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1、免疫耐受免疫耐受Immune toleranceImmune tolerance 1ppt课件*Definition *History （Early observations )*Mechanism Central TolerancePeripheral Tolerance*Induction (Acquired tolerance)Immunological Tolerance2ppt课件Immune tolerance or Immunological tolerance is the process by which the Immune system does not attack a
2、n antigen. Specific immunological unresponsiveness to a given antigen.It occurs in 2 forms: natural tolerance (self tolerance) and acquired tolerance (induced tolerance).Definition 3ppt课件Immune response vs tolerance Immune Response Immune ToleranceAntigen Yes YesLatency Yes YesAntigen specificity +
3、+Memory + + Response Strong no or weakFunction reject non-self protect self 4ppt课件Immune tolerance is an active process which is different from immunodeficiency or immunosuppression.Immunodeficiency:AdisorderorstateinwhichtheImmunesystemsabilitytofightinfectiousdiseaseiscompromisedorentirelyabsent.O
4、verallInabilityoftheimmunesystemtorespondtoabroadrangeofantigens.(geneticreasonorAIDS)Immunosuppression:Aconditionwheretheactivationorefficacyoftheimmunesystemisreduced(inducedbyanimmunosuppressantImmunetolerance5ppt课件Self tolerance:Individualsnormallydonotrespondtotheirself“antigens,i.e.,theyaretol
5、eranttoself.Thisisthebasisforself-nonselfdiscriminationbytheimmunesystemtoensureimmunesystemnottoattackself.Loss of self tolerance can lead to autoimmunity.Natural Tolerance (self tolerance): 6ppt课件InducedunresponsivenesstoforeignAgs.It can be used to facilitate transplantation or whentoleranceisnec
6、essary(acquiredtolerance)Acquired tolerance7ppt课件EarlyObservationsRayOwen,1945Dizygoticcattletwinsthatsharedthesameplacentawerebloodcellchimaeras,iecontainedbloodcellsoftwodifferenthaplotypesinadultsand,-thesetwohaplotypesco-existedintheadultswithoutmutualrejection.RayOwen8ppt课件Suchchimaericcattlewi
7、llexchangeskingraftswithoutrejection.Normally,ifcellsofoneofthetwohaplotypesweretransferredtoanadultcattleoftheotherhaplotype,thesewerepromptlyrejected.Thus,toleranceinthedizygotictwinsresultedfromthesharingoftheplacentainfetallife.9ppt课件During neonatal stage of life, or when immune system is develo
8、ping, all Ags present are recognized as self.Immune system becomes tolerant to these Ags.Burnets Hypothesis:(1949)10ppt课件11ppt课件Billingham and Medawar proved BurnetsHypothesisEarlyObservations12ppt课件ChimericmiceEarlyObservations13ppt课件1960NobelPrize14ppt课件HumanImmunologyVolume52,Issue2 15ppt课件*Defin
9、ition *History-Early observations*Mechanism *Induction Immunological Tolerance16ppt课件 Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self during their development in thymus and bone marrow.Mechanisms (Earlier )17ppt课件Tcelldevelopmentinth
10、ymus18ppt课件TcelldevelopmentinthymusThymusPeripheryCD4+8+CD4sp+CD8sp+CD4T+CD8T+CytotoxicHelperMHCIIMHCIIMHCIMHCICD4-8-19ppt课件Stagesofthymocytesdevelopment20ppt课件Positive selection: During positive selection Double-Positive T cells that can recognize self MHCs are selected for proliferation, and those
11、 T cells that do not recognize self MHC die via Apoptosis.Positive selection also assures TCR to recognizepeptide/MHC complex and also go with theappropriateCD4orCD8.Forexample,TCRsspecificforMHCIIneedtoretainCD4,andloseCD8.Ifthereverseoccurs,theywilldieviaapoptosis.Thesameis true for the T cells th
12、at are specific for MHC I,whichneedtoretainCD8,andloseCD4.Thymocytes are positive selected by MHC/self peptides21ppt课件Negativeselection:TcellsthatarestronglyactivatedbyselfMHCplex.Iftheyescapethiselimination,they may subsequently reactagainstselfantigens, andcauseAutoimmunedisease.Central Tolerance
13、is achieved by negative selection22ppt课件Avidity Model:AviditydependsontheaffinityoftheTCR-peptide/MHCinteractionandthedensityofthepeptide/MHConthethymicepithelialcell.Aviditydeterminesthestrengthofsignaldeliveredwhichdictatestheoutcome.Strongersignalsmaymeanlongersignalingoradditionalsignaling.23ppt
14、课件MixtureofcloneswithdifferentaffinitytoselfantigensPositiveselectedApoptosisbyneglectNegativeselectedApoptosisbyAICDReleasedtoPeripheralACartoonviewofpositiveandnegativeselection24ppt课件Insummary,PositiveselectionselectsforthoseTcellsthatreactwithMHC:selfantigen.Negativeselectioneliminatesthosethatr
15、eactstronglywithMHC:selfantigen.Thus,successfulTcelldifferentiationselectsforMHCrestrictedTCRswithlowaffinityforselfantigens.The rationale here is that a T cell that binds weakly to selfMHC/selfAntigenwillnotbeactivatedbutwillbeactivatedbyastrongerbindingtoselfMHC/ foreignAntigenSummary of central t
16、olerance25ppt课件KisielowandvonBoehmer1988-HY transgenic mice26ppt课件HaraldvonBoehmerHarvardMedicalSchool27ppt课件28ppt课件ApoptosisofnegativeselectedcellsaremediatedbytheBclapoptosispathway29ppt课件Paradox: DeletionofTcellsinthethymusrequireslocalexpressionofthecognatetissuespecificantigens(e.g.insulin,MBP)
17、.Whatcellinthethymusisexpressingself-proteins?Whatmakesthisparticularcelltoexpressallthesetissue-specificgenes?Central tolerance30ppt课件The answer:Alargevarietyoftissuespecificproteinsareexpressedinthethymusby MEC(medullaryepithelialcell)Central tolerance31ppt课件Tissue-restrictivegenesexpressedbyMECsB
18、utHow?32ppt课件CentraltoleranceAIRE(autoimmuneregulator):transcriptionfactorthatenablesectopicexpressioninthethymusofgenesusuallyconsideredtissue-specific33ppt课件NormalAIREknockoutFromM.Anderson,etal.(LaboratoryofC.BenoistandD.Mathis).JoslinDiabetesCenterandHarvardMedicalSchool;Science298:1395,2002Auto
19、antibodiesinAIREknockoutmice34ppt课件35ppt课件36ppt课件TRAspresentationinthymus37ppt课件Deletionofself-reactiveTcellsinthethymusAIRE (autoimmune regulator) is a putative transcription factor that stimulates expression of many self antigens in in the thymusDianeMathisandChristopheBenoistCentral tolerance38pp
20、t课件HumansexpressingadefectiveformofthetranscriptionfactorAIRE(autoimmuneregulator)developmultiorgan autoimmune disease.Autoimmunepolyendocrinopathy-candidiasis-ectodermaldystrophy(APECED)。APECED, also known as autoimmune polyendocrine syndrome-type1(APS-1), is a polyglandular disorder that classical
21、ly manifestsasspontaneous autoimmunity against the parathyroid and/or adrenalglands, and/or by a mucocutaneous candidiasis infection. Othercommon ailments includeautoimmune forms of premature ovarianfailure,hepatitis,anemia,diabetes,alopecia,andvitiligo.It seemed reasonableto hypothesize that APECED
22、 patients developmultiorgan autoimmunitybecause a defect in AIRE prevents ormodifies ectopic transcriptionof genes encoding peripheral tissue-restrictedantigensinthymicMECs.APECEDinhuman39ppt课件40ppt课件AIRE41ppt课件Tolerancetoselfdevelopedinthymus.Why?Self-reactivecellsdeletedinthymusIsself-antigensexpr
23、essedinthymus?where?MECscanexpressselfantigens.How?AIREdrivetheexpressionofselfantigensHowcanAIREdosuchajob?WhatregulatesAIREAIREresearchasanotherresearchmodel42ppt课件ImmatureBcellsaretestedforautoreactivitybeforetheyleavethebonemarrowB cell tolerance 43ppt课件Central B cell tolerance in a transgenic m
24、ouse modelB cell tolerance 44ppt课件Peripheral tolerance (Immune Regulation)Why we need a peripheral tolerance ?nSome antigens are not expressed in thymus or bone marrow, which leads to the possibility to trigger immune response.nNegative selection is incomplete: Middle to low affinity self-reactive c
25、lones are released to peripheral and can be activated under certain conditions.45ppt课件Peripheral tolerance is immune tolerance developed after T and B cells mature and enter the periphery. The cells are controlled through peripheral tolerance mechanisms. Mechanisms (Earlier )46ppt课件 Antigen sequestr
26、ationAntigen sequestration(lensofeye,spermatozoa):Antigennotseenbytheimmunesystem. Low MHC expressionLow MHC expression(i.e.hepatocytes):Lackorself-antigenpresentation.Immunologicallyprivilegedsites:OthermechanismsImmunologicalignorance47ppt课件APCTCRTcellTcellCD28ActivatedActivatedTcellsTcellsAPCTCRF
27、unctionalunresponsivenessNormal T cellresponseAnergy Apoptosis(activation-inducedcelldeath)APCDeletion APCBlockinactivationSuppression RegulatoryTcellPeripheralTcelltoleranceOffsignalsActivatedActivatedTcellTcell48ppt课件Anergyinducedwithoutco-stimulation*Mosttissuecellsdontexpressco-stimulationrecept
28、ors*ProfessionalAPCsdontexpressco-stimulationreceptorswithoutactivation49ppt课件PeripheralTcelltoleranceActivation-inducedCellDeath(AICD)*Persistentpresenceofself-antigengivesrepeatedstimulation50ppt课件PeripheralTcelltoleranceActivation-inducedCellDeath(AICD)51ppt课件Defect in Fas or FasL triggers Autoim
29、munityFasNormalFasLAutoimmunityandlymphoproliferativediseaseFasLFas+Fas-52ppt课件ALPS Patient: An unusual mutationHealthy female - at 18 months developed cervical adenopathy(颈淋巴结肿大). Biopsy showed reactive hyperplasiaDeveloped anemia with hypersplenism, hematuria, proteinuria and renal insufficiency d
30、ue to mesangial glomerulonephritis, then primary biliary infiltration. Evaluation at NIH: lymphadenopathy persists, ANA (+) 1:320, CD4-CD8- cells 25% of ab T cells, increased B cells; Fas surface expression is normalHeterozygous Fas splice mutation resulting in loss of exons 3, 4 (AA 52-96)WTFasPT22
31、866128 174 2142985197del52-96TMTM53ppt课件PeripheralTcelltoleranceRegulatorycells54ppt课件PeripheralTcelltoleranceIPEXDisease characteristics.IPEXsyndromeischaracterizedbythedevelopmentofoverwhelmingsystemicautoimmunityinthefirstyearoflife.Themajorityofaffectedmalesdiewithinthefirstyearoflifeofeithermet
32、abolicderangementsorsepsis;afewsurviveintothesecondorthirddecade.Diagnosis/testing.Diagnosisisbasedonclinicalfindings.FOXP3istheonlygenecurrentlyknowntobeassociatedwithIPEXsyndrome.Approximately50%ofmaleswithIPEXsyndromehavemutationsidentifiedinFOXP3.Moleculargenetictestingisclinicallyavailable.55pp
33、t课件OtherPeripheraltolerancedeterminantsCytokines：1.Limitedsupplyofpro-survivalcytokines(IL7forTcellandBAFFforBcells)；2.SecretionofsuppressivecytokinesTGF-beta,IL10Signalingpathways:NegativeregulatorsincludingPhosphotases、UbiqutinLigases。56ppt课件*Definition *History-Early observations*Mechanism *Induc
34、tion （acquired tolerance）Immunological Tolerance57ppt课件 1. Establish immune tolerance will facilitate organ transplantation, reduce the chance or autoimmune disease. 2. Breakdown of immune tolerance to enhance anti-tumor immune response or some viral infection which can escape the immune attack by i
35、nduce tolerance. Immune toleranceAutoimmune DiseaseTransplantation rejectionInfectionTumor+-Immune Tolerance in Clinic58ppt课件Antigendeterminesfortoleranceinduction59ppt课件InductionofImmuneTolerance1.Changetherouteofantigen:Oraluptake;veininjection;injectantigenintoimmuneprivilegedsites;2.Bonemarrowor
36、thymustransplantation;（mimiccentraltolerance）3.Desensitization(smalldose,multiplestimulation);4.InductionofTreg;60ppt课件BreakImmuneTolerance(Enhanceanti-tumorresponse)1.Injectionofexogenousantigen(endogenousantigenconcentratetoolow;2.Inductionofco-stimulation;3.Blockadeofinhibitoryreceptors;4.Adjustcytokinelevelbyrecombinantcytokinesorantibodies;61ppt课件SummaryDefinition of immune tolerance: natural vs acquiredCentral tolerance / Negative selection / AireMechanisms to reach peripheral tolerance /AICD /anergy/ TregsPractical methods to induce and break tolerance62ppt课件
