Nakatsuji Yuji
Department of Neurology, Osaka University Graduate School of Medicine.
Rinsho Shinkeigaku. 2014;54(12):972-4. doi: 10.5692/clinicalneurol.54.972.
Approximately one-third of patients with multiple sclerosis (MS) exhibit markedly high-level-expression of Sema4A. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is critical for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. We investigated whether recombinant Sema4A abrogates the efficacy of IFN-β in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Administration of Sema4A concurrently with IFN-β abrogated the efficacy of IFN-β. These effects of Sema4A were attributed to promote Th1 and Th17 differentiation and to increase adhesive activation of T cells to endothelial cells, even in the presence of IFN-β.Thus unresponsiveness to IFN-β treatment of MS patients with high Sema4A was also confirmed by model mice EAE. We recommend assaying Sema4A first, and then selecting DMD other than IFN-β for patients with high Sema4A.
约三分之一的多发性硬化症（MS）患者表现出Sema4A的高水平表达。MS患者树突状细胞（DC）上Sema4A的表达增加，并以金属蛋白酶依赖的方式从这些细胞中脱落。DC来源的Sema4A对Th17细胞分化至关重要，Sema4A水平高的MS患者表现出Th17细胞偏移。此外，Sema4A水平高的患者残疾更严重，且对干扰素-β（IFN-β）治疗无反应。我们研究了重组Sema4A是否会消除IFN-β在实验性自身免疫性脑脊髓炎（EAE，一种MS动物模型）小鼠中的疗效。Sema4A与IFN-β同时给药会消除IFN-β的疗效。Sema4A的这些作用归因于促进Th1和Th1细胞分化以及增加T细胞对内皮细胞的黏附激活，即使在存在IFN-β的情况下也是如此。因此，EAE模型小鼠也证实了Sema4A水平高的MS患者对IFN-β治疗无反应。我们建议首先检测Sema4A，然后为Sema4A水平高的患者选择除IFN-β之外的其他治疗方法。
