Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

中文翻译：

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调节性 T 细胞通过减轻视神经脊髓炎谱系障碍的炎症反应来防止脑损伤

视神经脊髓炎谱系障碍（NMOSD）主要是一种抗水通道蛋白4（anti-AQP4）自身抗体介导的中枢神经系统特发性炎性脱髓鞘疾病。全身和局部炎症反应在 NMOSD 的病理生理学中起关键作用。然而，尚未在 NMOSD 中研究关键免疫调节剂 CD4+CD25+ 叉头盒 P3+ (Foxp3) 调节性 T 细胞 (Tregs) 的作用。招募了 25 名抗 AQP4 阳性 NMOSD 患者和 21 名健康对照 (HC) 患者。通过流式细胞术评估外周血中 T 细胞亚群和 Treg 的频率。此外，使用来自 NMOSD 的抗 AQP4 抗体阳性患者的纯化免疫球蛋白 G 和注射到成年 C57BL/6J 雌性成年小鼠脑中的人补体，建立了 NMOSD 模型。通过流式细胞术、组织切片和实时定量聚合酶链反应分析浸润到 NMOSD 小鼠脑损伤中的 Treg。在我们的 NMOSD 小鼠模型中还评估了星形胶质细胞丢失、脱髓鞘和炎症反应。最后，我们检查了 Tregs 的消耗和过继转移的影响。与 HCs 相比，急性期 NMOSD 患者外周血总 T 细胞中 Tregs，尤其是幼稚 Tregs 的百分比显着降低。在我们的动物模型中，CD4+ T 细胞中 Treg 的数量和比例在 NMOSD 小鼠的病变中增加。Tregs 的消耗显着增强了这些小鼠的星形胶质细胞损失和脱髓鞘，而 Tregs 的过继转移减轻了脑损伤。机械地，Tregs 的缺失诱导更多的巨噬细胞浸润、小胶质细胞激活和 T 细胞侵袭，并调节巨噬细胞/小胶质细胞向经典激活表型发展，释放更多趋化因子和促炎细胞因子。相反，Tregs 在 NMOSD 小鼠中转移改善的免疫细胞浸润，包括巨噬细胞、中性粒细胞和 T 细胞，并使巨噬细胞和小胶质细胞偏向另一种激活表型，从而降低趋化因子和促炎细胞因子的水平。Tregs 可能是通过抑制 NMOSD 后的炎症反应来改善脑损伤的关键免疫调节剂。Tregs 在 NMOSD 小鼠中转移改善的免疫细胞浸润，包括巨噬细胞、中性粒细胞和 T 细胞，并使巨噬细胞和小胶质细胞偏向另一种激活表型，从而降低趋化因子和促炎细胞因子的水平。Tregs 可能是通过抑制 NMOSD 后的炎症反应来改善脑损伤的关键免疫调节剂。Tregs 在 NMOSD 小鼠中转移改善的免疫细胞浸润，包括巨噬细胞、中性粒细胞和 T 细胞，并使巨噬细胞和小胶质细胞偏向另一种激活表型，从而降低趋化因子和促炎细胞因子的水平。Tregs 可能是通过抑制 NMOSD 后的炎症反应来改善脑损伤的关键免疫调节剂。