The analysis of Ig transgenic mice revealed that endogenous H chain are rearranged and expressed. These endogenous H chains have unique joining characteristics quite distinct from the H chains obtained from normal mice. Furthermore, preliminary data suggest that somatic hypermutation of rearranged Ig genes is found in splenic B cells, bone marrow B cells and in splenic B cells of young unimmunized kappa-/-, transgenic mice carrying functional rearranged H chain. We also found mutated lambda light chain genes from bone marrow B cells with characteristic markers of immature B cells. These results suggest endogenous Ig rearrangements and somatic mutations in bone marrow IgM+ B cells could be taking place at the early B cell development. It is therefore tempting to speculate that the same molecular mechanism regulates the diversity of antibody repertoire as a consequence of negative and/or positive selection by internal and external antigens. The primary goal of this project is to accomplish the following aims: (1) to determine the genetic contribution of specific transgene and background genes in the regulation of transgene expression and selection. (2) To determine what stage of B cell development, and how early in the ontogeny of B cells is somatic hypermutation taking place. (3) To determine whether somatic mutation is a consequence of negative selection followed by positive selection. These studies are important for our understanding of B cell development and mechanisms regulating the primary B cell repertoire. It will provide insights into the question of whether there are crucial developmental checkpoints involving interactions between surface immunoglobulin molecules and specific ligands at each one of these stages.
