Proteolysis breaks tolerance toward intact alpha345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for alpha345NC1 hexamers

Florina Olaru, Xu-Ping Wang, Wentian Luo, Linna Ge, Jeffrey H Miner, Sandra Kleinau, Xochiquetzal Geiger, Andrew Wasiluk, Laurence Heidet, Arthur Richard Kitching, Dorin-Bogdan Borza

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Goodpasture disease is an autoimmune kidney disease mediated by autoantibodies against noncollagenous domain 1 (NC1) monomers of alpha3(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 alpha345NC1 hexamers but not alpha3NC1 monomers. The mechanisms eliciting these anti-GBM autoantibodies were investigated in mouse models recapitulating this phenotype. Wild-type and FcgammaRIIB(-/-) mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoantibodies specific for alpha345NC1 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 alpha345NC1 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 alpha345NC1 hexamers and induced anti-GBM Ab GN. These findings indicate that tolerance toward autologous intact alpha345(IV) collagen is established in hosts expressing this Ag, even though autoreactive B cells specific for alpha345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic alpha345NC1 hexamers. This provides a mechanism eliciting autoantibodies specific for alpha345NC1 hexamers, which are restricted to noninflammatory IgG subclasses and are nonnephritogenic. In Alport syndrome, lack of tolerance toward alpha345(IV) collagen promotes production of alloantibodies to alpha345NC1 hexamers, including proinflammatory IgG subclasses that mediate posttransplant anti-GBM nephritis.
Original languageEnglish
Pages (from-to)1424 - 1432
Number of pages9
JournalJournal of Immunology
Volume190
Issue number4
DOIs
Publication statusPublished - 2013

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