Renal involvement in systemic lupus erythematosus (SLE), termed lupus nephritis (LN), occurs in about 60% of patients and is a leading cause of morbidity and mortality. Membranous lupus nephritis (MLN) (class V) is described in 15% to 40% of renal biopsies in these patients. The proposed pathogenesis of all classes LN is the glomerular deposition of immune complexes containing auto-antibodies. Three hypotheses describing how immune complexes containing nephritigenic antibodies are deposited in glomeruli have been proposed, deposition of circulating immune complexes, binding of anti-nuclear antibodies to antigens """"""""planted"""""""" in the glomerulus, and cross reactivity of anti-nuclear antibodies with glomerular constituents. A proteomic approach, similar to that proposed in this application, was used to determine that an auto-antibody to the M-type phospholipase A2 receptor (PLA2R) is responsible for immune complex deposition in idiopathic membranous nephropathy. This antibody is present in 70% to 80% of patients with idiopathic membranous nephropathy, but it is not present in patients with MLN. This suggests a new hypothesis that patients with MLN develop unique auto-antibodies against an endogenous component of the glomerular capillary. The current proposal will use proteomic approaches that were successfully employed by our group in idiopathic membranous nephropathy to identify and verify specific glomerular proteins to which autoantibodies that cause MLN are directed.
The expected outcomes of the proposed studies will be the identification of specific target proteins for nephritigenic autoantibodies that induce membranous lupus nephritis (MLN). The impact of the proposed studies will be confirmation of a common pathophysiology for idiopathic and lupus membranous nephropathy, identification of a biomarker for Class V MLN that allows early diagnosis, definition of a biomarker for MLN that can be used to follow efficacy of treatment, and development of new therapeutic strategies based on identification of the epitope to which nephritigenic autoantibodies are directed. Additionally, definition of the target for nephritigenic autoantibodies and comparison with autoantibodies found in murine models of LN will allow development of a mouse model of MLN.
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