This is a research project to study the regulation of self-reactive B cells. The approach will be to construct mutant mice, which carries rearranged H and L chain genes in the germ line position of JH and JL, thus allowing the rearranged VH transgene to go through class switch and mutation. We propose to introduce the V genes (vH and VL) of a well-characterized anti-DNA antibody 564 that arose spontaneously in NZBxSWR mice: an animal model that develops Systemic lupus erythematosus (SLE). We will determine 1) what is the fate of B-lymphocytes that express a self-reactive antibody H and L chain at various stages of B cell development and differentiation. 2) How are self-reactive B cells regulated in mice of normal genetic constitution versus in mice that have autoimmune predisposition and have dysfunctional B cells? 3) How far-reaching are the effects of the knock-in gene in the predisposing background, and will these effects be demonstrative of positive selection of clones expressing this gene? We are particularly interested in seeing the effect of the transgenes in the context of other genes that are currently known to predispose mice to autoimmune diseases as well as in genetic backgrounds that are known to result in dysregulated B cell function. These studies should provide important insights into normal mechanisms of B-cell tolerance and how and when during the B cell development these mechanisms fail in autoimmune background animal.
