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Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

发布于：2013年5月27日    文字：【大】【中】【小】

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Blood.2013 May 21. [Epub ahead of print]

Frimat M, Tabarin F, Dimitrov JD, Poitou C, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT.

INSERM UMRS 872, Cordeliers Research Center, Paris, France;

Abstract:

The atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormalities of the complement system leading to alternative pathway (AP) overactivation and by glomerular endothelial damage, thrombosis and mechanical hemolysis. Mutations per se are not sufficient to induce aHUS and non-specific primary triggers are required for disease manifestation. We sought to investigate if hemolysis-derived heme contribute to aHUS pathogenesis. We confirmed that heme activates complement AP in normal human serum, releasing C3a, C5a and sC5b9. We demonstrated that heme-exposed endothelial cells also activate the AP, resulting in cell-bound C3 and C5b-9. This was exacerbated in aHUS by genetic abnormalities associated with AP overactivation. Heme interacted with C3 close to the thioester bond, induced homophilic C3 complexes and promoted formation of an overactive C3/C5 convertase. Heme induced decreased MCP and DAF expression on endothelial cells, giving to FH a major role in complement regulation. Finally, heme promoted a rapid exocytosis of Weibel Palade bodies, with membrane expression of P-selectin, known to bind C3b and trigger the AP, and with the release of the pro-thrombotic von Willebrand factor. These results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS

摘要：

目前认为aHUS发病是在补体旁路调节异常的易感性基础上、同时存在非特异诱发因素（最常见为感染）。本文章发现溶血来源的亚铁血红素可以激活正常人血清中的补体旁路，释放C3a、C5a和sC5b-9。亚铁血红素处理后的内皮细胞可以活化补体，导致细胞表面出现C3和C5b-9。亚铁血红素与C3结合部位接近内酯健，产生亲同种抗原的C3复合物，从而促进活性强的C3、C5转化酶形成。亚铁血红素可诱导内皮细胞表面MCP和DAF表达减少。亚铁血红蛋白还可促进内皮细胞Weibel Palade小体胞吐作用，从而内皮细胞表面的P选择素表达增加和vWF释放增加，P选择素可结合C3b并激活补体旁路途径。因此，溶血产生的亚铁血红素可促进aHUS内皮细胞损伤和血栓形成。

http://www.ncbi.nlm.nih.gov/pubmed/23692858 [abstract]