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）：多发性硬化症（MS）研究主要集中在白质（WM）病理上，但是最近对晚期疾病的MS组织的研究表明皮层损害是残疾的重要相关性。由有组织的晚期脑膜炎驱动；皮质脱髓鞘（CDM）病变缺乏巨噬细胞和淋巴细胞浸润。由于在这个晚期呈主动脱髓鞘的皮质病变稀疏，因此很难表征皮质损伤背后的机制。我们先前的资助研究重点是早期活检和尸检病例，并揭示了CDM的发生。可能是炎症的；脑膜炎的炎症很突出。这些发现与最近的MRI报告非常相关，证明了早期MS的皮质损伤。在最近的实验报告中，我们提出了有关脑膜炎和皮质病理学在促进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，并且与早期脑膜炎有关。我们将在早期MS队列中定义CDM的频率和程度，并确定其与早期和晚期疾病中脑膜骨料的关系。我们提出，在蛛网膜下腔（SAS）的早期，来自周围和脑膜抗原呈递细胞（APC）的髓磷脂特异性T细胞（APC）之间接触。扩展髓磷脂特异性T细胞；并生成新的记忆细胞，这些记忆细胞通过CSF传播到宫颈淋巴结（LN），从而促进下型DM。我们将表征SAS中的T细胞和APC，并定义T细胞APC触点的性质。我们的初步数据证明了SAS和CDM病变中的髓磷脂巨噬细胞。我们假设CDM会产生巨噬细胞/树突状细胞，这些细胞用髓磷脂抗原和轴承运输决定因素，表明能够通过CSF访问淋巴结并永久免疫（自动）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。我们已经确定了MS早期脑膜炎。我们建议这些早期的脑膜骨料为SAS中的持久淋巴骨料奠定了基础，这些淋巴骨料在渐进式MS中造成了持续的皮质损伤。我们将表征这些浸润物，以表明早期淋巴骨料特征的适应症。我们发现T细胞炎症在早期CDM中可能是突出的，但比WM病变更短暂。我们提出这种瞬时炎症与在皮质T细胞上的LN运输趋化因子的表达有关，从而促进其快速退出。我们将研究这些运输决定因素的CDM和WM病变中的T细胞。我们提出CDM和炎症介导皮质损伤，该亚型DM将通过与基于WM的病变中观察到的机制进行的机制。我们将表征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DM的靶标和机制CDM和WM病变。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病理学的致病性相关性；基于我们独特的表型组织资源；并具有辨别新的治疗靶标的潜力。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，但是最近的研究表明，称为皮质的脑表面广泛脱髓鞘的证据，这被认为是造成渐进式残疾的重要原因。目前的提案研究MS早期疾病患者的皮质病变，以便更好地了解组织损伤的机制以及与白质MS病变的关系。为了更好地理解疾病起步，进化和进展的发病机理，以期最终为MS患者制定更有效的治疗策略，需要研究早期MS及其与白质病理的关系的研究及其与白质病理学的关系。