多发性硬化中适应性免疫细胞的致病机制
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摘要
多发性硬化(multiple sclerosis, MS)是发生于中枢神经系统(central nervous system, CNS)的慢性进行性免疫炎性疾病,伴随少突胶质细胞、神经元和轴索的破坏。近年来研究发现,外周淋巴细胞(包括T细胞、B细胞及其亚群)在中枢神经系统的浸润作为MS的早期标志之一,在其发病和发展中起到重要作用,但其中许多细胞亚群的具体作用机制尚不明确。该综述通过总结最新研究结果,探讨外周适应性免疫细胞与中枢神经系统炎症关系以及不同种类适应性免疫细胞在MS中行使的功能。
Multiple sclerosis(MS) is a chronic progressive inflammatory disease with highly heterogeneous, chronic inflammatory and demyelinating perivascular lesions within the central nervous system(CNS). Recent studies have found that as one of the early signs of MS, the infiltration of the peripheral lymphocytes(including T cells, B cells and their subsets) in CNS plays an important role in the initiation and development of the disease. However, the specific function of these cells remains unclear. Here we give an overview on how peripheral adaptive immune cells present in CNS inflammation and summarize the latest researches of MS pathogenesis in order to understand how adaptive immune cells may contribute to the disease.
Multiple sclerosis(MS) is a chronic progressive inflammatory disease with highly heterogeneous, chronic inflammatory and demyelinating perivascular lesions within the central nervous system(CNS). Recent studies have found that as one of the early signs of MS, the infiltration of the peripheral lymphocytes(including T cells, B cells and their subsets) in CNS plays an important role in the initiation and development of the disease. However, the specific function of these cells remains unclear. Here we give an overview on how peripheral adaptive immune cells present in CNS inflammation and summarize the latest researches of MS pathogenesis in order to understand how adaptive immune cells may contribute to the disease.
引文
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[2]孙博,李呼伦.在多发性硬化的免疫病理过程中不同免疫细胞的作用.中国免疫学杂志,2015,31:1585-90
[3]Chavan SS,Pavlov VA,Tracey KJ.Mechanisms and therapeutic relevance of neuro-immune communication.Immunity,2017,46:927-42
[4]Bielekova B,Goodwin B,Richert N,et al.Encephalitogenic potential of the myelin basic protein peptide(amino acids83-99)in multiple sclerosis:results of a phase II clinical trial with an altered peptide ligand.Nat Med,2000,6:1167-75
[5]Stern JN,Yaari G,Vander Heiden JA,et al.B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.Sci Transl Med,2014,6:248ra107
[6]Prinz M,Priller J.The role of peripheral immune cells in the CNS in steady state and disease.Nat Neurosci,2017,20:136-44
[7]Hussain RZ,Hayardeny L,Cravens PC,et al.Immune surveillance of the central nervous system in multiple sclerosis--relevance for therapy and experimental models.J Neuroimmunol,2014,276:9-17
[8]Drago D,Basso V,Gaude E,et al.Metabolic determinants of the immune modulatory function of neural stem cells.JNeuroinflammation,2016,13:232
[9]Ransohoff RM,Hafler DA,Lucchinetti CF.Multiple sclerosis--a quiet revolution.Nat Rev Neurol,2015,11:134-42
[10]Boulicault D,Duddy M.NICE approval of dimethyl fumarate could benefit thousands living with relapsingremitting multiple sclerosis.Neurodegener Dis Manag,2015,5:7-10
[11]Dolati S,Babaloo Z,Jadidi-Niaragh F,et al.Multiple sclerosis:therapeutic applications of advancing drug delivery systems.Biomed Pharmacother,2017,86:343-53
[12]Dendrou CA,Fugger L,Friese MA.Immunopathology of multiple sclerosis.Nat Rev Immunol,2015,15:545-58
[13]Xiao J,Yang R,Biswas S,et al.Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis.Int J Mol Sci,2015,16:9283-302
[14]Kallaur AP,Lopes J1,Oliveira SR,et al.Immuneinflammatory and oxidative and nitrosative stress biomarkers of depression symptoms in subjects with multiple sclerosis:increased peripheral inflammation but less acute neuroinflammation.Mol Neurobiol,2016,53:5191-202
[15]Legroux L,Arbour N.Multiple sclerosis and T lymphocytes:an entangled story.J Neuroimmune Pharmacol,2015,10:528-46
[16]Henderson AP,Barnett MH,Parratt JD,et al.Multiple sclerosis:distribution of inflammatory cells in newly forming lesions.Ann Neurol,2009,66:739-53
[17]Fischer MT,Sharma R,Lim JL,et al.NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.Brain,2012,135:886-99
[18]Yamasaki R,Lu H,Butovsky O,et al.Differential roles of microglia and monocytes in the inflamed central nervous system.J Exp Med,2014,211:1533-49
[19]Dargahi N,Katsara M,Tselios T,et al.Multiple sclerosis:immunopathology and treatment update.Brain Sci,2017,7:E78
[20]Kraus V,Srivastava R,Kalluri SR,et al.Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease.Neurology,2014,82:470-3
[21]Wu C,Ivars F,Anderson P,et al.Endothelial basement membrane lamininα5 selectively inhibits T lymphocyte extravasation into the brain.Nat Med,2009,15:519-27
[22]Larochelle C,Alvarez JI,Prat A.How do immune cells overcome the blood-brain barrier in multiple sclerosis?FEBS Lett,2011,585:3770-80
[23]Corcione A,Casazza S,Ferretti E,et al.Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis.Proc Natl Acad Sci USA,2004,101:11064-9
[24]Winges KM,Gilden DH,Bennett JL,et al.Analysis of multiple sclerosis cerebrospinal fluid reveals a continuum of clonally related antibody-secreting cells that are predominantly plasma blasts.J Neuroimmunol,2007,192:226-34
[25]Mistry N,Abdel-Fahim R,Mougin O,et al.Cortical lesion load correlates with diffuse injury of multiple sclerosis normal appearing white matter.Mult Scler,2014,20:227-33
[26]Obermeier B,Mentele R,Malotka J,et al.Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis.Nat Med,2008,14:688-93
[27]Bell JS,Spencer JI,Yates RL,et al.The cortical bloodbrain barrier in multiple sclerosis:a gateway to progression?J Neurol,2018,265:966-7
[28]Clarelli F,Liberatore G,Sorosina M,et al.Pharmacogenetic study of long-term response to interferon-βtreatment in multiple sclerosis.Pharmacogenomics J,2017,17:84-91
[29]Kumar BV,Connors TJ,Farber DL.Human T cell development,localization,and function throughout life.Immunity,2018,48:202-13
[30]Polman CH,O'Connor PW,Havrdova E,et al.Arandomized,placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med,2006,354:899-910
[31]Steinman L.A brief history of TH17,the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage.Nat Med,2007,13:139-45
[32]Popescu BF,Lucchinetti CF.Pathology of demyelinating diseases.Annu Rev Pathol,2012,7:185-217
[33]Lalive PH,Neuhaus O,Benkhoucha M,et al.Glatiramer acetate in the treatment of multiple sclerosis:emerging concepts regarding its mechanism of action.CNS Drugs,2011,25:401-14
[34]Compston A,Coles A.Multiple sclerosis.Lancet,2002,359:1221-31
[35]Rostami A,Ciric B.Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination.J Neurol Sci,2013,333:76-87
[36]Volpe E,Battistini L,Borsellino G.Advances in T helper17 cell biology:pathogenic role and potential therapy in multiple sclerosis.Mediators Inflamm,2015,2015:475158
[37]Codarri L,Gyülvészi G,Tosevski V,et al.RORγT drives production of the cytokine GM-CSF in helper T cells,which is essential for the effector phase of autoimmune neuroinflammation.Nat Immunol,2011,12:560-7
[38]杨帆,顔光涛,李涛.多发性硬化相关T细胞免疫机制的研究进展.免疫学杂志,2013,29:452-6
[39]Tzartos JS,Friese MA,Craner MJ,et al.Interleukin-17production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.Am J Pathol,2008,172:146-55
[40]Kleinewietfeld M,Hafler DA.Regulatory T cells in autoimmune neuroinflammation.Immunol Rev,2014,259:231-44
[41]McGeachy MJ,Stephens LA,Anderton SM.Natural recovery and protection from autoimmune encephalomyelitis:contribution of CD4+CD25+regulatory cells within the central nervous system.J Immunol,2005,175:3025-32
[42]Martin AJ,Zhou L,Miller SD.MicroRNA-managing the TH-17 inflammatory response.Nat Immunol,2009,10:1229-31
[43]Camperio C,Muscolini M,Volpe E,et al.CD28 ligation in the absence of TCR stimulation up-regulates IL-17Aand pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes.Immunol Lett,2014,158:134-42
[44]Bin Dhuban K,d'Hennezel E,Nashi E,et al.Coexpression of TIGIT and FCRL3 identifies Helios+human memory regulatory T cells.J Immunol,2015,194:3687-96
[45]Friese MA,Jakobsen KB,Friis L,et al.Opposing effects of HLA class I molecules in tuning autoreactive CD8+Tcells in multiple sclerosis.Nat Med,2008,14:1227-35
[46]Serafini B,Rosicarelli B,Magliozzi R,et al.Dendritic cells in multiple sclerosis lesions:maturation stage,myelin uptake,and interaction with proliferating T cells.JNeuropathol Exp Neurol,2006,65:124-41
[47]Bianchini E,De Biasi S,Simone AM,et al.Invariant natural killer T cells and mucosal-associated invariant Tcells in multiple sclerosis.Immunol Lett,2017,183:1-7
[48]Lolli F,Martini H,Citro A,et al.Increased CD8+T cell responses to apoptotic T cell-associated antigens in multiple sclerosis.J Neuroinflammation,2013,10:94
[49]Willing A,Leach OA,Ufer F,et al.CD8+MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis.Eur J Immunol,2014,44:3119-28
[50]Annibali V,Ristori G,Angelini DF,et al.CD161(high)CD8+T cells bear pathogenetic potential in multiple sclerosis.Brain,2011,134:542-54
[51]Gonzalez H,Pacheco R.T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases.J Neuroinflammation,2014,11:201
[52]Sato S,Yamamoto K,Matsushita T,et al.Copy number variations in multiple sclerosis and neuromyelitis optica.Ann Neurol,2015,78:762-74
[53]Maimaitijiang G,Shinoda K,Nakamura Y,et al.Association of decreased percentage of Vδ2+Vγ9+γδTcells with disease severity in multiple sclerosis.Front Immunol,2018,9:748
[54]Schneider P.The role of APRIL and BAFF in lymphocyte activation.Curr Opin Immunol,2005,17:282-9
[55]Palanichamy A,Apelts in L,Kuo T C,et al.Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis.Sci Transl Med,2014,6:248ra106
[56]Frischer JM,Bramow S,Dal-Bianco A,et al.The relation between inflammation and neurodegeneration in multiple sclerosis brains.Brain,2009,132:1175-89
[57]Claes N,Fraussen J,Stinissen P,et al.B cells are multifunctional players in multiple sclerosis pathogenesis:insights from therapeutic interventions.Front Immunol,2015,6:642
[58]Spadaro M,Gerdes LA,Krumbholz M,et al.Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis.Neurol Neuroimmunol Neuroinflamm,2016,3:257
[59]Blauth K,Soltys J,Matschulat A,et al.Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants.Acta Neuropathol,2015,130:765-81
[60]陈清清,桑道乾.多发性硬化相关B细胞免疫机制的研究进展.临床神经病学杂志,2017,30:157-9
[61]Kinnunen T,Chamberlain N,Morbach H,et al.Specific peripheral B cell tolerance defects in patients with multiple sclerosis.J Clin Invest,2013,123:2737-41
[62]Fraussen J,Claes N,de Bock L,et al.Targets of the humoral autoimmune response in multiple sclerosis.Autoimmun Rev,2014,13:1126-37
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