Insulin dependent diabetes mellitus (IDDM) in humans and NOD mice is an autoimmune disease caused by the selective destruction of pancreatic beta cells by autoreactive T lymphocytes. In addition to the well characterize loss of T cell tolerance to islet autoantigens, the presence of anti-islet antibodies highlights a concomitant dysregulation of B cell tolerance to these antigens. The requisite role of B cells in diabetogenesis has recently been established in studies of B cell deficient NOD mice where were found to be protected from insulitis and diabetes. Whether the role of B cells in NOD diabetogenesis is mediated by the activated autoreactive B cells and whether this role involves antigen presentation by B cells is unknown. In the present proposal we plan to study the mechanisms underlying the role of B cells in NOD diabetogenesis. Thus, specific Aim 1 will be focused on elucidating the contribution of MHC class I- and class II-mediated antigen presentation by B cells to NOD diabetogenesis.
In specific Aim 2 we propose studies to assess the contribution of the autoreactive subset of B cells to NOD diabetogenesis by skewing the NOD B cell repertoire away from diabetes associated Ig specificities.
Specific aim 3 will address the importance of C3-mediated B cell activation and antigen uptake in the development of anti-islet autoantibodies and diabetogenesis in NOD mice. Finally, in specific aim 4 we will pursue studies aimed at elucidating the regulation of self-reactive B cells in the NOD microenvironment. Insights into the mechanisms by which B cells contribute to the etiology of autoimmune diabetes will provide the basis for the design of novel strategies for the prevention of IDDM.
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