Mapping the genes that predispose to murine lupus

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Summary) )To elucidate the T cell – B cell mechanisms involved lupus pathogenesis, the PI has used an induced model of murine lupus, the parent-into-F1 model of graft-vs.-host disease (GVHD). Using B6D2F1 mice as hosts, DBA/2 (DBA) parental T cell transfers result in lupus specific autoantibodies and lupus nephritis (chronic GVHD) whereas B6 parental T cell donors cause elimination of host B cells and no lupus specific autoantibodies (acute GVHD). The PI has demonstrated that these two divergent outcomes are strongly associated with differential parental CD4 IL-2 production e.g. B6 CD4 T cells are strong IL-2 producers and promote a donor cytotoxic T cell response whereas DBA CD4 T cell IL-2 production is profoundly impaired resulting in skewing towards T follicular helper cells, host B cell activation and autoantibody formation. The BXD Recombinant Inbred (BXDRI) lines are > 100 lines of backcrosses of the B6 and DBA parents that have been successfully used in gene mapping. In an earlier study, the PI and collaborators used a limited number of BXD strains and demonstrated the feasibility of using BXD splenocytes as donors into B6D2F1 mice to induce acute or chronic GVHD. Genetic analysis and mapping tools have advanced significantly since then and the number of BXD strains has nearly tripled. Using the PàF1 model, we propose to: Aim 1. Map the gene variants that predispose to lupus-like cGVHD phenotype. In collaboration with Dr. Robert Williams who has developed many of the new BXDRI lines we will test a larger number of BXD strains as donors into B6D2 mice and map the genes important in chronic GVHD lupus phenotype. Aim 2. Map the sequence variants involved in defective CD4 IL-2 production and determine their linkage to lupus-like cGVHD. In vitro IL-2 production by BXD CD4 T cells will be tested and the genes for the IL-2 defect mapped as well as the concordance between BXD strains that exhibit both defective CD4 IL-2 production in vitro and chronic cGVHD in vivo. These results will address the hypothesis that a primary asymptomatic defect in CD4 IL-2 production in humans could predispose to lupus. Successful mapping of the gene variants that modulate lupus-like GVHD will define new molecular mechanisms, complex networks of interactions among cells and tissues, and define homologous mechanisms with potential applicability to human lupus.