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

Anderson, R. P., Degano, P., Godkin, Andrew James ORCID: https://orcid.org/0000-0002-1910-7567, Jewell, D. P. and Hill, A. V. 2000. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nature Medicine 6 (3) , pp. 337-342. 10.1038/73200

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Adult, Age of Onset, Amino Acid Sequence, Celiac Disease/epidemiology, Celiac Disease/genetics, Celiac Disease/immunology, Cells, Cultured, Epitopes/chemistry, Epitopes/immunology, Female, Gliadin/chemistry, Gliadin/immunology, Gliadin/pharmacology, Great Britain/epidemiology, HLA-DQ Antigens/genetics, HLA-DQ Antigens/immunology, Humans, Interferon-gamma/biosynthesis, Interleukin-10/biosynthesis, Lymphocyte Activation, Lymphocytes/drug effects, Lymphocytes/immunology, Male, Middle Aged, Molecular Sequence Data, Peptide Fragments/immunology, Peptide Fragments/pharmacology, Prevalence, T-Lymphocytes/immunology
Publisher:	Nature Publishing Group
ISSN:	1078-8956
Last Modified:	27 Oct 2022 10:13
URI:	https://orca.cardiff.ac.uk/id/eprint/69355

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