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非典型溶血性尿毒症综合征患者的补体因子H功能障碍会导致补体在血小板上沉积并使其活化。

Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.

作者信息

Ståhl Anne-lie, Vaziri-Sani Fariba, Heinen Stefan, Kristoffersson Ann-Charlotte, Gydell Karl-Henrik, Raafat Reem, Gutierrez Alberto, Beringer Ortraud, Zipfel Peter F, Karpman Diana

机构信息

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.

出版信息

Blood. 2008 Jun 1;111(11):5307-15. doi: 10.1182/blood-2007-08-106153. Epub 2008 Feb 11.

Abstract

Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations in the C-terminal of factor H (FH). FH binds to platelets via the C-terminal as previously shown using a construct consisting of short consensus repeats (SCRs) 15 to 20. A total of 4 FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, and E1198Stop) in patients with aHUS, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared with normal FH, detected by flow cytometry. Washed platelets taken from the 4 patients with aHUS during remission exhibited C3 and C9 deposition, as well as CD40-ligand (CD40L) expression indicating platelet activation. Combining patient serum/plasma with normal washed platelets led to C3 and C9 deposition, CD40L and CD62P expression, aggregate formation, and generation of tissue factor-expressing microparticles. Complement deposition and platelet activation were reduced when normal FH was preincubated with platelets and were minimal when using normal serum. The purified FH-E1198Stop mutant added to FH-deficient plasma (complemented with C3) allowed considerable C3 deposition on washed platelets, in comparison to normal FH. In summary, mutated FH enables complement activation on the surface of platelets and their activation, which may contribute to the development of thrombocytopenia in aHUS.

摘要

非典型溶血性尿毒症综合征(aHUS)可能与补体因子H(FH)C末端的突变有关。如先前使用由短共有重复序列(SCR)15至20组成的构建体所示,FH通过C末端与血小板结合。对4例aHUS患者中SCR15(C870R)和SCR20(V1168E、E1198K和E1198Stop)的FH突变进行了研究,以探讨它们在血小板表面激活补体的能力。通过流式细胞术检测,与正常FH相比,纯化的FH-E1198Stop突变体与正常洗涤血小板的结合减少。4例缓解期aHUS患者的洗涤血小板表现出C3和C9沉积,以及表明血小板活化的CD40配体(CD40L)表达。将患者血清/血浆与正常洗涤血小板混合导致C3和C9沉积、CD40L和CD62P表达、聚集体形成以及表达组织因子的微粒生成。当正常FH与血小板预孵育时,补体沉积和血小板活化减少,而使用正常血清时则降至最低。与正常FH相比,添加到FH缺陷血浆(补充C3)中的纯化FH-E1198Stop突变体可使洗涤血小板上有大量C3沉积。总之,突变的FH可使血小板表面补体激活及其活化,这可能有助于aHUS中血小板减少症的发生。

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