Mechanisms of Multiple Sclerosis Tissue Pathology

多发性硬化症组织病理学机制

• 批准号: 8259696
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259696
• 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; repaired; research study; tissue resource; trafficking; white matter; white matter change

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.

多发性硬化症（MS）研究主要集中在白质（WM）病理上，但是最近的研究 在晚期疾病的MS组织上表明皮质损伤是残疾的重要相关。被驱动 通过有组织的晚期脑膜炎；和皮质脱髓鞘（CDM）病变缺乏巨噬细胞和 淋巴细胞浸润。由于在这个后期积极脱髓鞘的皮质病变很少 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 和尸检病例和揭示CDM的发生较早发生；可能是炎症的；脑膜炎的炎症是 著名的。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 与最近的实验报告有关的音乐会，我们提出了有关脑膜作用的新假设 促进MS疾病过程的炎症和皮质病理。我们假设皮质病理学 可以是MS的早期事件，并且与早期脑膜炎有关。我们将定义频率和 CDM在早期MS队列中的范围，并确定其与晚期和晚期脑膜骨料的关系 疾病。我们提出了来自周围和脑膜抗原的髓磷脂特异性T细胞之间的接触 呈现细胞（APC）发生在蛛网膜下腔（SAS）的早期；扩展髓磷脂特异性T细胞；和 通过CSF生成新的记忆细胞，该记忆细胞通过CSF促进宫颈淋巴结（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接触的性质。我们的初步数据 在SAS和CDM病变中展示了髓磷脂巨噬细胞。我们假设CDM生成 巨噬细胞/树突状细胞用髓磷脂抗原和轴承运输决定因素指示 通过CSF和永久免疫获得淋巴结的能力。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 渐进式MS中正在进行的皮质损伤。我们将表征这些浸润物以提早指示 淋巴骨料特征。我们发现T细胞炎症在早期CDM中可能很突出，但更短暂 比WM病变。我们提出这种瞬时炎症与LN运输趋化因子的表达有关 促进其快速退出的皮质T细胞。我们将研究CDM和WM病变中的T细胞 贩运决定因素。我们提出CDM和炎症介导皮层损伤，该亚皮亚DM将会 按照与基于WM的病变观察到的机制进行的。我们将描述和定义 皮质病变中炎症性和神经退行性病理学之间的关系，并比较CDM 与DM的靶标和机制有关的WM病变。这些针对小说的实验 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；建造 在我们独特的表型组织资源上；并具有辨别新的治疗靶标的潜力。

项目成果

Pathologic heterogeneity persists in early active multiple sclerosis lesions.

• DOI: 10.1002/ana.24163
• 发表时间: 2014-05
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Metz, Imke;Weigand, Stephen D.;Popescu, Bogdan F. G.;Frischer, Josa M.;Parisi, Joseph E.;Guo, Yong;Lassmann, Hans;Brueck, Wolfgang;Lucchinetti, Claudia F.
• 通讯作者: Lucchinetti, Claudia F.

Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.

• DOI: 10.1093/brain/awn098
• 发表时间: 2008-07
• 期刊: BRAIN
• 影响因子: 14.5
• 作者: Lucchinetti, C. F.;Gavrilova, R. H.;Metz, I.;Parisi, J. E.;Scheithauer, B. W.;Weigand, S.;Thomsen, K.;Mandrekar, J.;Altintas, A.;Erickson, B. J.;Koenig, F.;Giannini, C.;Lassmann, H.;Linbo, L.;Pittock, S. J.;Brueck, W.
• 通讯作者: Brueck, W.

The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica.

• DOI: 10.1111/bpa.12099
• 发表时间: 2014-01
• 期刊: Brain pathology (Zurich, Switzerland)
• 作者: Lucchinetti CF;Guo Y;Popescu BF;Fujihara K;Itoyama Y;Misu T
• 通讯作者: Misu T

Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2.

• DOI: 10.1084/jem.20081241
• 发表时间: 2008-10-27
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Hinson, Shannon R.;Roemer, Shanu F.;Lucchinetti, Claudia F.;Fryer, James P.;Kryzer, Thomas J.;Chamberlain, Jayne L.;Howe, Charles L.;Pittock, Sean J.;Lennon, Vanda A.
• 通讯作者: Lennon, Vanda A.

Inflammatory cortical demyelination in early multiple sclerosis.

• DOI: 10.1056/nejmoa1100648
• 发表时间: 2011-12-08
• 期刊: The New England journal of medicine
• 作者: Lucchinetti CF;Popescu BF;Bunyan RF;Moll NM;Roemer SF;Lassmann H;Brück W;Parisi JE;Scheithauer BW;Giannini C;Weigand SD;Mandrekar J;Ransohoff RM
• 通讯作者: Ransohoff RM