Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome
Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome
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DOI：
10.1182/blood-2007-02-071472
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发表时间：
2007-09-01
期刊：
影响因子：
20.3
通讯作者：
Zipfel, Peter F.
中科院分区：
文献类型：
--
作者：
Jozsi, Mihaly;Strobel, Stefanie;Zipfel, Peter F.
非典型形式的肾病溶血性尿毒综合征（阿胡斯）与补体调节缺陷有关。除了补体调节因子的突变之外，还报告了阿胡斯患者的因子H（FH）特异性自身抗体。本研究的目的是了解这些自身抗体在阿胡斯中的作用。首先，使用重组FH片段和竞争抗体定位来自5名不相关阿胡斯患者的FH自身抗体的结合位点。对于所有5种自身抗体，结合位点定位于FH C-末端。在功能测定中，分离的患者IgG抑制FH与C3 b的结合。此外，自身抗体阳性患者血浆引起绵羊红细胞溶血增强，过量添加FH可逆转该现象。这些结果表明，阿胡斯相关FH自身抗体模拟C-末端FH突变的作用，因为它们通过阻断其C-末端识别区来抑制FH在细胞表面的调节功能。
The atypical form of the kidney disease hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. In addition to mutations in complement regulators, factor H (FH)specific autoantibodies have been reported for aHUS patients. The aim of the present study was to understand the role of these autoantibodies in aHUS. First, the binding sites of FH autoantibodies from 5 unrelated aHUS patients were mapped using recombinant FH fragments and competitor antibodies. For all 5 autoantibodies, the binding site was localized to the FH C-terminus. In a functional assay, isolated patient IgG inhibited FH binding to C3b. In addition, autoantibody positive patients' plasma caused enhanced hemolysis of sheep erythrocytes, which was reversed by adding FH in excess. These results suggest that aHUS associated FH autoantibodies mimic the effect of C-terminal FH mutations, as they inhibit the regulatory function of FH at cell surfaces by blocking its C-terminal recognition region.