This application seeks support for elucidating the role of the SLAMF receptors in the pathogenesis of Systemic Lupus Erythematosus (SLE) with the ultimate goal to develop SLAMF-based therapeutic strategies that can be applied to SLE patients. Because of the outcomes of our studies with cells derived from SLE patients and our exciting findings with genetically altered mice, which develop lupus-related autoimmunity, we now have the systems in place to dissect how cell interaction mechanisms and signaling initiated by the SLAMF receptors contribute to the control of tolerance to autoantigens and to the pathogenesis of human SLE. These insights and tools are the basis for a Program Project application entitled: """"""""SLAM FAMILY RECEPTOR CONTROLLED PATHWAYS TO SLE"""""""" for three interlinked projects and two supporting Cores. Project #1 The SlamfS, Slamf5 and Slamf6 receptor-induced pathways to murine lupus. PL: Cox Terhorst, Beth Israel Deaconess Medical Center. Project #2 Functional analyses of human and mouse SLAMF4""""""""SLAMF2 receptor / ligand interactions in murine and human SLE. PL: Arlene Sharpe, Department of Microbiology and Immunobiology, Harvard Medical School. Project #3 Function of human SLAMF receptors in SLE immune cells. PL: George Tsokos, Beth Israel Deaconess Medical Center. Core A Genetic Mouse Core.PL: Ninghai Wang, Beth Israel Deaconess Medical. Center Core B Administrative Core.PL Cox Terhorst, Beth Israel Deaconess Medical Center.

Public Health Relevance

Results of these studies should lead to 1) better diagnostic tools to complement currently used indexes, 2) reliable and specific biomarkers to monitor and hopefully predict disease actlvitiy and 3) novel treatment protocols for SLE patients to replace or add to immunosuppressive drugs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Johnson, David R
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Beth Israel Deaconess Medical Center
United States
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Wang, Ninghai; Keszei, Marton; Halibozek, Peter et al. (2016) Slamf6 negatively regulates autoimmunity. Clin Immunol 173:19-26
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2016) Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A 113:9321-6
McArdel, Shannon L; Terhorst, Cox; Sharpe, Arlene H (2016) Roles of CD48 in regulating immunity and tolerance. Clin Immunol 164:10-20
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