Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder.
Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder.
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调节性 T 细胞通过减轻视神经脊髓炎谱系疾病的炎症反应来防止脑损伤
DOI：
10.1186/s12974-021-02266-0
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发表时间：
2021-09-15
影响因子：
9.3
通讯作者：
Tian DS
中科院分区：
文献类型：
--
作者：
Ma X;Qin C;Chen M;Yu HH;Chu YH;Chen TJ;Bosco DB;Wu LJ;Bu BT;Wang W;Tian DS
视神经肌萎缩症谱系障碍（Neuromyoptica spectrum disorder，NMOSD）是一种主要由抗水通道蛋白4（anti-aquaporin 4，anti-AQP 4）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，关键的免疫调节剂CD 4 + CD 25+叉头盒P3+（Foxp 3）调节性T细胞（TcR）的作用尚未在NMOSD中研究。25例抗AQP 4阳性NMOSD患者和21例健康对照（HC）入选。采用流式细胞术检测外周血T细胞亚群和T细胞亚群的频率。此外，使用来自具有NMOSD的抗AQP 4抗体阳性患者的纯化免疫球蛋白G和人补体注射到雌性成年C57 BL/6 J小鼠的脑中建立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小鼠脑病变中的TdR。还在我们的NMOSD小鼠模型中评价了星形胶质细胞损失、脱髓鞘和炎症反应。最后，我们研究了TdR耗竭和过继转移的影响。与HC相比，NMOSD患者急性期外周血总T细胞中的T细胞，尤其是幼稚T细胞的百分比显著降低。在我们的动物模型中，在患有NMOSD的小鼠的病变中，T细胞在CD 4 + T细胞中的数量和比例增加。TdR的消耗显著增强了这些小鼠中星形胶质细胞的损失和脱髓鞘，而TdR的过继转移减轻了脑损伤。从机制上讲，缺乏TGFAP诱导了更多的巨噬细胞浸润、小胶质细胞活化和T细胞侵袭，并将巨噬细胞/小胶质细胞向经典活化表型调节，释放更多的趋化因子和促炎细胞因子。相比之下，Tcl 3转移改善了NMOSD小鼠中的免疫细胞浸润，包括巨噬细胞、嗜中性粒细胞和T细胞，并使巨噬细胞和小胶质细胞倾向于另一种活化表型，从而降低趋化因子和促炎细胞因子的水平。TdR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。在线版本包含补充材料，可通过10.1186/s12974-021-02266-0获得。
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. The online version contains supplementary material available at 10.1186/s12974-021-02266-0.
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影响因子：
9.9
作者：
Araki M;Matsuoka T;Miyamoto K;Kusunoki S;Okamoto T;Murata M;Miyake S;Aranami T;Yamamura T
通讯作者：
Yamamura T
DOI：
10.1136/jnnp-2018-317969
发表时间：
2018-09
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Kaneko K;Sato DK;Nakashima I;Ogawa R;Akaishi T;Takai Y;Nishiyama S;Takahashi T;Misu T;Kuroda H;Tanaka S;Nomura K;Hashimoto Y;Callegaro D;Steinman L;Fujihara K;Aoki M
通讯作者：
Aoki M
影响因子：
3.3
作者：
Cho, Eun Bin;Cho, Hye-Jin;Kim, Byoung Joon
通讯作者：
Kim, Byoung Joon
影响因子：
82.9
作者：
Liesz, Arthur;Suri-Payer, Elisabeth;Veltkamp, Roland
通讯作者：
Veltkamp, Roland
影响因子：
12.8
作者：
Peres, Raphael S.;Donate, Paula B.;Cunha, Fernando Q.
通讯作者：
Cunha, Fernando Q.