Susceptibility to anti-glomerular basement membrane disease and goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice

Raghuram Kalluri, Theodore M. Danoff, Hirokazu Okada, Eric G. Neilson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

Abstract

We developed a new mouse model of human anti-glomerular basement membrane (GBM) disease to better characterize the genetic determinants of cell-mediated injury. While all major histocompatibility complex (MHC) haplotypes (H.2(a, k, s, b, and d)) immunized with α3 NC1 domains of type IV collagen produce anti-α3(IV) NC1 antibodies that cross-react with human Goodpasture [anti-GBM/anti-α3(IV) NC1] autoantibodies, only a few strains developed nephritis and lung hemorrhage associated with Goodpasture syndrome. Crescentic glomerulonephritis and lung hemorrhage were MHC-restricted in haplotypes H-2(s, b, and d) (Aβ/Aα region in H-2(s)) and associated with the emergence of an IL-12/Th1-like T cell phenotype. Lymphocytes or anti- α3(IV) NC1 antibodies from nephritogenic strains transfer disease to syngeneic recipients. However, passive transfer of isogenic α3(IV) NC1 antibodies into -/- T cell receptor-deficient mice failed to produce nephritis. Finally, nephritis and its associated IL-12/Th1-like T cell response attenuate in disease-susceptible mice tolerized orally to α3(IV) collagen before immunization. Our findings suggest collectively, as a hypothesis, that anti-GBM antibodies in mice only facilitate disease in MHC haplotypes capable of generating nephritogenic lymphocytes with special T cell repertoires.

Original languageEnglish (US)
Pages (from-to)2263-2275
Number of pages13
JournalJournal of Clinical Investigation
Volume100
Issue number9
DOIs
StatePublished - Nov 1 1997

Keywords

  • Anti-basement membrane disease
  • Goodpasture syndrome
  • Major histocompatibility complex
  • Type IV collagen
  • α3(IV) NC1

ASJC Scopus subject areas

  • Medicine(all)

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