Genetic Dissection of the defect in the SLAM-receptor.........

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

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