End stage renal disease is a major health care problem in the U.S. Glomerulonephritis is the third leading cause of end stage renal disease. Most cases of glomerulonephritis are of autoimmune origin but the etiologic antigen is usually not known. In the autoimmune glomerulonephritis Goodpasture's disease, the etiologic antigen is known to be a chain of type IV collagen, a3(IV) NC1, found in the glomerular basement membrane of the kidney. Despite identification of this antigen, much remains unknown about initiation, disease progression, and control. We have developed a model, experimental autoimmune glomerulonephritis, which recapitulates Goodpasture's disease. We have identified the immunodominant T cell epitope on a3(IV) NC1 and showed that the antigen causes spreading to other epitopes on a3 and a4 (IV)NC1 but not to additional glomerular antigens, (intra- and intermolecular epitope spreading). We also present evidence that a feedback loop between the kidney and its draining lymph node may be involved in epitope spreading and generation of regulatory T cells which appear in the nephritic kidneys. Other models have shown that epitope spreading is associated with amplification of immune response and disease progression, and that interruption of epitope spreading can ameliorate disease expression. We hypothesize that epitope spreading occurs to a discrete number of identifiable epitopes, that recruitment of effector and regulatory T-cells in the closed-loop environment of the kidney and kidney draining lymph node with local antigen processing are mechanisms of disease induction and regulation, and that induction of an early regulatory T cell response may ameliorate the natural course of the disease. In the present proposal we will 1) identify T cell immunodominant and subdominant spread epitopes on a3(IV) and a3(IV)NC1 proteins, 2) study the mechanisms involved in epitope spreading, and 3) assess the effect of regulatory T cells on the initiation and progression of experimental autoimmune glomerulonephritis. We hypothesize that interruption of the local kidney lymph node feed back loop and amplification of regulatory T cell response will ameliorate the course and down-regulate disease expression. Since experimental autoimmune glomerulonephritis recapitulates Goodpasture's disease in man, the information should lead to a better understanding of the pathogenesis and possible intervention in human disease.
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