免疫耐受医学知识.pptx

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,免疫耐受,Immune tolerance,Lu,Linrong,Institute,of Immunology,ZJU,Lu.Linrong,observations,),*Mechanism,Central Tolerance,Peripheral Tolerance,*Induction (Acquired tolerance),Immunological Tolerance,免疫耐受医学知识讲座,第2页,Immune tolerance,or,Immunological tolerance,is the process by which the Immune system does not attack an antigen.,Specific,immunological,unresponsiveness,to a given antigen.,It occurs in 2 forms:natural tolerance(self tolerance)and acquired tolerance(induced tolerance).,Definition,免疫耐受医学知识讲座,第3页,Immune response vs tolerance,Immune Response Immune Tolerance,Antigen,Yes,Yes,Latency,Yes,Yes,Antigen specificity,+,Memory,+,Response Strong,no or weak,Function reject non-self protect self,免疫耐受医学知识讲座,第4页,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 absent.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 tolerance,免疫耐受医学知识讲座,第5页,Self tolerance:,Individuals normally do not respond 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):,免疫耐受医学知识讲座,第6页,Induced,unresponsiveness to,foreign Ags,.,It can be used to facilitate transplantation or when tolerance is necessary(acquired tolerance),Acquired tolerance,免疫耐受医学知识讲座,第7页,Early Observations,Ray Owen,1945,Dizygotic cattle twins that shared the same placenta were,blood cell chimaeras,ie contained blood cells of two different haplotypes in adults and,-these two haplotypes co-existed in the adults without mutual rejection.,Ray Owen,免疫耐受医学知识讲座,第8页,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,tolerance in the dizygotic twins resulted from the sharing of the placenta in fetal life.,Early Observations,免疫耐受医学知识讲座,第9页,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.,In 1953,Billingham,Brent and Medawar demonstrated that immunological tolerance could be acquired by introduction of donor cells during fetal development tolerance permanent and Ag specific.,Burnets Hypothesis:(1949)Medawars experiment(1953),Early Observations,免疫耐受医学知识讲座,第10页,Billingham and Medawar,proved,Burnets Hypothesis,Early Observations,免疫耐受医学知识讲座,第11页,Early Observations,Chimeric,mice,免疫耐受医学知识讲座,第12页,1960,Nobel Prize,免疫耐受医学知识讲座,第13页,Human Immunology,Volume 52,Issue 2,免疫耐受医学知识讲座,第14页,*Definition,*History-Early observations,*Mechanism,*Induction,Immunological Tolerance,免疫耐受医学知识讲座,第15页,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),免疫耐受医学知识讲座,第16页,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 assures TCR,to recognize self-peptide/MHC complex and also 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 peptides,免疫耐受医学知识讲座,第17页,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 selection,免疫耐受医学知识讲座,第18页,Mixture of clones with different affinity to self antigens,Positive selected,Apoptosis by neglect,Apoptosis by AICD-Negative selected,Released to Peripheral,A Cartoon view of positive and negative selection,免疫耐受医学知识讲座,第19页,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.,免疫耐受医学知识讲座,第20页,Apoptosis of negative selected cells are,mediated by the Bcl apoptosis pathway,免疫耐受医学知识讲座,第21页,In summary,Positive selection selects for those T cells 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 will not be activated but will be activated by a stronger binding to self MHC/,foreign,Antigen,Summary of central tolerance,免疫耐受医学知识讲座,第22页,Kisielow and von Boehmer 1988 -,HY transgenic mice,HY transgenic mice made by isolating TCR a and b chain cDNAs from CD8+CTL clone derived from H-2,b,female mouse.This TCR recognizes a male-specific peptide bound to H-2D,b,.,The HY TCR transgene promotes the development of SP CD8 but not CD4 T cells in H-2,d/b,but not in H-2,d/d,mice.,Evidence for positive selection,Female H-2,d/b,Female H-2,d/d,“selecting”“non-selecting”,Background Backgrounds,免疫耐受医学知识讲座,第23页,Evidence for Negative selection.,免疫耐受医学知识讲座,第24页,Kisielow and von Boehmer 1988 -,HY transgenic mice,Harald von Boehmer,Harvard Medical School,免疫耐受医学知识讲座,第25页,免疫耐受医学知识讲座,第26页,Ligands for Positive and Negative Selection,Ligands are necessary for both positive and negative selection.,(self-endogenous peptide/MHC complexes presented by stromal and hematopoietic cells,）,low dose,high dose,免疫耐受医学知识讲座,第27页,Paradox,:,It is critical to delete thymocytes expressing TCRs that would react with self peptides presented by MHC molecules on BM-derived APCs in the periphery.Some peptides are derived from circulating blood cells or serum components.,Deletion of T cells in the thymus also requires local expression of the 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 tolerance,免疫耐受医学知识讲座,第28页,The answer:,A large variety of tissue specific proteins are expressed in the thymus,by MEC,(medullary epithelial cell),Central tolerance,免疫耐受医学知识讲座,第29页,Tissue-restrictive genes expressed by MECs,But How?,免疫耐受医学知识讲座,第30页,Central tolerance,AIRE(,autoimmune regulator,),:transcription factor that enables ectopic expression in the thymus of genes usually considered tissue-specific,免疫耐受医学知识讲座,第31页,Normal,AIRE knockout,From M.Anderson,et al.(Laboratory of C.Benoist and D.Mathis).,Joslin Diabetes Center and Harvard Medical School;Science 298:1395,Spontaneous Autoimmune disease in AIRE knockout mice,Autoantibodies,免疫耐受医学知识讲座,第32页,Spontaneous Autoimmune disease in AIRE knockout mice,Organ-Specific lymphocyte infiltrations,免疫耐受医学知识讲座,第33页,Deletion of self-reactive T cells in the thymus,AIRE(autoimmune regulator)is a putative transcription factor,that stimulates expression of many self antigens in in the thymus,Diane Mathis and Christophe Benoist,Central tolerance,Diane and Chris visiting ZJU,免疫耐受医学知识讲座,第34页,TSAs presentation in thymus,免疫耐受医学知识讲座,第35页,Humans expressing a defective form of the transcription factor AIRE(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 parathyroid 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,defect in AIRE prevents or modifies ectopic transcription,of genes encoding peripheral tissue-restricted antigens in thymic,MECs,.,APECED in human,免疫耐受医学知识讲座,第36页,免疫耐受医学知识讲座,第37页,AIRE,Structure&Expression,免疫耐受医学知识讲座,第38页,Tolerance to self developed in thymus.Why?,Self-reactive cells deleted in thymus,Is self-antigens expressed in thymus?where?,MECs can express self antigens.How?,AIRE drive the expression of self antigens,How can AIRE do such a job?What regulates AIRE,AIRE research as a research model,免疫耐受医学知识讲座,第39页,Immature B cells are tested for autoreactivity before they leave the bone marrow,B cell tolerance,免疫耐受医学知识讲座,第40页,Central B cell tolerance in a transgenic mouse model,B cell tolerance,免疫耐受医学知识讲座,第41页,Peripheral tolerance(Immune Regulation),Why we need a peripheral tolerance?,Some antigens are not expressed in thymus or bone marrow,which leads to the possibility to trigger immune response.,Negative selection is incomplete:Middle to low affinity self-reactive clones are released to peripheral and can be activated under certain conditions.,免疫耐受医学知识讲座,第42页,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),免疫耐受医学知识讲座,第43页,Antigen sequestration,(lens of eye,spermatozoa):,Antigen not seen by the immune system.,Low MHC expression,(i.e.hepatocytes):,Lack or self-antigen presentation.,Immunologically privileged sites:,Other mechanisms,Immunological ignorance,交感性眼炎,免疫耐受医学知识讲座,第44页,Peripheral tolerance,免疫耐受医学知识讲座,第45页,Anergy induced without co-stimulation,*Most tissue cells dont express co-stimulation receptors,*Professional APCs dont express co-stimulation receptors without activation,免疫耐受医学知识讲座,第46页,Peripheral T cell tolerance,Activation-induced Cell Death(AICD),*Persistent presence of self-antigen gives repeated stimulation,免疫耐受医学知识讲座,第47页,Peripheral T cell tolerance,Activation-induced Cell Death(AICD),免疫耐受医学知识讲座,第48页,Defect in Fas or FasL triggers Autoimmunity in mice,Fas,Normal,Fas L,Autoimmunity and,lymphoproliferative,disease,Fas L,Fas+,Fas-,免疫耐受医学知识讲座,第49页,ALPS Patient:An unusual mutation,Healthy female-at 18 months developed cervical,adenopathy(,颈淋巴结肿大,).,Biopsy showed reactive hyperplasia,D,eveloped anemia with hypersplenism,hematuria,proteinuria and renal insufficiency due 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 normal,Heterozygous Fas splice mutation resulting in loss of exons 3,4(AA 52-96),WT Fas,PT 2,28,66,128,174,214,298,51 97,del 52-96,TM,TM,免疫耐受医学知识讲座,第50页,Peripheral T cell tolerance,Regulatory cells,免疫耐受医学知识讲座,第51页,Peripheral T cell tolerance,IPEX,Disease 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 second 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.,免疫耐受医学知识讲座,第52页,Other Peripheral tolerance determinants,Cytokines,：,1.Limited supply of pro-survival cytokines,(IL7 for T cell and BAFF for B cells),；,2.Secretion,of suppressive cytokines TGF-beta,IL10,Signaling pathways:,Inhibitory receptors;negative regulators including Phosphotases,、,Ubiqutin Ligases,。,免疫耐受医学知识讲座,第53页,*Definition,*History-Early observations,*Mechanism,*Induction,（,acquired tolerance,）,Immunological Tolerance,免疫耐受医学知识讲座,第54页,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 induce tolerance.,Immune tolerance,Autoimmune Disease,Transplantation rejection,Infection,Tumor,+,-,Immune Tolerance in Clinic,免疫耐受医学知识讲座,第55页,Antigen determines for tolerance induction,Immune response vs Immune tolerance,免疫耐受医学知识讲座,第56页,Induction of Immune Tolerance,1.Change the route of antigen:Oral uptake;vein injection;inject antigen into immune privileged sites;,2.Bone marrow or thymus transplantation;,（,mimic central tolerance,）,3.Desensitization(small dose,multiple stimulation);,4.Induction of Treg;,免疫耐受医学知识讲座,第57页,Break Immune Tolerance,(Enhance anti-tumor response),1.Injection of exogenous antigen(for many tumor antigens,endogenous antigen concentrate too low);,2.Induction of co-stimulation;,3.Blockade of inhibitory receptors;,4.Depletion of Tregs,4.Adjust cytokine level by recombinant cytokines or antibodies;,免疫耐受医学知识讲座,第58页,Summary,Definition of immune tolerance:natural vs acquired,Central tolerance,/,Negative selection,/,Aire,Mechanisms to reach peripheral tolerance,/AICD,/anergy/,Tregs,Practical methods to induce and break tolerance,免疫耐受医学知识讲座,第59页,