In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope.
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.
Anderson
R P
RP
Institute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK. bob.anderson@ndm.ox.ac.uk
Degano
P
P
Godkin
A J
AJ
Jewell
D P
DP
Hill
A V
AV
D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D005903:Gliadin / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D015995:Prevalence; D013601:T-Lymphocytes / Q000276:immunology*; D011503:Transglutaminases / Q000378:metabolism*; D006113:United Kingdom / Q000453:epidemiology
D000939:Epitopes; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D010446:Peptide Fragments; D016753:Interleukin-10; D007371:Interferon-gamma; D005903:Gliadin; D011503:Transglutaminases