ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE

点击翻译按钮获取中文摘要

DESCRIPTION (Adapted from Investigator's Abstract): Anti-GBM disease in humans is associated with rapidly progressive glomerulonephritis, anti-a3(IV)NC1 collagen antibodies, and sometimes pulmonary hemorrhage. Anti-GBM disease with kidney and lung involvement is typically referred to as Goodpasture syndrome. Although the primary target for autoantibodies from patients with anti-GBM disease has been identified as the a3(IV)NC1 collagen, its role in the immunopathology of this disease has not been investigated. The long term objective of this proposal is to study the pathogenesis of anti-glomerular basement membrane (GBM) disease in mice immunized with a3 chain of type IV collagen. Initially, as part of specific aim 1, the investigators will continue the characterization of murine anti-GBM disease. Their preliminary experiments show that immunization with a3(IV) collagen produces organ specific inflammatory renal disease mimicking human anti-GBM disease in Goodpasture syndrome in genetically susceptible inbred mice. While all inbred strains of mice immunized with the antigen produced IgG1/Th2-like anti-GBM antibodies that cross react with human Goodpasture autoantibodies, only a select few major histocompatibility complex haplotypes (MHC) developed inflammatory disease in organ tissues. Crescentic glomerulonephritis and lung hemorrhage were restricted to MHC haplotypes H-2 s,b, and d that express additional IL-2 and IgG2a/Th1-like responses which map to the Ab/Aa region of H-2s; immune response genes in HLA-DR/DQ correspond to this region in humans predisposed to Goodpasture syndrome. As the second part of this aim, antibodies and immune cells from mice with anti-GBM disease will be passively and adoptively transferred, respectively, into native recipients. The transfer of disease, will evaluate the contribution of various effector mechanisms. Knockout mice deficient in B cells, T cells and cytokines will also be used to further investigate the contributions of these immune cells and cytokines on disease expression. The molecular determinants of the B-lymphocyte response in mice with nephritis will be examined in specific aim 2. In the first part of the second specific aim we will make a3(IV)NC1 collagen-specific monoclonal antibodies from susceptible and non-susceptible mice. The monoclonal antibodies will be tested in passive transfer experiments for their capacity to induce anti-GBM disease. The disease-inducing and/or non-inducing monoclonals will be further studied to identify the antigen-binding epitopes using synthetic peptides derived from the murine a3(IV)NC1 collagen amino acid sequence. A select panel of monoclonals will be used as immunogens in rabbits and rats to in the hopes of identifying a cross-reactive idiotype. The mouse model described in this proposal closely resembles human anti-GBM disease and Goodpasture syndrome in is immunopathology and in the specificity of its polyclonal autoantibody repertoire. Successful completion of this project should provide new experimental information regarding the processes that govern the pathogenesis of human anti-GBM disease.