title: Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers.
abstract: Goodpasture disease is an autoimmune kidney disease mediated by autoantibodies against noncollagenous domain 1 (NC1) monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis (GN). We identified a novel type of human IgG4-restricted anti-GBM autoantibodies associated with mild nonprogressive GN, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti-GBM autoantibodies were investigated in mouse models recapitulating this phenotype. Wild-type and FcγRIIB(-/-) mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoantibodies specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause GN. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3(-/-) Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG Abs specific for α345NC1 hexamers, which were not subclass restricted. As heterologous Ag in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a, and IgG2b autoantibodies specific for α345NC1 hexamers and induced anti-GBM Ab GN. These findings indicate that tolerance toward autologous intact α345(IV) collagen is established in hosts expressing this Ag, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α345NC1 hexamers. This provides a mechanism eliciting autoantibodies specific for α345NC1 hexamers, which are restricted to noninflammatory IgG subclasses and are nonnephritogenic. In Alport syndrome, lack of tolerance toward α345(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including proinflammatory IgG subclasses that mediate posttransplant anti-GBM nephritis.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Florina
authors.initials: F
authors.lastname: Olaru
authors.forename: Xu-Ping
authors.initials: XP
authors.lastname: Wang
authors.forename: Wentian
authors.initials: W
authors.lastname: Luo
authors.forename: Linna
authors.initials: L
authors.lastname: Ge
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Sandra
authors.initials: S
authors.lastname: Kleinau
authors.forename: Xochiquetzal J
authors.initials: XJ
authors.lastname: Geiger
authors.forename: Andrew
authors.initials: A
authors.lastname: Wasiluk
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology*; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000276:immunology*; D024141:Collagen Type IV / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D059748:Proteolysis
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D007074:Immunoglobulin G; C057112:type IV collagen alpha3 chain