Murine complement C4 is not required for experimental autoimmune encephalomyelitis
Murine complement C4 is not required for experimental autoimmune encephalomyelitis
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DOI：
10.1002/glia.20093
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发表时间：
2005-01-01
期刊：
影响因子：
6.2
通讯作者：
Barnum, SR
中科院分区：
文献类型：
--
作者：
Boos, LA;Szalai, AJ;Barnum, SR
体外研究表明，髓鞘和髓鞘衍生蛋白既能激活经典补体途径，又能激活替代补体途径。最近，研究表明，缺乏B因子的小鼠已经减弱了实验性自身免疫性脑脊髓炎(EAE)，EAE是多发性硬化症的动物模型。B因子是激活替代途径所需的一种蛋白质。经典通路在EAE发病机制中的相对作用尚不清楚。为了解决这个问题，我们用缺乏C4(C4(-/-))的小鼠进行了EAE，C4是一种完全激活经典途径所需的蛋白质。我们发现，与补体系统完全完整的对照组相比，C4基因的缺失并没有显著改变髓鞘少突胶质细胞诱导的EAE的发病时间、严重程度和节奏。我们观察到两种小鼠的细胞浸润(CD11b(+)巨噬细胞和CD3(+)T细胞)和脱髓鞘的水平相似。尽管如此，核糖核酸酶保护分析显示，在患有EAE的C4(-/-)小鼠中，几种促炎细胞因子的水平增加了两到四倍，包括白介素β(IL-1β)、白介素18(IL-18)、肿瘤坏死因子-α(TNF-α)、IP-10和RANTES。这些结果支持了小鼠补体在脱髓鞘疾病发病机制中的作用是通过替代途径实现的结论。(C)2004年Wiley-Liss公司
In vitro studies have demonstrated that myelin and myelin-derived proteins activate both the classical and alternative complement pathways. More recently, studies have shown that mice deficient in factor B, a protein required for activation of the alternative pathway, have attenuated experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. The relative contribution of the classical pathway to the pathogenesis of EAE has remained unexplored. To address this question, we performed EAE using mice deficient in C4 (C4(-/-)), a protein required for full activation of the classical pathway. We found that deletion of the C4 gene does not significantly change either the time of onset or the severity and tempo of myelin oligodendrocyte-induced EAE compared with controls with a fully intact complement system. We observed similar levels of cellular infiltration (CD11b(+) macrophages and CD3(+) T cells) and demyelination in the two kinds of mice. Despite this, ribonuclease protection assays demonstrated a two- to fourfold increase in several pro-inflammatory cytokines in C4(-/-) mice with EAE, including interleukin-beta (IL-1beta), IL-18, tumor necrosis factor-alpha (TNF-alpha), IP-10, and RANTES. These results support the conclusion that the contribution of murine complement to the pathogenesis of demyelinating disease is realized via the alternative pathway. (C) 2004 Wiley-Liss, Inc.