The membrane attack complex of complement causes severe demyelination associated with acute axonal injury
The membrane attack complex of complement causes severe demyelination associated with acute axonal injury
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DOI：
10.4049/jimmunol.168.1.458
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发表时间：
2002-01-01
影响因子：
4.4
通讯作者：
Morgan, BP
中科院分区：
文献类型：
--
作者：
Mead, RJ;Singhrao, SK;Morgan, BP
补体与人类脱髓鞘疾病多发性硬化症和模拟多发性硬化症中所见脱髓鞘的动物模型的病理学有关。然而，补体系统中负责体内脱髓鞘的成分仍然没有确定。在这项研究中，我们表明，C6-缺陷（C6（-））PVG/c大鼠，无法形成膜攻击复合物（MAC）。在Ab介导的实验性自身免疫性脑脊髓炎模型中，当与匹配的C6-充足（C6（+））大鼠相比时，没有表现出脱髓鞘和显著降低的临床评分。C6（+）大鼠出现静脉周围脱髓鞘，伴有大量单个核细胞浸润和轴索损伤。在C6（-）大鼠中既未观察到脱髓鞘也未观察到轴突损伤，而单核细胞浸润水平与C6（+）大鼠中观察到的水平相当。将C6重构为C6（-）大鼠产生的病理学和临床疾病与C6（+）大鼠无区别。我们得出结论，脱髓鞘和轴突损伤发生在抗体的存在下，需要激活整个补体级联反应，包括MAC沉积。在没有MAC沉积的情况下，补体激活导致调理作用和过敏毒素的产生; C5 a和C3 a不足以引发脱髓鞘。
Complement is implicated in pathology in the human demyelinating disease multiple sclerosis and in animal models that mimic the demyelination seen in multiple sclerosis. However, the components of the complement system responsible for demyelination in vivo remain unidentified. In this study, we show that C6-deficient (C6(-)) PVG/c rats, unable to form the membrane attack complex (MAC). exhibit no demyelination and significantly reduced clinical score in the Ab-mediated experimental autoimmune encephalomyelitis model when compared with matched C6-sufficient (C6(+)) rats. In C6(+) rats, perivenous demyelination appeared, accompanied by abundant mononuclear cell infiltration and axonal injury. Neither demyelination nor axonal damage was seen in C6(-) rats, whereas levels of mononuclear cell infiltration were equivalent to those seen in C6(+) rats. Reconstitution of C6 to C6(-) rats yielded pathology and clinical disease indistinguishable from that in C6(+) rats. We conclude that demyelination and axonal damage occur in the presence of Ab and require activation of the entire complement cascade, including MAC deposition. In the absence of MAC deposition, complement activation leading to opsonization and generation of the anaphylatoxins; C5a and C3a is insufficient to initiate demyelination.