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）的研究主要集中在白质（WM）病理上，然而最近的研究

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.

病理确认的曲霉多发性硬化症的临床和放射学光谱。

• 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.

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

神经霉素炎患者Optica患者的Aquaporin-4结合自身抗体通过下调EAAT2损害谷氨酸的转运。

• 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.

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

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