RESUMO
Autoimmunity against the Goodpasture antigen α3IV-NC1 results in crescentic glomerulonephritis (GN). Both antibodies and T cells directed against α3IV-NC1 have been implicated in disease development and progression. Using the model of experimental autoimmune glomerulonephritis (EAG) in DBA/1 mice, we aimed to characterize the frequency and function of α3IV-NC1-specific CD4(+) T cells in the kidneys. DBA/1 mice repeatedly immunized with human α3IV-NC1 developed necrotizing/crescentic GN. Kidneys with crescentic GN contained CD4(+) cells responding to α3IV-NC1 with the production of IFN-γ or IL-17A, demonstrating the accumulation of both α3IV-NC1-specific TH1 and TH17 cells. To test the functional relevance of TH1 and TH17 cells, EAG was induced in DBA/1 mice deficient in IFN-γR, IL-17A or IL-23p19. Mice of all knockout groups mounted α3IV-NC1 IgG, developed nephrotic range proteinuria, and IgG deposition to the glomerular basement membranes at levels similar to immunized wild-type mice. However, all knockout groups showed significantly fewer glomerular crescents and attenuated tubulointerstitial damage. Our results suggest that both α3IV-NC1-specific TH1 and TH17 cells accumulate in the kidneys and are crucial for the development of necrotizing/crescentic GN.
Assuntos
Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade , Colágeno Tipo IV/imunologia , Glomerulonefrite/imunologia , Rim/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Autoantígenos/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/prevenção & controle , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-17/imunologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos DBA , Camundongos Knockout , Proteinúria/imunologia , Proteinúria/metabolismo , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Células Th1/metabolismo , Células Th17/metabolismo , Receptor de Interferon gamaRESUMO
Mouse experimental autoimmune glomerulonephritis, a model of human antiglomerular basement membrane disease, depends on both Ab and T cell responses to the Goodpasture Ag noncollagenous domain 1 of the α3-chain of type IV collagen (α3IV-NC1). The aim of our study was to further characterize the T cell-mediated immune response. Repeated immunization with mouse α3IV-NC1 caused fatal glomerulonephritis in DBA/1 mice. Although two immunizations were sufficient to generate high α3IV-NC1-specific IgG titers, Ab and complement deposition along the glomerular basement membranes, and a nephrotic syndrome, two additional immunizations were needed to induce a necrotizing/crescentic glomerulonephritis. Ten days after the first immunization, α3IV-NC1-specific CD4(+) cells producing TNF-α, IFN-γ, or IL-17A were detected in the spleen. With the emergence of necrotizing/crescentic glomerulonephritis, â¼0.15% of renal CD4(+) cells were specific for α3IV-NC1. Using peptides spanning the whole α3IV-NC1 domain, three immunodominant T cell epitopes were identified. Immunization with these peptides did not lead to clinical signs of experimental autoimmune glomerulonephritis or necrotizing/crescentic glomerulonephritis. However, mice immunized with one of the peptides (STVKAGDLEKIISRC) developed circulating Abs against mouse α3IV-NC1 first detected at 8 wk, and 50% of the mice showed mild proteinuria at 18-24 wk due to membranous glomerulopathy. Taken together, our results suggest that autoreactive T cells are able to induce the formation of pathologic autoantibodies. The quality and quantity of α3IV-NC1-specific Ab and T cell responses are critical for the phenotype of the glomerulonephritis.