Mechanisms of Multiple Sclerosis Tissue Pathology

多发性硬化症(MS)的研究主要集中在白质(WM)病理上，然而最近的研究 在晚期疾病的多发性硬化症组织上，表明皮质损伤是残疾的重要相关因素；是 有组织的晚期脑膜炎症；皮质脱髓鞘(CDM)损害缺乏巨噬细胞和 淋巴细胞渗入。由于活跃的脱髓鞘皮质损害在这个晚期是稀疏的，所以很难 描述大脑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上 尸检多发性硬化症病例，发现CDM发生得较早；可以是炎症性的；脑膜炎是 很突出。这些发现与最近的MRI报告显示早期MS的皮质损害有很好的相关性。 结合最近的实验报告，我们对脑膜的作用(S)提出了新的假设 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 可能是多发性硬化症的早期事件，并与早期脑膜炎症有关。我们将定义频率和 早期MS队列中CDM的程度及其与早期和晚期脑膜聚集物的关系 疾病。我们建议外周的髓鞘特异性T细胞与脑膜抗原接触。 提呈细胞(APC)早期发生在蛛网膜下腔(SAS)，扩增髓鞘特异性T细胞； 产生新的记忆细胞，通过脑脊液运输到颈淋巴(LN)，促进软膜下DM。我们会 确定SAS中T细胞和APC的特征，并确定T细胞与APC接触的性质。我们的初步数据 在SAS和CDM病变中均可见髓鞘巨噬细胞。我们假设清洁发展机制产生 巨噬细胞/树突状细胞携带髓鞘抗原，并携带指示 能够通过脑脊液获得淋巴结，并保持(自动)免疫。我们的目标是确定这些细胞是否 有成熟的树突状表型。我们已经确定了MS早期的脑膜炎。我们建议 这些早期的脑膜聚集物为SA中持久的淋巴聚集物奠定了基础，从而推动了 进展性多发性硬化症的持续皮质损害我们将对这些浸润性病变进行特征化，以寻找早期迹象 淋巴聚集特征。我们发现T细胞炎症可能在早期CDM中显著，但更多是一过性的 而不是西医病变。我们认为这种短暂性炎症与LN转运趋化因子的表达有关。 促进其快速退出的皮质T细胞。我们将检测CDM和WM皮损中的T细胞 人口贩运的决定因素。我们认为CDM和炎症介导了皮质损伤，而硬膜下DM将 继续进行的机制不同于那些观察到的以西医为基础的病变。我们将描述和定义 皮质病变中炎症和神经退行性病变的关系，并比较CDM 与DM的靶点和机制有关的西医损害。这些实验解决了新的 假说；提供了一个难得的机会来评估动物数据与多发性硬化症病理的致病相关性；建立 基于我们独特的表型良好的组织资源；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.