Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225 Düsseldorf, Germany.
Department of Psychiatry, University of Münster, 48149 Münster, Germany.
Int J Mol Sci. 2017 Nov 2;18(11):2306. doi: 10.3390/ijms18112306.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4⁺ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性脱髓鞘疾病。它影响着全球超过 200 万人，主要是年轻人，并可能导致进行性神经功能障碍。趋化因子及其受体已被证明在实验性自身免疫性脑脊髓炎（EAE）的发病机制中起着关键作用，EAE 是一种通过髓鞘蛋白主动免疫或致脑炎 CD4 ⁇ T 细胞转移诱导的啮齿动物疾病模型，可再现 MS 的临床和神经病理学特征。趋化因子配体-受体相互作用协调白细胞的迁移，并影响多种病理生理细胞过程，包括树突状细胞（DC）的抗原呈递和细胞因子的产生。C-C 类趋化因子 17（CCL17）和 22（CCL22）及其 C-C 趋化因子受体 4（CCR4）已被证明在稳态和炎症反应中发挥重要作用。在这里，我们概述了 CCR4 及其配体在中枢自身免疫中的参与。我们综述了多发性硬化症的关键临床研究以及动物实验研究，这些研究证明了 CCR4、CCL17 和 CCL22 在 EAE 发病机制中的功能作用。最后，我们讨论了新开发的 CCR4 拮抗剂和人源化抗 CCR4 抗体治疗多发性硬化症的治疗潜力。
