Systemic Lupus Erythematosus (SLE) is a heterogeneous disorder characterized by autoimmunity and the development of progressive immune complex renal disease. The pathogenesis of SLE is complex and multi- factorial;substantial clinical and experimental data supports roles for auto-antibodies, immune complexes, apoptosis, and effector T-cells in the development of SLE. Disturbances in the complement system are strongly associated with the development and progression of many forms of SLE particularily lupus nephrits. Complement activation results in the production of anaphylatoxins, C3a and C5a, which signal through ubiquitiously expressed G-protein coupled receptors (C3aR and C5aR). Signaling via the C3aR and C5aR have historically thought to function to active innate immune responses. The studies contained in this proposal are desinged to define and characterize the ability of C3aR and C5aR to alter adaptive immune responses in a biologically relevant complement depedent model of human disease, namely the MRL/lpr mouse model of lupus nephritis. Mice with targeted deletions of C3aR and C5aR as well as mice deficient in both the C3aR and the C5aR have been back-crossed 9 generations on to the MRL/lpr genetic background. Comparative studies of renal injury and immunologic responses including antigent presenting cell function, T-cell, and B-cell function will be performed. Additionally, experiments investigating renal parenchymal reponses in terms of cellualr proliferation, extra-cellular matrix production, and apoptosis will be performed. These studies are designed to advance our understanding of the mechanisms by which complement activation products modulate cellular immune responses and renal parenchymal responses in immune mediated renal injury.
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