免疫應(yīng)答概論2lightchains(or)2heavychains(5isotypes:IgG,M,A,D,E)2Bindingsites(Divalent)SecretedintocirculationBindsSolubleAntigen2Chains/(95%)or/(5%)1Bindingsite(Monovalent)MembraneBound,NotSecretedBindsAntigenComplexedwithMHCZap70fynlckgezVVCCCH1CH2CH3CH2CH3CH1CLCLVLVLVHVHedzIga/IgbIga/IgbBlk,FynorLynBandTLymphocyteAntigenReceptorsBDC2021/4/272XPID:X-linkedpolyendocrinopathy,immunedysfunctionanddiarrheaXLAAD:“AutoimmunityAllergicDysreg”Scurfingene(Foxp3/JM2)Immunopathogenesis:Th2Cytokines,abnormalactivation(Il-4,5,13)

-Scurfy+Nude:NoAutoimmunity

-CD4+intoNude:Disease

-BoneMarrowintoirradiated:NoDisease

-RequireAntigenStimulationforDisease

-MixedChimera:NoDiseaseBDC2021/4/273HumanLeukocyteAntigenhumanMHCcell-surfaceproteinsimportantinselfvs.nonselfdistinctionpresentpeptideantigenstoTcellsCLASSI:A,B,CCLASSII:DR,DQ,DPHLAJ.Noble2021/4/274TheHumanLeukocyteAntigenComplex(6p21.31)DPDQDRBCAClassII

(1.1Mb)ClassIIIClassI(2.2Mb)ComplementandCytokinesClassI-likegenesandpseudogenesFrequentRecombinationRecombinationisRareTelomereCentromereRecombinationisRare(0.7Mb)BDC2021/4/275a3b2a1a2a1a2b1b2Binds8-10mersExpressedonmostNucleatedcellsPresentsCytosolicProteinstoCD8+TcellsBinds13-25mersExpressedonAPCs,Macs,Bcells,activatedTcellsPresentsVesicularProteinstoCD4+TcellsClassI ClassIIHLAClassIandIIMoleculesHaveaDistinctStructureandFunctionBDC2021/4/2760501

020103010302ciscisDQA1 DQB1transDQA1*0301/DQB1*0201DQA1*0501/DQB1*0302DQA1*0501/DQB1*0201DQA1*0301/DQB1*0302MaternalPaternalCisandTrans-ClassIIDimerizationBDC2021/4/277DQB1*0402Asp57Leu56-chain-chainBDCBDC2021/4/278HLA-Peptide:TCRCDR1CDR2CDR3CDR3CDR2CDR1NH3+COO-TCRalphaTCRbeta2Helixα1HelixBDC2021/4/279Co-Stimulation

TCellAPCCTLA-4-CD28+CD154(CD40L)CD2CD58CD40B7(+)IL-1,IL-6,TNFIL-10TGF(-)TCR-MHCBDC2021/4/2710AbsenceofSignal2ActivationClonalAnergyorDeletionTCRMHCAPCToleranceTCellTCRMHCAPCSignal1+Signal2B7TCellcytokinesCD28The2-SignalModelofLymphocyteActivationBDC2021/4/2711MHC/self-peptideCD4MHC/VbCD4CD4+VbxTcell

APCActivatedautoreactiveCD4+TCRVbxTH1cell

TCRVbxTCRVbx(1)expansionofCD4+,autoreactiveTH1cellsspecificforautoantigens(2)migrationandinfiltrationoftheseselfreactiveCD4+TH1cellsintotissuesandinductionofinflammationandautoimmunity(3)inductionofregulatorycellswhichcontrolthegrowthandactivationofthepathogenicautoreactiverepertoireofCD4+TcellsInductionofCD4+TH1mediatedautoimmunity:Aparadigmforthepathogenesisofrheumatoidarthritis,multiplesclerosisandtypeIdiabetesL.Chess20022021/4/2712TH1CD4+cellsTH2CD4+cellsCD8orCD4suppressorprecursorCD8orCD4suppressoreffectorActivatedCD4Tcellspeptide/APC

RegulatoryimmunityCD4/CD8interactions(-)(-)TheControlofActivatedCD4+TCellsbyRegulatoryTcellsApoptosisRestingCD4TcellsIL-12/IFN-gIL-4NKTcells/CD4+CD25+cellsCD4+CD25-cells(-)(-)IL-10IFN-gL.Chess20022021/4/2713TcellactivationisregulatedbysignalsderivedfromtheTCR/CD3/CD4complexandtheCD40LandCD28/CTLA-4co-stimulatorymolecules

gedzzCD3MHCclassII

a,b

TCRhhPeptideantigenCD4+

TCell

AntigenPresentingCell(APC)VaVbCaCbCD4AntigenspecificTCRsignalsCD40CD40LsignalCD28/CTLA-4CD80(B7.1)/CD86(B7.2)lckCo-stimulatorysignals(-)/[+][+]L.Chess20022021/4/2714gedVaCaCbVbzzp56lck

peptideCD3CD28CD40LFA-3LFA-1ICAM-1MHCIIB7CD40LCD4CD45TCRCD2CD4+TCellAPC/BcellhhMolecularInteractionsofHelperTCellsandAPCB7CTLA-4VLA-1CollagenCD80/CD86L.Chess20022021/4/2715MHC/peptideTCRQa-1/VbActivatedCD4+TcellRestingCD4+TcellDown-regulationofActivatedCD4+TCellsTcellactivationinducesexpressionoffunctionalTcellsurfacemoleculesRegulatoryCD8+TcellTCR

(anti-Qa-1/Vb)

ActivatedCD8+Tcell(+)(-)TCRAPCTCRLateActivatedCD4+TcellVLA-1CollagenCD40LMigrationofsitesofinflammationInductionandactivationofBcellsAPCsCD25L.Chess20022021/4/2716ActivatedTH1CD4+TCellCD4+Cell(TH2)CD4+Cell(TH0)DR3,DR4,,DQ8/insulinpeptide

CD2Macrophage/dendriticcellFcR

IFN-g

IL-12CD40LCD40a,b,TCRIL-1,TNF,LT,NO,PGE-2BCell?anti-insulin,GADabanti-MogIL-4ImmunopathophysiologyofDiabetes?AntibodymediatedinjuryDendriticcell/APCCD40LIL-4CD40LCD8+CTLFasLperforinbcelldeathbisletcellsL.Chess20022021/4/2717InnateImmuneSystem:Toll-likereceptoractivationofAPC

TCellCD28B7TCR-MHCLPSTollLikeReceptor(patternRecognitionR)IL-1,6,12“Signal3”Signal2Signal1AnitgenPresentingCell(APC)BDC2021/4/2718Th1vs.Th2CD4TCellsTh1IL-12fordifferentiationCytokines:

Interferon-

Interleukin-2IntracellularPathogensCD8CytotoxicityDelayedTypeHypersensitivityMacrophageActivationTh2IL-4fordifferentiationCytokines:

Inerluekin-4

Inter