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STEC-HUS, atypical HUS and TTP are all diseases of complement activation
发布于：2013年4月8日 文字：【大】【中】【小】
Nat Rev Nephrol. 2012 Nov;8(11):622-33. doi: 10.1038/nrneph.2012.195. Epub 2012 Sep 18.
STEC-HUS, atypical HUS and TTP are all diseases of complement activation
Source
Clinical ResearchCenterfor Rare Diseases, Aldo e CeleDaccò, Mario Negri Institute for Pharmacological Research, Via G. B. Camozzi 3, Ranica, 24020Bergamo,Italy.
Abstract
Haemolyticuraemic syndrome (HUS) and thrombotic thrombocytopaenicpurpura (TTP) are diseases characterized by microvascular thrombosis, with consequent thrombocytopaenia, haemolyticanaemia and dysfunction of affected organs. Advances in our understanding of the molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor.In this Review, we discuss data indicating that complement hyperactivation is a common pathogenetic effector that leads to endothelial damage and microvascular thrombosis in all three diseases. In STEC-HUS, the toxin triggers endothelial complement deposition through the upregulation of P-selectin and possibly interferes with the activity of complement regulatory molecules. In aHUS, mutations in the genes coding for complement components predispose to hyperactivation of the alternative pathway of complement. In TTP, severe ADAMTS13 deficiency leads to generation of massive platelet thrombi, which might contribute to complement activation.
More importantly, evidence is emerging that pharmacological targeting of complement with the anti-C5 monoclonal antibody eculizumab can effectively treat not only aHUS for which it is indicated, but also STEC-HUS and TTP in some circumstances.
STEC-HUS, a HUS 和 TTP均为补体激活导致的疾病
溶血尿毒综合症(HUS)和血栓性血小板减少性紫癜(TTP)均是以微血管血栓形成以及后续发生的血小板减少、溶血性贫血及受累器官功能受损为特点的疾病。疾病分子机制研究的进展使我们认识到(TMA可以分为)三种不同的疾病：由产志贺毒素的大肠杆菌引起的典型溶血尿毒综合征(STEC-HUS)、由遗传性或者获得性补体成分缺陷引起的非典型性溶血尿毒综合症以及由ADAMTS13-循环中裂解vWF的金属蛋白酶-缺陷引起的TTP。在这篇综述中，我们探讨了一些研究数据。这些数据提示，补体过度激活导致的内皮细胞损伤以及微血管血栓形成是这三种疾病共同的发病机制。在STEC-HUS中，志贺毒素可能通过上调P选择素或者影响补体调控因子的活性来增加内皮细胞表面的补体沉积。在aHUS中，补体旁路途径的过度激活是源于某些编码补体蛋白的基因的缺陷。在TTP中，ADAMTS13的严重缺失导致了血小板血栓的大量形成，而血小板血栓的形成也可能会导致补体的激活。更重要的是，最近的研究证据提示，以补体蛋白为靶点的药物-如抗C5单克隆抗体(依库丽单抗)-不但可以有效治疗aHUS，在某些情况下对STEC-HUS和 TTP也有疗效。