Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production ofautoantibodies against a wide spectrum of self-antigens, especially from the cell nucleus. Geneticpredisposition is an important contributor to susceptibility to SLE in both humans and animals. Genes inmultiple pathways participate in mediating disease pathogenesis, and epistatic interactions amongst thesegenes influence the severity of disease. One group includes genes whose products are active inphysiologic pathways of waste disposal mechanisms in the body, and includes genes involved in removalof circulating immune complexes and apoptotic cells by the mononuclear phagocyte system. The secondgroup encodes genes that regulate thresholds for tolerance and activation of T and B lymphocytes.This project is part of an interactive PPG, which seeks to address the overall hypothesis that mutationsin one or more of the seven SLAM-family genes affect pathways that contribute to tolerance to selfantigensin humans and mice. Collectively, our observations made in humans and mice strongly supportthisSpecifically we will:
Aim 1. test the hypothesis that the SLAM-Family-locus {CD244<->Ly108} governs CD4 T cell and antigenpresenting cell functions in the C57BL/6 mouse.
Aim 2. test the hypothesis that deletion of the {CD244<->Ly108} genomic interval causes loss of tolerancetoward chromatin in C57BL/6 mice.
Aim 3. test the hypothesis that SLAM-family genes derived from 129Sv mice contribute to the developmentof lupus upon introduction into the {CD244<->Ly108}-/- C57BL/6 mouse.Together these experiments should clarify the interplay between APC, T and B cells governed by theSLAM-Family genes and their control of susceptibility to murine lupus. The results of these studies shouldsuggest therapeutic strategies that can be applied to SLE patients.
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