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.
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-2a, k, s, b, and d) immunized with alpha3 NC1 domains of type IV collagen produce anti-alpha3(IV) NC1 antibodies that cross-react with human Goodpasture [anti-GBM/anti-alpha3(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-2s, b, and d (A beta/A alpha region in H-2s) and associated with the emergence of an IL-12/Th1-like T cell phenotype. Lymphocytes or anti-alpha3(IV) NC1 antibodies from nephritogenic strains transfer disease to syngeneic recipients. However, passive transfer of isogenic alpha3(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 alpha3(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.
Kalluri
R
R
Penn Center for Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia 19104, USA.
Danoff
T M
TM
Okada
H
H
Neilson
E G
EG
D019264:Adoptive Transfer; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology; D003094:Collagen / Q000276:immunology*; D005802:Genes, MHC Class II; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007116:Immunization, Passive; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology*; D008168:Lung / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D018664:Interleukin-12; D015847:Interleukin-4; D003094:Collagen