Complement (C) plays an important role in host defense;however, activated C is a double-edged sword that has the potential to cause significant damage to host tissues. To prevent C-mediated autologous injury, host cells express a number of C regulatory proteins on their surface. Among such molecules are two GPI anchored proteins: DAF and CD59, which inhibit C activation at the C3 cleavage and membrane attack complex (MAC) assembly step, respectively. DAP and CD59 may also regulate adaptive immunity through C-independent mechanisms. For example, GPI-anchored molecules like DAP and CD59 may participate in lymphocyte signaling as lipid rafts components and DAF has been identified as a ligand for an activation associated lymphocyte receptor CD97. In our preliminary studies using MRL/lpr mice, a murine model of systemic lupus erythematosus (SLE), we have found that DAP-/- and CD59-/- MRL/Ipr mice developed exacerbated skin disease and increased lymphoproliferation and autoantibody production. The overall objective of this proposal is to elucidate the protective mechanisms of DAF and CD59 in MRL/Ipr mice. Our hypothesis is that DAF and CD59 regulate SLE both at the inductive and effector phases of the disease. We further postulate that the role of DAF and CD59 in the effector phase of SLE is C-dependent, whereas their role in the inductive phase of the disease is C-independent. Our aims are: 1). To dissect the C-dependent and independent functions of DAE and CD59 in MRL/lpr mice. 2). To dissect the local versus the systemic effect of DAF and CD59 in MRL/lpr mice. 3).To uncover the specific C mediators (C3a, C5a or MAC) responsible for end organ injury in MRL/lpr-DAF-/- and MRL/lpr-CD59-/- mice. 4). To determine if the protective effect of DAE and CD59 is specific to the MRL/lpr mouse strain. Results of this proposal will shed new light on the pathogenesis of SLE and may reveal novel regulatory functions of DAF and CD59 in adaptive immunity. Such results should facilitate the development of innovative therapeutic strategies for human SLE.