Systemic Lupus Erythematosus (SLE) nephritis is considered to be the prototype of human disease mediated by pathogenic immune complexes. However, neither the participating immune reactants nor the mechanisms of glomerular immune deposit formation (GIDF) in this disorder are completely understood. The reasons why certain individuals get severe nephritis and others with elevated circulating autoantibody and immune complex levels do not is enigmatic. Furthermore, the long-term effect of various treatment regiment in such patients is of debatable benefit. The overall objective of the proposed research is to develop an understanding of the events leading to GIDF and subsequent injury in SLE. Ultimately through this understanding, a rational approach to alter these events can be planned.
The specific aims of this proposal are to identify and characterize the immune reactants involved in SLE nephritis and determine the mechanism(s) of GIDF in SLE. These studies will utilize MRL-lpr/lpr mice, an autoimmune strain that develops an accelerated form of SLE associated with severe glomerulonephritis and the production of anti-DNA antibodies, and an existing library of immune reagents derived from these animals, including monoclonal anti-DNA antibodies, anti-immunoglobulins and anti-idiotypic antibodies. The characterization of nephritogenic antibodies in murine SLE will involve a detailed analysis of the immunoglobulins eluted from MRL-lpr/lpr kidneys including definition of their ligand binding properties, charge, subclass, idiotypic repertoire, as well as anti-idiotypic and anti-immunoglobulin activity. The mechanism(s) of GIDF will be analyzed using nucleic acid antigens and autoantibodies, including immunoglobulins eluted from nephritic kidneys and monoclonal antibodies that share idiotypes with these eluted immunoglobulins. The capacity of each of these immune reagents to localize within the glomerulus and then initiate IDF will be studied in vitro by direct binding studies of radiolabeled reagent to isolated normal glomeruli, and in vivo by measurement of glomerular binding after passive administration of radiolabeled immune reactants to normal mice. The precise localization of these reagents will be further detailed by autoradiography, immunofluorescence and electron microscopy.
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