Major Histocompatibility Complex–linked Control of Autoimmunity

A lthough the MHC is a key genetic component in au-toimmune disease, our knowledge of the mechanisms by which the molecules encoded within the MHC influence autoimmune processes remains incomplete. Because of the linkage disequilibrium that exists among the class I, II, and III genes within the HLA complex in humans and the homologous MHC complex in rodents, the absolute contribution of the individual loci has been difficult to dissect. However, it is clear from association and linkage studies of autoimmune diseases in humans as well as from various forms of analyses in the mouse and rat for diseases such as spontaneous autoimmune diabetes and experimentally induced encephalomyelitis, arthritis, and thyroiditis, that class II molecules are a primary (but not always the sole) basis of the HLA–MHC association. One area of intense investigation and speculation has been stimulated by the demonstration that particular class II molecules have positive , neutral, or negative association with human autoimmune diabetes (1, 2). Much of the experimental work to understand the contribution of class II alleles to autoimmunity has used the nonobese diabetic (NOD) mouse, a model of spontaneous diabetes. Although analysis of the few intra-MHC recom-binants available has pointed to the importance of the class II region in autoimmune diabetes (3), transgenic introduction of class II molecules into the NOD mouse has provided the most persuasive evidence of the essential role of particular class II molecules in the autoimmune process (4– 7). In addition, the disease diminution that has been afforded by the introduction of nondiabetogenic I-E or I-A class II molecules has created models that are hoped to mimic the protection observed in human autoimmune diabetes by certain HLA class II molecules that are negatively associated with disease. However, the mechanism by which the introduced nondiabetogenic class II molecules prevent diabetes remains a point of controversy. Originally, one leading hypothesis was that the introduced class II molecule led to the deletion of self-reactive cells. However, evidence to support this hypothesis was not found, leading several groups to dismiss this possibility (8–12). In particular, Mathis et al. (9) introduced by transgenesis into the NOD mouse an islet-specific, I-A g7 –restricted TCR derived from a pathogenic clone, BDC2.5 (13). Such TCR-transgenic NOD mice became diabetic with increased frequency and at a somewhat earlier time than normal NOD mice. Introduction of the E ␣ transgene, which protects NOD mice from disease, failed to alter the …