The overall goal of this PPG is to understand how SLAM family (Slamf) members control pathways that regulate the development of systemic lupus erythematosus (SLE). Project 2 will investigate the role of SLAMF2 (CD48) interactions with its binding partner SLAMF4 (CD244,2B4) in controlling immune cell function, establishment and maintenance of tolerance and development of SLE immune cell abnormalities. Based on our published and preliminary data we hypothesize that SLAMF2 and SLAMF4 regulate T cell and APC function, control immune tolerance, and contribute to autoimmunity-related pathology in mice and patients with SLE. Studies in mice and patients with SLE will test this hypothesis by performing complementary and closely interactive experiments.
o Specific Aim #1 : To test the hypothesis that Slamf4 on the surface of mouse APC regulates the balance between T cell activation and tolerance in the pathogenesis of SLE.
o Specific Aim #2 : To test the hypothesis that Slamf2 regulates the balance between T cell activation and tolerance in the pathogenesis of SLE.
o Specific Aim #3 : To test the hypothesis that the SLAMF2 and SLAMF4 receptors function aberrantly in peripheral blood immunocytes isolated from SLE patients.
Our mechanistic studies (genetic manipulation of S1-AI /IF2 and 4 in mice and silencing in human immunocytes), coupled with in vivo and in vitro use of stimulatory and inhibitory Abs, will generate proposals for therapeutic interventions in human SLE and therefore underscore the significance of the proposed studies.
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