In both humans and the NOD mouse model, insulin dependent diabetes (IDDM) results from autoimmune destruction of pancreatic beta cells by T lymphocytes. Thus far, it is not known which specific subpopulations of antigen presenting cells (APCs - B lymphocytes, macrophages or dendritic cells) contribute to the development and activation of diabetogenic T lymphocytes. Preliminary data show that B lymphocytes play an essential role, since disease incidence is completely inhibited in a stock of NOD mice made B lymphocyte deficient by congenic transfer of a functionally disrupted Ig-mu allele (NOD.Ig-mu null). Preliminary data also show that B lymphocytes are the only APC population that can immunologically process glutamic acid decarboxylase (GAD), which may be the earliest beta cell antigen targeted by autoreactive T lymphocytes in NOD mice. In addition, an epitope in GAD that is reported to be preferentially presented by APC to autoreactive T lymphocytes in both NOD mice and human IDDM patients is highly homologous with a segment of the Coxsackie virus P2-C protein. Thus Coxsackie virus infection may provide a cross-reactive antigenic trigger for the activation of diabetogenic GAD autoreactive T lymphocytes in genetically susceptible individuals. Furthermore, normally quiescent, diabetogenic T lymphocytes may still develop in B lymphocyte deficient NOD.Ig-mu null mice if other subpopulations of APC have the capacity to generate mimics of beta cell autoantigens from infectious agents such as Coxsackie virus. To test this hypothesis, the investigators will pursue two major aims. The first is to determine whether B lymphocytes are required for the development as well the functional activation of T lymphocytes capable of responding to various GAD-derived peptides in NOD mice. The second is to determine if IDDM resistance in NOD.Ig-mu null mice can be abrogated by priming with GAD derived peptides or a Coxsackie viral infection that may bypass the normal requirement for B lymphocytes to generate antigenic epitopes from native GAD. These studies will provide insights to the basic mechanisms by which beta cell antigens are presented to autoreactive T lymphocytes in IDDM, and how these processes may be influenced by a Coxsackie viral infection.
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