Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis.
Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis.
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DOI：
10.1186/s40478-022-01472-y
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发表时间：
2022-11-21
影响因子：
7.1
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中科院分区：
文献类型：
--
作者：
拉斯穆森脑炎（RE）是一种罕见的儿童神经系统疾病，以进行性单侧功能丧失、半球萎缩和耐药癫痫为特征。受影响的脑组织表现出细胞毒性t细胞浸润、小胶质细胞活化和神经元死亡的迹象，暗示了炎症性疾病的过程。最近的研究已经确定了RE中炎症的分子相关性，但细胞类型特异性机制尚不清楚。我们使用单核rna测序（snRNA-seq）来评估从两名患有RE的儿童切除的脑组织中多种细胞类型的基因表达。我们发现，与两名年龄匹配的未受影响的脑组织和两名I型局灶性皮质发育不良（FCD）的个体相比，转录上不同的小胶质细胞群富含RE。具体来说，RE组织中的小胶质细胞表现出与细胞因子信号、干扰素介导途径和t细胞激活相关的基因表达增加。我们使用四个手术切除组织的空间蛋白质组学分析来扩展这些发现，以检查病理背景下小胶质细胞的表达谱。空间聚集成结节的小胶质细胞表达动态免疫调节标志物（PD-L1, CD14, CD11c）， t细胞活化标志物（CD40, CD80），并且物理上靠近不同的CD4+和CD8+淋巴细胞群。这些发现有助于阐明RE复杂的免疫微环境。在线版本包含补充材料，可在10.1186/s40478-022-01472-y获得。
Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types in brain tissue resected from two children with RE. We found transcriptionally distinct microglial populations enriched in RE compared to two age-matched individuals with unaffected brain tissue and two individuals with Type I focal cortical dysplasia (FCD). Specifically, microglia in RE tissues demonstrated increased expression of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation. We extended these findings using spatial proteomic analysis of tissue from four surgical resections to examine expression profiles of microglia within their pathological context. Microglia that were spatially aggregated into nodules had increased expression of dynamic immune regulatory markers (PD-L1, CD14, CD11c), T-cell activation markers (CD40, CD80) and were physically located near distinct CD4+ and CD8+ lymphocyte populations. These findings help elucidate the complex immune microenvironment of RE. The online version contains supplementary material available at 10.1186/s40478-022-01472-y.
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影响因子：
3
作者：
Andoh M;Koyama R
通讯作者：
Koyama R
影响因子：
3.7
作者：
Ghaleb AM;Bialkowska AB;Snider AJ;Gnatenko DV;Hannun YA;Yang VW;Schmidt VA
通讯作者：
Schmidt VA
影响因子：
7.1
作者：
Kenkhuis B;Somarakis A;de Haan L;Dzyubachyk O;IJsselsteijn ME;de Miranda NFCC;Lelieveldt BPF;Dijkstra J;van Roon-Mom WMC;Höllt T;van der Weerd L
通讯作者：
van der Weerd L
影响因子：
5.6
作者：
Czapski GA;Strosznajder JB
通讯作者：
Strosznajder JB
影响因子：
4.4
作者：
Clarner, Tim;Janssen, Katharina;Kipp, Markus
通讯作者：
Kipp, Markus