Robert Paul Anderson

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 (α1*0501, β1*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.

Definitive T cell epitope mapping for a human disease: gluten challenge in coeliac disease identifies a dominant transglutaminase-deamidated T cell epitope

Antigen-specific immunotherapy has been proven to be an effective means of preventing and treating antigen-driven immune disease in experimental animals. Human diseases with strong human lymphocyte antigen (HLA) associations such as multiple sclerosis, rheumatoid arthritis and juvenile diabetes are believed to be driven by autoantigens and/or environmental antigens that mimic autoantigens. However, human diseases are generally not amenable to study until clinically manifest, when the pathologic immune response is chronic. In animal models, autoimmune disease can be triggered by immunization with a single peptide derived from a critical autoantigen. This peptide corresponds to a dominant T cell epitope. However, as disease progresses, the immune response diversifies and multiple peptide epitopes derived from the original autoantigen, as well as other proteins in the target tissue, are recognized by cognate T cells. This process is termed epitope spreading and has prevented definitive identification of T cell epitopes and antigens that initiate human disease.