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Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200-1:300) that is induced by dietary exposure to wheat gliadins (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (alpha1*0501, beta1*0201), which is present in over 90% of CD patients. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge, it has been unclear whether a 'dominant' T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57-73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.

Original publication

DOI

10.1038/73200

Type

Journal article

Journal

Nat Med

Publication Date

03/2000

Volume

6

Pages

337 - 342

Keywords

Adult, Age of Onset, Amino Acid Sequence, Celiac Disease, Cells, Cultured, Epitopes, Female, Gliadin, HLA-DQ Antigens, Humans, Interferon-gamma, Interleukin-10, Lymphocyte Activation, Lymphocytes, Male, Middle Aged, Molecular Sequence Data, Peptide Fragments, Prevalence, T-Lymphocytes, Transglutaminases, United Kingdom