Kyran Elizabeth L, Robinson Christine, Kocovski Pece, Li Zhenjiang, Dang Phuc T, Hale Matthew W, Orian Jacqueline M
aDepartment of Biochemistry and Genetics, La Trobe Institute for Molecular SciencebDepartment of Psychology, School of Psychology and Public Health, La Trobe University, Victoria, Australia.
Neuroreport. 2018 Jan 3;29(1):19-24. doi: 10.1097/WNR.0000000000000920.
Emotional and cognitive deficits and associated hippocampal damage observed in multiple sclerosis (MS) are now recognized as primary disease manifestations. However, the pathological substrate of these dysfunctions is unclear. In the experimental autoimmune encephalomyelitis (EAE) MS model, impaired hippocampal-dependent functions are concomitant with severe microglial reactivity and neurodegeneration, but reports vary with respect to evidence of lymphocytic infiltration, raising questions as to the nature of the underlying neurodegenerative mechanisms. Our investigations of EAE-induced inflammation across the hippocampal formation showed CD3 infiltration only in regions adjacent to inflamed meningeal membranes interposed between the ventral aspect of the hippocampus and the dorsal aspect of the mid-brain, but widespread microglial reactivity across the structure. Regions that contact the lateral ventricles do not show inflammation, but CD3 cells are observed in the adjacent ventricular space and choroid plexus, suggesting that microglial reactivity in these regions results from exposure to proinflammatory mediators released into the ventricles. These data indicate that multiple pathophysiological mechanisms underlie hippocampal damage during EAE. Treatment with the immunomodulator FTY720 eliminates microglial reactivity across the whole structure, suggesting potential benefit for neuropsychological symptoms in MS.
在多发性硬化症（MS）中观察到的情绪和认知缺陷以及相关的海马损伤现在被认为是主要的疾病表现。然而，这些功能障碍的病理基础尚不清楚。在实验性自身免疫性脑脊髓炎（EAE）MS模型中，海马依赖性功能受损与严重的小胶质细胞反应性和神经变性同时存在，但关于淋巴细胞浸润的证据报告各不相同，这引发了对潜在神经退行性机制本质的质疑。我们对EAE诱导的海马结构炎症的研究表明，CD3浸润仅出现在海马腹侧和中脑背侧之间插入的发炎脑膜附近的区域，但整个结构中广泛存在小胶质细胞反应性。与侧脑室接触的区域未显示炎症，但在相邻的脑室空间和脉络丛中观察到CD3细胞，这表明这些区域的小胶质细胞反应性是由于暴露于释放到脑室中的促炎介质所致。这些数据表明，EAE期间海马损伤存在多种病理生理机制。用免疫调节剂FTY720治疗可消除整个结构中的小胶质细胞反应性，这表明对MS的神经心理症状可能有益。
