CD8 T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery
CD8 T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery
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DOI：
10.1093/brain/awp003
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发表时间：
2009-05-01
期刊：
影响因子：
14.5
通讯作者：
Wiendl, Heinz
中科院分区：
文献类型：
--
作者：
Schwab, Nicholas;Bien, Christian G.;Wiendl, Heinz
拉斯穆森脑炎（RE）是一种罕见的儿童神经系统疾病，其特征是单侧半球炎症，进行性神经功能缺损和顽固性局灶性癫痫。细胞毒性CD 8 T细胞对神经元和星形胶质细胞的破坏被认为是这种神秘疾病的致病机制。我们测试了这一假设，通过分析的克隆组成和T细胞受体（TCR）库的CD 4和CD 8 T细胞互补决定区3（CDR 3）光谱从外周血和相应的中枢神经系统标本。严重扰动的TCR库中发现脑浸润从所有标本（n 5）。外周血分析证实克隆扩增（n 14）属于CD 8 T细胞亚群，而CD 4细胞显示正态分布。通过组织化学在相应的CNS标本中分析了其中一些扩增。染色显示含有细胞毒性分子颗粒酶B的V特异性T细胞与NeuN神经元和GFAP星形胶质细胞紧密贴壁。相应的CNS/血液标本的分析显示重叠，但也CNS限制性的某些TCR克隆型的扩增，这表明在靶器官本身的T细胞的扩增。外周血样本（n 5）的纵向分析表明，随着时间的推移，特异性CD 8 T细胞克隆的优势，但也纵向持久性。V/J使用、CDR 3的长度和CDR 3氨基酸的生物化学特征表明与没有共享克隆的共同驱动抗原相关的高度相似性。综上所述，我们的数据有力地支持了抗原驱动的MHC I类限制性，CD 8 T细胞介导的对中枢神经系统中神经元和星形胶质细胞的攻击主导RE发病机制的假设。
Rasmussen encephalitis (RE) is a rare neurological disorder of childhood characterized by uni-hemispheric inflammation, progressive neurological deficits and intractable focal epilepsy. Destruction of neurons and astrocytes by cytotoxic CD8 T cells has been proposed as a pathogenic mechanism underlying this enigmatic disorder. We tested this hypothesis by analysing the clonal composition and T-cell receptor (TCR) repertoire of CD4 and CD8 T cells using complementarity determining region 3 (CDR3) spectratyping from peripheral blood and corresponding CNS specimens. Severe perturbations of the TCR repertoire were found in brain infiltrates from all specimens (n 5). Clonal expansions, as evidenced by peripheral blood analysis (n 14), belonged to the CD8 T-cell subset, while CD4 cells showed normal distributions. Some of those expansions were analysed in the respective CNS specimens by histochemistry. The stainings showed V specific T cells containing the cytotoxic molecule granzyme B and lying in close appositions to NeuN neurons and GFAP astrocytes. Analysis of corresponding CNS/blood specimens revealed overlapping but also CNS-restricted expansions of certain TCR clonotypes suggesting expansions of T cells within the target organ itself. Longitudinal analysis of peripheral blood samples (n 5) demonstrated dominance but also longitudinal persistence of specific CD8 T-cell clones over time. The V/J usage, length of the CDR3, and biochemical characteristics of the CDR3 amino acids suggested high similarities putatively related to common driving antigen(s) without shared clones. Taken together, our data strongly support the hypothesis of an antigen-driven MHC class-I restricted, CD8 T cell-mediated attack against neurons and astrocytes in the CNS dominating the pathogenesis in RE.