Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Department of Oncology, Lausanne University Hospital and University of Lausanne, and Ludwig Institute for Cancer Research Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Cell Rep. 2019 Oct 8;29(2):378-390.e4. doi: 10.1016/j.celrep.2019.09.002.
Multiple sclerosis (MS) is a common autoimmune disease of the CNS. Although an association between MS and inflammatory bowel diseases is observed, the link connecting intestinal immune responses and neuroinflammation remains unclear. Here we show that encephalitogenic Th17 cells infiltrate the colonic lamina propria before neurological symptom development in two murine MS models, active and adoptive transfer experimental autoimmune encephalomyelitis (EAE). Specifically targeting Th17 cell intestinal homing by blocking the α4β7-integrin and its ligand MAdCAM-1 pathway impairs T cell migration to the large intestine and dampens EAE severity in the Th17 cell adoptive transfer model. Mechanistically, myelin-specific Th17 cells proliferate in the colon and affect gut microbiota composition. The beneficial effect of blocking the α4β7-integrin and its ligand MAdCAM-1 pathway on EAE is interdependent with gut microbiota. Those results show that disrupting myelin-specific Th17 cell trafficking to the large intestine harnesses neuroinflammation and suggests that the gut environment and microbiota catalyze the encephalitogenic properties of Th17 cells.
多发性硬化症（MS）是一种常见的中枢神经系统自身免疫性疾病。尽管观察到 MS 与炎症性肠病之间存在关联，但肠道免疫反应与神经炎症之间的联系仍不清楚。在这里，我们在两种实验性自身免疫性脑脊髓炎（EAE）模型（主动和过继转移 EAE）中显示，致脑炎性 Th17 细胞在神经系统症状出现之前就浸润到结肠固有层。通过阻断 α4β7 整合素及其配体 MAdCAM-1 途径特异性靶向 Th17 细胞肠道归巢，可损害 T 细胞向大肠的迁移，并在 Th17 细胞过继转移模型中减轻 EAE 的严重程度。从机制上讲，髓鞘特异性 Th17 细胞在结肠中增殖，并影响肠道微生物群落组成。阻断 α4β7 整合素及其配体 MAdCAM-1 途径对 EAE 的有益作用与肠道微生物群相互依赖。这些结果表明，破坏髓鞘特异性 Th17 细胞向大肠的迁移可以控制神经炎症，并表明肠道环境和微生物群促进了 Th17 细胞的致脑炎特性。
