This proposal is part of a systematic effort to functionally dissect the complex genetic leading to systemic lupus erythematosis (SLE or lupus). Essentially, our approach has been to use genome wide scanning to identity susceptibility loci contributing to the development of SLE, to transfer these loci onto the non-autoimmune C57BL/6 (B6) background, to determine a reproducible phenotype conferred by the interval, and to determine the lineage(s) in which the susceptibility locus is expressed. We identified 3 genomic intervals from NZM2410 that contributed to the development of glomerulonephritis. One of these, B6.NZMc7 [containing Sle3/5 on chromosome 7] develop low titers of IgG anti-nuclear antibodies, elevated CD4:CD8 ratios and mild-to-moderate immune complex glomerulonephritis (GN). We have recently completed a set of bone marrow adoptive transfer studies with B6.NZMc7 congenic mice. The NZMc7 locus was functionally expressed on bone-marrow-derived cells but not on radioresistant host cells. Moreover,, the elevated CD4:CD8 phenotype could be reconstituted in radiation chimeras. Using Ly5-marked congenic strains and B6 host mice, additional experiments surprisingly demonstrated that the elevated DD4:CD8 ratio was not an intrinsic property of the T cells, and that a trend toward an elevated ratio could also been seen within the single-positive thymocytes. Preliminary data also indicated that the low-penetrant autoantibodies were not due to expression of the NZMc7 locus in B cells. Taken together, these data suggests that the effect is mediated by a bone-marrow-derived, non-B-cell antigen presenting cell (APC) present both in the thymus and secondary lymphoid organs. We propose that these APCs are dendritic cells, and may be the recently described lymphoid organs. We propose that these APCs are dendritic cells, and may be the recently described lymphoid subset, which are thought to be regulatory in nature. To test these hypotheses, we propose three Specific Aims: 1) to test the prediction that B6.NMc7 non-B-cell APCs are responsible for the elevated CD4:CD8 ratio; 2) to test the prediction that B6:NZMc7 dendritic cells have an altered threshold for inducing negative selection; and 3) to test the prediction that there is a difference in the kinetics of proliferation and apoptosis induced by BB6.NZMc7 APCs.
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