Cross-reactive epitopes and their role in food allergy

Allergenic cross-reactivity among food allergens complicates the diagnosis and management of food allergy. This can result in many patients being sensitized (having allergen-specific IgE) to foods without exhibiting clinical reactivity. Some food groups such as shellfish, fish, tree nuts, and peanuts have very high rates of cross-reactivity. In contrast, relatively low rates are noted for grains and milk, whereas many other food families have variable rates of cross-reactivity or are not well studied. Although classical cross-reactive carbohydrate determinants are clinically not relevant, α-Gal in red meat through tick bites can lead to severe reactions. Multiple sensitizations to tree nuts complicate the diagnosis and management of patients allergic to peanut and tree nut. This review discusses cross-reactive allergens and cross-reactive carbohydrate determinants in the major food groups, and where available, describes their B-cell and T-cell epitopes. The clinical relevance of these cross-reactive B-cell and T-cell epitopes is highlighted and their possible impact on allergen-specific immunotherapy for food allergy is discussed. Allergenic cross-reactivity among food allergens complicates the diagnosis and management of food allergy. This can result in many patients being sensitized (having allergen-specific IgE) to foods without exhibiting clinical reactivity. Some food groups such as shellfish, fish, tree nuts, and peanuts have very high rates of cross-reactivity. In contrast, relatively low rates are noted for grains and milk, whereas many other food families have variable rates of cross-reactivity or are not well studied. Although classical cross-reactive carbohydrate determinants are clinically not relevant, α-Gal in red meat through tick bites can lead to severe reactions. Multiple sensitizations to tree nuts complicate the diagnosis and management of patients allergic to peanut and tree nut. This review discusses cross-reactive allergens and cross-reactive carbohydrate determinants in the major food groups, and where available, describes their B-cell and T-cell epitopes. The clinical relevance of these cross-reactive B-cell and T-cell epitopes is highlighted and their possible impact on allergen-specific immunotherapy for food allergy is discussed. Allergenic cross-reactivity can be clinically manifest or irrelevant. In vitro diagnosis of food allergy and its management is often hampered by cross-reacting food proteins.1Cox A.L. Eigenmann P.A. Sicherer S.H. Clinical relevance of cross-reactivity in food allergy.J Allergy Clin Immunol Pract. 2021; 9: 82-99Abstract Full Text Full Text PDF PubMed Google Scholar,2Sinson E. Ocampo C. Liao C. Nguyen S. Dinh L. Rodems K. et al.Cross-reactive carbohydrate determinant interference in cellulose-based IgE allergy tests utilizing recombinant allergen components.PLoS One. 2020; 15e0231344Crossref PubMed Scopus (7) Google Scholar IgE binding to cross-reactive clinically irrelevant allergens results in false-positive results on in vitro diagnostic tests. However, unidentified sources of cross-reactive allergens of clinical relevance may lead to unintentional exposure and allergic reactions, posing a health risk for the affected individuals. The concept of cross-reactivity between related or unrelated allergen sources is extensively addressed in the literature. However, this information is often not accompanied with data on identifying specific allergens or epitopes. The most common view in the current literature is that cross-reactive allergenic proteins present with a high primary amino acid sequence identity of above 70%.3Bublin M. Breiteneder H. Cross-reactivities of non-homologous allergens.Allergy. 2020; 75: 1019-1022Crossref PubMed Scopus (7) Google Scholar However, relevant IgE-binding epitopes are often below 20 amino acids in length and allow for a much better assessment of allergenic cross-reactivity.4Matsuo H. Yokooji T. Taogoshi T. Common food allergens and their IgE-binding epitopes.Allergol Int. 2015; 64: 332-343Abstract Full Text Full Text PDF PubMed Google Scholar In addition, shared cross-reactive T-cell epitopes could explain some of the clinical desensitization to food allergens observed after successful pollen immunotherapy5Furci F. Ricciardi L. Plant food allergy improvement after grass pollen sublingual immunotherapy: a case series.Pathogens. 2021; 10: 1412Crossref PubMed Scopus (0) Google Scholar; however, the cross-reactive T-cell epitopes have been studied for very few allergens. Well-characterized cross-reactive B-cell and T-cell epitopes between food allergens will not only assist in developing more specific and accurate molecular diagnosis but also contribute to the development of lead candidates for targeted immunotherapy. In this review, we summarize the basic concepts of allergenic cross-reactivity, discuss about protein and carbohydrate epitopes, and provide an overview of the cross-reactive allergens belonging to the major food allergen groups. Cross-reactivity in allergy is a broad term used to define the ability of (secondary) allergen(s) to recognize IgE antibodies and/or invoke a cellular (T-cell, mast cell, or basophil) response in the body upon exposure, which has been already sensitized to a primary (initiator) allergen that shares 1 or more epitope with the secondary allergen. These shared regions are defined as cross-reactive epitopes. IgE cross-reactivity is often recognized when allergic symptoms arise to an allergen source without prior exposure. However, IgE cross-reactivity might be clinically manifest or irrelevant. IgE cross-reactivity can be defined as the relationship between 1 antibody and 2 or more allergens.6Aalberse R.C. Assessment of allergen cross-reactivity.Clin Mol Allergy. 2007; 5: 2Crossref PubMed Scopus (72) Google Scholar Sensitization occurs to a primary allergen via a TH2 response, leading to the generation of allergen-specific IgE antibodies.7Sampson H.A. O’Mahony L. Burks A.W. Plaut M. Lack G. Akdis C.A. Mechanisms of food allergy.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Google Scholar These IgE antibodies may be to and/or to epitopes on the R.C. IgE-binding a PubMed Scopus Google Scholar the is to a food source via or the primary allergen-specific IgE antibodies are to recognize these secondary allergens via cross-reactive epitopes, and may lead to on and mast in and clinical symptoms The secondary allergen may be a or allergen in that may or may not be of primary allergic by R.C. Assessment of allergen cross-reactivity.Clin Mol Allergy. 2007; 5: 2Crossref PubMed Scopus (72) Google R.C. Assessment of sequence and PubMed Scopus Google Scholar In some the of exposure may between the primary and secondary allergen. primary to may via but secondary exposure and cross-reactive IgE binding to occurs via S. K. et to allergens in and their cross-reactivity to Allergy Immunol. PubMed Scopus Google Scholar In addition, the IgE binding to the secondary allergen may be as with that to the primary on the of cross-reactive epitopes and binding these in to the and amino acid sequence or of the secondary a in the clinical relevance of IgE cross-reactivity. T-cell cross-reactivity can be defined as the of to more 1 M. G. G. H. cross-reactivity and of Immunol. 2020; Scopus Google Scholar T-cell cross-reactivity is possible for binding and in as a that has to recognize a of be Immunol. PubMed Scopus Google Scholar However, in of allergenic T-cell cross-reactivity, the most and is sequence of the T-cell cross-reactive among related allergen L. S. et epitope allergen is a major determinant of Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar cross-reactive T-cell epitope is to and IgE is the 1 T-cell epitope and its cross-reactivity to food allergens and S. S. 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T. et of on and T-cell of major allergen 2020; 75: PubMed Scopus Google Scholar The clinically relevant cross-reactive allergens belonging to the major food groups are and a overview on the current on cross-reactive or T-cell epitopes and are the most allergen sources of the and the cross-reactivity of their allergens. Sensitization to peanut can be with to other of the such as and with tree nuts, or with to sensitized to other and to allergy to 1 other T. T. S. C. et of to in Allergy Immunol. Scopus Google M. S. M. et of peanut allergic with in to tree nuts and other Allergy Immunol. 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