As the most common form of glomerulonephritis throughout the world, IgA nephropathy (IgAN) continues to be a major financial and social burden. We believe that the pathogenesis of IgAN is usually 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 a 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 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 C57B1/6) that differ in severity of virally-induced IgAN.
The Specific Aims of this proposal are to: 1) determine if the polarity of helper T cells towards type 2 (Th2) versus type 1 (Thi) is a critical determinant of the severity of IgAN; 2) offer direct assessment of the contribution of the B cell response to Th2 cytokines to the genesis of IgAN; 3) assess the role of non-lymphoid cells' response to T cell cytokines in the genesis of IgAN; 4) evaluate the applicability of our hypothesis to the immune response in humans. To achieve this last goal, we will reconstitute a functional human immune system in congenitally immunodeficient mice. In all experiments, we will compare the frequency and severity of IgAN provoked by immunization and challenge with virus among the various groups of mice, and correlate these parameters to the polarity of the antigen-specific T cell cytokine responses and IgA glycosylation. As our experiments unfold, we anticipate gaining insights not only to the pathogenesis of this currently incurable and poorly treated form of glomerulonephritis, but also to gain information about the factors that govern the character of immune responses to microbes and other antigens that gain access to mammals via mucosal routes.
