1、Type 1 diabetes No cure;therapy is insulin for life;physiologic glycaemic control never achievedIncidence increasing by 5%every 5 years;costs 1 billion of UK NHS budgetExcess morbidity and mortalityAnti-insulin:healthAnti-insulin:diseasePeakmanhttp:/www.uchsc.edu/misc/diabetes/eisenbook.htmlCD8 T-ce
2、llHLA IInfiltrating CD4+,CD8+T cellsAnti-T cell therapies are effectiveIslet cell autoantibodies diseaseCD4 T-cellHLA IITCREpitopeCD4TregType 1 diabetes is T cell mediatedIsletautoantigenAPCPeakmanThe Immune SystemInnate Rapid Microbial Defense Adaptive Immune System ActivationAcquired(Adaptive)Long
3、-lived Microbial Defense Neoplasm surveillance Autoimmunity,Transplantation Rejection&AtopyBDCThe Innate Immune System Antimicrobial Peptides(e.g.,Defensins,Cathelicidins)Phagocytes(Macrophages,Neutrophils,Monocytes,Dendritic Cells)Pattern Recognition Receptors Alternative Complement System NK Cells
4、 B1B Cells*Aspects of both the innate and adaptive immune systemBDCSelected Pattern Recognition Receptors:Toll-like ReceptorsTLR:Selected Ligands:Role in Immunity:Localization:TLR1PGN,Zymosan,LipoproteinsAntifungal&AntibacterialDendritic Cells,Macrophages,T Cells,B Cells,EpitheliumTLR2TLR6TLR4LPSAnt
5、ibacterialTLR5FlagellinTLR11?TLR9CpGAntibacterial&AntiviralTLR3dsRNA AntiviralTLR7ssRNATLR8ssRNATLR10?Selected Pattern Recognition Receptors:Other FamiliesReceptorSelected LigandsRole in ImmunityLocalizationNOD ProteinsNOD1PGN(Gm-)AntibacterialCytoplasmicNOD2PGN(Gm+&-)AntibacterialCytoplasmicCD14LBP
6、:LPS,PGNAntibacterial(with TLR4)Serum&Phagocyte CellSurfaceC-type LectinsMacrophageMannose Receptor(MMR),DC-SIGN,DEC-205Glycoproteins orGlycolipidsAntibacterial,Antiviral,AntifungalMacrophage,DCsSurfactant A,D(Collectin Family)LPS,Lipoproteins,OligosaccharidesOpsonization of Bacteria,Virus&Fungi;Cyt
7、okineStimulation;Apoptotic CellClearanceSoluble in theLungsMBP/MBLMannose groupson bacterialcarbohydratesComplement Activation(Antibacterial&Antiviral)SerumScavengerReceptorsSR-A,CD36LPS,LTA,PGNAntibacterial;ApoptoticCell ClearanceMacrophages,EndotheliumThe Adaptive Immune System Cell-mediated Immun
8、ity(Cytotoxicity)T cells CD4+(Th1&Th2)CD8+(Tc1&Tc2)Humoral Immunity(Antibody production)B CellsBDCTh1 and Th2 CD4+T Cells IL-12 induces differentiation Cytokine Production:Interferon-Interleukin-2 Intracellular Pathogens Macrophage Activation Delayed Type Hypersensitivity IL-4 induces differentiatio
9、n Cytokine Production:Interleukin-4Interleukin-5Interleukin-13 Extracellular Pathogens B Cell activation&IgE Eosinophil responses Immediate Type HypersensitivityBDCHuman Leukocyte Antigenhuman MHCcell-surface proteinsimportant in self vs.nonself distinctionpresent peptide antigens to T cellsCLASS I:
10、A,B,CCLASS II:DR,DQ,DPHLAJ.NobleThe Human Leukocyte Antigen Complex (6p21.31)DP DQ DR B C AClass II (1.1 Mb)Class IIIClass I (2.2Mb)Complement and CytokinesClass I-like genesand pseudogenesFrequent Recombination Recombinationis RareTelomereCentromere Recombinationis Rare(0.7Mb)BDCa3b2a1a2a1a2b1b2Bin
11、ds 8-10mersExpressed on most Nucleated cellsPresents Cytosolic Proteins to CD8+T cellsBinds 13-25mersExpressed on APCs,Macs,B cells,activated T cellsPresents Vesicular Proteins to CD4+T cellsClass IClass IIHLA Class I and II Molecules Have a Distinct Structure and FunctionBDCAntigenEndocytosisT Cell
12、 ReceptorPeptideMHC IIT cell Recognition of Antigen on an APCT Cell ReceptorPeptideLPSTLR4MHC II“Signal 1”“Signal 2”“Signal 3”IL-1 IL-6IL-12CD28B7IL-12 ReceptorSignal 1:SpecificitySignal 2:ActivationSignal 3:DifferentiationT cell Activation by an Activated APCAbsence of Signal 2ActivationClonal Aner
13、gy or DeletionTCRMHCAPCToleranceT CellTCRMHCAPCSignal 1+Signal 2B7T CellcytokinesCD28The 2-Signal Model of Lymphocyte ActivationBDCImmunological tolerance Definition:specific immune unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen(tolerogen vs immunogen)Signi
14、ficance:All individuals should be tolerant of their own antigens(self-tolerance);breakdown-autoimmunity The induction of tolerance could be exploited to treat autoimmune diseases Mechanisms of tolerance must first be understoodFathmanMechanisms of unresponsiveness to self antigens Central tolerance
15、Immature self-reactive T lymphocytes that recognize self antigens in the thymus undergo negative selection(deletion)Peripheral tolerance Mature self-reactive T lymphocytes that escape central tolerance and recognize self antigens in peripheral tissues can be inactivated(),killed(deletion)or regulate
16、d(suppressed)“Clonal ignorance”Mature self-reactive lymphocytes do not respond to self antigensin non-inflamed settingsFathmanRequirements for the development of an autoimmune diseaseNature Immunology(9):759-761(2001)FathmanActivated TH1 CD4+T CellCD4+Cell(TH2)CD4+Cell(TH0)DR3,DR4,DQ8/insulin peptide CD2Macrophage/dendritic cellFc R IFN-g IL-12CD40LCD40a,b,TCRIL-1,TNF,LT,NO,PGE-2B Cell?anti-insulin,GAD ab anti-MogIL-4Immunopathophysiology of Diabetes?Antibody mediated injuryDendritic cell/APCCD40LIL-4CD40LCD8+CTLFasLperforin cell death islet cellsL.Chess 2002Decio L.EizirikDecio L.Eizirik
