NEPHRITOGENIC EPITOPES IN GOODPASTURES SYNDROME

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Description (Adapted from Investigator's Abstract): Glomerulonephritis in man is a major cause of morbidity, mortality and end stage renal disease (ESRD) leading to dialysis or transplantation. Autoimmune disease causes most forms of glomerulonephritis. Multiple pathogenic factors are involved in the final expression of glomerulonephritis including the deposition of antibodies and cell mediated immunity. Numerous models have been extensively studied to clarify pathogenic mechanisms, but most likely are induced by methods not directly relevant to man. This investigator has developed a model to examine the pathogenesis of Goodpasture's syndrome, a disease associated with antibody to the glomerular basement membrane, progressive crescentic glomerulonephritis and pulmonary hemorrhage. His studies suggest that a variety of antibodies develop after immunization with the responsible antigen, and that only a subset of these antibodies actually cause disease. Post-translational modification may be critical for expression of the pathogenic antigen. The PI hypothesizes that post-transcriptional modification of the amino acids constituting the immunizing antigen influences its ability to cause nephritis. The specific aims are to utilize biochemical and molecular methods to 1) identify the antigens which induce the glomerulonephritis, 2) determine if post-translational modification of the amino acids are present and what these modifications might be, and 3) examine the effect of alternation of these modifications on disease induction and course. Strong evidence indicates that the antigen which causes glomerulonephritis in this model is the same antigen or is located on the same protein that causes Goodpasture's syndrome in man. This model provides an opportunity for further study of pathogenic events in autoimmune glomerulonephritis and permits investigations of pathogenesis that cannot be accomplished in vitro. Information derived from this model will provide a better understanding of Goodpasture's syndrome and other types of autoimmune glomerulonephritis. Further, the knowledge resultant from these investigations may provide a basis for the eventual development of specific therapeutic interventions for Goodpasture's syndrome.