Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy.
Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy.
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DOI：
10.1084/jem.20171285
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发表时间：
2018-04-02
期刊：
影响因子：
--
通讯作者：
Koh S
中科院分区：
文献类型：
--
作者：
Xu D;Robinson AP;Ishii T;Duncan DS;Alden TD;Goings GE;Ifergan I;Podojil JR;Penaloza-MacMaster P;Kearney JA;Swanson GT;Miller SD;Koh S
Xu等人首次在难治性癫痫患者中进行了研究，利用无偏流式细胞术方法显示了脑浸润性外周源性免疫细胞的表型、激活状态、细胞因子谱和引起神经元凋亡的能力与癫痫发作严重程度之间的直接相关性。小儿耐药癫痫的病理生理机制尚不清楚。对29例遗传性（局灶性皮质发育不良）或获得性（脑软化症）癫痫患儿切除脑组织中炎性白细胞的流式细胞术分析显示，血源性炎性髓样细胞和记忆性CD4+和CD8+ T细胞在脑组织中明显浸润。促炎（IL-17 -和产生gm - csf） γδ T细胞集中在致癫痫病变中，其数量与疾病严重程度呈正相关。相反，调节性T （T reg）细胞的数量与疾病严重程度呈负相关。相应地，使用kainic酸模型的癫痫持续状态，我们发现γδ T细胞和il - 17ra缺陷小鼠以及T reg细胞受体的癫痫发作活动都有所改善，而T reg细胞缺失会增加癫痫发作的严重程度。此外，IL-17和GM-CSF在脑切片培养中均诱导神经元高兴奋性。这些研究支持了外周源性先天和适应性促炎免疫反应在顽固性癫痫发病机制中的主要病理作用，并建议测试免疫调节疗法。
Xu et al. provide the first study in patients with intractable epilepsy showing a direct correlation between the phenotype, activation state, cytokine profiles, and ability to cause neuronal apoptosis of brain-infiltrating peripherally derived immune cells with seizure severity using an unbiased flow cytometric approach. The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17– and GM-CSF–producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell– and IL-17RA–deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.
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