James W. Thomas II, M.D.
Mechanisms that regulate immune tolerance and why they fail in autoimmune disorders such at type 1 diabetes
Antibody production, or humoral immunity, is a highly effective mechanism for host defense because the developing B cell repertoire generates an enormous number of immune receptors that become immune effectors as antibodies. Because many of the immune receptors produced during B cell development also react with self antigens (i.e. are autoreactive), mechanisms are necessary to prevent the emergence of potentially toxic B cell clones and antibodies. The mechanisms that maintain this autoreactivity in check are broadly termed â€œimmune tolerance.â€ Every immune response must first negotiate checkpoints of immune tolerance before effective host defense can be generated. In autoimmune diseases, these checkpoints fail and autoagressive clones emerge. Among these, loss of B cell tolerance as manifest by anti-insulin antibodies is a harbinger of autoimmune beta cell destruction in the pancreas that causes type 1 (insulin dependent) diabetes. To study this event at the cellular and molecular level, our laboratory has generated mice that harbor insulin autoantibodies as B cell receptor transgenes. T1D prone NOD mice that harbor an Ig heavy chain transgene permit us to investigate a population of insulin binding B cells in the repertoire. We find that these insulin specific B cells promote T1D in the NOD mouse model. In addition, we have discovered that some of these B cells invade islets and express receptors that may bind antigens other than insulin. Capturing the antigen receptors on these B cells provides a means to discover new beta cell autoantigens that are targets in T1D. Further, a new line of transgenic mice is being generated in which the anti-insulin V regions are targeted to the Ig locus. Studies in these will identify, for the first time, when and where immune tolerance is lost, allowing anti-insulin B cells to undergo class switch recombination and differentiation into antibody producing cells. Studies in the laboratory investigate how the action of helper and regulatory T cells alter this critical immune response.