MHC class I and autoimmune diabetes.

The cause of failed self tolerance, resulting in autoimmunity is unknown, although genetic linkage to genes within the MHC class II region have been well described. We present evidence that failed self tolerance in autoimmune diabetes appears to be secondary to an antigen presenting cell defect; the diabetic antigen presenting cells fail to deliver fragments of endogenous antigens to the cell surface in the groove of MHC class I. In the diabetic NOD mouse model, this correlates with a rare allele at the Tap-1 locus, a gene that controls proper MHC class I assembly by providing fragments of endogenous peptides into the endoplasmic reticulum. We propose that MHC class I presentation of self peptides may represent a normal pathway for tolerance induction and interruption of this important class I function from any cause, including the MHC class II-linked Tap-1 and Tap-2 genes, which may result in autoreactivity.