J Clin Invest. 2014 Mar;124(3):1228-41. doi: 10.1172/JCI71544. Epub 2014 Feb 24.
In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.
在中枢神经系统 (CNS) 中，尚未确定专门用于免疫监视的途径，以防止自身免疫性神经炎症性疾病中出现针对 CNS 的免疫反应。在这里，我们确定了一种免疫细胞从大脑迁移的途径，该途径与脑前迁移流 (RMS) 有关，RMS 是新产生神经元的前脑来源。评估荧光标记的白细胞在小鼠中的迁移情况表明，DC 通过 RMS 从 CNS 迁移到颈淋巴结 (CxLNs)，在那里它们将抗原呈递给 T 细胞。用单核细胞隔离药物 fingolimod 阻断免疫细胞迁移的药理学干预会影响 CxLN 中的抗 CNS T 细胞反应，并调节多发性硬化症 (MS) 小鼠模型中的实验性自身免疫性脑脊髓炎 (EAE) 严重程度。fingolimod 治疗还通过改变 CxLN 中的 DC 介导的 Treg 功能并破坏 CNS 免疫耐受，在一种疾病抗性转基因小鼠品系中引发 EAE。这些数据描述了一种起源于 CNS 的免疫细胞途径，能够在外周抑制针对 CNS 的免疫反应。此外，这些数据提供了有关 fingolimod 治疗如何在某些情况下加剧 CNS 神经炎症的见解，并表明 CNS 外的局部治疗干预有可能选择性地改变针对 CNS 的免疫。
