Evidence-based 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
- 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. Publications were compiled with the help of Matthew von Hendy of Green Heron Research Resources, assisted by John Bianchi of Revivicor. Matthew is an accomplished research librarian with more than 20 years of professional experience working in a variety of government and technical libraries. He has worked at the EPA, NASA and the National Academies of Sciences where his work was cited in 10 different National Academies reports.
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
|AUTHORS||DATE||TITLE & ABSTRACT||PUBLICATION/LINK||KEYWORDS|
|Abdallah MA, Larson EA.||2018||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.
|SD Med Assoc. 2018 Oct;71(10):463-5.||South Dakota|
|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|
|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|
|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|
|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|
|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|
|Altrich ML, Blum SP, Foster SM.||2015||**Alpha-Gal IgE Sensitization in the United States: Surveillance Update.|
RATIONALE: Galactose-alpha-1,3-galactose (alpha-gal), is a crossreactive carbohydrate moiety found in red meats such as beef, pork and lamb and is associated with a delayed IgE response. A link to lone star tick bites was established by researchers at the University of Virginia and although the mechanism of sensitization is not clearly elucidated, it remains the primary suspect.
METHODS: A retrospective review of national laboratory data was conducted for alpha-gal IgE testing performed in 2012 and 2013, utilizing data with de-identified patient health information only when the source location could be identified. This data was mapped according to 6 geographical regions and compared to the July 2011 CDC published map of lone star tick populations.
RESULTS: For the total data set, 37% displayed positive results for alphagal IgE. In the subset of samples that could be tied to a source location, the positive rate declined to 33%. The regions with the highest prevalence of positive samples continue to overlap with the location of the lone star tick with a positive rate as high as 46% in TN and AR. In other non-lone star tick regions the positive rates varied from 8% to 17%.
CONCLUSIONS: The overall positive rate of samples tested in 2012- 2013 decreased compared to 2009-2011, and the total number of tests increased, suggesting there is more screening of patients potentially exposed to the lone star tick. The overall regional prevalence rates continue to support the hypothesis that lone star tick bites trigger the development of the alpha gal allergy.
|Journal of Allergy and Clinical Immunology. 2015 Feb 1;135(2):AB37.||North America; United States; prevalence|
|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|
|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.
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|
|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|
|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.||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.||Sanchez-Vidaurre; glycan; cross-reactive carbohydrate determinant; Neu5Gc; N-glycolylneuraminic acid|
|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.||In ALLERGY 2019 Aug 1 (Vol. 74, pp. 155-156). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY.||Europe; vector; Ixodes ricinus|
|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|
|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; 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.||Blood group|
|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.||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.||In GLYCOBIOLOGY 2018 Dec 1 (Vol. 28, No. 12, pp. 1080-1081). JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA: OXFORD UNIV PRESS INC.||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|
|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.||In ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY 2015 Nov 1 (Vol. 115, No. 5, pp. A71-A71). 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA: ELSEVIER SCIENCE INC.||geography; distribution; West Coast; California; prevalence|
|Arslan LG.||2017||Red meat allergy induced by tick bites: A Norwegian case report.|
Summary: Food allergies, especially delayed hypersensitivity reactions, are often challenging for both patients and clinicians. Here, we report the case of a 64-year-old man who had allergic reactions six hours after eating a meal containing red meat. He reported that he had several tick bites in months before the reaction. High serum specific IgE levels of alpha-gal confirmed the diagnosis of alpha-gal allergic reaction with delayed onset after red meat ingestion caused by tick bite.
|European annals of allergy and clinical immunology. 2017 Jul;49(4):186.||Europe; Norway|
|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|
|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; Vermont; idiopathic anaphylaxis|
|Baker MG, Sampson HA.||2018||Phenotypes and endotypes of food allergy: A path to better understanding the pathogenisis and prognosis of food allergy.|
• 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|
|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|
|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.||In ALLERGY 2019 Aug 1 (Vol. 74, pp. 509-509). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY.||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.
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 Nov 1;55(7):492-7.||review article; Europe; France|
|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; 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 Jan 1;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, 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 uncover Sensitisation 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, 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|
|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 . 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|
|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.
|EuropeanJournal of Dermatology. 2017 Jan 1;27(1):3-9.||review article; Europe; Switzerland|
|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|
|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 Jul 28:100054.||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|
|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|
|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 Jun 1;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 Feb 1;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 Sep 1;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|
|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|
|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|
|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 No 10;3(11): 1140-2||pan-vaccine|
|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 72(12): 2044-2047.|
|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.
|Sci Rep 8: 14224.|
|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 Immunol 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, 49(3), e301.|
|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 8(1733).|
|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 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 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.
|Lancet Infect Dis 14(10): 916-917.|
|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 , UK , and China . 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 . 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 , 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.|
|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 55(8) 501.||Medication; pharmaceutical; pharmacy; vaccination; vaccine; review article; primary care physician; pharmacy; pharmacist; perioperative care|
|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.
|Eur Ann Allergy Clin Immunol 47(5): 161-162.||Europe; Italy|
|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 1(3): 302-303.||oral consumption of gelatin; gelatine; food|
|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 3(6): 982-983.||biologic; biological agent; monoclonal antibody; mAb|
|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|
|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 73(5): 1131-1134.|
|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.
|J Immunol 203(4): 813-824.|
|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 200(1 Supplement): 104.106.|
|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|
|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.(123): 1807-1814.||allergen; cross-reactivity; cross-reaction; flounder roe; hirame; sushi|
|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 71(3): 421-425.||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 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.
|Allergol Int 68(3): 296-300.|
|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.
|J Allergy Clin Immunol Pract 5(5): 1425-1426.|
|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.||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 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 141(2): AB192.|
|Choudhary S, Iweala OI, Addison CT, & Commins SP.||2019||Tick Salivary 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 143(2): AB252-AB252.|
|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 141(2): AB199.|
|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 139(2): AB125.|
|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.
|N Engl J Med 358(11): 1109-1117.||prevalence|
|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.|
|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 Jun 25.||diagnosis; management; primary care|
|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, 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.
|Curr Allergy Asthma Rep 10: 29-33.|
|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 121(2): S25-S25.|
|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.
|Curr Allergy Asthma Rep 15(1): 492.||review article|
|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 358(25): 2735-2736.|
|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 143(2, Suppl. S): AB35.|
|Commins SP, James HR, Kelly LA, Pochan SL, Workma, 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 127(5): 1286-1293.e1286.||ectoparasite; parasite; non-tick vector; helminth|
|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 125(2): AB119.|
|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 65(1): 16-20.||review article|
|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 134(1): 108-115.|
|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 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.
|Am J Respir Crit Care Med 185(7): 723-730.|
|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 124(4): 652-657.||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.
|Curr Allergy Asthma Rep 13(1): 72-77.|
|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 25(2): 24-28.|
|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.
|Curr Opin Allergy Clin Immunol 13(4): 354-359.||review article|
|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 123(2): 426-433.e422.|
|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 135(2): AB205.|
|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|
|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.
|The Journal of Immunology 196(1 Supplement): 191.125-191.125.|
|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 49(5): 615-625.|
|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 129(2): AB80-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.
|Front Immunol 10: 1056.|
|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 7(1): 13-15.|
|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 94(1): 35-42.|
|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 Tick Borne Dis 9(5): 1354-1357.|
|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 35(38): 5089-5094.|
|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.
|Parasit Vectors 12(1): 154.|
|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.|
|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.
|Br J Anaesth 123(1): e65-e81.|
|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|
|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.
|Ann Allergy Asthma Immunol.|
|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|
|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 56(7/8): 533-538.||vector; cross-reactivity; hymenoptera; food; diet; dairy; rennet; cheese|
|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.
|Anesth Analg 129(5): 1242-1248.||review article; perioperative care; pharmacy; pharmaceutical; medication; surgery; hospitalization; medical products|
|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.
|Clin Med Insights Oncol 8: 91-94.|
|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 Oncol 10(14): 2133-2140.|
|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 (=29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study.
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 83(3): 623-631.|
|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 , but this is the first case in which cofactors, well-known amplifiers of reactions to α-Gal , 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 Clin Belg 68(3): 206-209.|
|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.|
|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.
|Frontiers in Immunology. 2020;11:1532.||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.
|J Allergy Clin Immunol 115(5): 1029-1035.|
|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 121(5): S115.|
|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 74(2): 174-179.|
|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|
|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 4(3): 303-311.|
|Fischer J.||2015||Food Allergy through Tick Bites a new Health Risk?|
No abstract available
|Allergologie 38(4): 194-195.|
|Fischer J, Biedermann T.||2016||Verzögerte Soforttyp-Allergie gegen rotes Fleisch und Innereien: aktueller Wissensstand zu einem neuen Krankheitsbild.|
In der In-vitro-Allergiediagnostik hat die Entwicklung hin zu Einzelkomponenten statt die Verwendung von Gesamtextrakten in den letzten Jahren große Fortschritte gebracht. Besonders eindrücklich ist die Identifizierung von neuen Krankheitsentitäten, die mit dem Nachweis von IgE-Antikörpern gegen bestimmte Einzelkomponenten einhergehen. Eine besondere Bedeutung kommt der verzögerten Soforttypallergie gegen rotes Fleisch und Innereien zu. Dieses Krankheitsbild ist im deutschsprachigen Raum häufiger als zunächst angenommen und wird wahrscheinlich immer noch unterdiagnostiziert. Betroffene Patienten reagieren verzögert mit Typ-I-Reaktionen auf rotes Fleisch oder, etwas früher, nach Verzehr von Innereien. Bei allen Patienten können IgE-Antikörper gegen das Oligosaccharid Galaktose-α-1,3-Galaktose, kurz αGal, nachgewiesen werden. Betroffene müssen auch α-Gal-haltige Medikamente wie Cetuximab oder Gelatine-haltige Volumenersatzmittel meiden. Das Krankheitsbild, das auch α-Gal-Syndrom genannt wird, ist insofern neuartig als es sich um eine Soforttypallergie gegen einen Zucker und nicht gegen ein Protein handelt. Da viele Patienten eine Krankengeschichte mit wiederholten Schüben einer akuten Urtikaria oder von Angioödemen aufweisen, sollte das α-Gal-Syndrom Dermatologen geläufig sein.
Delayed immediate-type hypersensitivity to red meat and innards: current insights into a novel disease entity.
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 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 72(5): 764-771.|
|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 134(3): 755-759.e751.|
|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 72(10): 1540-1547.||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 J Int 25: 55-62.|
|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 8(4): 345-348.|
|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. 2018 Oct 23;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, 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 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, 135(2), AB206.|
|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.
|Allergol Int 68(1): 127-129||Asia; Japan; diet; foods; organ meats; intestine; fish eggs; flounder eggs|
|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.||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|
|Gallili 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.
|In: Springer seminars in immunopathology 1993 Sep 1 (Vol. 15, No. 2-3, pp. 155-171). Springer-Verlag.||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. Antibodies.|
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 140(1): 1-11|
|Galili U.||2018||[BOOK] The natural anti-gal antibody as foe turned friend in medicine. Chapter 7: Anti-Gal IgE Mediates Allergies to Red Meat.|
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.
|Academic Press; 2017 Sep 5:117-128.|
|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, 168(2), 352-363.|
|Galili U, Avila JL, editors.||2012||[BOOK] α–Gal and Anti–Gal: α1, 3–Galactosyltransferase, α–Gal Epitopes, and the Natural Anti–Gal Antibody Subcellular Biochemistry (Subcellular Chemistry Vol. 32)|
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, 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.|
|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, 3(2), 175-185.|
|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|
|García-Menaya JM, Cordobés-Durán C, Gómez-Ulla J, Zambonino MA, Mahech, AC, Chiarella GM, Giangrande N, Bobadilla-González P.||2016|