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. (1)
8 different inbred strains of mice reflecting a diversity of MHC haplotypes were selected for immunization with a3(IV) NC1 domains. 12 wk later, SJL mice (H-2s) emerged as strong ne- phritic responders, with the highest urine protein, followed by the moderate responders, B6 (H-2b), BALB/c (H-2d), and DBA/2 (H-2d). A/J (H-2a), AKR (H-2k), and CBA (H-2k) were nonnephritic and had normal levels of urine protein. SJL mice with anti-GBM disease had full to partial crescents in 45% of their glomeruli, compared with none in the nonre- sponder mice, and 20–22% in B6 and DBA/2 mice. DBA/2 mice, unlike BALB/c, A/J, and (A/J x SJL) F1 mice, respond to immunization with a3(IV) NC1 domain, with disease limited to the kidneys. DBA/2 mouse lungs had no inflammation present and lacked anti–a3(IV) NC1 antibodies along the ABM.
All mice injected with a3(IV) NC1 domains developed high titers of circulating anti–a3(IV) NC1 antibodies regard- less of whether they developed cellular infiltrates and renal in- jury, suggesting that the intensity of the antibody response is not a selective determinant of susceptibility to disease. The circulating, kidney-, and lung-bound antibodies from SJL mice were quite specific for native bovine and recombinant human a3(IV) NC1 domain.
8 wk after immunization, A/J, A.TL, B10.A, and B10.BR mice did not have significant increases in urine protein or serum creatinine levels, compared with CFA-injected control mice. Histopathological evaluation of kidneys and lungs in these animals also revealed no tissue abnormalities. However, at the same time point, SJL, B6, B10, B10.S, B10.S(9R), and A.SW mice demonstrated an increase in urine protein. The presence or absence of glomerulonephritis among B10, B10.S, B10.S(9R), B10.BR, and B10.A recombinant mice indicates that glomerular inflammation is linked to a subregion of the MHC; differences among SJL, A.SW, and A/J mice were confirmatory.
Binding was observed to the dimers and mono- mers of type IV collagen NC1 hexamer. Some additional faint reactivity can be seen, with bands above the dimers, which could represent partially digested type IV collagen protomer. Lung tissue from DBA/2, A/J, and (A/J x SJL) F1 mice that did not bind anti–a3(IV) NC1 antibody in vivo contained comparable amounts of target antigen by Western blot as the ABM of SJL mice with lung hemorrhage.
All mice demonstrated significant levels of the IgG1/Th2-like isotype, whereas only SJL and A.SW nephritic mice showed significant titers for IgG2a/Th1-like isotype.
The BSA-fed or un-fed mice immunized with antigen revealed increases in urine protein and serum creatinine levels. Histological exam- ination of kidneys from these mice demonstrated crescentic glomerulonephritis with interstitial infiltrates. However, mice immunized with antigen after being prefed NC1 domains (both 700- and 65-ug doses) showed a substantial decrease in numbers of crescents, and complete amelioration of the interstitial disease.
Helper T cells coordinate the preference for emerging ef- fector cell or antibody repertoires probably as a net balance of Th1 and Th2 response, respectively. Production of IgG1 is part of an IL-4/Th2-like response in mice, and IgG2a is part of an IL-12/Th1-like response; these cytokines and antibody isotypes are not the only ones involved in this se- lection but they are reasonable markers of these dual path- ways. While this effect is not entirely binary, there are some peptides that favor strongly Th1 and Th2 responses, some of which are MHC-linked and based on strength of peptide/MHC interaction with TcR. SJL, A.SW, and B10.S mice have a strong cell-mediated effector response in addition to the production of antibody, whereas A/J mice demonstrate only an antibody response that by itself is insufficient to produce glomerulonephritis. when nephritogenic antibodies from SJL and A/J mice were passively transferred into (A/J x SJL) F1 recip- ients, there was no autoimmune glomerulonephritis. This criti- cal experiment suggests that anti-GBM antibodies, regardless of isotype, are not alone sufficient to produce nephritis. How- ever, in an allotype-compatible and disease-susceptible haplo- type, antibodies from nonsusceptible mice can be nephrito- genic. Such experiments, performed in (BALB/cx CA21) F1 recipients, clearly speak to the role of nonhumoral mecha- nisms in the expression of anti-GBM injury. These nonhumoral mechanisms may depend on T cell repertoires directed by MHC class II genes.