醫(yī)學(xué)神經(jīng)生物學(xué)：神經(jīng)免疫

神經(jīng)免疫Neuroimmune教學(xué)內(nèi)容1.神經(jīng)免疫學(xué)概論

神經(jīng)系統(tǒng)和免疫系統(tǒng)的異同點及雙向調(diào)節(jié)2.中樞神經(jīng)系統(tǒng)的免疫反應(yīng)

中樞神經(jīng)系統(tǒng)的特殊細(xì)胞、結(jié)構(gòu)及免疫反應(yīng)3.神經(jīng)系統(tǒng)免疫性疾病與神經(jīng)免疫相關(guān)性疾病

NeuroimmunologyNeuroimmunologyisafieldcombiningneuroscience,thestudyofthenervoussystem,

andimmunology,thestudyoftheimmunesystem.NervoussystemImmunesystemInnervationRegulationSympatheticinnervationofthespleenIntermediolateralnucleus中間外側(cè)核①能夠接受刺激；②具有識別能力；③呈現(xiàn)應(yīng)答反應(yīng)；④免疫細(xì)胞和神經(jīng)細(xì)胞的細(xì)胞膜上存在某些相似，

甚至相同的表面標(biāo)志物和受體；

GABAa/GABAb,DR1-5,Thy1/CD90Ach,Catecholamines⑤具有記憶功能。Similarity

NeuronalsynapseImmunologicalsynapseDifference①特異性；②記憶能力。BidirectionalinteractionbetweenneuralsystemandimmunesystemImmunereactioninCNSCellsinvolvedStructureofCNSImmunereaction

ImmunereactioninCNSCellsinvolved

EndothelialcellsMicrogliaAstrocytesOligodendrocytesNeuronsMicroglia

5-20%DerivedfromhematopoieticprogenitorsintheyolksacandenterthebrainduringembryonicdevelopmentFormingtheinnateimmunesystemofCNS造血前體細(xì)胞ThedevelopmentalrelationshipbetweenmicrogliaandmacrophagesRamifiedActivatedMicroglia“Sanitaryengineers”PhenotypicpolarizationofmicrogliaInvolvementofmicrogliaininnateandadaptiveimmunityPRR模式識別受體TLRs,RIG?I-likereceptors(RLRs),NOD-likereceptors(NLRs)andC?typelectinreceptorPAMP病原體相關(guān)分子模式TLR3-,TLR4-andTLR7-dependentinflammatorysignalling干擾素調(diào)節(jié)因子InflammagingNeuronsCX3CL1Neuron-derivedsignalsandrestingmicrogliaNeuronsExpressionofGABAAandGABABreceptorsinmicrogliaandastrocytesTheeffectsofinflammatorystimuliontheGABAergicsystemThemodulatoryeffectsoftheGABAergicsystemonneuroinflammationAstrocytes

纖維型原漿型Fibrous(inwhitematter),protoplasmic(ingreymatter),andradial20-40%ofallgliaLowexpressionofMHCandcostimulatorymolecules14APRIL2016|VOL532|NATURE|195GliomacellsandM2?likemicrogliaOligodendrocytesSensitivetoNO,glutamateandapoptoticstimuliRelativelyinert,rarelyparticipateintheimmuneresponseImmunereactioninCNS

StructureofCNS

bloodbrainbarrier/immuneprivilege

內(nèi)腔基底膜周細(xì)胞內(nèi)皮細(xì)胞緊密連接星形膠質(zhì)細(xì)胞腳板InnervascularBMOuterparenchymalBMDoesthelymphaticsystem

---awebofvesselsthathelpsclearwasteandtransportimmunecellsinthebody---extendintothebrainorstopintheneck?Meninges上矢狀竇硬腦膜蛛網(wǎng)膜軟腦膜Tcellmarker:CD3eLymphaticendothelialcellmarker:Lyve-1Nature2015上矢狀竇橫竇TheMeningealLymphaticsEnabletheDrainageofMacromoleculesandImmuneCellsTodeepcervicallymphnodes

頸深淋巴結(jié)BreakthroughoftheYearLymphaticvessels:Thebrain'swell-hiddensecretScienceImmunereactioninCNS

StructureofCNSimmuneprivilege

①缺乏抗原提呈細(xì)胞；②免疫細(xì)胞上MHC和Costimulatorymolecules的

表達非常低；③受較強的免疫抑制細(xì)胞控制；④有大量的免疫抑制因子。Blood–brainbarrierinhealthanddiseaseImmunereactioninCNSAbnormalimmunereactioninCNSOver-activationofmicrogliaIncreaseincytokinesChangesintheimmuneprivilegeenvironmentTNF-αIFN-γ抗原提呈炎性反應(yīng)TNF-αIL-1NOTH1靜息態(tài)的小膠質(zhì)細(xì)胞Over-activationofmicrogliaNameSourceTargetcellsFunctionIFN-

MicrogliaAstrocytesLymphocytesMicrogliaNeurons↑MHCⅡ，iNOS↑MHCⅠTNF-

MicrogliaAstrocytesNeuronsAstrocytesMicroglia↑MHCⅠ↑NO,gluatmate↑CSFIL-1βMicrogliaAstrocytesAstrocytesNeuronsInflammationIL-6MicrogliaAstrocytesNeuronsNeuronaltoxicityAbnormalimmunereactioninCNSIncreaseincytokinesAbnormalimmunereactioninCNSChangesintheimmuneprivilegeenvironmentIninfectionsorpathologicalconditions,activationofmicrogliaandastrocytestriggersanantigen-specificornon-specificimmuneresponseinCNS.Neuroimmunologicaldiseases

MS多發(fā)性硬化

GBS格林-巴利綜合癥

MG

重癥肌無力

NDD神經(jīng)退行性病

AD,

PD,ALS…WhatisMultipleSclerosis?MultipleSclerosis(MS)isanchronicinflammatorydemyelinatingdiseaseofthebrainandspinalcord.Klüver-BarreramyelinstainingHumanNervousSystemAreasaffectedbyMSBrainSpinalcordOpticnervesMSpathogenesis

1.Geneticfactors

2.Environmentalfactors

3.Viralinfection

4.Autoimmunemechanisms

(1)aleadingroleofcell-mediatedimmunity

(2)apotentialroleofhumoralimmunity

Geneticfactors單核苷酸多態(tài)性GeneticfactorsTcellspredominateinMSbrainlesionsLancetNeurol.2015LancetNeurol.2016FeaturesofacaseofMOG-antibody-associatedencephalomyelitis少突膠質(zhì)細(xì)胞糖蛋白Myelinoligodendrocyteglycoprotein,MOGMyelindegradationproductsActivatedcomplementInflammationinMultipleSclerosisGenderEAEcanbeinducedinmice,rats,guineapigs,rabbitsandprimates.Theantigensinrodentsarespinalcordhomogenate,purifiedmyelin,myelinproteins,orpeptidesoftheseproteins.EAEisalsotheprototypeforT-cell-mediatedautoimmune.Experimentalallergicencephalomyelitis(EAE)model實驗性變態(tài)反應(yīng)性腦脊髓炎InducedwithmyelinproteinMBPPassivetransferofTcells髓鞘堿性蛋白＋完全弗氏佐劑分級表現(xiàn)0無癥狀1鼠尾張力障礙2單側(cè)后肢的癱瘓3雙后肢癱瘓伴有前肢無力4四肢癱瘓5瀕死狀態(tài)或死亡EAEscoresGBSisarapid-onsetmuscleweaknesscausedbytheimmunesystemdamagingtheperipheralnervoussystem.Guillain–Barrésyndrome(GBS)急性炎性脫髓鞘性多發(fā)性神經(jīng)炎空腸彎曲菌GBSpathogenesis

1.Infection

2.Autoimmunemechanisms

(1)aleadingroleofcell-mediatedimmunity

(2)apotentialroleofhumoralimmunity

Campylobacterjejuni,CJMGisaneuromusculardiseasethatleadstofluctuatingmuscleweaknessandfatigue.Myastheniagravis(MG)重癥肌無力MGpathogenesis

1.Geneticfactors

2.Viralinfection

3.Autoimmunemechanisms

(1)aleadingroleofhumoralimmunity(2)asupportingroleofComplement

(3)Tcells(4)Thymus

CirculatingantibodiesthatblocknAChRADisachronicneurodegenerativedisease.Thesymptomisdifficultyinrememberingrecentevents(short-termmemoryloss).Asthediseaseadvances,symptomscanincludeproblemswithlanguage,disorientation,moodswings,lossofmotivation,notmanagingselfcare,andbehavioralissues.NDD---Alzheimer'sdiseaseAmyloidogenicprocessingofamyloidprecursorproteinActivationofmicrogliabyamyloidβ病原體相關(guān)分子模式Science，31March2016Microgliaengulfsynapticelementsviacomplementsignalinginpre-plaqueADbrainsOver-pruningsynapsesmaydriveearly-stageAlzheimer’sdisease.Alzheimer’smaybecausedbyhaywireimmunesystemeatingbrainconnections失控[11C](R)-PK11195PETimagesofapatientwithpredominantlyleft-hemisphericfrontotemporallobardementia額顳葉癡呆MarkerofactivatedmicrogliaChangesinmicrogliaandastrocytesinAlzheimer’sdiseaseADPatientADmouse