Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers

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

Research output: Contribution to journalArticle

19 Scopus citations

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-GBMautoantibodies 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.

Original languageEnglish (US)
Pages (from-to)1424-1432
Number of pages9
JournalJournal of Immunology
Volume190
Issue number4
DOIs
StatePublished - Feb 15 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Olaru, F., Wang, X. P., Luo, W., Ge, L., Miner, J. H., Kleinau, S., Geiger, X. J., Wasiluk, A., Heidet, L., Kitching, A. R., & Borza, D. B. (2013). Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers. Journal of Immunology, 190(4), 1424-1432. https://doi.org/10.4049/jimmunol.1202204