Faculty of Medicine, University of New South Wales, National Innovation Centre, Australian Technology Park, Eveleigh, NSW, Australia.
J Neuroimmunol. 2010 Dec 15;229(1-2):98-106. doi: 10.1016/j.jneuroim.2010.07.010. Epub 2010 Sep 17.
Antibody deposition and complement activation, especially membrane attack complex (MAC) formation are considered central for immune mediated demyelination. To examine the role of MAC in immune mediated demyelination, we studied experimental allergic neuritis (EAN) in Lewis rats deficient in complement component 6 (C6) that cannot form MAC. A C6 deficient Lewis (Lewis/C6-) strain of rats was bred by backcrossing the defective C6 gene, from PVG/C6- rats, onto the Lewis background. Lewis/C6- rats had the same C6 gene deletion as PVG/C6- rats and their sera did not support immune mediated haemolysis unless C6 was added. Active EAN was induced in Lewis and Lewis/C6- rats by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA), and Lewis/C6- rats had delayed clinical EAN compared to the Lewis rats. Peripheral nerve demyelination in Lewis/C6- was also delayed but was similar in extent at the peak of disease. Compared to Lewis, Lewis/C6- nerves had no MAC deposition, reduced macrophage infiltrate and IL-17A, but similar T cell infiltrate and Th1 cytokine mRNA expression. ICAM-1 and P-selectin mRNA expression and immunostaining on vascular endothelium were delayed in Lewis C6- compared to Lewis rats' nerves. This study found that MAC was not required for immune mediated demyelination; but that MAC enhanced early symptoms and early demyelination in EAN, either by direct lysis or by sub-lytic induction of vascular endothelial expression of ICAM-1 and P-selectin.
抗体沉积和补体激活，尤其是膜攻击复合物（MAC）的形成，被认为是免疫介导的脱髓鞘的核心。为了研究 MAC 在免疫介导的脱髓鞘中的作用，我们研究了在补体成分 6（C6）缺乏的Lewis 大鼠中发生的实验性变应性神经炎（EAN），这些大鼠无法形成 MAC。通过将缺陷的 C6 基因从 PVG/C6-大鼠回交至 Lewis 背景中，培育了 C6 缺乏的 Lewis（Lewis/C6-）大鼠。Lewis/C6-大鼠具有与 PVG/C6-大鼠相同的 C6 基因缺失，除非添加 C6，否则其血清不能支持免疫介导的溶血。用牛周围神经髓鞘在完全弗氏佐剂（CFA）中免疫Lewis 和 Lewis/C6-大鼠可诱导活跃的 EAN，与 Lewis 大鼠相比，Lewis/C6-大鼠的临床 EAN 出现延迟。Lewis/C6-大鼠的周围神经脱髓鞘也延迟，但在疾病高峰期的程度相似。与 Lewis 大鼠相比，Lewis/C6-大鼠的神经中没有 MAC 沉积，巨噬细胞浸润和 IL-17A 减少，但 T 细胞浸润和 Th1 细胞因子 mRNA 表达相似。与 Lewis 大鼠的神经相比，Lewis/C6-大鼠的神经中 ICAM-1 和 P-选择素 mRNA 表达和血管内皮免疫染色延迟。这项研究发现，MAC 不是免疫介导的脱髓鞘所必需的；但是 MAC 通过直接溶解或通过亚溶解诱导血管内皮 ICAM-1 和 P-选择素的表达，增强了 EAN 的早期症状和早期脱髓鞘。
