The Impact of Fc gamma Receptor Signaling on Lupus-Induced Atherosclerosis



 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of autoantibodies recognizing self-antigens. Clinical manifestation of lupus includes nephritis, pericarditis. Recent studies have implicated that lupus accelerates atherosclerosis, and accounts for premature mortality. Autoantibodies contribute to the pathology of lupus by recruiting and activating innate-immune effector cells. Interaction between Fcγ receptors (FcγR) expressed on inflammatory cells and B-lymphocytes to autoantibody-autoantigen immune complexes (IC) promote inflammatory responses associated with lupus and atherosclerosis. FcγRs are classified into activating and inhibitory receptors. Activating FcγRs are involved in innate immune cellular functions and inflammatory responses. The inhibitory FcγRIIb regulates the inflammatory response initiated by the activating FcγRs and control antibody production by regulating B lymphocyte activation. Autoantibodies in lupus and oxidized low-density lipoprotein immune complexes (oxLDL-IC) generated during hyperlipidemia could bind to the activating and/or inhibitory FcγRs and contribute to the inflammatory processes. Interestingly, FcγRIIb polymorphisms have been implicated as a risk factor for lupus and coronary artery disease. Furthermore, FcγRIIb deficiency has been shown to regulate type I interferon response, implicated in the pathogenesis of lupus and atherosclerosis. These studies suggest that crosstalk between inhibitory FcγRIIb and type I interferon response could contribute to the pathogenesis of lupus-induced atherosclerosis. Although the presence of autoantibodies has been reported in lupus patients and animal models, the contribution of FcγRs to the initiation and/or progression of lupus-induced atherosclerosis has not been studied. The central hypothesis of this proposal is that FcγRs play an important role in the progression of lupus-induced premature atherosclerosis. To test this hypothesis, we will complete the following aims: Aim 1. To determine molecular mechanism(s) by which FcγRIIb signaling modulate lupus-induced atherosclerosis, Aim 2. To determine crosstalk between inhibitory FcγRIIb and type I IFN signaling contributing to lupus-induced atherosclerosis, and Aim 3. Investigate the role of human FcγR in promoting inflammatory responses associated with lupus-induced atherosclerosis. The proposed studies will be significant because they will provide novel information supporting the contention that FcγR signaling pathways may represent a novel therapeutic target for interventions aimed at ameliorating the vascular complications of autoimmune diseases, an area that is in dire need for development.