Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Abstract

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, ∼0.15% 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.

The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma

“…To date, studies reporting an active biological role of tumstatin have not used an inactive recombinant collagen fragment to illustrate the specificity of the response 9 19 24 . The specificity of the collagen IV NCI fragment has been shown using peptides and scrambled controls in in vivo models and support the hypothesis that tumstatin is the biologically active molecule 25 .…”

Advances of the experimental models of idiopathic membranous nephropathy (Review)

“…Zhang et al (56) used mice immunized with α3nc1 to develop clinical and histopathological features of iMn. The extent and quality of autoimmunity against α3nc1 and T-cell responses are critical to the severity of nephropathy (57). compared with other models, the prominent advantage is that regulation of gene expression is possible since mice are used.…”

Basement membranes and autoimmune diseases

“…Histopathologic examination of kidneys shows only rare crescents or inflammation, and rather reveals BM “spikes” using silver stain, with granular capillary loop IgG and complement C3 and C5–9 deposits detected by immunofluorescence, and thickened BM, subepithelial electron dense deposits, and foot process effacement by electron microscopy. Hopfer and colleagues report similar histopathology after two immunizations with either human or mouse recombinant Ag [73, 122]. The mechanism by which anti-α3NC1 induces MN lesions is not understood.…”

“…In murine EAG, GN is typically mild compared to aggressive GN seen in patients. Nonetheless, Th1 and Th17 cells accumulate in mouse kidneys with late necrotizing GN induced with human α3NC1 [73, 121], and TNFα-, IFNγ-, or IL17A-producing CD4+ T cells reactive with mouse α3NC1 can be isolated from spleens and kidneys of DBA/1 mice immunized with homologous Ag [122]. …”

“…Exogenous human Ag colocalizes with IgG in glomerular capillary walls, prompting speculation that anti-α3NC1 IgG bind heterologous α3NC1 planted in the capillary wall by binding either specific podocyte receptors [125, 126] or anionic sites in the glomerular filter, analogous to mechanisms underlying idiopathic MN in man and mouse [27]. With more aggressive immunization in DBA/1 mice (3 boosts), renal disease evolves to crescentic GN [122]. …”