Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.
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DOI：
10.1182/blood.v106.11.723.723
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发表时间：
2005-10
期刊：
影响因子：
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通讯作者：
D. Motto;A. Chauhan;Guojing Zhu;J. Homeister;Colin B. Lamb;K. Desch;Weirui Zhang;H. Tsai;D. Wagner;D. Ginsburg
中科院分区：
文献类型：
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作者：
D. Motto;A. Chauhan;Guojing Zhu;J. Homeister;Colin B. Lamb;K. Desch;Weirui Zhang;H. Tsai;D. Wagner;D. Ginsburg
血栓性血小板减少性紫癜（TTP）是由vwf切割蛋白酶ADAMTS13缺乏引起的一种危及生命的疾病。本研究表明，adamts13缺陷小鼠存活正常，但vwf介导的血小板内皮相互作用明显延长。引入遗传背景CASA/Rk（一种血浆vWF升高的小鼠品系）导致adamts13缺陷小鼠亚群出现自发性血小板减少症，并显著降低生存率。用志贺毒素（来自与人类相关疾病溶血性尿毒症综合征相关的细菌病原体）攻击这些小鼠，导致一种与人类TTP非常相似的显著综合征。令人惊讶的是，血浆vWF水平与TTP严重程度之间没有相关性，这表明存在与vWF不同的TTP修饰基因。这些数据表明，在ADAMTS13缺乏的情况下，微生物来源的毒素（或可能的其他内皮损伤来源）以及其他遗传易感性因素需要触发TTP。
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness caused by deficiency of the vWF-cleaving protease ADAMTS13. Here we show that ADAMTS13-deficient mice are viable and exhibit normal survival, although vWF-mediated platelet-endothelial interactions are significantly prolonged. Introduction of the genetic background CASA/Rk (a mouse strain with elevated plasma vWF) resulted in the appearance of spontaneous thrombocytopenia in a subset of ADAMTS13-deficient mice and significantly decreased survival. Challenge of these mice with shigatoxin (derived from bacterial pathogens associated with the related human disease hemolytic uremic syndrome) resulted in a striking syndrome closely resembling human TTP. Surprisingly, no correlation was observed between plasma vWF level and severity of TTP, implying the existence of TTP-modifying genes distinct from vWF. These data suggest that microbe-derived toxins (or possibly other sources of endothelial injury), together with additional genetic susceptibility factors, are required to trigger TTP in the setting of ADAMTS13 deficiency.