Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome
Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome
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DOI：
10.1016/j.molimm.2006.08.024
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发表时间：
2007-03-01
影响因子：
3.6
通讯作者：
Atkinson, John P.
中科院分区：
文献类型：
--
作者：
Liszewski, M. Kathryn;Leung, Marilyn K.;Atkinson, John P.
补体调节蛋白的突变易导致阿胡斯的发展。大约50%的患者在三种补体控制蛋白（因子H、因子1或膜辅因子蛋白（MCP; CD 46））中的一种中携带突变。另一种与MCP密切相关的膜调节剂。衰变加速因子（CD 55）迄今为止没有显示与阿胡斯相关，并继续进行研究。本研究的目的是比较MCP和MCP的调节特性，并评估MCP的改变如何导致补体调节异常。我们采用了中国仓鼠卵巢（CHO）细胞转染补体激活的模型系统。四种有规律表达的MCP和MCP亚型通过旁路途径抑制C3 b沉积。MCP对经典途径无明显抑制作用，而MCP对经典途径无明显抑制作用。大多数MCP-aHUS患者是杂合子，仅表达野生型蛋白的25-50%。因此，我们分析了野生型MCP水平降低的影响，发现表达水平降低的细胞在抑制旁路途径激活方面效率较低。此外，在5名阿胡斯患者中鉴定出的以正常水平表达的功能失调的MCP突变体（S206 P），即使表达水平增加10倍，也不能防止CHO细胞上的C3 b扩增。我们的研究结果增加了新的信息，相对于必要的适当表达水平的MCP和进一步牵连的替代途径在疾病过程中，如阿胡斯。爱思唯尔有限公司出版
Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor 1, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP. decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCP-aHUS are heterozygous and express only 25-50% of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS. Published by Elsevier Ltd.