Immune-mediated glomerular diseases result from adaptive responses against glomerular structures or responses against circulating soluble or cellular antigens which manifest in the glomeruli. Anti-glomerular basement membrane (GBM) glomerulonephritis (GN) is caused by immunity against the Goodpasture antigen α3IV-NC1. Formation and renal deposition of anti-α3IV-NC1 IgG are central events leading to manifestation of anti-GBM GN. However, clinical and experimental evidence also suggest a fundamental role for T cells in disease pathogenesis.
Immunization of DBA/1 mice with α3IV-NC1 causes crescentic GN with features similar to anti-GBM disease. In this experimental autoimmune glomerulonephritis (EAG), we can identify α3IV-NC1-specific CD4+ TH1 and TH17 cells in inflamed kidneys. Our results further indicate that both TH1 and TH17 cells participate in the formation of necrotizing/crescentic GN. The current project therefore has two main focuses. The first aim is to characterize mechanisms that control autoreactive T cells and progression of renal disease to crescentic GN in EAG. We will determine the impact of regulatory T cells as well as of IL-6, a central regulator of inflammation, in this process. The second aim is to characterize autoreactive CD4+ T cells in human glomerular diseases. In cooperation with the Hamburg GN Registry, we will apply our sensitive assays developed for detection of α3IV-NC1-specific CD4+ T cells in EAG for the identification and characterization of PLA2R1- and THSD7A-specific CD4+ T cells in autoantibody-positive individuals with membranous nephropathy and of proteinase 3 and myeloperoxidase-specific CD4+ T cells in individuals with ANCA-associated GN. In summary, the results of our work will lead to a better understanding of autoreactive T cell mediated processes in renal damage and might identify potential targets for novel antigen-based treatment strategies for autoimmune kidney diseases.
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