Serafini Barbara, Rosicarelli Barbara, Veroni Caterina, Zhou Ling, Reali Camilla, Aloisi Francesca
From the Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy (BS, BR, CV, FA) and GlaxoSmithKline Shanghai Research and Development Center, Zhangjiang Hi-Tech Park, TAU, Pudong, China, Neuroscience Shanghai (LZ, CR).
J Neuropathol Exp Neurol. 2016 Sep;75(9):877-88. doi: 10.1093/jnen/nlw063. Epub 2016 Jul 13.
Ectopic B-cell follicle-like structures (ELS) are found in the meninges of patients with secondary progressive multiple sclerosis (SPMS). Because cells expressing the transcriptional regulator retinoic acid receptor-related orphan receptor-γt (RORγt) and producing interleukin 17 (IL17), e.g. T helper 17 cells and lymphoid tissue inducer (LTi) cells, have been implicated in the formation of ELS, we studied RORγt and IL17 expression in brain tissue from patients with SPMS an assessed their relationships to immune infiltrates and meningeal ELS. By immunohistochemistry, small numbers of RORγt-positive cells were detected in the meninges of 6 of 12 SPMS cases analyzed. RORγt-positive cells were localized in B-cell follicles or aggregates and nearby diffuse meningeal infiltrates, and predominantly co-expressed CD3. Only a few RORγt-positive, CD3-negative cells were observed, suggesting the presence of group 3 innate lymphoid cells, which comprise the LTi cell subset. Some IL17-positive cells, co-expressing in part RORγt and predominantly CD3, were found in meningeal B-cell follicles from 4 SPMS cases. Rare RORγt-positive and IL17-positive cells were detected in white matter. Gene expression analysis of laser dissected meningeal infiltrates and white matter lesions confirmed low frequencies and virtual absence of RORγt and IL17 signals, respectively. Thus, there is selective migration or survival of RORγt-positive cells in MS patient meninges and an association of these cells with ELS.
异位B细胞滤泡样结构（ELS）见于继发进展型多发性硬化（SPMS）患者的脑膜中。由于表达转录调节因子视黄酸受体相关孤儿受体γt（RORγt）并产生白细胞介素17（IL17）的细胞，如辅助性T细胞17（Th17）和淋巴组织诱导细胞（LTi），与ELS的形成有关，我们研究了SPMS患者脑组织中RORγt和IL17的表达，并评估了它们与免疫浸润和脑膜ELS的关系。通过免疫组织化学，在分析的12例SPMS病例中的6例脑膜中检测到少量RORγt阳性细胞。RORγt阳性细胞定位于B细胞滤泡或聚集物以及附近的弥漫性脑膜浸润中，且主要共表达CD3。仅观察到少数RORγt阳性、CD3阴性细胞，提示存在包括LTi细胞亚群在内的3型固有淋巴细胞。在4例SPMS病例的脑膜B细胞滤泡中发现了一些IL17阳性细胞, 部分共表达RORγt且主要共表达CD3。在白质中检测到罕见的RORγt阳性和IL17阳性细胞。对激光显微切割的脑膜浸润和白质病变进行基因表达分析证实，RORγt和IL17信号的频率分别较低且几乎不存在。因此，在MS患者脑膜中存在RORγt阳性细胞的选择性迁移或存活，且这些细胞与ELS有关。
