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Type1diabetes
Nocure;therapyisinsulinforlife;physiologicglycaemiccontrolneverachievedIncidenceincreasingby~5%every5years;costs~£1billionofUKNHSbudgetExcessmorbidityandmortalityAnti-insulin:healthAnti-insulin:diseasePeakman/misc/diabetes/eisenbook.htmlType1diabetesNocure;thera1CD8T-cellHLAIInfiltratingCD4+,CD8+TcellsAnti-TcelltherapiesareeffectiveIsletcellautoantibodiesdiseaseCD4T-cellHLAIITCREpitopeCD4TregType1diabetesisTcellmediatedIsletautoantigenAPCPeakmanCD8HLAIInfiltratingCD4+,CD2TheImmuneSystemInnateRapidMicrobialDefenseAdaptiveImmuneSystemActivationAcquired(Adaptive)Long-livedMicrobialDefenseNeoplasmsurveillanceAutoimmunity,TransplantationRejection&AtopyBDCTheImmuneSystemInnateAcquire3TheInnateImmuneSystemAntimicrobialPeptides(e.g.,Defensins,Cathelicidins)Phagocytes(Macrophages,Neutrophils,Monocytes,DendriticCells)PatternRecognitionReceptorsAlternativeComplementSystemNKCellsB1BCells**AspectsofboththeinnateandadaptiveimmunesystemBDCTheInnateImmuneSystemBDC4SelectedPatternRecognitionReceptors:Toll-likeReceptorsTLR:SelectedLigands:RoleinImmunity:Localization:TLR1PGN,Zymosan,LipoproteinsAntifungal&AntibacterialDendriticCells,Macrophages,TCells,BCells,EpitheliumTLR2TLR6TLR4LPSAntibacterialTLR5FlagellinTLR11?TLR9CpGAntibacterial&AntiviralTLR3dsRNAAntiviralTLR7ssRNATLR8ssRNATLR10??SelectedPatternRecognitionR5SelectedPatternRecognitionReceptors:OtherFamiliesSelectedPatternRecognitionR6TheAdaptiveImmuneSystemCell-mediatedImmunity(Cytotoxicity)TcellsCD4+(Th1&Th2)CD8+(Tc1&Tc2)HumoralImmunity(Antibodyproduction)BCellsBDCTheAdaptiveImmuneSystemBDC7Th1andTh2CD4+TCellsTh1IL-12inducesdifferentiationCytokineProduction:
Interferon-
Interleukin-2IntracellularPathogensMacrophageActivationDelayedTypeHypersensitivityTh2IL-4inducesdifferentiationCytokineProduction:
Interleukin-4
Interleukin-5
Interleukin-13ExtracellularPathogensBCellactivation&IgEEosinophilresponsesImmediateTypeHypersensitivityBDCTh1andTh2CD4+TCellsTh1Th28HumanLeukocyteAntigenhumanMHCcell-surfaceproteinsimportantinselfvs.nonselfdistinctionpresentpeptideantigenstoTcellsCLASSI:A,B,CCLASSII:DR,DQ,DPHLAJ.NobleHumanLeukocyteAntigenCLASSI9TheHumanLeukocyteAntigenComplex(6p21.31)DPDQDRBCAClassII(1.1Mb)ClassIIIClassI(2.2Mb)ComplementandCytokinesClassI-likegenesandpseudogenesFrequentRecombination
RecombinationisRareTelomereCentromere
RecombinationisRare(0.7Mb)BDCTheHumanLeukocyteAntigenCo10a3b2a1a2a1a2b1b2Binds8-10mersExpressedonmostNucleatedcellsPresentsCytosolicProteinstoCD8+TcellsBinds13-25mersExpressedonAPCs,Macs,Bcells,activatedTcellsPresentsVesicularProteinstoCD4+TcellsClassI ClassIIHLAClassIandIIMoleculesHaveaDistinctStructureandFunctionBDCa3b2a1a2a1a2b1b2Binds8-10mers11AntigenAPCEndocytosisTCellReceptorPeptideMHCIICD4+
TcellTcellRecognitionofAntigenonanAPCAntigenAPCEndocytosisTCellRe12CD4+
TcellTCellReceptorPeptideLPSTLR4AntigenPresentingCell(APC)MHCII“Signal1”“Signal2”“Signal3”IL-1IL-6IL-12CD28B7IL-12ReceptorSignal1:SpecificitySignal2:ActivationSignal3:DifferentiationTcellActivationbyanActivatedAPCCD4+TCellReceptorPeptideLPS13AbsenceofSignal2ActivationClonalAnergyorDeletionTCRMHCAPCToleranceTCellTCRMHCAPCSignal1+Signal2B7TCellcytokinesCD28The2-SignalModelofLymphocyteActivationBDCAbsenceofSignal2ActivationC14ImmunologicaltoleranceDefinition:specificimmuneunresponsivenesstoanantigenthatisinducedbyexposureoflymphocytestothatantigen(tolerogenvsimmunogen)Significance:Allindividualsshouldbetolerantoftheirown antigens(self-tolerance);breakdown-->autoimmunityTheinductionoftolerancecouldbeexploitedtotreatautoimmunediseasesMechanismsoftolerancemustfirstbeunderstoodFathmanImmunologicaltoleranceDefinit15MechanismsofunresponsivenesstoselfantigensCentraltoleranceImmatureself-reactiveTlymphocytesthatrecognizeselfantigensinthethymusundergonegativeselection(deletion)PeripheraltoleranceMatureself-reactiveTlymphocytesthatescapecentraltoleranceandrecognizeselfantigensinperipheraltissuescanbeinactivated(anergy),killed(deletion)orregulated(suppressed)“Clonalignorance”Matureself-reactivelymphocytesdonotrespondtoselfantigens
innon-inflamedsettingsFathmanMechanismsofunresponsiveness16Requirementsforthedevelopment
ofanautoimmunediseaseNatureImmunology(9):759-761(2001)FathmanRequirementsforthedevelopme17ActivatedTH1CD4+TCellCD4+Cell(TH2)CD4+Cell(TH0)DR3,DR4,,DQ8/insulinpeptide
CD2Macrophage/dendriticcellFcR
IFN-gIL-12CD40LCD40a,b,TCRIL-1,TNF,LT,NO,PGE-2BCell?anti-insulin,GADabanti-MogIL-4ImmunopathophysiologyofDiabetes?AntibodymediatedinjuryDendriticcell/APCCD40LIL-4CD40LCD8+CTLFasLperforincelldeathisletcellsL.Chess2002ActivatedTH1CD4+TCellCD4+18DecioL.EizirikDecioL.Eizirik19DecioL.EizirikDecioL.Eizirik20Type1diabetes
Nocure;therapyisinsulinforlife;physiologicglycaemiccontrolneverachievedIncidenceincreasingby~5%every5years;costs~£1billionofUKNHSbudgetExcessmorbidityandmortalityAnti-insulin:healthAnti-insulin:diseasePeakman/misc/diabetes/eisenbook.htmlType1diabetesNocure;thera21CD8T-cellHLAIInfiltratingCD4+,CD8+TcellsAnti-TcelltherapiesareeffectiveIsletcellautoantibodiesdiseaseCD4T-cellHLAIITCREpitopeCD4TregType1diabetesisTcellmediatedIsletautoantigenAPCPeakmanCD8HLAIInfiltratingCD4+,CD22TheImmuneSystemInnateRapidMicrobialDefenseAdaptiveImmuneSystemActivationAcquired(Adaptive)Long-livedMicrobialDefenseNeoplasmsurveillanceAutoimmunity,TransplantationRejection&AtopyBDCTheImmuneSystemInnateAcquire23TheInnateImmuneSystemAntimicrobialPeptides(e.g.,Defensins,Cathelicidins)Phagocytes(Macrophages,Neutrophils,Monocytes,DendriticCells)PatternRecognitionReceptorsAlternativeComplementSystemNKCellsB1BCells**AspectsofboththeinnateandadaptiveimmunesystemBDCTheInnateImmuneSystemBDC24SelectedPatternRecognitionReceptors:Toll-likeReceptorsTLR:SelectedLigands:RoleinImmunity:Localization:TLR1PGN,Zymosan,LipoproteinsAntifungal&AntibacterialDendriticCells,Macrophages,TCells,BCells,EpitheliumTLR2TLR6TLR4LPSAntibacterialTLR5FlagellinTLR11?TLR9CpGAntibacterial&AntiviralTLR3dsRNAAntiviralTLR7ssRNATLR8ssRNATLR10??SelectedPatternRecognitionR25SelectedPatternRecognitionReceptors:OtherFamiliesSelectedPatternRecognitionR26TheAdaptiveImmuneSystemCell-mediatedImmunity(Cytotoxicity)TcellsCD4+(Th1&Th2)CD8+(Tc1&Tc2)HumoralImmunity(Antibodyproduction)BCellsBDCTheAdaptiveImmuneSystemBDC27Th1andTh2CD4+TCellsTh1IL-12inducesdifferentiationCytokineProduction:
Interferon-
Interleukin-2IntracellularPathogensMacrophageActivationDelayedTypeHypersensitivityTh2IL-4inducesdifferentiationCytokineProduction:
Interleukin-4
Interleukin-5
Interleukin-13ExtracellularPathogensBCellactivation&IgEEosinophilresponsesImmediateTypeHypersensitivityBDCTh1andTh2CD4+TCellsTh1Th228HumanLeukocyteAntigenhumanMHCcell-surfaceproteinsimportantinselfvs.nonselfdistinctionpresentpeptideantigenstoTcellsCLASSI:A,B,CCLASSII:DR,DQ,DPHLAJ.NobleHumanLeukocyteAntigenCLASSI29TheHumanLeukocyteAntigenComplex(6p21.31)DPDQDRBCAClassII(1.1Mb)ClassIIIClassI(2.2Mb)ComplementandCytokinesClassI-likegenesandpseudogenesFrequentRecombination
RecombinationisRareTelomereCentromere
RecombinationisRare(0.7Mb)BDCTheHumanLeukocyteAntigenCo30a3b2a1a2a1a2b1b2Binds8-10mersExpressedonmostNucleatedcellsPresentsCytosolicProteinstoCD8+TcellsBinds13-25mersExpressedonAPCs,Macs,Bcells,activatedTcellsPresentsVesicularProteinstoCD4+TcellsClassI ClassIIHLAClassIandIIMoleculesHaveaDistinctStructureandFunctionBDCa3b2a1a2a1a2b1b2Binds8-10mers31AntigenAPCEndocytosisTCellReceptorPeptideMHCIICD4+
TcellTcellRecognitionofAntigenonanAPCAntigenAPCEndocytosisTCellRe32CD4+
TcellTCellReceptorPeptideLPSTLR4AntigenPresentingCell(APC)MHCII“Signal1”“Signal2”“Signal3”IL-1IL-6IL-12CD28B7IL-12ReceptorSignal1:SpecificitySignal2:ActivationSignal3:DifferentiationTcellActivationbyanActivatedAPCCD4+TCellReceptorPeptideLPS33AbsenceofSignal2ActivationClonalAnergyorDeletionTCRMHCAPCToleranceTCellTCRMHCAPCSignal1+Signal2B7TCellcytokinesCD28The2-SignalModelofLymphocyteActivationBDCAbsenceofSignal2ActivationC34ImmunologicaltoleranceDefinition:specificimmuneunresponsivenesstoanantigenthatisinducedbyexposureoflymphocytestothatantigen(tolerogenvsimmunogen)Significance:Allindividualsshouldbetolerantoftheirown antigens(self-tolerance);breakdown-->autoimmunityTheinductionoftolerancecouldbeexploitedtotreatautoimmunediseasesMechanismsoftolerancemustfirstbeunderstoodFathmanImmunologicaltoleranceDefinit35MechanismsofunresponsivenesstoselfantigensCentraltoleranceImmatureself-reactiv
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