On autoimmunity -- lessons from coeliac disease

Coeliac disease is a prevalent polygenic disorder caused by a harmful immune response to cereal gluten proteins. Previously the condition was considered an inflammatory, food hypersensitivity disorder, but presence of diagnostic autoantibodies, specific killing of enterocytes and autoimmune type of genetics advocate that coeliac disease rightfully can be considered an autoimmune condition with gluten as the driver of the autoimmune pathologies. As with most autoimmune diseases, the single most genetic factor in coeliac disease is MHC. The primary association is with HLA-DQ2.5, HLA-DQ2.2 and HLA-DQ8. These HLA molecules present gluten epitopes to CD4+ T cells – cells that conceptually serve as the master regulators of the immune reactions leading to disease. Gluten epitopes recognised by T cells are typically deamidated, and this deamidation is mediated by the enzyme transglutaminase 2 (TG2). Strikingly, coeliac disease patients have highly disease specific autoantibodies to TG2, and these antibodies are only produced in subjects who carry the coeliac disease associated HLA molecules when they consume gluten. It is hardly coincidental that TG2 is implicated in T-cell epitope formation and being the target for autoantibodies. Evidence suggests that B cells with their surface immunoglobulin antigen receptor, both cells specific for gluten and for TG2, serve as antigen presenting cells for gluten-reactive T cells thereby amplifying the anti-gluten T-cell response. Antigen receptors of disease-relevant T and B cells can be studied in detail by use of HLA-DQ:gluten tetramers and by use of labelled antigen (TG2 and gluten) that bind to surface IgA and IgM of gut plasma cells. The tracking of gluten specific T-cell clonotypes by HLA-DQ:gluten tetramer staining and antigen-receptor sequencing has revealed that such T cell clonotypes can persist for decades. The immunological scar imposed by gluten sensitisation has implication for design of immune therapies of coeliac disease, and this observation is relevant for treatment of other autoimmune diseases.