Critical role of the C-terminal domains of factor H in regulating complement activation at cell surfaces
Critical role of the C-terminal domains of factor H in regulating complement activation at cell surfaces
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DOI：
10.4049/jimmunol.177.9.6308
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发表时间：
2006-11-01
影响因子：
4.4
通讯作者：
Pangburn, Michael K.
中科院分区：
文献类型：
--
作者：
Ferreira, Viviana P.;Herbert, Andrew P.;Pangburn, Michael K.
血浆蛋白因子H主要控制补体旁路途径的激活。已知H因子的C末端参与保护宿主细胞免受补体攻击。在本研究中，我们表明，结构域19-20单独能够区分宿主样细胞和补体激活细胞。此外，虽然因子H具有三个C3 b结合位点，但与细胞结合的C3 b的结合几乎可以被位于结构域19-20中的单个位点完全抑制。H因子的所有调节活性均由N-末端四个结构域表达，但这些对细胞结合的C3 b的活性被分离的重组结构域19-20（rH 19-20）抑制。与N-末端位点的直接竞争不太可能解释这一点，因为流体相C3 b的调节不受结构域19-20的影响。最后，我们表明，除了分离的rH 19-20正常人血清导致积极的补体介导的裂解通常非活化绵羊红细胞和人类红细胞，具有膜结合的补体调节剂的中度裂解。两者合计，结果突出了与其他补体调节蛋白相比，H因子所表现出的细胞表面保护功能的重要性。这些结果也可以解释为什么非典型溶血尿毒综合征患者的突变影响结构域19-20可以维持补体稳态血浆中，而他们的补体系统攻击红细胞，血小板，内皮细胞和肾组织。
The plasma protein factor H primarily controls the activation of the alternative pathway of complement. The C-terminal of factor H is known to be involved in protection of host cells from complement attack. In the present study, we show that domains 19-20 alone are capable of discriminating between host-like and complement-activating cells. Furthermore, although factor H possesses three binding sites for C3b, binding to cell-bound C3b can be almost completely inhibited by the single site located in domains 19-20. All of the regulatory activities of factor H are expressed by the N-terminal four domains, but these activities toward cell-bound C3b are inhibited by isolated recombinant domains 19-20 (rH 19-20). Direct competition with the N-terminal site is unlikely to explain this because regulation of fluid phase C3b is unaffected by domains 19-20. Finally, we show that addition of isolated rH 19-20 to normal human serum leads to aggressive complement-mediated lysis of normally nonactivating sheep erythrocytes and moderate lysis of human erythrocytes, which possess membrane-bound regulators of complement. Taken together, the results highlight the importance of the cell surface protective functions exhibited by factor H compared with other complement regulatory proteins. The results may also explain why atypical hemolytic uremic syndrome patients with mutations affecting domains 19-20 can maintain complement homeostasis in plasma while their complement system attacks erythrocytes, platelets, endothelial cells, and kidney tissue.