免疫学课件Lu免疫耐受和免疫调节2014

Immune tolerance&Immune Regulation Lu,LinrongInstitute of Immunology,ZJULu.Lhttp:/ tolerance or Immunological tolerance is the process by which the Immune system does not attack an antigen.It is a kind of specific immunological unresponsiveness to a given antigen.It occurs in 2 forms:Natural tolerance(self tolerance)Acquired tolerance(induced tolerance).Definition 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)Induced unresponsiveness to foreign Ags.It can be used to facilitate transplantation or when tolerance is necessary(acquired tolerance)Acquired toleranceImmune toleranceImmune 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).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,-these two haplotypes co-existed in the adults without mutual rejection.Ray OwenSuch 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.Billingham and Medawars experimentCBACBACBACBABalb/cA/JA/J:H-2a;CBA:H-2k;Balb/c:H-2dChimeric miceT cell develop in the thymusPositive 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 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.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 peptidesdeath by neglect!Negative selection:T cells that are strongly activated by self MHC plus self peptides need to be eliminated in the thymus.If they escape this elimination,they may subsequently react against self antigens,and cause Autoimmune disease.Central Tolerance is achieved by negative selectionAvidity 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.Positive selection vs Negative selection Affinity/Avidity modelIn 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 AntigenSummary of central toleranceKisielow and von Boehmer 1988 -HY transgenic miceHarald von BoehmerHarvard Medical SchoolParadox: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 toleranceThe answer:A large variety of tissue specific proteins are expressed in the thymus by MEC(medullary epithelial cell)But How?Central toleranceTissue-restrictive genes expressed by MECsBut How?Central tolerance AIRE(autoimmune regulator):transcription factor that enables ectopic expression in the thymus of genes usually considered tissue-specificNormalAIRE knockoutFrom M.Anderson,et al.(Laboratory of C.Benoist and D.Mathis).Joslin Diabetes Center and Harvard Medical School;Science 298:1395,2002AIRE knockout lead to autoimmune diseases Autoantibodies in AIRE knockout miceDeletion 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 toleranceDiane and Chris visiting ZJUTSAs presentation in thymusHumans expressing a defective form of the transcription factor AIRE(autoimmune regulator)develop multiorgan autoimmune disease.Autoimmune polyendocrino