Wu Jean, Arends Jon, Borillo Jason, Zhou Cindy, Merszei Justin, McMahon John, Lou Ya-Huan
Department of Diagnostic Sciences, Dental Branch, Medical School, University of Texas Health Science Center at Houston, Baylor College of Medicine, Houston, TX 77030, USA.
J Immunol. 2004 Apr 1;172(7):4567-74. doi: 10.4049/jimmunol.172.7.4567.
The anti-glomerular basement membrane (GBM) Ab has been regarded as a prototypical example of pathogenic autoantibodies. However, the mechanism for elicitation of this Ab remains unknown. In the present paper, we report that the Ab to diverse GBM Ags was induced by a single nephritogenic T cell epitope in a rat model. The T cell epitope pCol(28-40) of noncollagen domain 1 of collagen type IV alpha3 chain not only uniformly induced severe glomerulonephritis but also elicited anti-GBM Ab in 76% of the immunized rats after prominent glomerular injury. Furthermore, we demonstrated that the anti-GBM Ab was not related to the peptidic B cell epitope nested in pCol(28-40); that is, 1) elimination of the B cell epitope, either by substitution of the critical residues of the B cell epitope or by truncation, failed to abrogate anti-GBM Ab production, and 2) the anti-GBM Ab, eluted from the diseased kidneys, reacted only with native GBM, but not with pCol(28-40). Confocal microscopy and immunoprecipitation further demonstrated that the eluted anti-GBM Ab recognized conformational B cell epitope(s) of multiple native GBM proteins. We conclude that autoantibody response to diverse native GBM Ags was induced by a single nephritogenic T cell epitope. Thus, anti-GBM Ab may actually be a consequence of T cell-mediated glomerulonephritis.
抗肾小球基底膜（GBM）抗体一直被视为致病性自身抗体的典型例子。然而，引发这种抗体的机制仍不清楚。在本文中，我们报告在大鼠模型中，针对多种GBM抗原的抗体是由单个致肾炎性T细胞表位诱导产生的。IV型胶原α3链非胶原结构域1的T细胞表位pCol(28 - 40)不仅能一致地诱发严重的肾小球肾炎，还能在显著的肾小球损伤后，使76%的免疫大鼠产生抗GBM抗体。此外，我们证明抗GBM抗体与嵌套在pCol(28 - 40)中的肽性B细胞表位无关；也就是说，1）通过替换B细胞表位的关键残基或进行截短来消除B细胞表位，均不能消除抗GBM抗体的产生，并且2）从患病肾脏洗脱的抗GBM抗体仅与天然GBM反应，而不与pCol(28 - 40)反应。共聚焦显微镜和免疫沉淀进一步证明，洗脱的抗GBM抗体识别多种天然GBM蛋白的构象性B细胞表位。我们得出结论，针对多种天然GBM抗原的自身抗体反应是由单个致肾炎性T细胞表位诱导的。因此，抗GBM抗体实际上可能是T细胞介导的肾小球肾炎的结果。
