Alport alloantibodies but not Goodpasture autoantibodies induce murine glomerulonephritis: protection by quinary crosslinks locking cryptic α3(IV) collagen autoepitopes in vivo.
The noncollagenous (NC1) domains of alpha3alpha4alpha5(IV) collagen in the glomerular basement membrane (GBM) are targets of Goodpasture autoantibodies or Alport posttransplant nephritis alloantibodies mediating rapidly progressive glomerulonephritis. Because the autoepitopes but not the alloepitopes become cryptic upon assembly of alpha3alpha4alpha5NC1 hexamers, we investigated how the accessibility of B cell epitopes in vivo influences the development of glomerulonephritis in mice passively immunized with human anti-GBM Abs. Alport alloantibodies, which bound to native murine alpha3alpha4alpha5NC1 hexamers in vitro, deposited linearly along the mouse GBM in vivo, eliciting crescentic glomerulonephritis in Fcgr2b(-/-) mice susceptible to Ab-mediated inflammation. Goodpasture autoantibodies, which bound to murine alpha3NC1 monomer and dimer subunits but not to native alpha3alpha4alpha5NC1 hexamers in vitro, neither bound to the mouse GBM in vivo nor induced experimental glomerulonephritis. This was due to quinary NC1 crosslinks, recently identified as sulfilimine bonds, which comprehensively locked the cryptic Goodpasture autoepitopes in the mouse GBM. In contrast, non-crosslinked alpha3NC1 subunits were identified as a native target of Goodpasture autoantibodies in the GBM of squirrel monkeys, a species susceptible to Goodpasture autoantibody-mediated nephritis. Thus, crypticity of B cell autoepitopes in tissues uncouples potentially pathogenic autoantibodies from autoimmune disease. Crosslinking of alpha3alpha4alpha5NC1 hexamers represents a novel mechanism averting autoantibody binding and subsequent tissue injury by posttranslational modifications of an autoantigen.
Luo
Wentian
W
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Wang
Xu-Ping
XP
Kashtan
Clifford E
CE
Borza
Dorin-Bogdan
DB
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody; D024141:Collagen Type IV / Q000276:immunology* / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007518:Isoantibodies / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000276:immunology*; D017434:Protein Structure, Tertiary
D001323:Autoantibodies; D001324:Autoantigens; C466620:COL4A4 protein, human; C549554:Col4a5 protein, mouse; D024141:Collagen Type IV; D000939:Epitopes; D007518:Isoantibodies; C057112:type IV collagen alpha3 chain