title: 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.
authors.affiliation: Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland; Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; helmut.hopfer@usb.ch h.mittruecker@uke.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hopfer
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; and.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hünemörder
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Treder
authors.affiliation: Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Turner
authors.affiliation: Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Paust
authors.affiliation: Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.affiliation: Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hopfer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Marlies
authors.initials: M
authors.lastname: Sachs
authors.affiliation: Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Biranda
authors.initials: B
authors.lastname: Bucher-Kocaoglu
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; and.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ahrens
authors.affiliation: Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; and helmut.hopfer@usb.ch h.mittruecker@uke.de.
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Mittrücker
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D024141:Collagen Type IV / Q000378:metabolism* / Q000633:toxicity; D016207:Cytokines / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000633:toxicity; D015433:Glomerulonephritis, Membranous / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007114:Immunization; D051379:Mice; D010455:Peptides / Q000276:immunology* / Q000633:toxicity; D011507:Proteinuria / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; C057112:type IV collagen alpha3 chain