Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
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DOI：
10.1056/nejmoa0910500
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发表时间：
2010-07-22
期刊：
影响因子：
--
通讯作者：
Hudson BG
中科院分区：
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作者：
Pedchenko V;Bondar O;Fogo AB;Vanacore R;Voziyan P;Kitching AR;Wieslander J;Kashtan C;Borza DB;Neilson EG;Wilson CB;Hudson BG
在古德帕斯病中，循环自身抗体与肾小球基底膜(GBM)中IV型胶原的非胶原性-1(NC1)结构域结合。组织结合自身抗体表位的特异性和分子结构尚不清楚。一些Alport综合征患者在肾移植后发生Alport‘s肾炎，这种肾炎是由抗GBM同种异体抗体介导的。我们比较了古德帕斯病和Alport‘s肾移植后肾炎抗体表位的构象，以期找到抗GBM肾炎发病机制的线索。我们使用了一种酶联免疫吸附试验来确定循环自身抗体和肾脏结合抗体对NC1域的特异性。对57例古巴斯病患者进行了循环抗体检测，并对14例古巴斯病患者和2例Alport‘s肾移植后肾炎患者进行了肾结合抗体检测。利用嵌合分子和α345NC1六聚体的三维模型推导出关键表位区域的分子结构。在古德帕斯病患者中，抗α3NC1单体的自身抗体和抗α5NC1单体的抗体(较少结合α4NC1单体的抗体)都结合在肾脏和肺中，这表明α3NC1和α5NC1单体作为自身抗原发挥了作用。抗肾小球基底膜病确诊时高抗体滴度与最终肾功能丧失有关。结合不同表位的抗体包括α5NC1单体中的EA区和α3NC1单体中的EA和EB区，但它们不与天然的交联型α345NC1六聚体结合。相反，在Alport‘s移植后肾炎患者中，同种异体抗体与完整六聚体中α5NC1亚单位的EA区结合，解离后结合减少。古德帕斯普病的发展可以被认为是一种自身免疫性“构象病”，涉及α345NC1六聚体的四级结构的扰动，导致α3NC1亚单位和α5NC1亚单位的致病性构象变化，进而引发自身免疫反应。(由国家糖尿病、消化和肾脏疾病研究所资助。)
In Goodpasture’s disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport’s post-transplantation nephritis, which is mediated by alloantibodies against the GBM, occurs after kidney transplantation in some patients with Alport’s syndrome. We compared the conformations of the antibody epitopes in Goodpasture’s disease and Alport’s post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis. We used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture’s disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture’s disease and 2 patients with Alport’s post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the α345NC1 hexamer. In patients with Goodpasture’s disease, both autoantibodies to the α3NC1 monomer and antibodies to the α5NC1 monomer (and fewer to the α4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the α3NC1 and α5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region EA in the α5NC1 monomer and regions EA and EB in the α3NC1 monomer, but they did not bind to the native cross-linked α345NC1 hexamer. In contrast, in patients with Alport’s post-transplantation nephritis, alloantibodies bound to the EA region of the α5NC1 subunit in the intact hexamer, and binding decreased on dissociation. The development of Goodpasture’s disease may be considered an autoimmune “conformeropathy” that involves perturbation of the quaternary structure of the α345NC1 hexamer, inducing a pathogenic conformational change in the α3NC1 and α5NC1 subunits, which in turn elicits an autoimmune response. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)