Kalluri R, Danoff T M, Okada H, Neilson E G
Penn Center for Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia 19104, USA.
J Clin Invest. 1997 Nov 1;100(9):2263-75. doi: 10.1172/JCI119764.
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.
我们开发了一种新的人类抗肾小球基底膜(GBM)疾病小鼠模型,以更好地描述细胞介导损伤的遗传决定因素。虽然用IV型胶原的α3 NC1结构域免疫所有主要组织相容性复合体(MHC)单倍型(H-2a、k、s、b和d)都会产生与人类Goodpasture [抗GBM/抗α3(IV) NC1]自身抗体发生交叉反应的抗α3(IV) NC1抗体,但只有少数品系会发生与Goodpasture综合征相关的肾炎和肺出血。新月形肾小球肾炎和肺出血在H-2s、b和d单倍型中受MHC限制(H-2s中的Aβ/Aα区域),并与IL-12/Th1样T细胞表型的出现有关。来自致肾炎品系的淋巴细胞或抗α3(IV) NC1抗体可将疾病转移给同基因受体。然而,将同基因α3(IV) NC1抗体被动转移到T细胞受体缺陷的小鼠中未能引发肾炎。最后,在免疫前经口服α3(IV)胶原耐受的疾病易感小鼠中,肾炎及其相关的IL-12/Th1样T细胞反应会减弱。我们的研究结果共同提出一个假设,即小鼠中的抗GBM抗体仅在能够产生具有特殊T细胞库的致肾炎淋巴细胞的MHC单倍型中促进疾病发生。