Mechanisms of Multiple Sclerosis Tissue Pathology

描述（由申请人提供）：多发性硬化症（MS）的研究主要集中在白质（WM）病理上，然而最近对晚期MS组织的研究表明，皮质损伤是残疾的重要相关因素；是由有组织的晚期脑膜炎症引起的；皮质脱髓鞘（CDM）病变缺乏巨噬细胞和淋巴细胞浸润。由于活跃脱髓鞘皮层病变在这个晚期是稀疏的，因此很难描述皮层损伤背后的机制。我们之前资助的研究重点是早期活检和尸检MS病例，发现CDM发生得很早；可引起炎症；脑膜炎症很明显。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症和皮质病理在促进MS疾病过程中的作用的新假设。我们假设皮质病理可能是MS的早期事件，并且与早期脑膜炎症有关。我们将定义早期MS队列中CDM的频率和范围，并确定其与早期和晚期疾病中脑膜聚集物的关系。我们提出髓鞘特异性T细胞与脑膜抗原呈递细胞（APCs）之间的接触发生在蛛网膜下腔（SAS）的早期；扩大髓磷脂特异性T细胞；并产生新的记忆细胞，通过脑脊液传输到颈部淋巴结（LN），促进基底下糖尿病。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。我们的初步数据表明，在SAS和CDM病变中均存在髓磷脂富集的巨噬细胞。我们假设CDM产生巨噬细胞/树突状细胞，携带髓鞘抗原和运输决定因素，表明有能力通过脑脊液进入淋巴结并维持（自身）免疫。我们的目的是表征这些细胞是否具有成熟的树突状表型。我们已经发现早期多发性硬化症时的脑膜炎症。我们认为这些早期的脑膜聚集为SAS中持久的淋巴样聚集奠定了基础，这些淋巴样聚集导致进展性多发性硬化症中持续的皮质损伤。我们将描述这些浸润的早期淋巴样聚集特征。我们发现t细胞炎症可能在早期CDM中突出，但比WM病变更短暂。我们认为这种短暂的炎症与皮层T细胞上LN运输趋化因子的表达有关，这促进了它们的快速退出。我们将检查CDM和WM病变中的T细胞，以寻找这些运输决定因素。我们提出CDM和炎症介导皮质损伤，而基底下DM的发生机制与在WM基础病变中观察到的机制不同。我们将描述和定义皮层病变中炎症和神经退行性病理之间的关系，并就DM的靶点和机制比较CDM和WM病变。这些实验提出了新的假设；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；建立在我们独特的良好表型组织资源；并且具有发现新的治疗靶点的潜力。公共卫生相关性：MS的大多数治疗和研究工作都集中在白质病变上，然而最近的研究表明，大脑表面（称为皮层）广泛的脱髓鞘被认为是进行性残疾的一个重要原因。为了更好地了解组织损伤的潜在机制，以及它与MS白质病变的关系，目前的建议是研究MS早期疾病患者的皮质病变。为了更好地了解疾病发生、演变和进展的发病机制，需要研究早期MS皮质脱髓鞘的原因及其与白质病理的关系，并希望最终为MS患者制定更有效的治疗策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Most treatment and research efforts in MS have focused on white matter lesions, however recent studies indicate evidence for widespread demyelination of the brain surface called the cortex, which is thought to be an important cause of progressive disability. The current proposal studies cortical lesions from MS patients with early disease, in order to better understand the mechanisms underlying the tissue damage, and how it relates to white matter MS lesions. Studies examining the causes of cortical demyelination in early MS and its relationship to white matter pathology are needed in order to better understand the pathogenesis of disease initiation, evolution, and progression, in the hope of ultimately developing more effective therapeutic strategies for MS patients.