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

Abstract

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.