Mechanisms of Multiple Sclerosis Tissue Pathology

多发性硬化症组织病理学机制

• 批准号: 7883294
• 负责人: Claudia F. Lucchinetti
• 金额: $ 32.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883294
• 关键词: Acute; Acute Disseminated Encephalomyelitis; Address; Affect; Antibodies; Antigen-Presenting Cells; Antigens; Apoptosis; Attention; Autopsy; B-Lymphocytes; Biopsy; Brain; CCL21 gene; CD27 Antigens; CD3 Antigens; CD8B1 gene; Cells; Cervical; Cervical lymph node group; Complement; Data; Demyelinations; Dendritic Cells; Deposition; Diffuse; Disease; Elements; Event; Evolution; Experimental Autoimmune Encephalomyelitis; Frequencies; Funding; Immune; Immunity; In Situ; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Interleukin-17; Lesion; Leukocyte Trafficking; Ligands; Lymphocyte; Lymphocytic Infiltrate; Lymphoid; Lymphoid Tissue; MHC Class II Genes; MS4A1 gene; Magnetic Resonance Imaging; Mediating; Memory; Meningeal; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Myelin Associated Glycoprotein; Nature; Nerve Degeneration; Neurites; Neuromyelitis Optica; Neurons; Oligodendroglia; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Performance; Peroxidases; Phase; Phenotype; Plasma Cells; Process; Progressive Disease; Reporting; Research; Research Personnel; Role; S100A9 gene; Scheme; Series; Staging; Subarachnoid Space; Surface; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; White Matter Disease; animal data; base; chemokine; cohort; density; design; disability; experience; granzyme B; human tissue; injury and repair; lymph nodes; macrophage; neuropathology; new therapeutic target; novel; public health relevance; repaired; research study; tissue resource; trafficking; white matter; white matter change

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.

描述（由申请人提供）：多发性硬化（MS）研究主要集中在白色物质（WM）病理学上，然而，最近对晚期疾病MS组织的研究表明，皮质损伤是残疾的重要相关因素;由组织化晚期脑膜炎症驱动;皮质脱髓鞘（CDM）病变缺乏巨噬细胞和淋巴细胞浸润。由于活跃的脱髓鞘皮质病变在这个晚期阶段是稀疏的，因此很难描述皮质损伤背后的机制。我们先前资助的研究集中在早期活检和尸检MS病例上，发现CDM发生早期;可能是炎症性的;脑膜炎症很突出。这些研究结果与最近的MRI报告显示皮质损伤在早期MS。在最近的实验报告一致，我们提出了新的假设脑膜炎症和皮质病理学的作用（S）在促进MS疾病的过程。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相关。我们将在早期MS队列中确定CDM的频率和程度，并确定其与早期和晚期疾病中脑膜聚集体的关系。我们提出来自外周的髓鞘特异性T细胞和脑膜抗原呈递细胞（APC）之间的接触发生在蛛网膜下腔（SAS）的早期;扩增髓鞘特异性T细胞;并产生新的记忆细胞，其通过CSF运输到颈淋巴结（LN），促进软膜下DM。我们将在SAS中表征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病变中的载髓鞘巨噬细胞。我们假设CDM产生巨噬细胞/树突状细胞，其负载有髓鞘抗原，并具有指示通过CSF进入淋巴结和维持（自身）免疫的能力的运输决定簇。我们的目标是表征这些细胞是否具有成熟的树突状表型。我们已经确定在早期MS脑膜炎症。我们建议这些早期脑膜聚集体设置阶段，为长期持久的淋巴聚集体在SAS驱动进行性MS皮质损伤。我们将表征这些浸润的早期淋巴聚集体字符的迹象。我们发现，T细胞炎症可能是突出的早期CDM，但更短暂的WM病变。我们提出这种短暂的炎症与皮质T细胞上LN运输趋化因子的表达有关，这些趋化因子促进了它们的快速退出。我们将检查CDM和WM病变中的T细胞是否存在这些运输决定因素。我们建议CDM和炎症介导皮质损伤，软膜下DM将继续从WM为基础的病变中观察到的机制不同。我们将描述和定义皮质病变中炎症和神经退行性病变之间的关系，并比较CDM和WM病变与DM的靶点和机制。这些实验解决了新的假设;提供了一个难得的机会来评估动物数据与MS病理学的致病相关性;建立在我们独特的良好表型组织资源的基础上;并具有识别新治疗靶点的潜力。公共卫生关系：MS的大多数治疗和研究工作都集中在白色物质病变上，然而最近的研究表明，称为皮质的大脑表面广泛脱髓鞘的证据，这被认为是进行性残疾的重要原因。目前的提案研究了早期MS患者的皮质病变，以更好地了解组织损伤的机制，以及它如何与白色物质MS病变相关。为了更好地了解疾病的发生、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色病变的关系，以期最终为MS患者制定更有效的治疗策略。