Recent evidence increasingly points to the importance of antibodies specific for RNA antigens in the pathogenesis of SLE. Using a novel mouse model in which RNA-specific B cells are generated and easily tracked, and in which clinical SLE pathologies are recapitulated, new and critical information on the pathogenesis of SLE will be obtained. The mouse line to be used, 564Igi, was generated in our laboratory and has already made an important contribution to the emerging understanding of the role played by TLRs, in particular TLR7, in the development of SLE. In this system, on the non-autoimmune C57BL/6 background, most RNA-reactive B cells undergo receptor editing, while those that retain their RNA-specificity become anergic by multiple criteria. Yet class-switched pathogenic autoantibodies are produced by a T-independent, but TLR7-dependent mechanism. Thus, either anergic RNA-specific IgM+ B cells are capable of activation and differentiation into IgG producing cells in response to self-antigen, or a subpopulation of these cells is able to evade anergy, namely those that have undergone CSR in the bone marrow during B cell development in response to self-antigen encounter. In the current proposal, these two models will be tested in detail. In either case, the signals required for differentiation into antibody producing cells and the extent to which there are contributions from non-B cells will be determined. Finally, the effect of autoimmune-prone backgrounds on the regulation of RNA-specific B cells in the 564Igi system will be studied. These experiments will help unravel the mechanisms by which RNA-specific B cells become activated and produce pathogenic autoantibodies in SLE.