As the most common form of glomerulonephritis throughout the world, IgA nephropathy (IgAN) continues to be a major financial and social burden. We believe the pathogenesis of IgAN is related to dysregulation of the mucosal immune response, particularly to viral pathogens. We have therefore established an experimental model of IgAN in mice by immunization and challenge with common rodent respiratory pathogen (Sendai virus), for which the immune response is genetically restricted. Based upon prior clinical and experimental observations and our new data, we hypothesize. Based upon prior clinical and experimental observations and our new data, we hypothesize that the genetically determined T cell repertoire of a host determines susceptibility to IgAN, in association with other factors. We will emphasize complementary studies in two strains of mice (BALB/c and C57BL/6) that differ in severity of virally-induced IgAN.
The Specific Aims of this proposal are to:1) demonstrate that differences in IgA glycosylation are critical determinants of nephritis, and assess a possible contribution of non-Ig humoral factors; 2) investigate viral replication in and antigen presentation to virus-specific T cells by mesangial cells in culture; 3) determine the influence of the interaction of mesangial cells with monocytes/macrophages on selected functions of each cell lineage, measure modulation of such effects by immune complexes, and quantify any differences in such altered cell functions between the strains; and 4) define the elements of the immune response that lead to severe versus load nephritis, by reconstitution of immuno-deficient mice with genetically engineered lymphocytes, and repolarization of cytokine responses. These studies offer the potential for significant insights into the pathogenesis of IgAN and new therapeutic approaches. These studies also will aid understanding of regulation of the mucosal immune response, which is pertinent to mucosal vaccine development. The influence of the cytokine response to infectious mucosal pathogens is a major theme shared by the other Projects; we will also utilize the resources of Hybridoma Core B.
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