Glomerulopathy induced by immunization with a peptide derived from the goodpasture antigen α3IV-NC1.

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 alpha 3-chain of type IV collagen (alpha 3IV-NC1). The aim of our study was to further characterize the T cell-mediated immune response. Repeated immunization with mouse alpha 3IV-NC1 caused fatal glomerulonephritis in DBA/1 mice. Although two immunizations were sufficient to generate high alpha 3IV-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, alpha 3IV-NC1-specific CD4(+) cells producing TNF-alpha, IFN-gamma, or IL-17A were detected in the spleen. With the emergence of necrotizing/crescentic glomerulonephritis, similar to 0.15% of renal CD4(+) cells were specific for alpha 3IV-NC1. Using peptides spanning the whole alpha 3IV-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 alpha 3IV-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 alpha 3IV-NC1-specific Ab and T cell responses are critical for the phenotype of the glomerulonephritis.