The identification of key mechanisms and molecules involved in tertiary lymphoid organ formation in the central nervous system in MP4-induced experimental autoimmune encephalomyelitis

多发性硬化症(MS)是中枢神经系统(CNS)的一种慢性炎症性疾病，被认为是自身免疫性疾病。虽然T细胞的作用已经得到了广泛的研究，但B细胞才刚刚开始引起人们的主要关注。最近发现继发性进展性多发性硬化症患者脑膜中的B细胞排列成淋巴滤泡样结构，我们在B细胞依赖的小鼠MP4诱导的实验性自身免疫性脑脊髓炎(EAE)中发现并鉴定了类似的三级淋巴器官(TLO)。本研究的目的是确定MP4免疫的C57BL/6小鼠小脑内B细胞聚集和TLO形成的关键机制和分子。在目标1中，将对非和弥漫性B细胞浸润物、B细胞聚集物和TLO进行RNA微阵列，并将数据与B细胞非依赖性髓鞘少突胶质细胞糖蛋白(MOG)：35-55模型和次级淋巴器官(SLO)中CNS浸润物的表达谱进行比较。指定的标记物的表达将通过qRT-PCR和免疫组织化学来确认。为了将结果初步转换为多发性硬化症的设置，我们还将在多发性硬化症大脑切片上寻找最有希望的分子，这些切片包含/不包含B细胞聚集体/毛囊。目的2研究淋巴组织诱导物(LTI)细胞和表达TH17细胞在MP4模型TLO形成中的作用。

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) and supposed to be of autoimmune nature. While the role of T cells has been extensively studied, B cells have just begun to attract major attention. It was recently shown that B cells organize themselves into lymphoid follicle-like structures in the meninges of patients with secondary progressive MS and we have identified and functionally characterized similar tertiary lymphoid organs (TLO) in the B cell-dependent murine MP4-induced experimental autoimmune encephalomyelitis (EAE). The aim of this proposal is to identify key mechanisms and molecules involved in B cell aggregation and TLO formation in the cerebellum of MP4-immunized C57BL/6 mice. In Aim 1 RNA microarrays will be performed on non- and diffuse B cell infiltrates, B cell aggregates and TLO and the data will be compared to the expression profiles of CNS infiltrates in the B cell-independent myelin oligodendrocyte glycoprotein (MOG):35-55 model and of secondary lymphoid organs (SLO). The expression of designated markers will be confirmed by qRT-PCR and immunohistochemistry. In an attempt to perform an initial translation of the results to the setting of MS we will also search for the most promising molecules on MS brain sections that contain/do not contain B cell aggregates/follicles. Aim 2 will study the contribution of lymphoid tissue inducer (LTi) cells and podoplanin expressing TH17 cells to TLO formation in the MP4 model.