Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, Japan.
Department of Neurology, Brigham and Women's Hospital Biomedical Research Institute, 60 Fenwood Rd, Boston, MA, USA.
Brain. 2019 Apr 1;142(4):916-931. doi: 10.1093/brain/awz012.
The mechanism underlying the progression of relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS), characterized by accumulating fixed disability, is yet to be fully understood. Although alterations in the gut microbiota have recently been highlighted in multiple sclerosis pathogenesis, the mechanism linking the altered gut environment with the remote CNS pathology remains unclear. Here, we analyse human CD4+ memory T cells expressing the gut-homing chemokine receptor CCR9 and found a reduced frequency of CCR9+ memory T cells in the peripheral blood of patients with SPMS relative to healthy controls. The reduction in the proportion of CCR9+ cells among CD4+ memory T cells (%CCR9) in SPMS did not correlate with age, disease duration or expanded disability status scale score, although %CCR9 decreased linearly with age in healthy controls. During the clinical relapse of both, relapsing-remitting multiple sclerosis and neuromyelitis optica, a high proportion of cells expressing the lymphocyte activating 3 gene (LAG3) was detected among CCR9+ memory T cells isolated from the CSF, similar to that observed for mouse regulatory intraepithelial lymphocytes. In healthy individuals, CCR9+ memory T cells expressed higher levels of CCR6, a CNS-homing chemokine receptor, and exhibited a regulatory profile characterized by both the expression of C-MAF and the production of IL-4 and IL-10. However, in CCR9+ memory T cells, the expression of RORγt was specifically upregulated, and the production of IL-17A and IFNγ was high in patients with SPMS, indicating a loss of regulatory function. The evaluation of other cytokines supported the finding that CCR9+ memory T cells acquire a more inflammatory profile in SPMS, reporting similar aspects to CCR9+ memory T cells of the elderly healthy controls. CCR9+ memory T cell frequency decreased in germ-free mice, whereas antibiotic treatment increased their number in specific pathogen-free conditions. Here, we also demonstrate that CCR9+ memory T cells preferentially infiltrate into the inflamed CNS resulting from the initial phase and that they express LAG3 in the late phase in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Antibiotic treatment reduced experimental autoimmune encephalomyelitis symptoms and was accompanied by an increase in CCR9+ memory T cells in the peripheral blood. Antibodies against mucosal vascular addressin cell adhesion molecule 1 (MADCAM1), which is capable of blocking cell migration to the gut, also ameliorated experimental autoimmune encephalomyelitis. Overall, we postulate that the alterations in CCR9+ memory T cells observed, caused by either the gut microbiota changes or ageing, may lead to the development of SPMS.
复发缓解型多发性硬化（RRMS）向继发进展型多发性硬化（SPMS）进展的机制，其特征是累积固定残疾，目前尚未完全了解。尽管肠道微生物群的改变最近在多发性硬化症的发病机制中得到了强调，但与远端中枢神经系统病理学相关的肠道环境改变的机制仍不清楚。在这里，我们分析了表达肠道归巢趋化因子受体 CCR9 的人 CD4+记忆 T 细胞，发现 SPMS 患者外周血中 CCR9+记忆 T 细胞的频率降低相对于健康对照组。SPMS 中 CD4+记忆 T 细胞中 CCR9+细胞的比例（%CCR9）的减少与年龄、疾病持续时间或扩展残疾状态量表评分无关，尽管健康对照组中%CCR9 随年龄呈线性下降。在 RRMS 和视神经脊髓炎的临床复发期间，从 CSF 中分离出的 CCR9+记忆 T 细胞中检测到大量表达淋巴细胞激活 3 基因（LAG3）的细胞，类似于在小鼠调节上皮内淋巴细胞中观察到的情况。在健康个体中，CCR9+记忆 T 细胞表达更高水平的 CNS 归巢趋化因子受体 CCR6，并表现出具有 C-MAF 表达和产生 IL-4 和 IL-10 的调节特征。然而，在 CCR9+记忆 T 细胞中，RORγt 的表达特异性上调，并且 SPMS 患者产生高水平的 IL-17A 和 IFNγ，表明其调节功能丧失。对其他细胞因子的评估支持了这样一种发现，即 CCR9+记忆 T 细胞在 SPMS 中获得了更具炎症特征的报告，类似于老年健康对照组中 CCR9+记忆 T 细胞的方面。在无菌小鼠中，CCR9+记忆 T 细胞的频率降低，而抗生素治疗在特定病原体无的情况下增加了它们的数量。在这里，我们还证明 CCR9+记忆 T 细胞优先浸润到初始阶段引起的炎症性中枢神经系统，并在多发性硬化症的实验性自身免疫性脑脊髓炎小鼠模型的后期阶段表达 LAG3。抗生素治疗减轻了实验性自身免疫性脑脊髓炎的症状，并伴随着外周血中 CCR9+记忆 T 细胞的增加。针对粘膜血管地址素细胞黏附分子 1（MADCAM1）的抗体，能够阻止细胞向肠道迁移，也改善了实验性自身免疫性脑脊髓炎。总的来说，我们假设观察到的 CCR9+记忆 T 细胞的改变，无论是由肠道微生物群的改变还是衰老引起的，都可能导致 SPMS 的发展。
