Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Neurology Section, Veterans Affairs (VA) North Texas Health Care System, Dallas, TX, United States.
Front Immunol. 2022 Aug 10;13:970486. doi: 10.3389/fimmu.2022.970486. eCollection 2022.
The complement system has been involved in the pathogenesis of multiple neuroinflammatory and neurodegenerative conditions. In this review, we evaluated the possible role of complement activation in multiple sclerosis (MS) with a focus in progressive MS, where the disease pathogenesis remains to be fully elucidated and treatment options are limited. The evidence for the involvement of the complement system in the white matter plaques and gray matter lesions of MS stems from immunohistochemical analysis of post-mortem MS brains, serum and cerebrospinal fluid biomarker studies, and animal models of Experimental Autoimmune Encephalomyelitis (EAE). Complement knock-out studies in these animal models have revealed that this system may have a "double-edge sword" effect in MS. On the one hand, complement proteins may aid in promoting the clearance of myelin degradation products and other debris through myeloid cell-mediated phagocytosis. On the other, its aberrant activation may lead to demyelination at the rim of progressive MS white matter lesions as well as synapse loss in the gray matter. The complement system may also interact with known risk factors of MS, including as Epstein Barr Virus (EBV) infection, and perpetuate the activation of CNS self-reactive B cell populations. With the mounting evidence for the involvement of complement in MS, the development of complement modulating therapies for this condition is appealing. Herein, we also reviewed the pharmacological complement inhibitors that have been tested in MS animal models as well as in clinical trials for other neurologic diseases. The potential use of these agents, such as the C5-binding antibody eculizumab in MS will require a detailed understanding of the role of the different complement effectors in this disease and the development of better CNS delivery strategies for these compounds.
补体系统参与了多种神经炎症和神经退行性疾病的发病机制。在这篇综述中，我们评估了补体激活在多发性硬化症（MS）中的可能作用，重点关注进展性 MS，其发病机制仍未完全阐明，治疗选择有限。补体系统参与 MS 脑白质斑块和灰质病变的证据来自 MS 死后大脑、血清和脑脊液生物标志物研究以及实验性自身免疫性脑脊髓炎（EAE）动物模型的免疫组化分析。这些动物模型中的补体敲除研究表明，该系统在 MS 中可能具有“双刃剑”效应。一方面，补体蛋白可能通过髓样细胞介导的吞噬作用帮助清除髓鞘降解产物和其他碎片。另一方面，其异常激活可能导致进展性 MS 白质病变边缘的脱髓鞘以及灰质中的突触丢失。补体系统还可能与 MS 的已知危险因素相互作用，包括 EBV 感染，并使 CNS 自身反应性 B 细胞群体持续激活。随着补体在 MS 中的作用的证据越来越多，针对这种疾病的补体调节疗法的开发具有吸引力。在此，我们还回顾了已在 MS 动物模型以及其他神经疾病的临床试验中进行测试的药理学补体抑制剂。这些药物的潜在用途，如在 MS 中使用 C5 结合抗体依库珠单抗，需要详细了解不同补体效应物在该疾病中的作用，并开发出更好的这些化合物在中枢神经系统中的递药策略。
