Differences between diabetes susceptible and resistant mouse strains in the major histocompatability complex class II mediated antigen processing and presentation of an important pancreatic autoantigen, glutamic acid decarboxylase (GAD-65)

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease in which destruction of the insulin producing, islet beta cells of the pancreas is mediated by CD4 and CD8 T cells. In young NOD mice, spontaneous B cell and T cell responses to several beta cell antigens, including glutamic acid decarboxylase-65 (GAD-65), arise prior to clinical disease. Susceptibility to IDDM has been linked to as many as 20 genetic loci. The locus conferring greatest susceptibility to IDDM lies within the major histocompatability complex (MHC), indicating that APC and their antigen processing machinery play a central role in the induction of disease. Implied in this view is that one or more of the genetic loci may involve an aspect of antigen processing and presentation.; We studied the role of MHC II mediated antigen processing and presentation of an important diabetogenic autoantigen, GAD-65, in the initiation and propagation of IDDM. APCs from diabetes susceptible (NOD) and resistant (NOR) mice were compared and differences were observed in both the number of GAD-65 determinants presented, and in the relative amount of presentation of a given determinant by APC from the spleens of these two mouse strains. In particular, NOR mice readily presented a determinant from whole GAD-65 (p524-538) to which regulatory T cells have been described, indicating that efficient induction of regulatory T cells may be crucial to protection from disease.; The enhanced antigen processing of GAD-65 determinants by NOR APC was reflected in the heightened natural processing of islet derived GAD-65 ex vivo. Accordingly, presentation of the regulatory determinant p524-538, and the relatively poor presentation of a putatively pathogenic determinant (p530-543) by NOR pancreatic dendritic cells (DC) were observed. In contrast, APC from the spleen of NOD mice failed to present the regulatory p524 determinant. Further, pancreatic DC from NOD mice consistently presented the pathogenic p530 determinant from whole GAD-65 ex vivo. Thus, differences in MHC II mediated antigen presentation of both pathogenic and regulatory beta cell autoantigenic determinants by APC of diabetes susceptible and resistant mouse strains may account, at least in part, for differences in susceptibility to IDDM.