The regulatory role of natural killer cells in multiple sclerosis
The regulatory role of natural killer cells in multiple sclerosis
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DOI：
10.1093/brain/awh219
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发表时间：
2004-09-01
期刊：
影响因子：
14.5
通讯作者：
Yamamura, T
中科院分区：
文献类型：
--
作者：
Takahashi, K;Aranami, T;Yamamura, T
多发性硬化症是一种慢性脱髓鞘疾病，推测其自身免疫性发病机制。多发性硬化症患者在疾病早期通常表现为复发和缓解交替发生。我们之前发现，在大多数处于缓解状态的多发性硬化症患者中，自然杀伤（NK）细胞在其表面含有异常高频率表达CD95 （Fas）的细胞（>36.0%）。在这篇文章中，我们报道了在这些“CD95(+) NK高”的患者中，NK细胞可能会主动抑制潜在的致病性自身免疫T细胞，这些T细胞可以介导中枢神经系统的炎症反应。利用来自缓解状态的“CD95(+) NK高”或“CD95(+) NK低”多发性硬化症患者的外周血单个核细胞（PBMCs），我们研究了NK细胞耗竭对记忆T细胞对髓鞘碱性蛋白（MBP）反应的影响，髓鞘碱性蛋白是多发性硬化症的主要靶抗原。当我们在消耗CD56(+) NK细胞后刺激“CD95(+) NK高”多发性硬化症的PBMCs时，大量CD4(+) T细胞（1/2000至1/200）通过分泌干扰素(IFN)- γ迅速对MBP做出反应，而在NK细胞存在的情况下，无法检测到这种对MBP的快速T细胞反应。无论NK细胞是否耗尽，我们也没有在缓解期的“CD95(+) NK低”多发性硬化症患者或健康受试者中检测到对MBP的记忆反应。表达CD16（另一种NK细胞标记物）的细胞耗竭也导致“CD95(+) NK高”多发性硬化症患者外周血中mbp反应性CD4(+) T细胞分泌ifn - γ。此外，我们发现来自“CD95+ NK高”多发性硬化症的NK细胞可以在体外抑制自体mbp特异性T细胞克隆抗原驱动的ifn - γ分泌。这些结果表明NK细胞可能以抗原非特异性的方式调节自身免疫记忆T细胞的激活，以维持“CD95(+) NK高”多发性硬化症患者的临床缓解。
Multiple sclerosis is a chronic demyelinating disease of presumed autoimmune pathogenesis. The patients with multiple sclerosis typically shows alternating relapse and remission in the early stage of illness. We previously found that in the majority of multiple sclerosis patients in a state of remission, natural killer (NK) cells contain unusually high frequencies of the cells expressing CD95 (Fas) on their surface (>36.0%). Here we report that in such 'CD95(+) NK-high' patients, NK cells may actively suppress potentially pathogenic autoimmune T cells that can mediate the inflammatory responses in the CNS. Using peripheral blood mononuclear cells (PBMCs) derived from 'CD95(+) NK-high' or 'CD95(+) NK-low' multiple sclerosis in a state of remission, we studied the effect of NK cell depletion on the memory T cell response to myelin basic protein (MBP), a major target antigen of multiple sclerosis. When we stimulated PBMCs of the 'CD95(+) NK-high' multiple sclerosis after depleting CD56(+) NK cells, a significant proportion of CD4(+) T cells (1/2000 to 1/200) responded rapidly to MBP by secreting interferon (IFN)-gamma, whereas such a rapid T cell response to MBP could not be detected in the presence of NK cells. Nor did we detect the memory response to MBP in the 'CD95(+) NK-low' multiple sclerosis patients in remission or healthy subjects, regardless of whether NK cells were depleted or not. Depletion of cells expressing CD16, another NK cell marker, also caused IFN-gamma secretion from MBP-reactive CD4(+) T cells in the PBMCs from 'CD95(+) NK-high' multiple sclerosis. Moreover, we showed that NK cells from 'CD95+ NK-high' multiple sclerosis could inhibit the antigen-driven secretion of IFN-gamma by autologous MBP-specific T cell clones in vitro. These results indicate that NK cells may regulate activation of autoimmune memory T cells in an antigen non-specific fashion to maintain the clinical remission in 'CD95(+) NK-high' multiple sclerosis patients.