Wu Jean, Borillo Jason, Glass William F, Hicks John, Ou Ching-Nan, Lou Ya-Huan
Department of Basic Science, Dental Branch, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Kidney Int. 2003 Oct;64(4):1292-301. doi: 10.1046/j.1523-1755.2003.00227.x.
Anti-glomerular basement membrane (GBM) glomerulonephritis is among the earliest recognized human autoimmune diseases. However, the etiology of anti-GBM glomerulonephritis remains unclear. We have previously shown that CD4+ T cells, specific to alpha3 NC1 of type IV collagen (Col4alpha3NC1), were able to induce anti-GBM glomerulonephritis in Wistar-Kyoto (WKY) rats. In the present study, we continued to map the nephritogenic T cell epitope in Col4alpha3NC1.
Synthetic peptides, which covered Col4alpha3NC1, were used as immunogens to induce glomerulonephritis in WKY rats. T-cell and B-cell responses to the peptides in the animals were analyzed.
One potent nephritogenic T-cell epitope, pCol(28-40) (SQTTANPSCPEGT), was identified. A single immunization with pCol(28-40) induced extremely severe glomerulonephritis in all 23 rats. Renal pathology revealed nearly 100% of glomeruli with crescentic lesions or tuft necrosis in 21 animals. pCol(28-40) elicited a T-cell response to the peptide; T cells isolated from rats immunized with recombinant Col4alpha3NC1 reacted with pCol(28-40). pCol(28-40) elicited a peptide specific antibody response, which did not react with polypeptide Col4alpha3NC1 or native GBM. An 11-mer peptide, pCol(a30-40) (Ac-TTANPSCPEGT), was further mapped to be the core of the T-cell epitope in pCol(28-40). As expected, immunization with pCol(a30-40) induced severe glomerulonephritis in 10 out of 19 rats.
Our study not only demonstrated that a single T-cell epitope of Col4alpha3NC1 is sufficient to induce severe glomerulonephritis, but also provides a unique model for studying T-cell-mediated mechanisms in anti-GBM glomerulonephritis pathogenesis.
抗肾小球基底膜（GBM）肾小球肾炎是最早被认识的人类自身免疫性疾病之一。然而，抗GBM肾小球肾炎的病因仍不清楚。我们之前已经表明，对IV型胶原（Col4alpha3NC1）的α3 NC1具有特异性的CD4 + T细胞能够在Wistar - Kyoto（WKY）大鼠中诱导抗GBM肾小球肾炎。在本研究中，我们继续绘制Col4alpha3NC1中致肾炎性T细胞表位。
覆盖Col4alpha3NC1的合成肽被用作免疫原，以在WKY大鼠中诱导肾小球肾炎。分析了动物体内对这些肽的T细胞和B细胞反应。
鉴定出一个有效的致肾炎性T细胞表位pCol(28 - 40)（SQTTANPSCPEGT）。用pCol(28 - 40)单次免疫在所有23只大鼠中均诱导出极其严重的肾小球肾炎。肾脏病理学显示在21只动物中近100%的肾小球有新月体病变或毛细血管袢坏死。pCol(28 - 40)引发了对该肽的T细胞反应；从用重组Col4alpha3NC1免疫的大鼠中分离出的T细胞与pCol(28 - 40)发生反应。pCol(28 - 40)引发了肽特异性抗体反应，该反应不与多肽Col4alpha3NC1或天然GBM发生反应。一个11聚体肽pCol(a30 - 40)（Ac - TTANPSCPEGT）被进一步确定为pCol(28 - 40)中T细胞表位的核心。正如预期的那样，用pCol(a30 - 40)免疫在19只大鼠中的10只中诱导出严重的肾小球肾炎。
我们的研究不仅证明了Col4alpha3NC1的单个T细胞表位足以诱导严重的肾小球肾炎，而且为研究抗GBM肾小球肾炎发病机制中T细胞介导的机制提供了一个独特的模型。
