*Definition*History（Earlyobservations

)*Mechanism CentralTolerance PeripheralTolerance*Induction(Acquiredtolerance)ImmunologicalToleranceImmunetoleranceor‘Immunologicaltolerance'istheprocessbywhichtheImmunesystemdoesnotattackanantigen.Specificimmunologicalunresponsivenesstoagivenantigen.Itoccursin2forms:naturaltolerance(selftolerance)andacquiredtolerance(inducedtolerance).DefinitionImmuneresponsevstoleranceImmunetoleranceisanactiveprocesswhichisdifferentfromimmunodeficiencyorimmunosuppression.Immunodeficiency:

AdisorderorstateinwhichtheImmunesystem’sabilitytofightinfectiousdiseaseiscompromisedorentirelyabsent.OverallInabilityoftheimmunesystemtorespondtoabroadrangeofantigens(geneticreasonorAIDS).Immunosuppression:

Aconditionwheretheactivationorefficacyoftheimmunesystemisreduced(inducedbyanimmunosuppressant).ImmunetoleranceSelftolerance:Individualsnormallydonotrespondtotheir"self“antigens,i.e.,theyare"tolerant"toself.Thisisthebasisforself-nonselfdiscriminationbytheimmunesystemtoensureimmunesystemnottoattackself.Lossofselftolerancecanleadtoautoimmunity.NaturalTolerance(selftolerance):Induced

unresponsivenesstoforeignAgs.Itcanbeusedtofacilitatetransplantationorwhentoleranceisnecessary(acquiredtolerance)AcquiredtoleranceEarlyObservations

RayOwen,1945Dizygoticcattletwinsthatsharedthesameplacentawerebloodcellchimaeras,iecontainedbloodcellsoftwodifferenthaplotypesinadultsand,-thesetwohaplotypesco-existedintheadultswithoutmutualrejection.RayOwenSuchchimaericcattlewillexchangeskingraftswithoutrejection.Normally,ifcellsofoneofthetwohaplotypesweretransferredtoanadultcattleoftheotherhaplotype,thesewerepromptlyrejected.Thus,toleranceinthedizygotictwinsresultedfromthesharingoftheplacentainfetallife.EarlyObservations

Burnet’sHypothesis:(1949)–Medawar’sexperiment(1953)EarlyObservations

BillinghamandMedawar

provedBurnet’sHypothesisEarlyObservations

EarlyObservations

Chimeric

mice1960

NobelPrizeHumanImmunology

Volume52,Issue2

*Definition*History-Earlyobservations*Mechanism*InductionImmunologicalTolerance

Centraltolerance

isthemechanismbywhichnewlydevelopingTcellsandBcellsarerenderednon-reactivetoselfduringtheirdevelopmentinthymusandbonemarrow.Mechanisms(Earlier)Positiveselection:

DuringpositiveselectionDouble-PositiveTcellsthatcanrecognizeselfMHCsareselectedforproliferation,andthoseTcellsthatdonotrecognizeselfMHCdieviaApoptosis.

PositiveselectionassuresTCR

torecognizeself-peptide/MHCcomplexandalsogowiththeappropriateCD4orCD8.Forexample,TCR‘sspecificforMHCIIneedtoretainCD4,andloseCD8.Ifthereverseoccurs,theywilldieviaapoptosis.ThesameistruefortheTcellsthatarespecificforMHCI,whichneedtoretainCD8,andloseCD4.ThymocytesarepositiveselectedbyMHC/selfpeptidesNegativeselection:

TcellsthatarestronglyactivatedbyselfMHCplusselfpeptidesneedtobeeliminatedinthethymus.complex.Iftheyescapethiselimination,theymaysubsequentlyreactagainstselfantigens,andcauseAutoimmunedisease.

CentralToleranceisachievedbynegativeselectionMixtureofcloneswithdifferentaffinitytoselfantigensPositiveselectedApoptosisbyneglectApoptosisbyAICD-NegativeselectedReleasedtoPeripheralACartoonviewofpositiveandnegativeselectionAvidityModel:AviditydependsontheaffinityoftheTCR-peptide/MHCinteractionandthedensityofthepeptide/MHConthethymicepithelialcell.Aviditydeterminesthestrengthofsignaldeliveredwhichdictatestheoutcome.Strongersignalsmaymeanlongersignalingoradditionalsignaling.ApoptosisofnegativeselectedcellsaremediatedbytheBclapoptosispathwayInsummary,PositiveselectionselectsforthoseTcellsthatreactwithMHC:selfantigen.NegativeselectioneliminatesthosethatreactstronglywithMHC:selfantigen.Thus,successfulTcelldifferentiationselectsforMHCrestrictedTCR'swithlowaffinityforselfantigens.TherationalehereisthataTcellthatbindsweaklytoselfMHC/selfAntigenwillnotbeactivatedbutwillbeactivatedbyastrongerbindingtoselfMHC/foreignAntigenSummaryofcentraltoleranceKisielowandvonBoehmer1988-HYtransgenicmiceHYtransgenicmicemadebyisolatingTCRaandbchaincDNAsfromCD8+CTLclonederivedfromH-2bfemalemouse.ThisTCRrecognizesamale-specificpeptideboundtoH-2Db.TheHYTCRtransgenepromotesthedevelopmentofSPCD8butnotCD4TcellsinH-2d/bbutnotinH-2d/dmice.EvidenceforpositiveselectionFemaleH-2d/bFemaleH-2d/d“selecting”“non-selecting”BackgroundBackgroundsEvidenceforNegativeselection.KisielowandvonBoehmer1988-HYtransgenicmiceHaraldvonBoehmerHarvardMedicalSchoolLigandsforPositiveandNegativeSelectionLigandsarenecessaryforbothpositiveandnegativeselection.(self-endogenouspeptide/MHCcomplexespresentedbystromalandhematopoieticcells）lowdosehighdoseParadox:ItiscriticaltodeletethymocytesexpressingTCRsthatwouldreactwithselfpeptidespresentedbyMHCmoleculesonBM-derivedAPCsintheperiphery.Somepeptidesarederivedfromcirculatingbloodcellsorserumcomponents.DeletionofTcellsinthethymusalsorequireslocalexpressionofthetissuespecificantigens(e.g.insulin,MBP).Whatcellinthethymusisexpressingself-proteins?Whatmakesthisparticularcelltoexpressallthesetissue-specificgenes?CentraltoleranceTheanswer:AlargevarietyoftissuespecificproteinsareexpressedinthethymusbyMEC(medullaryepithelialcell)CentraltoleranceTissue-restrictivegenesexpressedbyMECsButHow?Centraltolerance

AIRE(autoimmuneregulator):transcriptionfactorthatenablesectopicexpressioninthethymusofgenesusuallyconsideredtissue-specificNormalAIREknockoutFromM.Anderson,etal.(LaboratoryofC.BenoistandD.Mathis).JoslinDiabetesCenterandHarvardMedicalSchool;Science298:1395,2002SpontaneousAutoimmunediseaseinAIREknockoutmiceAutoantibodiesSpontaneousAutoimmunediseaseinAIREknockoutmiceOrgan-SpecificlymphocyteinfiltrationsDeletionofself-reactiveTcellsinthethymusAIRE(autoimmuneregulator)isaputativetranscriptionfactorthatstimulatesexpressionofmanyselfantigensininthethymusDianeMathisandChristopheBenoistCentraltoleranceDianeandChrisvisitingZJU2012TSAspresentationinthymusHumansexpressingadefectiveformofthetranscriptionfactorAIRE(autoimmuneregulator)developmultiorganautoimmunedisease.

Autoimmunepolyendocrinopathy-candidiasis-ectodermaldystrophy

(APECED)。APECED,alsoknownasautoimmunepolyendocrinesyndrome-type

1

(APS-1),isapolyglandulardisorderthatclassicallymanifests

asspontaneousautoimmunityagainsttheparathyroidand/oradrenal

glands,and/orbyamucocutaneouscandidiasisinfection.Othercommonailmentsinclude

autoimmuneformsofprematureovarianfailure,hepatitis,anemia,

diabetes,alopecia,andvitiligo.Itseemedreasonable

tohypothesizethatAPECEDpatientsdevelopmultiorganautoimmunity

becauseadefectinAIREpreventsormodifiesectopictranscription

ofgenesencodingperipheraltissue-restrictedantigensinthymic

MECs.APECEDinhumanAIREStructure&ExpressionTolerancetoselfdevelopedinthymus.Why?Self-reactivecellsdeletedinthymusIsself-antigensexpressedinthymus?where?MECscanexpressselfantigens.How?AIREdrivetheexpressionofselfantigensHowcanAIREdosuchajob?WhatregulatesAIREAIREresearchasaresearchmodelBcelltoleranceCentralBcelltoleranceinatransgenicmousemodelBcelltolerance

Peripheraltolerance

(ImmuneRegulation)

Whyweneedaperipheraltolerance?Someantigensarenotexpressedinthymusorbonemarrow,whichleadstothepossibilitytotriggerimmuneresponse.Negativeselectionisincomplete:Middletolowaffinityself-reactiveclonesarereleasedtoperipheralandcanbeactivatedundercertainconditions.Peripheraltolerance

isimmunetolerancedevelopedafterTandBcellsmatureandentertheperiphery.Thecellsarecontrolledthroughperipheraltolerancemechanisms.Mechanisms(Earlier)Antigensequestration(lensofeye,spermatozoa):Antigennotseenbytheimmunesystem.LowMHCexpression(i.e.hepatocytes):Lackorself-antigenpresentation.Immunologicallyprivilegedsites:OthermechanismsImmunologicalignorance交感性眼炎PeripheraltoleranceAnergyinducedwithoutco-stimulation*Mosttissuecellsdon’texpressco-stimulationreceptors*ProfessionalAPCsdon’texpressco-stimulationreceptorswithoutactivationPeripheralTcelltoleranceActivation-inducedCellDeath(AICD)*Persistentpresenceofself-antigengivesrepeatedstimulationPeripheralTcelltoleranceActivation-inducedCellDeath(AICD)DefectinFasorFasLtriggersAutoimmunityinmiceFasNormalFasLAutoimmunityandlymphoproliferativediseaseFasLFas+Fas-ALPSPatient:AnunusualmutationHealthyfemale-at18monthsdevelopedcervicaladenopathy(頸淋巴結(jié)腫大).Biopsyshowed‘reactivehyperplasia’Developedanemiawithhypersplenism,hematuria,proteinuriaandrenalinsufficiencyduetomesangialglomerulonephritis,thenprimarybiliaryinfiltration.EvaluationatNIH:lymphadenopathypersists,ANA(+)1:320,CD4-CD8-cells25%ofabTcells,increasedBcells;FassurfaceexpressionisnormalHeterozygousFassplicemutationresultinginlossofexons3,4(AA52-96)WTFasPT228661281742142985197del52-96TMTMPeripheralTcelltoleranceRegulatorycellsPeripheralTcelltolerance

IPEXOtherPeripheraltolerancedeterminantsCytokines：1.Limitedsupplyofpro-survivalcytokines(IL7forTcellandBAFFforBcells)；2.Secretion

ofsuppressivecytokinesTGF-beta,IL10Signalingpathways:Inhibitoryreceptors;negativeregulatorsincludingPhosphotases、UbiqutinLigases。*De