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 characterized 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 which were found to be diabetes-free. Whether the role of B cells in NOD diabetogenesis is mediated by the islet-reactive B cells and whether this role involves antigen presentation by B cells is unknown. The present application proposes studies focused on elucidating the mechanisms underlying the role of B cells in autoimmune NOD diabetes. Specifically, the contribution of MHC class II mediated antigen presentation by B cells to NOD diabetogenesis will be assessed. Additionally, the contribution of the autoreactive subset of B cells to NOD diabetogenesis will be determined by skewing the B cell repertoire from diabetes associated Ig specificities. 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.
| Bunnell, Stephen C; Singer, Andrew L; Hong, David I et al. (2006) Persistence of cooperatively stabilized signaling clusters drives T-cell activation. Mol Cell Biol 26:7155-66 |
| Singer, Andrew L; Bunnell, Stephen C; Obstfeld, Amrom E et al. (2004) Roles of the proline-rich domain in SLP-76 subcellular localization and T cell function. J Biol Chem 279:15481-90 |
