Considerable clinical evidence supports the participation of IgA immune complexes in mediating renal injury in patients with p rimary IgA nephropathy, Schonlein-Henoch purpura, and alcoholic liver cirrhosis-associated IgA nephritis. The immunopathologic events that occur subsequent to glomerular deposition of IgA immune complexes remain unknown. Our objective is to investigate the pathogenetic mechanisms through which IgA immune complexes, prepared with IgA from specific antigen-binding-myelomas, induce renal injury in experimental animals. The spectrum of renal histopathologic changes in patients of IgA-associated nephritis suggest the antigen plays an important role. The influence of the antigen on deposition, site of localization, and persistence of IgA immune complexes in the glomerulus will be examined. A chronic model of IgA nephropathy will be established to determine the role of antigen in glomerular injury and renal dysfunction. PResence of C3 along with IgA in renal deposits implicates complement as an inflammatory mediator in these disorders. The mechanism of complement activation and binding by IgA immune complexes will be determined. The relationship between complement activation and IgA immune complexes persistence, solubilization, or induction of histopathological changes in the glomerulus will be examined. Co-deposition of other immunoglobulin classes with IgA in renal biopsies of patients with IgA-associated nephritis poses the possibility of idiotypic-antiidiotypic interactions. The nephritogenic potential of IgA idiotype-antiidiotype complexes will be assessed. Specific receptors for IgA immune complexes on hepatic mononuclear phagocytes mediate their clearance from circulation. These receptors will be characterized and their distribution on other mononuclear cells will be identified. Tubulo-interstitial lesions in IgA nephropathy are considered poor prognostic marker. The ability of IgA complexes to activate inflammatory cells stimulation of oxidative burst reactions and induction of the leukocyte coagulant system will be examined. Analysis of the different factors involfed in initiating and mediating renal injury in a laboratory model of igA nephropathy combined with data from leukocytes effector responses to IgA immune complexes will provide an understanding of the pathogenetic processes involved in IgA-associated nephritides.
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