Multiple genes/multiple autoantigens role in type 1 diabetes

We hypothesize that Type 1 diabetes of humans and NOD mouse results from non-MHC genes, which determine susceptibility to T-cell autoimmunity. MHC class II alleles (and perhaps class I) determines the tissue targeted by these T-cells (DQ8/DQ2 Type 1 diabetes and Addison's disease, DQ2 or DQ8 for celiac disease). The high propensity for islet beta cells to be the target of autoimmunity we believe is the result of a peculiarity of the insulin B-chain peptide, such that it is a dominant beta cell-specific autoantigen. In the NOD mouse, autoreactive T-cells show a restricted Vα repertoire. The ability of selected class II molecules to prevent disease may relate to effects of these molecules (I-E, DQB1*0602, and so forth) on the T-cell repertoire. With improving assays for autoantibodies and T-cell autoimmunity and the availability of transgenic mouse, we believe that the aforementioned hypotheses can be thoroughly tested.