Mechanisms of Multiple Sclerosis Tissue Pathology

多发性硬化症组织病理学机制

• 批准号: 8065972
• 负责人: Claudia F. Lucchinetti
• 金额: $ 32.52万
• 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/8065972
• 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; Health; 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; 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(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；由有组织的晚期脑膜炎症驱动；皮质脱髓鞘(CDM)损害缺乏巨噬细胞和淋巴细胞渗透。由于活跃的脱髓鞘皮质损害在这个晚期是稀疏的，很难描述皮质损害背后的机制。我们之前资助的研究集中在早期活检和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；脑膜炎是突出的。这些发现与最近显示MS早期皮质损害的磁共振报告非常一致。结合最近的实验报告，我们提出了关于脑膜炎和皮质病理在促进MS疾病过程中的作用的新假说(S)。我们假设皮质病理可能是多发性硬化症的早期事件，并且与早期脑膜炎症有关。我们将确定早期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。我们认为，来自外周的髓鞘特异性T细胞与脑膜抗原提呈细胞(APC)之间的接触发生在蛛网膜下腔(SAS)早期；扩增髓鞘特异性T细胞；并产生新的记忆细胞，通过脑脊液(CSF)运输到颈淋巴(LN)，促进硬膜下DM。我们将描述SAS中T细胞和APC的特征，并确定T细胞与APC接触的性质。我们的初步数据显示，在SAS和CDM病变中都有髓鞘巨噬细胞。我们假设CDM产生的巨噬细胞/树突状细胞携带髓鞘抗原并携带运输决定因素，这些决定因素表明有能力通过脑脊液进入淋巴结并保持(自身)免疫。我们的目标是确定这些细胞是否具有成熟的树突状表型。我们已经确定了MS早期的脑膜炎症，我们认为这些早期的脑膜聚集物为SAS中持续存在的淋巴聚集物奠定了基础，这些淋巴聚集物在进展性MS中驱动着持续的皮质损害。我们将对这些浸润物进行特征分析，以寻找早期淋巴聚集物的特征。我们发现T细胞炎症可能在早期CDM中显著，但比WM病变更短暂。我们认为这种短暂的炎症与皮质T细胞上LN转运趋化因子的表达有关，这种表达促进了它们的快速退出。我们将检查CDM和WM病变中的T细胞以寻找这些转运决定因素。我们认为CDM和炎症介导了皮质损伤，而硬膜下DM的发生机制与西医损害不同。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，并就DM的靶点和机制比较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的基础上；并具有识别新治疗靶点的潜力。公共卫生相关性：多发性硬化症的大多数治疗和研究努力都集中在白质损害上，然而最近的研究表明，有证据表明大脑表面被称为皮质的广泛脱髓鞘，这被认为是进行性残疾的重要原因。目前的方案研究了患有早期疾病的多发性硬化症患者的皮质损害，以更好地了解组织损害的潜在机制，以及它与白质多发性硬化症损害的关系。为了更好地了解疾病的发生、发展和发展的机制，有必要研究MS早期皮质脱髓鞘的原因及其与白质病理的关系，以期最终为MS患者制定更有效的治疗策略。