The proposed studies are directed at clarifying the pathogenic mechanisms of the renal disease of systemic lupus erythematosus (SLE). Previous studies identified in patients with proliferative lupus glomerulonephritis a new set of autoantibodies, directed to the collagen- like region (CLR) of C1q molecules, a component of the complement system. These antibodies may prolong the persistence of immune deposits in glomeruli and alter their location. An experimental model in mice will be employed to determine if the antibodies to CLR will alter the fate of immune complexes in glomeruli. In patients with SLE a large number of autoantibodies exist in circulation. It is not known which of these antibodies, in addition to antibodies to DNA, contribute to the renal disease. Improved methods for recovery of antibodies from renal glomeruli will be evaluated using experimental models. With these methods antibodies will be recovered from glomeruli of patients who have died with SLE and the recovered antibodies will be characterized. Some evidence exists for the formation of covalent bonds between immune deposits and structural molecules of the glomerular basement membrane. The presence of covalent bonds will be established and the basement membrane molecules bound to immune reactants will be identified. Covalent binding of immune deposits to glomerular structures may be an important mechanism for prolonging their presence in kidneys. Studies will be conducted on the role of mononucleosomes in the formation of glomerular immune deposits. Nucleosomes will be prepared, radiolabeled, injected into mice and localization in glomeruli will be assessed. Once mononucleosomes deposit in glomeruli, antibodies to histones and antibodies to DNA will be injected to determine the extent and location of immune complex formation. The completion of these investigations should substantially enhance our knowledge of the pathogenic mechanisms in renal disease of patients with SLE.
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