B LYMPHOCYTE TOLERANCE IN HEALTH AND AUTOIMMUNITY

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The long term goal of the project is to understand how autospecific B cells are controlled, to determine whether or not autoimmune-prone strains of mice have intrinsic B cell tolerance defects and, if so, to localize the genes involved. As a basic for this study mice transgenic for functionally rearranged anti- H-2KkDk IgM antibody genes have been generated. In these mice B cells are clonally deleted in the presence of the appropriate H-2 class I antigens. The Specific Aims of this proposal are as follows. 1. The fate of autospecific B cells with respect to (i) the stage of development at which they encounter autoantigen, (ii) their IgD expression, and (iii) their cell lineage will be determined. Immature, mature unstimulated, and memory CD5+ and CD- B cells from anti-H-2k transgenic mice will be challenged in vivo and in vitro with self antigen then analyzed to assess whether or not autoreactive cells are deleted or functionally tolerized. 2. The role of T cells in the positive and negative selection of B cells will be analyzed in anti-H-2k transgenic mice. Normal and T cell depleted transgenic mice will be analyzed for B cell clonal diversification and antigen mediated-tolerance. 3. The impact on B cell tolerance of two apparently dominant autoimmune loci of the BXSB and NZB mouse strains will be analyzed in crosses with anti-H-2k transgenic mice. If a clear defect is observed the genetic basis will be sought through classical and molecular genetic approaches. 4. The existing IgM anti-H-2 transgenic lines and new anti-H-2 lines containing both mu and delta constant region heavy chain genes that are now being produced will be characterized. The level and tissue specificity of transgene expression and the extent of suppression endogenous immunoglobulin gene rearrangement will be analyzed. The IgM + IgD anti-H- 2KkDk mice will be used in Specific Aim 1, part (ii).