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 an a
2、ntigen.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 +Memory +R
3、esponse 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:A disorder or state in which the Immune systems ability to fight infectious disease is compromised or entirely abs
4、ent.Overall Inability of the immune system to respond to a broad range of antigens.(genetic reason or AIDS)Immunosuppression:A condition where the activation or efficacy of the immune system is reduced(induced by an immunosuppressant Immune tolerance5ppt课件Self tolerance:Individuals normally do not r
5、espond to their self“antigens,i.e.,they are tolerant to self.This is the basis for self-non self discrimination by the immune system to ensure immune system not to attack self.Loss of self tolerance can lead to autoimmunity.Natural Tolerance(self tolerance):6ppt课件Induced unresponsiveness to foreign
6、Ags.It can be used to facilitate transplantation or when tolerance is necessary(acquired tolerance)Acquired tolerance7ppt课件Early Observations Ray Owen,1945Dizygotic cattle twins that shared the same placenta were blood cell chimaeras,ie contained blood cells of two different haplotypes in adults and
7、,-these two haplotypes co-existed in the adults without mutual rejection.Ray Owen8ppt课件Such chimaeric cattle will exchange skin grafts without rejection.Normally,if cells of one of the two haplotypes were transferred to an adult cattle of the other haplotype,these were promptly rejected.Thus,toleran
8、ce in the dizygotic twins resulted from the sharing of the placenta in fetal life.9ppt课件During neonatal stage of life,or when immune system is developing,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 p
9、roved Burnets HypothesisEarly Observations12ppt课件Chimeric miceEarly Observations13ppt课件1960 Nobel Prize14ppt课件Human Immunology Volume 52,Issue 2 15ppt课件*Definition*History-Early observations*Mechanism*Induction Immunological Tolerance16ppt课件 Central tolerance is the mechanism by which newly developi
10、ng T cells and B cells are rendered non-reactive to self during their development in thymus and bone marrow.Mechanisms(Earlier)17ppt课件T cell development in thymus18ppt课件T cell development in thymusThymusPeripheryCD4+8+CD4sp+CD8sp+CD4T+CD8T+Cytotoxic HelperMHCIIMHCIIMHCIMHCICD4-8-19ppt课件Stages of thy
11、mocytes development20ppt课件Positive selection:During positive selection Double-Positive T cells that can recognize self MHCs are selected for proliferation,and those T cells that do not recognize self MHC die via Apoptosis.Positive selection also assures TCR to recognize peptide/MHC complex and also
12、go with the appropriate CD4 or CD8.For example,TCRs specific for MHC II need to retain CD4,and lose CD8.If the reverse occurs,they will die via apoptosis.The same is true for the T cells that are specific for MHC I,which need to retain CD8,and lose CD4.Thymocytes are positive selected by MHC/self pe
13、ptides21ppt课件Negative selection:T cells that are strongly activated by self MHC plus self peptides need to be eliminated in the plex.If they escape this elimination,they may subsequently react against self antigens,and cause Autoimmune disease.Central Tolerance is achieved by negative selection22ppt
14、课件Avidity Model:Avidity depends on the affinity of the TCR-peptide/MHC interaction and the density of the peptide/MHC on the thymic epithelial cell.Avidity determines the strength of signal delivered which dictates the outcome.Stronger signals may mean longer signaling or additional signaling.Positi
15、ve Selection vs Negative Selection23ppt课件Mixture of clones with different affinity to self antigensPositive selectedApoptosis by neglectNegative selectedApoptosis by AICDReleased to PeripheralA Cartoon view of positive and negative selection24ppt课件In summary,Positive selection selects for those T ce
16、lls that react with MHC:self antigen.Negative selection eliminates those that react strongly with MHC:self antigen.Thus,successful T cell differentiation selects for MHC restricted TCRs with low affinity for self antigens.The rationale here is that a T cell that binds weakly to self MHC/self Antigen
17、 will not be activated but will be activated by a stronger binding to self MHC/foreign AntigenSummary of central tolerance25ppt课件Kisielow and von Boehmer 1988 -HY transgenic mice26ppt课件Harald von BoehmerHarvard Medical School27ppt课件28ppt课件Apoptosis of negative selected cells are mediated by the Bcl
18、apoptosis pathway29ppt课件Paradox:Deletion of T cells in the thymus requires local expression of the cognate tissue specific antigens(e.g.insulin,MBP).What cell in the thymus is expressing self-proteins?What makes this particular cell to express all these tissue-specific genes?Central tolerance30ppt课件
19、The answer:A large variety of tissue specific proteins are expressed in the thymus by MEC(medullary epithelial cell)Central tolerance31ppt课件Tissue-restrictive genes expressed by MECsBut How?32ppt课件 Central tolerance AIRE(autoimmune regulator):transcription factor that enables ectopic expression in t
20、he thymus of genes usually considered tissue-specific33ppt课件NormalAIRE knockoutFrom M.Anderson,et al.(Laboratory of C.Benoist and D.Mathis).Joslin Diabetes Center and Harvard Medical School;Science 298:1395,2002Autoantibodies in AIRE knockout mice34ppt课件35ppt课件36ppt课件TRAs presentation in thymus37ppt
21、课件Deletion of self-reactive T cells in the thymusAIRE(autoimmune regulator)is a putative transcription factor that stimulates expression of many self antigens in in the thymusDiane Mathis and Christophe BenoistCentral tolerance38ppt课件Humans expressing a defective form of the transcription factor AIR
22、E(autoimmune regulator)develop multiorgan autoimmune disease.Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy(APECED)。APECED,also known as autoimmune polyendocrine syndrome-type 1(APS-1),is a polyglandular disorder that classically manifests as spontaneous autoimmunity against the para
23、thyroid and/or adrenal glands,and/or by a mucocutaneous candidiasis infection.Other common ailments include autoimmune forms of premature ovarian failure,hepatitis,anemia,diabetes,alopecia,and vitiligo.It seemed reasonable to hypothesize that APECED patients develop multiorgan autoimmunity because a
24、 defect in AIRE prevents or modifies ectopic transcription of genes encoding peripheral tissue-restricted antigens in thymic MECs.APECED in human 39ppt课件40ppt课件AIRE41ppt课件Tolerance to self developed in thymus.Why?Self-reactive cells deleted in thymusIs self-antigens expressed in thymus?where?MECs ca
25、n express self antigens.How?AIRE drive the expression of self antigensHow can AIRE do such a job?What regulates AIREAIRE research as another research model42ppt课件Immature B cells are tested for autoreactivity before they leave the bone marrowB cell tolerance 43ppt课件Central B cell tolerance in a tran
26、sgenic mouse 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-reacti
27、ve clones 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 (lens of eye,spe
28、rmatozoa):Antigen not seen by the immune system.(i.e.hepatocytes):Lack or self-antigen presentation.Immunologically privileged sites:Other mechanismsImmunological ignorance47ppt课件APCTCRCD28 APCTCRFunctionalunresponsivenessNormal T cellresponseAnergy Apoptosis(activation-inducedcell death)APCDeletion
29、 APC Block inactivationSuppression RegulatoryT cellPeripheral T cell toleranceOff signals48ppt课件Anergy induced without co-stimulation*Most tissue cells dont express co-stimulation receptors*Professional APCs dont express co-stimulation receptors without activation49ppt课件Peripheral T cell toleranceAc
30、tivation-induced Cell Death(AICD)*Persistent presence of self-antigen gives repeated stimulation50ppt课件Peripheral T cell toleranceActivation-induced Cell Death(AICD)51ppt课件Defect in Fas or FasL triggers AutoimmunityFasNormalFas LAutoimmunity and lymphoproliferative diseaseFas LFas+Fas-52ppt课件ALPS Pa
31、tient: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 due to mesangial glomerulonephritis,then primary biliary infiltration.Evaluation at NIH:lymph
32、adenopathy 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)WT Fas PT 228 66 128 174 214 298 51 97del 52-96TMTM53ppt课件Peripheral T cell toleranceRegulatory cells54ppt课件Periph
33、eral T cell tolerance IPEXDisease characteristics.IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life.The majority of affected males die within the first year of life of either metabolic derangements or sepsis;a few survive into the secon
34、d or third decade.Diagnosis/testing.Diagnosis is based on clinical findings.FOXP3 is the only gene currently known to be associated with IPEX syndrome.Approximately 50%of males with IPEX syndrome have mutations identified in FOXP3.Molecular genetic testing is clinically available.55ppt课件Other Periph
35、eral tolerance determinantsCytokines：1.Limited supply of pro-survival cytokines(IL7 for T cell and BAFF for B cells)；2.Secretion of suppressive cytokines TGF-beta,IL10Signaling pathways:Negative regulators including Phosphotases、Ubiqutin Ligases。56ppt课件*Definition*History-Early observations*Mechanis
36、m*Induction （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 b
37、y induce tolerance.Immune toleranceAutoimmune DiseaseTransplantation rejectionInfectionTumor+-Immune Tolerance in Clinic58ppt课件Antigen determines for tolerance induction59ppt课件Induction of Immune Tolerance1.Change the route of antigen:Oral uptake;vein injection;inject antigen into immune privileged
38、sites;2.Bone marrow or thymus transplantation;（mimic central tolerance）3.Desensitization(small dose,multiple stimulation);4.Induction of Treg;60ppt课件Break Immune Tolerance(Enhance anti-tumor response)1.Injection of exogenous antigen(endogenous antigen concentrate too low;2.Induction of co-stimulatio
39、n;3.Blockade of inhibitory receptors;4.Adjust cytokine level by recombinant cytokines or antibodies;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
