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 (GEM) 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 alpha 3 NC1 domains of type IV collagen produce anti-alpha 3(IV) NC1 antibodies that crossreact with human Goodpasture [anti-GBM/anti-alpha 3(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) (A beta/A alpha region in H-2(s)) and associated with the emergence of an IL-12/ Th1-like T cell phenotype. Lymphocytes or anti-alpha 3(IV) NC1 antibodies from nephritogenic strains transfer disease to syngeneic recipients. However, passive transfer of isogenic alpha 3(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 alpha 3(IV) collagen before immunization. Our findings suggest collectively, as a hypothesis, that anti-GEM antibodies in mice only facilitate disease in MHC haplotypes capable of generating nephritogenic lymphocytes with special T cell repertoires.