In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope

Abstract

Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200–1:300)¹ that is induced by dietary exposure to wheat gliadins² (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (α1*0501, β1*0201), which is present in over 90% of CD patients³. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones^4,5,6 and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge^7,8,9, 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 responses¹⁰, 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.