Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
J Immunol. 2012 Nov 1;189(9):4640-7. doi: 10.4049/jimmunol.1201904. Epub 2012 Oct 1.
There is mounting evidence indicating an important role for complement in the pathogenesis of cerebral ischemia-reperfusion injury, or ischemic stroke. The role of the alternative complement pathway in ischemic stroke has not been investigated, and there is conflicting data on the role of the terminal pathway. In this study, we show that compared with wild-type mice, mice deficient in the alternative pathway protein factor B or mice treated with the alternative pathway inhibitor CR2-fH have improved outcomes after 60-min middle cerebral artery occlusion and 24-h reperfusion. Factor B-deficient or CR2-fH-treated mice were protected in terms of improved neurologic function and reduced cerebral infarct, demyelination, P-selectin expression, neutrophil infiltration, and microthrombi formation. Mice deficient in both the classical and lectin pathways (C1q/MBL deficient) were also protected from cerebral ischemia-reperfusion injury, and there was no detectable C3d deposition in the ipsilateral brain of these mice. These data demonstrate that the alternative pathway is not alone sufficient to initiate complement activation and indicate that the alternative pathway propagates cerebral injury via amplification of the cascade. Deficiency of C6, a component of the terminal cytolytic membrane attack complex, had no effect on outcome after ischemic stroke, indicating that the membrane attack complex is not involved in mediating injury in this model. We additionally show that the protective effect of factor B deficiency and CR2-fH treatment is sustained in the subacute stage of infarct development, adding to the clinical relevance of these findings.
越来越多的证据表明，补体在脑缺血再灌注损伤或缺血性中风的发病机制中起着重要作用。替代补体途径在缺血性中风中的作用尚未得到研究，关于末端途径的作用也存在相互矛盾的数据。在这项研究中，我们表明与野生型小鼠相比，缺乏替代途径蛋白因子 B 的小鼠或用替代途径抑制剂 CR2-fH 治疗的小鼠在 60 分钟大脑中动脉闭塞和 24 小时再灌注后具有更好的结局。因子 B 缺乏或 CR2-fH 治疗的小鼠在神经功能改善和脑梗死、脱髓鞘、P-选择素表达、中性粒细胞浸润和微血栓形成减少方面受到保护。经典途径和凝集素途径（C1q/MBL 缺乏）均缺乏的小鼠也对缺血性再灌注损伤具有保护作用，并且这些小鼠的同侧大脑中没有检测到 C3d 沉积。这些数据表明替代途径不足以单独启动补体激活，并表明替代途径通过级联放大来传播脑损伤。补体终末细胞溶解膜攻击复合物的成分 C6 的缺乏对缺血性中风后的结局没有影响，表明膜攻击复合物不参与介导该模型中的损伤。我们还表明，因子 B 缺乏和 CR2-fH 治疗的保护作用在梗死发展的亚急性期持续存在，这增加了这些发现的临床相关性。
