Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
Neurochem Int. 2019 Nov;130:104348. doi: 10.1016/j.neuint.2018.11.023. Epub 2018 Dec 1.
Reserch progresses in understanding the pathogenicity of multiple sclerosis (MS) in the last couple of decade has enabled us to develop new drug entities available in the clinic. However, we still have not succeeded in preventing conversion from relapsing-remitting MS (RR-MS) to secondary progressive MS (SP-MS) and curing this intractable form of MS. Furthermore, diagnosis is usually retrospective and subjective, relying on gradual worsening of neurological signs/symptoms. This is obviously due to the lack of understanding for the pathogenicity driving disease progression in MS and of reliable biomarkers reflecting the progressive or stationary disease status. Two relevant components are involved in brain pathology of SP-MS, neurodegeneration and inflammation. Neurodegeneration may occur spontaneously in a neuron-intrinsic manner under chronic inflammation, such as glutamate excitotoxicity, mitochondrial/oxidative injury with iron deposit in the brain, and loss of trophic support. Meanwhile, inflammation is usually associated with recurrent relapse and the cumulative infiltration of immune cells, including T cells, B cells, and myeloid cells of peripheral or CNS origin, could ignite the processes of neurodegeneration. Especially, the higher frequency of leptomeningeal follicle-like structures observed in SP-MS patients suggests that immune cells sheltered behind a blood-brain barrier is still active under smoldering CNS inflammation. Recent successes in Ocrelizumab for primary progressive in MS (PP-MS) and Siponimod for SP-MS reappraised the importance of immune cells for pathogenesis progressive MS. Accordingly, our recent comparative analysis between MS and its animal model, experimental autoimmune encephalomyelitis (EAE), raises a new possibility that ectopic expression of eomesodermin (Eomes) in helper T (Th) cells constitutes a previously unappreciated subset of Th cells with cytotoxic potential against neuronal cells. In this review article, I will summarize the mechanisms proposed on pathogenesis of SP-MS and propose a new pathogenic mechanism for neurodegeneration mediated by unique cytotoxic Th cells.
在过去的几十年中，人们对多发性硬化症 (MS) 发病机制的研究进展，使我们能够开发出临床上可用的新药物。然而，我们仍然未能成功预防从复发缓解型多发性硬化症 (RR-MS) 向继发进展型多发性硬化症 (SP-MS) 的转化，也无法治愈这种难治性多发性硬化症。此外，诊断通常是回顾性的和主观的，依赖于神经体征/症状的逐渐恶化。这显然是由于我们对多发性硬化症疾病进展的发病机制缺乏了解，也缺乏反映疾病进展或静止状态的可靠生物标志物。SP-MS 的脑病理学涉及两个相关成分，神经退行性变和炎症。在慢性炎症下，神经元内在的谷氨酸毒性、线粒体/氧化损伤伴铁沉积、营养支持丧失等，可能导致神经退行性变的自发性发生。同时，炎症通常与反复复发和免疫细胞的累积浸润有关，包括外周或中枢来源的 T 细胞、B 细胞和髓样细胞，这些细胞可能引发神经退行性变过程。特别是，在 SP-MS 患者中观察到更高频率的软脑膜滤泡样结构，表明在慢性中枢神经系统炎症下，血脑屏障后面的免疫细胞仍然活跃。奥瑞珠单抗治疗原发性进展型多发性硬化症 (PP-MS) 和西尼莫德治疗 SP-MS 的最新成功案例，重新评估了免疫细胞对进展性多发性硬化症发病机制的重要性。因此，我们最近对多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎 (EAE) 的比较分析提出了一种新的可能性，即辅助性 T (Th) 细胞中 Eomes 的异位表达构成了具有潜在神经毒性的 Th 细胞的一个以前未被认识的亚群。在这篇综述文章中，我将总结 SP-MS 发病机制的研究进展，并提出一个新的神经退行性变发病机制，即由独特的具有神经毒性的 Th 细胞介导。
