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.

中文翻译：

---

Sema4A参与效应期Th17细胞介导的神经炎症的加速

Sema4A在启动阶段是辅助T细胞（Th）活化和分化的调节剂，在实验性自身免疫性脑脊髓炎（EAE）和多发性硬化症（MS）的发病机理中起重要作用。但是，Sema4A在效应子阶段的作用仍然难以捉摸。我们旨在研究Sema4A在过继转移EAE模型的效应子阶段的作用。还详细检查了具有高Sema4A水平的MS患者的临床特征和细胞因子谱，以阐明Sema4A水平与MS患者疾病活动之间的相关性。我们过继性地将致脑炎的Th1或Th17细胞转移至野生型（WT）或Sema4A缺陷型（Sema4A KO）小鼠，并评估了症状的严重程度和中枢神经系统（CNS）中的细胞浸润。此外，我们分析了所有复发缓解型多发性硬化症（RRMS）的临床和放射学特征（n = 201），血清IFN-γ和IL-17A的水平（n = 86），IFN-β的完全缓解率（n = 38） ）参加本研究的患者。与WT受体小鼠相比，接受Th17偏斜的WT髓鞘少突胶质细胞糖蛋白（MOG）特异的致脑性T细胞的Sema4A KO受体小鼠表现出明显的临床得分降低。但是，当将Sema4A KO受体小鼠转移到Th1偏向性致脑病性T细胞后，与WT受体小鼠表现出相似的疾病活性。骨髓嵌合研究表明，造血细胞表达的Sema4A而不是中枢神经系统的驻留细胞，是增强Th17介导的神经炎症的原因。此外，与可比的IFN-γ水平相比，与Sema4A水平低的患者相比，Sema4A水平高的RRMS患者的IL-17A显着高于Sema4A水平低的RRMS患者，其疾病发作更早，疾病活动更严重且IFN-β无反应性。Sema4A不仅参与Th细胞的启动，而且参与效应期Th17细胞介导的神经炎症的加速，这可能有助于在血清Sema4A水平高的RRMS患者中观察到更高的疾病活性。