Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Neurology, Toyama University Hospital, Toyama, Japan.
J Neuroinflammation. 2020 Mar 13;17(1):82. doi: 10.1186/s12974-020-01757-w.
Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS.
We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-β (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study.
Sema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-β unresponsiveness than those with low Sema4A levels.
Sema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.
Sema4A 是辅助性 T 细胞（Th）在启动阶段激活和分化的调节剂，在实验性自身免疫性脑脊髓炎（EAE）和多发性硬化症（MS）的发病机制中发挥重要作用。然而，Sema4A 在效应阶段的作用仍不清楚。我们旨在研究 Sema4A 在过继转移 EAE 模型中的效应阶段的作用。还详细检查了 Sema4A 水平较高的 MS 患者的临床特征和细胞因子谱，以阐明 Sema4A 水平与 MS 患者疾病活动度之间的相关性。
我们将致脑炎 Th1 或 Th17 细胞过继转移至野生型（WT）或 Sema4A 缺陷型（Sema4A KO）小鼠，并评估中枢神经系统（CNS）内症状的严重程度和细胞浸润。此外，我们分析了本研究中纳入的所有复发性缓解型多发性硬化症（RRMS）患者的临床和影像学特征（n=201）、血清 IFN-γ 和 IL-17A 水平（n=86）、IFN-β 完全缓解率（n=38）。
接受 Th17 偏向性 WT 髓鞘少突胶质细胞糖蛋白（MOG）特异性致脑炎 T 细胞的 Sema4A KO 受体小鼠与 WT 受体小鼠相比，临床评分显著降低。然而，当转移 Th1 偏向性致脑炎 T 细胞时，Sema4A KO 受体小鼠的疾病活动与 WT 受体小鼠相似。骨髓嵌合体研究表明，表达于造血细胞而非中枢神经系统固有细胞上的 Sema4A 负责增强 Th17 介导的神经炎症。此外，与相当的 IFN-γ 水平相比，Sema4A 水平较高的 RRMS 患者的 IL-17A 水平显著升高，这些患者具有较高的 Sema4A 水平，其疾病发病更早，疾病活动度更严重，IFN-β 反应性差。
Sema4A 不仅参与 Th 细胞的启动，而且参与效应阶段 Th17 细胞介导的神经炎症的加速，这可能导致 Sema4A 血清水平较高的 RRMS 患者疾病活动度更高。
