自身耐受和免疫异常与免疫介导的炎症性疾病

自身耐受和免疫调节异常与免疫介导的炎症性疾病

吕昌龙中国医科大学免疫研究所ActivationEffectorTcellsNormal:reactionsagainstpathogensInflammatorydisease,e.g.reactionsagainstselfToleranceRegulatoryTcellsNoresponsetoselfControlledresponsetopathogensBalancinglymphocyteactivationandcontrol免疫调节的重要性

避免正常抗感染免疫应答过程中出现过量淋巴细胞活化造成组织损伤。防止不适当的抗自身抗原的免疫应答（“自身耐受”）。免疫调控机制失调会诱发免疫介导的炎症性疾病。免疫调节的方式免疫耐受中枢性耐受外周性耐受免疫细胞调节——调节性T细胞作用免疫耐受定义:

淋巴细胞接触抗原后被诱导的针对该抗原的特异性不应答。该种抗原被称为耐受原。意义:所个体均存在针对自身抗原的耐受性（称自身耐受）。打破自身耐受就会引起自身免疫性疾病。治疗价值：诱导耐受可用于预防移植排斥、治疗自身免疫性和变态反应性疾病。自身免疫自身免疫与自身免疫病：自身免疫：抗自身抗原的免疫应答。自身免疫病：自身免疫应答对机体造成病理性损伤。此种疾病通常被分类为“免疫介导的炎症性疾病”。总体特点:发生机制:易感基因+环境诱发全身性和器官特异性Theprincipalfateoflymphocytesthatrecognizeselfantigensinthegenerativeorgansisdeath(deletion),BUT:SomeBcellsmaychangetheirspecificity(called“receptorediting”)SomeCD4Tcellsmaydifferentiateintoregulatory(suppressive)TlymphocytesCentralandperipheraltoleranceFromAbbas,LichtmanandPillai.CellularandMolecularImmunology6thed,2007ConsequencesofselfantigenrecognitioninthymusFrom:Abbas&Lichtman,Cellular&MolecularImmunology5thed2003APCTCRTcellCD28

ActivatedTcellsAPCTCRFunctionalunresponsivenessNormalTcellresponseAnergyApoptosis(activation-inducedcelldeath)APCDeletionAPC

BlockinactivationSuppressionRegulatoryTcellPeripheraltoleranceOffsignalsActivatedTcellTcellanergy“Activation-inducedcelldeath”:deathofmatureTcellsuponrecognitionofselfantigensFromAbbasandLichtman.BasicImmunology2nded,2006BothpathwayscooperatetopreventreactionsagainstselfRegulatoryTcells

FromAbbas,LichtmanandPillai.CellularandMolecularImmunology6thed,2007TRegulatoryCellPropertiesPropertyNaturalTreg(nTreg)InducedTreg(iTreg)-Tr1InducedTreg(iTreg)-Th3DevelopmentThymusPeriphery(MALT)Periphery(MALT)PhenotypeCD4+CD25+CD127lowCD4+CD25-CD4+CD25+fromCD25-precursorsOtherAssociatedMarkersCTLA-4+GITR+Foxp3+CD45RBlowFoxp3-CD25low-variableCD45RBlowFoxp3+SuppressionContact-,Granzyme-Bdependent,makesTGFbetaIL-10mediatedTGFbetamediatedTargetCellsAPCandEffectorTCellsEffectorTCellsUnknownCD28InvolvementThymicdevelopmentandmaintenanceinperipheryUnnecessaryfordevelopmentorfunctionUnnecessaryfordevelopmentorfunctioninvivoRoleSuppressionofautoreactiveTcells，anddendriticcellsMucosalimmunity,inflammatoryresponseMucosalimmunity,inflammatoryresponseinvitroExpansionTCR/CD28stimulationandIL-2CD3,IL-10,RetinoicAcidCD3,TGFbetaPeripheral(adaptive,inducible)regulatoryTcellsDevelopfrommatureCD4TcellsthatareexposedtopersistentantigenintheperipheryMaybegeneratedinallimmuneresponses,tolimitcollateraldamageCanbeinducedinvitro(stimulationofCD4T-cellsinpresenceofTGF+IL-2)WhatfactorsdeterminethebalanceofeffectorcellsandTreg?SignalsforthegenerationandmaintenanceofregulatoryTcellsAntigenrecognition,withorwithoutinflammation?TGF-(source?)Interleukin-2(originallyidentifiedasTcellgrowthfactor;majorfunctionistocontrolimmuneresponsesbymaintainingfunctionalTreg;worksviaStat5)LowlevelsofB7:CD28costimulationTranscriptionfactorFoxp3ManyactivatedTcells(notonlyTreg)maytransientlyexpressFoxp3cellulartherapywith

RegulatoryTcells?SomeautoimmunediseasesareassociatedwithdefectivegenerationorfunctionofTregsorresistanceofeffectorcellstosuppressionbyTregsWillcellulartherapywithexvivoexpandedTregbecomeareality?Therapeuticgoal:selectiveinductionoractivationofTreginimmunediseasesImmune-mediatedinflammatorydiseasesChronicdiseaseswithprominentinflammation,oftencausedbyfailureoftoleranceorregulationRA,IBD,MS,psoriasis,manyothersAffect2-5%ofpeople,incidenceincreasingMayresultfromimmuneresponsesagainstselfantigens(autoimmunity)ormicrobialantigens(Crohn’sdisease?)MaybecausedbyTcellsandantibodiesMaybesystemicororgan-specificPathogenesisofautoimmunitySusceptibilitygenesEnvironmentaltrigger(e.g.infections,tissueinjury)Failureofself-toleranceActivationofself-reactivelymphocytesImmuneresponsesagainstselftissuesPersistenceoffunctionalself-reactivelymphocytesGeneticsofautoimmunityHumanautoimmunediseasesarecomplexpolygenictraitsIdentifiedbygenome-wideassociationmappingSinglegenemutationsareusefulforpathwayanalysisSomepolymorphismsareassociatedwithmultiplediseasesMaycontrolgeneralmechanismsoftoleranceandimmuneregulationOthergeneticassociationsaredisease-specificMayinfluenceend-organdamageNOD2:polymorphismassociatedwith~25%ofCrohn’sdiseaseMicrobialsensorPTPN22:commonestautoimmunity-associatedgene;polymorphisminRA,SLE,othersPhosphataseCD25(IL-2R):associatedwithMS,others;genome-wideassociationmappingRoleinTregsGeneticsofautoimmunity:recentsuccessesofgenomicsInfectionsandautoimmunityInfectionstriggerautoimmunereactionsClinicalprodromes,animalmodelsAutoimmunitydevelopsafterinfectioniseradicated(i.e.theautoimmunediseaseisprecipitatedbyinfectionbutisnotdirectlycausedbytheinfection)Someautoimmunediseasesarepreventedbyinfections(type1diabetes,multiplesclerosis,others?--increasingincidenceindevelopedcountries):mechanismunknownThe“hygienehypothesis”卫生假说的内容

卫生假说指出，过敏性疾病的发病率不断上升与现代生活方式有关。高水平的生活环境和卫生条件同过敏性疾病发生的危险性增加密切相关。由于暴露于环境中微生物及其产物机会的减少，这些环境因素对过敏性疾病的预防潜能无论在质还是量方面都不能足够存在，结果导致免疫系统功能失衡，过敏性疾病发生。因此说，过敏性疾病的发生是基于患者同环境因素之间复杂相互作用的结果。

ThenatureofthediseaseisdeterminedbythetypeofdominantimmuneresponseTh1response:inflammation,autoantibodyproduction;autoimmunediseasesTh2response:IgE+eosinophil-mediatedinflammation;allergicreactionsTh17response:acute(andchronic?)inflammation;increasinglyrecognizedinimmune-mediateddiseasesTh1cells(IFN-g)Th2cells(IL-4,IL-5)Th17cells(IL-17)NaïveCD4TcellCD4subsets:generationandfunctionRegulatoryTcellsIFN-,IL-12:T-bet,Stat4IL-4:GATA3,Stat6TGF-+IL-6:

RORt,Stat3TGF-IL-2:Foxp3,Stat5Hostdefense:manymicrobesSystemicandorgan-specificautoimmunediseasesHostdefense:helminthsAllergicdiseasesHostdefense:fungi,bacteriaOrgan-specificautoimmunediseasesImmunologicaldiseasestendtobechronicandself-perpetuating,because–Theinitiatingtriggercanoftennotbeeliminated(selfantigen,commensalmicrobes)Theimmunesystemcontainsmanybuilt-inamplificationmechanismswhosenormalfunctionistooptimizeourabilitytocombatinfections“Epitopespreading”“Molecularminicry”Amplificationloopincell-mediatedimmunityCytokinesarepowerfulamplifiersofimmunereactionsAfteramicrobialinfection,activa-tedmicrobe-speci-ficTH1(mTH1)cellsmigratetotheinfectedorgan.

A.Molecularmimicry.

B.Epitopespre-ading.

C.Bystanderactivation.

D.Crypticantigen.Pathogenesisoforgan-specificautoimmunityCurrenttherapiestargetlatestagesofthereaction(lymphocyteactivation,inflamm