphylaxis to carrageenan-containing barium enema. We present a unique case of carrageenan allergy in a pediatric patient. |
Annals of Allergy, Asthma & Immunology. 2018 Nov 1;121(5):S119. | carrageenan; dairy; non-dairy substitutes |
| Kumar D, Sharma SR, Adegoke A, Kennedy A, Tuten HC, Li AY, Karim S. | 2022 | Recently evolved Francisella-like endosymbiont outcompetes an ancient and evolutionarily associated Coxiella-like endosymbiont in the lone star tick (Amblyomma americanum) linked to the Alpha-Gal Syndrome Background: Ticks are hematophagous arthropods that transmit various bacterial, viral, and protozoan pathogens of public health significance. The lone star tick (Amblyomma americanum) is an aggressive human-biting tick that transmits bacterial and viral pathogens, and its bites are suspected of eliciting the alpha-gal syndrome, a newly emerged delayed hypersensitivity following consumption of red meat in the United States. While ongoing studies have attempted to investigate the contribution of different tick-inherent factors to the induction of alpha-gal syndrome, an otherwise understudied aspect is the contribution of the tick microbiome and specifically obligate endosymbionts to the establishment of the alpha-gal syndrome in humans. Materials and Methods: Here we utilized a high-throughput metagenomic sequencing approach to cataloging the entire microbial communities residing within different developmental stages and tissues of unfed and blood-fed ticks from laboratory-maintained ticks and three new geographical locations in the United States. The Quantitative Insights Into Microbial Ecology (QIIME2) pipeline was used to perform data analysis and taxonomic classification. Moreover, using a SparCC (Sparse Correlations for Compositional data) network construction model, we investigated potential interactions between members of the microbial communities from laboratory-maintained and field-collected ticks. Results: Overall, Francisellaceae was the most dominant bacteria identified in the microbiome of both laboratory-raised and field-collected Am. americanum across all tissues and developmental stages. Likewise, microbial diversity was seen to be significantly higher in field-collected ticks compared with laboratory-maintained ticks as seen with a higher number of both Operational Taxonomic Units and measures of species richness. Several potential positive and negative correlations were identified from our network analysis. We observed a strong positive correlation between Francisellaceae, Rickettsiaceae, and Midichloriaceae in both developmental stages and tissues from laboratory-maintained ticks, whereas ovarian tissues had a strong positive correlation of bacteria in the family Xanthobacteraceae and Rhizobiaceae. A negative interaction was observed between Coxiellaceae and Francisellaceae in Illinois, and all the bacteria detected from ticks from Delaware were negatively correlated. Conclusion: This study is the first to catalog the microbiome of Am. americanum throughout its developmental stages and different tissue niches and report the potential replacement of Coxiellaceae by Francisellaceae across developmental stages and tissues tested except in ovarian tissues. These unique and significant findings advance our knowledge and open a new avenue of research to further understand the role of tick microbiome in tick-borne diseases and develop a holistic strategy to control alpha-gal syndrome. |
Frontiers in Cellular and Infection Microbiology. 2022 Apr 12;12 | tick; microbiome; etiology |
| Kumara KG, Suganthan S, Kumanan T. | 2013 | An incidental finding of congenital methaemoglobinaemia in a patient with an allergy. No abstract available |
Ceylon Medical Journal. 2013 Jun 22;58(2). | India |
| Kuravi K, Sorrells L, Rahman F, WALTERS A, Commins S, Bianchi J. | 2023 | Alpha Gal allergy and its connection to mammalian derived medical products. Rationale: Allergists have identified populations with high titers of anti-alpha-gal (galactose-alpha1,3-galactose) IgE due to a tick bite that adversely react after exposure to alpha-gal (e.g., alpha-gal syndrome (AGS)). The alpha-gal IgE sensitized individual has been well documented to experience adverse events after administration of mammalian-derived therapeutic products including anaphylactic shock and death. The aim of this study was to demonstrate presence of alpha gal in various medical products. Methods: Quantitation of the alpha gal epitope was determined via an indirect ELISA assay. In addition, IHC further confirmed the presence of alpha-α-gal in potential source material using AGS patient’s serum. The various products evaluated included bone powder, immunoglobulin isolates, thyroid derived therapeutic drugs, and heparin. Porcine a-gal knockout (devoid of a-gal) derived tissue or demineralized bone powder served as negative controls. Results: ELISA and IHC data indicates presence of alpha-gal in all bovine/porcine derived products irrespective of their source/ preparation/form. The relative amount of alpha gal present in these products exceeded 10,000,000 epitopes per mg. Conclusions: Alpha-gal persist at very high concentrations in all commercially available therapeutic products that were evaluated that may cause adverse reactions after exposure. More studies must be done to elucidate potential harm posed by the alpha-gal present in these products to the AGS patient population. Porcine alpha-gal knockout (devoid of alpha-gal, aka. GalSafe) products or tissue material could be less immunogenic and serve as an alternative to products derived from standard pigs. |
Journal of Allergy and Clinical Immunology. 2023 Feb 1;151(2):AB91. | Medical products; drugs; bone powder, immunoglobulin isolates, thyroid derived therapeutic drugs, heparin. Perioperative |
| KURAVI K, Sorrels L, Dandro A, Bianchi J, Choudhary S, Commins S | 2022 | Alpha gal allergy and its connection to cardiovascular bioprostheses. Alpha Gal Syndrome (AGS) is an allergy to mammalian food and medical products indicated by elevated anti-galactose α1,3 galactose (alpha-gal) IgE (>0.1kU/L) due to a tick bite. alpha-gal is a sugar molecule expressed in all mammals except humans and old-world primates. We previously showed that anti-alpha-gal IgE in AGS patient sera reacts with alpha-gal present in bovine/porcine derived medical products. The aim of this study is to quantitate alpha-gal present in cardiovascular bioprostheses and to determine the threshold of serum anti-alpha-gal IgE levels needed to react. |
Journal of Allergy and Clinical Immunology. 2022 Feb 1;149(2):AB94. | medical products; porcine products; bioprosthetic heart valves; bioprostheses |
| Kuravi KV, Sorrells LT, Nellis JR, Rahman F, Walters AH, Matheny RG, Choudhary SK, Ayares DL, Commins SP, Bianchi JR, Turek JW. | 2021 | Allergic response to medical products in patients with alpha-gal syndrome Background: Galactose-α-1,3-galactose (alpha-gal) is a carbohydrate that is ubiquitously expressed in all mammals except for primates and humans. Patients can become sensitized to this antigen and develop alpha-gal syndrome (AGS), or a red meat allergy. Symptoms range from generalized gastroenteritis and malaise to anaphylaxis, and in endemic areas, the prevalence can be as high as 20%. Although AGS patients commonly avoid alpha-gal by avoiding meat, patients have also developed symptoms due to animal-derived medical products and devices. With the rise in transcatheter aortic valve replacement, we investigate the immunogenicity of common cardiac materials and valves. Objective: To assess the in vitro immunoglobulin E response toward common medical products, including cardiac patch materials and bioprosthetic valves in patients with AGS. . Methods: Immunoblot and immunohistochemistry techniques were applied to assess immunoglobulin E reactivity to various mammalian derived tissues and medical products for patients with AGS. . Results: AGS serum showed strong reactivity to all of the commercially available, nonhuman products tested, including various decellularized cardiac patch materials and bioprosthetic aortic valves. AGS serum did not react to tissues prepared using alpha-gal knockout pigs. . Conclusions: Despite commercial decellularization processes, alpha-gal continues to be present in animal-derived medical products, including bioprosthetic valves. Serum from patients with AGS demonstrates a strong affinity for these products in vitro. This may have serious potential implications for sensitized patients undergoing cardiac surgery, including early valve failure and accelerated coronary artery disease. NOTE: drugs, supplements, and medical products found to contain alpha-gal:• Armour Thyroid (Allergan)-- a porcine thyroxine and triiodothyronine thyroid medication • Zenpep (Allergan)-- a porcine-derived pancreatic insufficiency medication composed of proteases, lipases, and amylase • EnteraGam (Entera Health, Cary, NC), a bovine immunoglobulin and immunoprotein isolate intended for the management of irritable bowel syndrome and inflammatory bowel disease • Pancreatin (Now Foods, Bloomingdale, Ill)-- an over-the-counter dietary aid • CorMatrix Cor™ PATCH-- an epicardial patch for cardiac tissue repair (a heart patch) • Cardiocel acellular collagen scaffold (LeMaitre Vascular, Burlington, Mass)-- used in heart and vascular repair • Photofix (decellularized bovine pericardium (Cryolife, Kennesaw, Ga)-- used in heart and vascular repair • ProCol bovine mesenteric vein (LeMaitre Vascular) • Epic Supra porcine bioprosthetic aortic valve (Abbott, Abbott Park, Ill) • Perimount Magna Ease (bovine bioprosthetic aortic valve (Edwards Lifesciences, Irvine, Calif) • CryoValve SG pulmonary valve decellularized human pulmonary valve conduit (Cryolife). |
The Journal of thoracic and cardiovascular surgery. 2021 Apr 9. | Pharmacy; pharmaceutical; medical products; drug; bioprosthetic heart valve; cardiac; cardiology; biological scaffolding; porcine; bovine; heart patch; surgery; perioperative |
| Kusuma A, Knulst AC. | 2009 | A rare case of meat allergy. A 48-year-old man developed three hours after eating pigs kidney an anaphylactic reaction consisting of general itching, malaise, urticaria, angioedema and hypotension. Later he also developed similar symptoms after eating organ as well as non-organ meat. Skin prick tests and specific IgE values were positive, as well as oral provocation tests. Remarkably the reaction occurred after one to four hours. Very recently such an allergy has been reported in American patients, in which IgE antibodies against galactose-α-1,3-galactose, a carbohydrate group in animal proteins appeared to be the explanation. This is the first case of such an allergy in Europe. |
Nederlands Tijdschrift voor Dermatologie en Venereologie 19(5):233-234. | Netherlands; Europe; kidney |
| Kutlu A, Unal D. | 2020 | Mammalian Meat Allergy Accompanied by Venom Allergy: A Review of 12 Cases Cross-reactivities Between Venom and Red Meat allergy? There has recently been an increase in mammalian meat allergy (MMA) in the Black Sea Region of Turkey. It has been associated with the expansion of tick populations.Tick bites appear to result in sensitization to the carbohydrate allergen galactose-alpha–1, 3-galactose, which is present in many types of mammalian meats. In this study, we have emphasized that Ixodes ricinus named tick type which is implicated in meat allergy, is found in domestic animals of Black Sea Region of Turkey. A new concept has been recently raized; suggesting that having an alpha-gal allergy is associated with an increased risk of sensitization to multiple venom spesific immunoglobulin (Ig) E. Our aim is to evaluate the clinical characteristics of adult patients with MMA and its relationship with insect sting reactions in Turkey. Patients referring to the allergy outpatient clinic with possible MMA were interviewed regarding reactions to a stinging insect. Demographic features and detailed histories of the patients were recorded. Skin prick test (SPT) with commercial beef extract and venom allergens, as well as prick to prick tests with raw beef and cooked beef were performed. Serum total IgE and beef meat specific IgE were measured. Of 50 interviewed patients, 12 patients (4 male [33,3%] and 8 female [66,6%]) had a history of venom hypersensitivity reaction. The mean age was 36.50±13.35 years (range:18–61). History of other allergic diseases was present in 8 (66.6%) patients. Both venom and meat allergy were confirmed with SPT or prick to prick tests in these 12 patients. Among these patients sensitization to honey bee venom was more frequent (83%). MMA and venom allergy are influenced by the same environmental exposures. We believe that there may be shared immunologic factors and similar antigens; making venom allergic patients more susceptible to MMA. |
Iranian Journal of Allergy, Asthma and Immunology. 2018:1-5. | Asia; Europe; Turkey; cross-reactivity; vector of sensitization; bee; insect |
| Kutluğ Ş, Hancıoğlu G, Kökçü Şİ, Sancak R, Öztürk F. | 2021 | Evaluation of red meat allergy patients and review of the literature. ackground. It was reported that prevalence of red meat allergy in children was higher in our country than in western populations. However, the diagnosis of these patients is often delayed. The aim of the study was to present the clinical and laboratory characteristics of our red meat allergy patients. Methods. The data were collected retrospectively from the files of children with red meat allergy. Also, 6 adults with red meat allergies were recorded in the families of the children. Patients with symptoms associated with red meat allergy and sensitive to beef or mutton in prick-to-prick tests were recorded. . Results. The median age of the 43 patients was 12 years (2-37), and 51% were male. Most of the patients were children (n=37, 86%). The median age was 10 years in children (2-17), and 54% were male. All of the children had dermatologic manifestations, 51% had respiratory symptoms, and 64% had anaphylaxis upon exposure to red meat. The anaphylaxis history was not associated with demographic, clinical and laboratory data. A total of 63% children had additional allergic diseases, and 75% of them were sensitive to both mutton and beef in prickto-prick tests. The median total IgE level of the children was 327 (20-3550) IU/mL, median eosinophil count was 210/mm3 (40-990) and mean vitamin D was 13.1 ± 1.2 mcg/L (n=27). Anaphylaxis occurred in 3 of 9 patients who received the open oral food challenge (OFC) test. After OFC, 3 patients continued to eat red meat without issues, and 1 patient was recommended to eat alternatives to red meat. . Conclusions. Clinical and laboratory findings were heterogeneous in children with red meat allergy. Anaphylaxis risk seems to be higher than other food allergies. OFC test is more helpful in both diagnosis and alternative red meat selection compared to laboratory findings. |
The Turkish Journal of Pediatrics. 2021 Sep;63(5):832-45. | Turkey |
| Kwak M, Somerville C, van Nunen S. | 2018 | A novel Australian tick Ixodes (Endopalpiger) australiensis inducing mammalian meat allergy after tick bite. Tick-induced mammalian meat allergy has become an emergent allergy world-wide after van Nunen et al. first described the association between tick bites and the development of mammalian meat allergy in 2007. Cases of mammalian meat allergy have now been reported on all 6 continents where humans are bitten by ticks, in 17 countries - Australia, United States of America (USA), Europe (France, Spain, Germany, Belgium, Switzerland, Sweden, United Kingdom, Italy, and Norway), Asia (Korea and Japan), Central America (Panama), South America (Brazil), and Africa (South Africa and Ivory Coast). To date, in each of these countries, bites from only a single tick species have been linked to the development of mammalian meat allergy: Ixodes holocyclus (Australia), Amblyomma americanum (USA), Ixodes ricinus (Europe), and Ixodes cajennense (Panama) are confirmed as culprits, and Ixodes nipponensis (Japan and Korea), Amblyomma sculptum (Brazil), Amblyomma variegatum (Ivory Coast), and Haemaphysalis longicornis (Japan) suspected of provoking mammalian meat allergy after tick bite. Other tick species remain to be formally identified (South Africa). Identification of tick species associated with development of mammalian meat allergy is crucial to the uptake of public health measures to prevent tick bites from culprit tick species, for both individuals living in these tick-endemic areas and those who choose to visit these regions. We report a tick associated with the enhancement of mammalian meat anaphylaxis after tick bite which is novel for both Australia and the world and establishes Ixodes (Endopalpiger) australiensis as a second tick species associated with mammalian meat allergy in Australia. |
Asia Pacific Allergy. 2018 Jul 23;8(3). | Australia; tick species; Ixodes australiensis; endopaliger; geographic distribution; geography |
| Lacy BE, Patel H, Guerin A, Dea K, Scopel JL, Alaghband R, Wu EQ, Mody R. | 2016 | Variation in care for patients with irritable bowel syndrome in the United States. |
PLoS One. 2016 Apr 26;11(4):e0154258. | epidemiology; geographic distribution; GI; gastroenterology; IBS; included because the maps suggest a potentially significant geographic overlap between AGS and GI issues |
| Lado P, Smith ML, Carstens BC, Klompen H. | 2020 | Population genetic structure and demographic history of the lone star tick, Amblyomma americanum (Ixodida: Ixodidae): new evidence supporting old records Range expansions are a potential outcome of changes in habitat suitability, which commonly result as a consequence of climate change. Hypotheses on such changes in the geographic distribution of a certain species can be evaluated using population genetic structure and demography. In this study we explore the population genetic structure, genetic variability, demographic history of, and habitat suitability for Amblyomma americanum , a North American tick species that is a known vector of several pathogenic microorganisms. We used a double digestion restriction site‐associated DNA sequencing technique (dd‐RAD seq) and discovered 8,181 independent single nucleotide polymorphisms (SNPs) in 189 ticks from across the geographic range of the species. Genetic diversity was low, particularly when considering the broad geographic range of this species. The edge populations were less diverse than populations belonging to the historic range, possibly indicative of a range expansion, but this hypothesis was not statistically supported by a test based on genetic data. Nonetheless, moderate levels of population structure and substructure were detected between geographic regions. For New England, demographic and species distribution models support a scenario where A. americanum was present in more northern locations in the past, underwent a bottleneck, and subsequently recovered. These results are consistent with a hypothesis that this species is re‐establishing in this area, rather than one focused on range expansion from the south. This hypothesis is consistent with old records describing the presence of A. americanum in the northeastern US in the early colonial period. |
Molecular Ecology. 2006 May;15(6):1643-56. | |
| Landwehr L, Smith L, Stricker W. | 2021 | P118 THE CLINICAL SPECTRUM OF ALPHA-GAL ALLERGY IN A MISSOURI PRACTICE. Introduction: Galactose-alpha-1,3 (alpha-gal) is a oligosaccharide found in non-primate mammalian cell membranes. Humans have recently been recognized as having severe delayed hypersensitivity reactions consequent to ingestion of alpha-gal-containing foods in the form of mammalian meat products (i.e. beef and pork). Primary sensitization is thought to occur via tick bites. The Lone Star tick, Amblyomma americanum, is considered a vector and is commonly found in Missouri. Methods: A retrospective chart review was conducted from an Allergy practice in Missouri of patients diagnosed with alpha-gal syndrome from 2013-2019. Results: There were a total of 68 patients diagnosed with alpha-gal syndrome over the period (2013-2019.) Patient demographics included mean age: 50.4 years (range 15-75), 44% were male (30/68) and 56% were female (38/68), mean alpha-gal IgE 17.6 kU/L (range 1.02-99). 42 patients were tested for serum IgE to beef and pork as well as skin prick test (SPT) to beef and pork. Of the 42 patients tested for sIgE to beef, 31 measured positive (positive= IgE >0.1 kU/L). Of the 42 patients tested for sIgE to pork, 30 tested positive. Of the 42 patients who underwent a SPT for beef, 8/42 were positive. Of the 42 patients who underwent a SPT for pork, 8/42 were positive. We found 44 subjects with histories and/or objective findings consistent with anaphylaxis using a 2 system definition. These 44 subjects had skin involvement and another system with 30 reporting respiratory symptoms, 13 reporting cardiovascular symptoms and 23 reporting gastrointestinal symptoms. 35 subjects reported emergency room care. 3 were hospitalized. The second group was defined as “skin only symptoms” which included pruritus, urticaria, and/or angioedema without evidence of systemic symptoms. 26 subjects were in this category. The mean IgE alpha gal was 18.9 in the anaphylaxis group and 13.6 in the skin only group. Symptom onset was 3-6 hours after ingestion in all subjects. Other triggers included venison (4), lamb (2), gelatin-containing medication (4) and milk (8). 1 subject had a porcine heart valve and did well if she avoided ingesting mammalian meat. 4 subjects reported resolution and 2 underwent negative office challenges to meat. Conclusion: Alpha-gal hypersensitivity is a serious medical concern as demonstrated but these 68 patients diagnosed in this mostly rural practice in Central Missouri over a 6 year period. Patients may experience a spectrum of symptoms ranging from skin-limited findings to severe-life threatening anaphylaxis. Our report emphasizes the importance of considering alpha gal sensitivity in patients presenting with varying allergic symptoms in absence of immediate allergen association. |
Annals of Allergy, Asthma & Immunology. 2021 Nov 1;127(5):S45. | Missouri |
| Lang J, Zhan J, Xu L, Yan Z. | 2006 | Identification of peptide mimetics of xenoreactive α-Gal antigenic epitope by phage display. The prevention of hyperacute rejection (HAR) triggered by interaction between the human natural antibody and xenoreactive antigenic epitope (Gal-α1, 3Gal) present on pig cells is the key to success in pig-to-human xenotransplantation. The phage display technology offers an effective strategy for screening peptides which can interact with the anti-Gal antibody to block α-Gal antigen binding site. Two peptide libraries, linear 7 peptide library and C7C library, were panned on the anti-B monoclonal antibody which has the characteristic of binding to the α-Gal antigenic epitope. After four rounds of panning, 22 positive phage clones were selected. Highly homologous sequence PT and STL existed among these selected peptides. Stachyose competitive ELISAs revealed that these peptides specifically bound to α-Gal antigen binding site. Eight peptide mimics of α-Gal antigenic epitope could inhibit the agglutination of pig red blood cells mediated by human sera in a dose-dependent manner. These results demonstrated that the selected peptides can mimic the conformational structure of α-Gal antigenic epitope and have the therapeutic potential in xenotransplantation. |
Biochemical and biophysical research communications. 2006 May 26;344(1):214-20. | peptide mimetics; cross-reactivity |
| Lang M, Corriger J, Haumonte Q, Thomas H, Nguyen-Grosjean VM, Pontier JP, Vaillant A, Beaudouin E. | 2018 | Allergie à α-galactose: un vêlage à fleur de peau. IntroductionLe galactose-α-1,3-galactose (α-Gal) est présent dans la glycosylation de nombreuses cellules, glycoprotéines et glycolipides chez les mammifères non primates. On le retrouve ainsi dans leurs abats, viandes et laits, mais aussi dans les gélatines alimentaires ou médicamenteuses, immunoglobulines, biomédicaments et tissus de xénogreffe (ex. bioprothèses porcines).MéthodesNous présentons le cas d’un agriculteur de 36 ans, aux antécédents de morsure de tique, sujet depuis plusieurs années à une urticaire aiguë récidivante. Le premier épisode, généralisé, est survenu après ingestion d’un aspic (gélatine de viande), les suivants 30 à 40 min après vêlage et consistant en des urticaires localisées au niveau des zones de contact avec le placenta et le liquide amniotique bovin et secondairement généralisées. D’autres épisodes sont rapportés, avec pour seul dénominateur commun l’ingestion de viande de porc plusieurs heures avant. Il n’est jamais retrouvé de cofacteur associé.RésultatsLes pricks aux aéroallergènes et trophallergènes courants étaient négatifs ; les pricks aux viandes ont mis en évidence un veau cru positif et un érythème sans papule pour le rognon de porc. L’enquête étiologique a été complétée par des prick-to-pricks au placenta et liquide amniotique bovins, pricks et IDR vis-à-vis du cétuximab et dosage d’IgE spécifiques à l’α-Gal, permettant de conforter le diagnostic d’hypersensibilité à l’α-Gal.DiscussionLa présence d’α-Gal a été récemment objectivée dans de nombreuses glycoprotéines du placenta et liquide amniotique bovins. Une série espagnole rapporte 3 cas d’urticaire de contact liés au vêlage, dont l’un associé à une atteinte respiratoire probablement consécutive à l’inhalation de glycoprotéines du liquide amniotique. La chronologie des réactions ne plaide pas pour une sensibilisation liée au vêlage.ConclusionCette nouvelle source d’exposition professionnelle pourrait avoir des conséquences médico-légales et justifier de mesures spécifiques pour les sujets allergiques à l’α-Gal travaillant en milieu vétérinaire ou agricole. |
Revue Française d'Allergologie. 2018 Apr 1;58(3):253. | occupational medicine; bovine amniotic fluid; placenta; farming; cattle |
| Langerak A, River G, Mitchell E, Cheema P, Shing M. | 2009 | Panitumumab Monotherapy in Patients with Metastatic Colorectal Cancer and Cetuximab Infusion Reactions: A Series of Four Case Reports. Purpose: Monoclonal antibodies against the epidermal growth factor receptor approved for treating metastatic colorectal cancer (mCRC) include cetuximab (a chimeric antibody) and panitumumab (a fully human antibody). Because these antibodies have differences in protein sequence, patients intolerant to one antibody might still tolerate the other. Four cases are presented from a US panitumumab compassionate-use program in which patients with mCRC who were intolerant to cetuximab received panitumumab. Patients and Methods: Eligible patients had failed previous fluoropyrimidine therapy with oxaliplatin- and irinotecan-containing chemotherapy, had cetuximab intolerance (ie, experienced an infusion reaction), and were unable to participate in a panitumumab clinical trial. For each patient, individual Federal Drug Administration-approved single-patient treatment use Investigational New Drug– and Institutional Review Board–approved protocols were used, informed consent was obtained, and data were collected independently by the investigator. Results: All 4 patients (2 men, 2 women) had received previous bevacizumab and premedications before cetuximab administration. In response to cetuximab, all 4 patients experienced Common Terminology Criteria for Adverse Events grade 3 or grade 4 infusion-reaction symptoms, which required acute therapy. Time from cetuximab discontinuation to panitumumab administration ranged from 8 days to 5 months. Panitumumab monotherapy was administered at approximately 6 mg/kg every 2 weeks. Two patients received premedications before panitumumab use. No physician reported any infusion reaction to panitumumab. One patient had stable disease, and 3 patients had disease progression. Conclusion: Though this small case series provides evidence that patients with mCRC intolerant to cetuximab can receive subsequent panitumumab monotherapy without experiencing infusion reactions, additional clinical testing is needed to definitively examine this finding. |
Clinical colorectal cancer. 2009 Jan 1;8(1):49-54. | Pharmacy; pharmaceutical; biologics; biological agents; monoclonal antibodies; mAb |
| Langley DB, Schofield P, Nevoltris D, Jackson J, Jackson KJ, Peters TJ, Burk M, Matthews JM, Basten A, Goodnow CC, van Nunen S. | 2022 | Genetic and structural basis of the human anti-α-galactosyl antibody response. Humans lack the capacity to produce the Galα1–3Galβ1–4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development. |
Proceedings of the National Academy of Sciences. 2022 Jul 12;119(28):e2123212119. | genetics; structural factors; cellular mechanism; biochemical mechanism |
| Lauer S, Burk M, Broadfoot A, Baumgart K, van Nunen S. | 2019 | ACUTE ADULT FCIES (FOOD CARBOHYDRATE-INDUCED ENTEROCOLITIS SYNDROME) TO MAMMALIAN MEAT AFTER TICK BITE: A NOVEL MECHANISM IN MAMMALIAN MEAT REACTIVITY. |
In INTERNAL MEDICINE JOURNAL 2019 Sep 1 (Vol. 49, pp. 23-24). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY. | gastroenterology; enterocolitis; FPIES; food-induced enterocolitis; FCIES |
| Laurent J, Rostoker RR, Bruneau GL. | 1987 | Is Adult Idiopathic Nephrotic Syndrome Food Allergy?. To evaluate the prevalence of food hypersensitivity in idiopathic nephrotic syndrome (INS), an oligoantigenic diet was given for 10 days to 13 patients with INS who had not steadily responded to corticosteroids; 5 of these patients were corticodependent, 3 were corticoresistant and 5 had multiple relapses. A history of allergy was present in 8 cases and an increase in total serum IgE levels in 6. Sensitivity to food antigens was documented by skin tests in 5, by the radioallergosarbent test (RAST) in 5 and by the human basophil degranulation test (HBDT) in 11. At the end of the oligoantigenic diet, proteinuria was significantly reduced in the 13 patients as compared to the initial level. It decreased by more than 50% in 9 patients and disappeared completely in 5. It seems that an oligoantigenic diet is helpful in cases of INS that do not respond to corticosteroids. This argues for a role of food hypersensitivity in this disease and suggests that avoidance of specific foods on the longer term may be of benefit. This diet must be tried in INS before the initiation of immunosuppressive therapy. |
Nephron. 1987;47(1):7-11. | Nephrology; nephrotic syndrome; kidney |
| Le TT, Tran TT, Ho HT, Vu AT, Lopata AL. | 2018 | Prevalence of food allergy in Vietnam: comparison of web-based with traditional paper-based survey. | World Allergy Organization Journal. 2018 Dec;11(1):16. | Asia; Vietnam; prevalence |
| Le TT, Tran TT, Ho HT, Vu AT, McBryde E, Lopata AL. | 2020 | The predominance of seafood allergy in Vietnamese adults: Results from the first population-based questionnaire survey. Background: Food allergy (FA) is a serious, costly and growing health problem worldwide. FA occurs in both children and adults; however, there is a paucity of information on FA prevalence and its clinical features in the adult population, especially in Asia. We sought to assess the prevalence of FAs in Vietnamese adults and the distribution of offending food items among different regions throughout Vietnam. . Methods: A nationwide, cross-sectional, population-based survey was conducted among University students aged 16–50 years. We used a structured, anonymous questionnaire, which was modified from recently published FA epidemiologic studies and based on European Academy of Allergy and Clinical Immunology (EAACI) guidelines, to collect data on FA prevalence, clinical presentations, and implicated food groups. Statistical analysis was performed to generate the prevalence of self-reported and doctor-diagnosed FA and to examine the association of key environmental factors and FA incidence in this population. . Results: Of the 14,500 surveys distributed, a total of 9,039 responses were returned, resulting in a response rate of 62.4%. Among participants who reported food-induced adverse reactions, 48.0% have repeated reactions. 18.0% of the participants perceived FA symptoms, but less than half of them sought medical services for confirmation (37.9%). Stratifying for true FA symptoms, the prevalence of self-reported FA was 11.8% and of doctor-diagnosed FA, 4.6%. The most common doctor-diagnosed FA was to crustacean (3.0%; 95% CI, 2.6–3.3), followed by fish (1.6%; 95% CI, 1.3–1.8), mollusk (1.3%; 95% CI, 1.0–1.5) and beef (1.0%; 95% CI, 0.8–1.2). The prevalence of doctor-diagnosed FA differed among participants living in urban (6.5%) and rural regions (4.9%) (P < 0.001). Atopic family history was the strongest predictor for FA (odds ratio 8.0; 95% CI, 6.2–10.4). . Conclusions: Seafood allergy among adults is predominant in Vietnam, followed by beef, milk, and egg, while peanut, soy, and tree nut allergy are much less common. Populations in rural regions have considerably less FA; however, the protective environmental factors have yet to be identified. |
World Allergy Organization Journal. 2020 Mar 1;13(3):100102. | Asia; Vietnam; prevalence |
| Le V, Browning R, Jerath M. | 2022 | Alpha-Gal Allergy: Characteristics of a Midwest Cohort. Rationale: Allergy to galactose-alpha-1,3-galactose is a novel food allergy, affecting a widespread area of the southeastern United States. Few studies have reported on common characteristics and conditions within regional cohorts. This study aims to characterize a cohort of alpha-gal patients within our practice in Saint Louis, Missouri. Methods: A total of 65 patients with alpha-gal allergy diagnosis were identified. Medical chart review was conducted to analyze demographic (age at presentation, gender), clinical (symptomatology, sensitivity), diagnostic (lab data), comorbid and atopic, and environmental (tick exposure, pets) characteristics. Results: The cohort had a female predominance (57%) with a median age at first presentation of 48 years. Mean alpha-gal and total IgE levels at time of presentation, if available, were 3.88 and 90.2, respectively. Most patients had inconsistent reactions (52%) with urticarial and/or gastrointestinal symptoms (52%), while 37% presented with anaphylaxis. Sensitivity to milk and/or gelatin was present in 46%. Most reported a history of atopic disease (77%). Additional comorbidities included GERD (46%), psychiatric disease (35%), hypertension (23%), hyperlipidemia (22%), diabetes (8%), and vascular disease (CAD or CVD, 6%). Finally, a very large majority reported a history of tick bites (86%), and more interestingly, most had pets (85%). Conclusions: In addition to atopic diseases, there is an increased prevalence of concurrent metabolic and psychiatric diseases. Furthermore, sensitivity to all mammal-derived products and proportion of pet owners are higher in our cohort than previously reported. |
Journal of Allergy and Clinical Immunology. 2022 Feb 1;149(2):AB209. | Midwest |
| Lee CJ, McGill SK. | 2023 | Food Allergies and Alpha-gal Syndrome for the Gastroenterologist. Purpose of Review: Food allergies are typically not considered as a cause of gastrointestinal (GI) distress without additional allergic symptoms, apart from celiac disease and eosinophilic esophagitis. However, recent reports of patients with alpha-gal syndrome who presented with GI-only symptoms like abdominal pain, vomiting, and diarrhea challenge this paradigm. Alpha-gal syndrome is an IgE-mediated allergy characterized by delayed reactions after eating mammalian meat or mammalian-derived products that contain galactose-alpha-1,3-galactose (alpha-gal). The purpose of this review is to discuss our current understanding of food allergies, GI illness, and the GI manifestations of alpha-gal syndrome. Recent Findings: Among Southeastern U.S. GI clinic patients who screened positive for serum alpha-gal IgE, a majority of patients reported significant symptom improvement on an alpha-gal-avoidant diet, suggesting that the allergy had played a role in their GI symptoms. Diagnosis of alpha-gal syndrome is typically made with concerning allergic symptoms, elevated alpha-gal specific IgE in the serum, and symptom improvement on an alpha-gal avoidant diet. Summary: Alpha-gal syndrome can cause a delayed allergic response that is increasingly recognized worldwide, including among patients with predominant GI symptoms. |
Current Gastroenterology Reports. 2023 Jan 27:1-0. | gastroenterology; GI-only phenotype |
| Lee CJ, McGill SK. | 2022 | S2459 Bad News Gummy Bears: A Case of Gastrointestinal-Isolated Alpha-Gal Allergy. Introduction: Galactose-α-1,3-galactose (alpha-gal) allergy is an IgE-mediated reaction to mammalian meat and dairy, with symptoms typically developing 3 to 6 hours after ingestion. Alpha-gal allergy with isolated gastrointestinal (GI) symptoms (abdominal pain, diarrhea, vomiting) without urticaria or anaphylaxis has been described. Case Description/Methods: A 49-year-old male presented to GI clinic with years of episodic cramping abdominal pain and 4-6 diarrheal stools daily. Colonoscopy, EGD, CT abdomen, and hydrogen breath testing were unrevealing. We diagnosed irritable bowel syndrome. Rifaximin briefly relieved symptoms. He did not tolerate tricyclic antidepressants. Serum alpha-gal IgE level was found to be elevated at 0.27 kU/L (reference range, < 0.1 kU/L) after the patient reported past tick bites. The patient stopped eating mammalian meat and symptoms improved but continued. He further excluded gelatin in the form of gummy bears, dairy, and carrageenan, which led to near resolution of symptoms. At a visit 2 years following allergy diagnosis, he reported one formed stool daily and no chronic abdominal pain. Self-challenging with foods that have small amounts of alpha gal, like a handful of gummy bears, had resulted in severe abdominal cramping. Discussion: The diagnosis of GI alpha-gal syndrome can be challenging because of delayed onset of symptoms after eating mammalian products, nonspecific GI complaints on presentation, and overlap with preexisting GI diseases. While sensitization is believed to be caused by a bite from the Lone Star tick, not all patients report a history of tick bites. Further studies are needed to better characterize GI alpha gal, but 2 cohort studies found that ∼75% of patients improved on a diet free of mammalian products. These diets are somewhat ill-defined in how strict they are, particularly whether they are just free of mammalian meat or all products containing alpha-gal. A stepwise approach is recommended, starting with mammalian meat, then dairy, and then gelatin, gelatin capsules, and mammalian food additives if symptoms persist. Our patient experienced improvement in symptoms with elimination of mammalian meat from his diet, but no resolution until he eliminated all alpha-gal, particularly gelatin and carrageenan. This case highlights the importance of a thorough history, increased awareness of foods containing alpha-gal, and the need for future prospective studies for improving early recognition and treatment of GI alpha gal. |
Official journal of the American College of Gastroenterology| ACG. 2022 Oct 1;117(10S):e1642. | gastroenterology; GI-only phenotype; gelatin; dairy; carrageenan; gummy bears; gummi bears |
| Lee EJ, Lee H, Park EM, Kang HJ, Kim SJ, Park CG. | 2021 | Immunoglobulin M and Immunoglobulin G Subclass Distribution of Anti-galactose-Alpha-1, 3-Galactose and Anti-N-Glycolylneuraminic Acid Antibodies in Healthy Korean Adults. Background: Human preformed antibodies (Abs), anti-galactose-alpha-1,3-galactose (Gal) and anti-N-glycolylneuraminic acid (Neu5Gc), can react with porcine antigens of wild-type pigs. To provide basic population data of the Abs for potential application in clinical xenotransplantation, we developed enzyme-linked immunosorbent assay methods and investigated the serum titers of anti-Gal and anti-Neu5Gc Abs, including immunoglobulin (Ig) M and IgG along with its subclasses, in humans. Methods: Anti-Gal and anti-Neu5Gc Abs serum titers were measured in 380 healthy Korean adults using the in-house enzyme-linked immunosorbent assays. The frequency and median values of anti-Gal and anti-Neu5Gc were measured, and their class and subclass distribution were evaluated. Results: The detection frequencies of anti-Gal were 99.2%, 95.0%, 23.2%, 94.5%, 12.4%, and 3.4% for IgM, IgG, IgG1, IgG2, IgG3, and IgG4, respectively. The detection frequencies of anti-Neu5Gc Abs were 87.4%, 96.6%, 1.6%, 46.3%, 0.0%, and 0.0% for IgM, IgG, IgG1, IgG2, IgG3, and IgG4, respectively. The median values of anti-Gal IgM (1001.6 ng/mL) and IgG (1198.3 ng/mL) were significantly higher than those of anti-Neu5Gc Abs (IgM, 328.4 ng/mL; IgG, 194.7 ng/mL; P < .001). IgG2 titers of both anti-Gal and anti-Neu5Gc Abs correlated better with the IgG class than the titers of other IgG subclasses. Conclusions: The titers of anti-Gal Abs were higher than those of anti-Neu5Gc Abs. IgG2 was the main IgG subclass in both anti-Gal and anti-Neu5Gc Abs. Variation in the titers of anti-Gal or anti-Neu5Gc Abs may partly explain the biological and immunologic changes that occur in recipients of xenotransplants. |
InTransplantation Proceedings 2021 Jun 1 (Vol. 53, No. 5, pp. 1762-1770). Elsevier. | xenotransplantation; IgG; IgM |
| Lee JH, Kim JH, Kim TH, Kim SC. | 2013 | Delayed mammalian meat-induced anaphylaxis confirmed by skin test to cetuximab. No abstract available |
The Journal of dermatology. 2013 Jul;40(7):577-8. | |
| Lee LY, Zhong Y, Leow SY, Lim SC, Wen H, Soh JY, Chiang WC, Delsing DJ, Lee BW, Huang CH. | 2020 | Allergy to prebiotic galacto-oligosaccharides: House dust mites—the putative |