14-博士研究課-生命科學(xué)前沿進(jìn)展-糖尿病-魏熾炬-2

Type1diabetes

Nocure;therapyisinsulinforlife;physiologicglycaemiccontrolneverachievedIncidenceincreasingby~5%every5years;costs~￡1billionofUKNHSbudgetExcessmorbidityandmortalityAnti-insulin:healthAnti-insulin:diseasePeakmanhttp:///misc/diabetes/eisenbook.htmlCD8T-cellHLAIInfiltratingCD4+,CD8+TcellsAnti-TcelltherapiesareeffectiveIsletcellautoantibodiesdiseaseCD4T-cellHLAIITCREpitopeCD4TregType1diabetesisTcellmediatedIsletautoantigenAPCPeakmanTheImmuneSystemInnateRapidMicrobialDefenseAdaptiveImmuneSystemActivationAcquired(Adaptive)Long-livedMicrobialDefenseNeoplasmsurveillanceAutoimmunity,TransplantationRejection&AtopyBDCTheInnateImmuneSystemAntimicrobialPeptides(e.g.,Defensins,Cathelicidins)Phagocytes(Macrophages,Neutrophils,Monocytes,DendriticCells)PatternRecognitionReceptorsAlternativeComplementSystemNKCellsB1BCells**AspectsofboththeinnateandadaptiveimmunesystemBDCSelectedPatternRecognitionReceptors:Toll-likeReceptorsTLR:SelectedLigands:RoleinImmunity:Localization:TLR1PGN,Zymosan,LipoproteinsAntifungal&AntibacterialDendriticCells,Macrophages,TCells,BCells,EpitheliumTLR2TLR6TLR4LPSAntibacterialTLR5FlagellinTLR11?TLR9CpGAntibacterial&AntiviralTLR3dsRNAAntiviralTLR7ssRNATLR8ssRNATLR10??SelectedPatternRecognitionReceptors:OtherFamiliesTheAdaptiveImmuneSystemCell-mediatedImmunity(Cytotoxicity)TcellsCD4+(Th1&Th2)CD8+(Tc1&Tc2)HumoralImmunity(Antibodyproduction)BCellsBDCTh1andTh2CD4+TCellsTh1IL-12inducesdifferentiationCytokineProduction:

Interferon-

Interleukin-2IntracellularPathogensMacrophageActivationDelayedTypeHypersensitivityTh2IL-4inducesdifferentiationCytokineProduction:

Interleukin-4

Interleukin-5

Interleukin-13ExtracellularPathogensBCellactivation&IgEEosinophilresponsesImmediateTypeHypersensitivityBDCHumanLeukocyteAntigenhumanMHCcell-surfaceproteinsimportantinselfvs.nonselfdistinctionpresentpeptideantigenstoTcellsCLASSI:A,B,CCLASSII:DR,DQ,DPHLAJ.NobleTheHumanLeukocyteAntigenComplex(6p21.31)DPDQDRBCAClassII(1.1Mb)ClassIIIClassI(2.2Mb)ComplementandCytokinesClassI-likegenesandpseudogenesFrequentRecombination

RecombinationisRareTelomereCentromere

RecombinationisRare(0.7Mb)BDCa3b2a1a2a1a2b1b2Binds8-10mersExpressedonmostNucleatedcellsPresentsCytosolicProteinstoCD8+TcellsBinds13-25mersExpressedonAPCs,Macs,Bcells,activatedTcellsPresentsVesicularProteinstoCD4+TcellsClassI ClassIIHLAClassIandIIMoleculesHaveaDistinctStructureandFunctionBDCAntigenAPCEndocytosisTCellReceptorPeptideMHCIICD4+

TcellTcellRecognitionofAntigenonanAPCCD4+

TcellTCellReceptorPeptideLPSTLR4AntigenPresentingCell(APC)MHCII“Signal1”“Signal2”“Signal3”IL-1IL-6IL-12CD28B7IL-12ReceptorSignal1:SpecificitySignal2:ActivationSignal3:DifferentiationTcellActivationbyanActivatedAPCAbsenceofSignal2ActivationClonalAnergyorDeletionTCRMHCAPCToleranceTCellTCRMHCAPCSignal1+Signal2B7TCellcytokinesCD28The2-SignalModelofLymphocyteActivationBDCImmunologicaltoleranceDefinition:specificimmuneunresponsivenesstoanantigenthatisinducedbyexposureoflymphocytestothatantigen(tolerogenvsimmunogen)Significance:Allindividualsshouldbetolerantoftheirown antigens(self-tolerance);breakdown-->autoimmunityTheinductionoftolerancecouldbeexploitedtotreatautoimmunediseasesMechanismsoftolerancemustfirstbeunderstoodFathmanMechanismsofunresponsivenesstoselfantigensCentraltoleranceImmatureself-reactiveTlymphocytesthatrecognizeselfantigensinthethymusundergonegativeselection(deletion)PeripheraltoleranceMatureself-reactiveTlymphocytesthatescapecentraltoleranceandrecognizeselfantigensinperipheraltissuescanbeinactivated(anergy),killed(deletion)orregulated(suppressed)“Clonalignorance”Matureself-reactivelymphocytesdonotrespondtoselfantigens

innon-inflamedsettingsFathmanRequirementsforthedevelopment

ofanautoimmunediseaseNatureImmunology(9):759-761(2001)FathmanActivatedTH1CD4+TCellCD4+Cell(TH2)CD4+Cell(TH0)DR3,DR4,,DQ8/insulinpeptide

CD2Macrophage/dendriticcellFcR

IFN-gIL-12CD40LCD40a,b,TCRIL-1,TNF,LT,NO,PGE-2