Mechanisms of Multiple Sclerosis Tissue Pathology

多发性硬化（MS）的研究主要集中在白色物质（WM）的病理，但最近的研究 提示皮质损伤是残疾的重要相关因素; 组织化晚期脑膜炎;皮质脱髓鞘（CDM）病变缺乏巨噬细胞， 淋巴细胞浸润由于活跃的脱髓鞘皮质病变在这个晚期阶段是稀疏的，因此很难确定。 描述皮层损伤背后的机制我们之前资助的研究集中在早期活检 和尸检MS病例，并揭示CDM发生早期;可以是炎症性的;脑膜炎是 突出。这些发现与最近的MRI报告显示早期MS的皮质损伤有很好的相关性。 与最近的实验报告一致，我们提出了关于脑膜炎的作用的新假设， 炎症和皮质病理在促进MS疾病过程中的作用。我们假设大脑皮层病理学 可能是MS的早期事件，并与早期脑膜炎有关。我们将定义频率， 早期MS队列中CDM的程度，并确定其与早期和晚期MS中脑膜聚集体的关系。 疾病我们建议接触髓鞘特异性T细胞从周边和脑膜抗原 呈递细胞（APC）在蛛网膜下腔（SAS）早期出现;扩增髓鞘特异性T细胞;和 产生新的记忆细胞，通过CSF运输到颈部淋巴结（LN），促进软膜下DM。我们将 表征SAS中的T细胞和APC并定义T细胞-APC接触的性质。我们的初步数据 在SAS和CDM病变中显示充满髓鞘的巨噬细胞。我们假设CDM产生 巨噬细胞/树突状细胞，载有髓鞘抗原并携带指示 通过CSF进入淋巴结并保持（自身）免疫的能力。我们的目标是确定这些细胞 具有成熟的树突状表型。我们已经确定在早期MS脑膜炎，我们建议 这些早期脑膜聚集体为SAS中的长期淋巴聚集体奠定了基础， 进行性多发性硬化中持续的皮质损伤。我们将描述这些浸润的早期指征， 淋巴聚集特征我们发现T细胞炎症在早期CDM中可能是突出的，但更短暂， 而不是WM病变。我们认为这种短暂的炎症与LN运输趋化因子的表达有关， 皮质T细胞，促进其快速退出。我们将检查CDM和WM病变中的T细胞， 贩运决定因素。我们提出CDM和炎症介导皮质损伤，软膜下DM将 通过不同于WM损伤中观察到的机制进行。我们将描述和定义 皮质病变中炎症和神经退行性病理学之间的关系，并比较CDM 和WM病变与DM的靶点和机制的关系。这些实验针对的是小说 假设;提供了评估动物数据与MS病理学致病相关性的难得机会;建立 基于我们独特的良好表型组织资源;并具有识别新治疗靶点的潜力。

Multiple sclerosis (MS) research has largely focused on white matter (WM) pathology, however recent studies on MS tissue from late stage disease suggest cortical damage is an important correlate of disability; is driven by organized late meningeal inflammation; and cortical demyelinated (CDM) lesions lack macrophage and lymphocytic infiltrates. Since actively demyelinating cortical lesions are sparse at this late stage, it is difficult to characterize the mechanisms behind the cortical damage. Our prior funded research focused on early biopsy and autopsy MS cases and revealed CDM occurs early; can be inflammatory; and meningeal inflammation is prominent. These findings correlate well with recent MRI reports demonstrating cortical damage in early MS. In concert with recent experimental reports, we propose novel hypotheses about the role(s) of meningeal inflammation and cortical pathology in promoting the MS disease process. We hypothesize cortical pathology can be an early event in MS, and is related to early meningeal inflammation. We will define the frequency and extent of CDM in an early MS cohort and determine its relationship to meningeal aggregates in early and late disease. We propose contact between myelin-specific T cells from the periphery and meningeal antigen presenting cells (APCs) occurs early in the subarachnoid space (SAS); expands myelin-specific T cells; and generates new memory cells which traffic to cervical lymph nodes (LN) via CSF, promoting subpial DM. We will characterize T cells and APCs in the SAS and define the nature of T cell-APC contacts. Our preliminary data demonstrates myelin laden macrophages in both SAS and CDM lesions. We hypothesize CDM generates macrophage/dendritic cells laden with myelin antigen and bearing trafficking determinants indicative of capability to access lymph nodes via CSF and perpetuate (auto)immunity. We aim to characterize if these cells have a mature dendritic phenotype. We have identified meningeal inflammation during early MS. We propose these early meningeal aggregates set the stage for long-lasting lymphoid aggregates in the SAS which drive ongoing cortical damage in progressive MS. We will characterize these infiltrates for indications of early lymphoid aggregate character. We find T-cell inflammation may be prominent in early CDM, but more transient than WM lesions. We propose this transient inflammation relates to expression of LN trafficking chemokines on cortical T cells which facilitate their rapid exit. We will examine T cells in CDM and WM lesions for these trafficking determinants. We propose CDM and inflammation mediate cortical injury, and that subpial DM will proceed by mechanisms distinct from those observed in WM based lesions. We will characterize and define relationships between inflammatory and neurodegenerative pathology in cortical lesions, and compare CDM and WM lesions with respect to targets and mechanisms of DM. These experiments addressing novel hypotheses; provide a rare opportunity to assess pathogenic relevance of animal data to MS pathology; build upon our unique well phenotyped tissue resources; and carry the potential to discern new therapeutic targets.