BACKGROUND Recent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases. METHODS To investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls. RESULTS Gene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia. CONCLUSIONS We suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.

中文翻译：

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脑膜炎症改变了多发性硬化患者皮质灰质中 TNF 信号的平衡。

背景 继发性进行性多发性硬化症的皮层病理学最近的研究表明，更严重的临床病程和伴有显着神经元/胶质细胞丢失和小胶质细胞活化的扩展软膜下灰质病变的存在与脑膜炎症有关，包括淋巴样部分病例的蛛网膜下腔结构。方法 为了研究促炎和细胞毒性分子从脑膜扩散到下层灰质的分子后果，我们对来自 20 个死后多发性硬化症大脑的运动皮层进行了基因表达谱分析，有或没有实质性脑膜炎症和 10非神经控制。结果灰质病变和正常灰质的基因表达谱不仅证实了实质性的病理细胞变化，这在脑膜炎症增加的多发性硬化病例中最为明显，而且还证明了与炎症反应相关的多个基因/通路的上调。特别是，与对照相比，MS 病例中涉及肿瘤坏死因子 (TNF) 信号传导的基因显着失调。发现脑膜炎症增加与 TNF 信号平衡从 TNFR1/TNFR2 和 NFkB 介导的抗凋亡途径向灰质中 TNFR1 和 RIPK3 介导的促凋亡/促凋亡信号转导相关。 RT-PCR 分析证实了这一点。发现 TNFR1 优先在 MS 皮质灰质中的神经元和少突胶质细胞上表达，而 TNFR2 主要由星形胶质细胞和小胶质细胞表达。结论 我们认为，多发性硬化脑膜蛛网膜下腔通过浸润免疫细胞产生的炎症环境，由于 TNF 信号平衡的变化，导致潜在灰质脱髓鞘和神经退行性病变增加。