Multiple Sclerosis (MS) is the most common cause of acquired neurological disability in young adults, pathologically characterized by leukocyte infiltration of the central nervous system, demyelination of the white and grey matter, and subsequent axonal loss. Microglia are proposed to play a role in MS lesion formation, however previous literature has not been able to distinguish infiltrated macrophages from microglia. Therefore, in this study we utilize the microglia-specific, homeostatic markers TMEM119 and P2RY12 to characterize their immunoreactivity in MS grey matter lesions in comparison to white matter lesions. Furthermore, we assessed the immunological status of the white and grey matter lesions, as well as the responsivity of human white and grey matter derived microglia to inflammatory mediators. We are the first to show that white and grey matter lesions in post-mortem human material differ in their immunoreactivity for the homeostatic microglia-specific markers TMEM119 and P2RY12. In particular, whereas immunoreactivity for TMEM119 and P2RY12 is decreased in the center of WMLs, immunoreactivity for both markers is not altered in GMLs. Based on data from post-mortem human microglia cultures, treated with IL-4 or IFNγ+LPS and on counts of CD3+ or CD20+ lymphocytes in lesions, we show that downregulation of TMEM119 and P2RY12 immunoreactivity in MS lesions corresponds with the presence of lymphocytes and lymphocyte-derived cytokines within the parenchyma but not in the meninges. Furthermore, the presence of TMEM119+ and partly P2RY12+ microglia in pre-active lesions as well as in the rim of active white and grey matter lesions, in addition to TMEM119+ and P2RY12+ rod-like microglia in subpial grey matter lesions suggest that blocking the entrance of lymphocytes into the CNS of MS patients may not interfere with all possible effects of TMEM119+ and P2RY12+ microglia in both white and grey matter MS lesions.

中文翻译：

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多发性硬化症白质和灰质病变中小胶质细胞TMEM119和P2RY12免疫反应性的调节取决于其炎性环境。

多发性硬化症（MS）是年轻人获得性神经功能障碍的最常见原因，其病理特征是中枢神经系统白细胞浸润，白质和灰质脱髓鞘以及随后的轴突丢失。提议小胶质细胞在MS病变的形成中起作用，但是以前的文献未能将浸润的巨噬细胞与小胶质细胞区分开。因此，在这项研究中，我们利用小胶质细胞特异性的稳态标记TMEM119和P2RY12来表征其与白质病变相比在MS灰质病变中的免疫反应性。此外，我们评估了白和灰质病变的免疫状态，以及人类白和灰质衍生的小胶质细胞对炎症介质的反应性。我们是第一个显示死后人类物质中的白色和灰色物质病变对稳态小胶质细胞特异性标记TMEM119和P2RY12的免疫反应性不同的人。特别地，尽管在WMLs中心降低了对TMEM119和P2RY12的免疫反应性，但在GMLs中两种标记物的免疫反应性均未改变。根据使用IL-4或IFNγ+ LPS处理的死后人类小胶质细胞培养物的数据以及病变中CD3 +或CD20 +淋巴细胞的计数，我们显示MS病变中TMEM119和P2RY12免疫反应性的下调与淋巴细胞和实质内有淋巴细胞衍生的细胞因子，但在脑膜中则没有。此外，在活动前病变以及活动性白和灰质病变的边缘，存在TMEM119 +和部分P2RY12 +小胶质细胞，