1、免疫应答概论免疫应答概论2 light chains(or)2 heavy chains(5 isotypes:IgG,M,A,D,E)2 Binding sites(Divalent)Secreted into circulationBinds Soluble Antigen2 Chains/(95%)or/(5%)1 Binding site(Monovalent)Membrane Bound,Not SecretedBinds Antigen Complexed with MHCZap 70fynlck e ez zV V C C CH1CH2CH3CH2CH3CH1CLCLVLVLVH
2、VHe e z zIg/IgIg/IgBlk,Fyn or LynB and T Lymphocyte Antigen ReceptorsBDC2020/11/42XPID:X-linked polyendocrinopathy,immune dysfunction and diarrhea XLAAD:“Autoimmunity Allergic Dysreg”Scurfin gene(Foxp3/JM2)Immunopathogenesis:Th2 Cytokines,abnormal activation(Il-4,5,13)-Scurfy+Nude:No Autoimmunity-CD
3、4+into Nude:Disease-Bone Marrow into irradiated:No Disease-Require Antigen Stimulation for Disease-Mixed Chimera:No DiseaseBDC2020/11/43Human Leukocyte Antigenhuman MHCcell-surface proteinsimportant in self vs.nonself distinctionpresent peptide antigens to T cellsCLASS I:A,B,CCLASS II:DR,DQ,DPHLAJ.N
4、oble2020/11/44The 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)BDC2020/11/45 3 211 2211221122Binds 8-10
5、mersExpressed 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 FunctionBDC2020/11/460501 02010301 0302 ci
6、scisDQA1 DQB1transDQA1*0301/DQB1*0201DQA1*0501/DQB1*0302DQA1*0501/DQB1*0201DQA1*0301/DQB1*0302MaternalPaternalCis and Trans-Class II DimerizationBDC2020/11/47DQB1*0402Asp57 Leu56 -chain-chainBDCBDC2020/11/48HLA-Peptide:TCRCDR1CDR2CDR3CDR3CDR2CDR1NH3+COO-TCRalphaTCRbeta2 Helix1 HelixBDC2020/11/49Co-S
7、timulation TCellAPCCTLA-4-CD28+CD154(CD40L)CD2CD58CD40B7(+)IL-1,IL-6,TNFIL-10TGF(-)TCR-MHCBDC2020/11/410Absence of Signal 2ActivationClonal Anergy or DeletionTCRMHCAPCToleranceT CellTCRMHCAPCSignal 1+Signal 2B7T CellcytokinesCD28The 2-Signal Model of Lymphocyte ActivationBDC2020/11/411MHC/self-pepti
8、deCD4MHC/VCD4CD4+V x T cell APCActivated autoreactive CD4+TCR V x TH1 cell TCR VxTCR Vx(1)expansion of CD4+,autoreactive TH1 cells specific for autoantigens(2)migration and infiltration of these self reactive CD4+TH1 cells into tissues and induction of inflammation and autoimmunity(3)induction of re
9、gulatory cells which control the growth and activation of the pathogenic autoreactive repertoire of CD4+T cellsInduction of CD4+TH1 mediated autoimmunity:A paradigm for the pathogenesis of rheumatoid arthritis,multiple sclerosis and type I diabetesL.Chess 20022020/11/412TH1 CD4+cellsTH2 CD4+cells CD
10、8 or CD4 suppressor precursorCD8 or CD4 suppressor effectorActivated CD4 T cellspeptide/APC Regulatory immunityCD4/CD8 interactions(-)(-)The Control of Activated CD4+T Cells by Regulatory T cellsApoptosisResting CD4 T cellsIL-12/IFN-IL-4NKT cells/CD4+CD25+cellsCD4+CD25-cells(-)(-)IL-10IFN-L.Chess 20
11、022020/11/413T cell activation is regulated by signals derived from the TCR/CD3/CD4 complex and the CD40L and CD28/CTLA-4 co-stimulatory molecules e e z z z zCD3MHC class II,TCRh h h hPeptide antigenCD4+T Cell Antigen Presenting Cell(APC)V V C C CD4Antigen specific TCR signalsCD40CD40LsignalCD28/CTL
12、A-4CD80(B7.1)/CD86(B7.2)lckCo-stimulatory signals(-)/+L.Chess 20022020/11/414 e e V C C V z zz zp56 lck peptideCD3CD28CD40LFA-3LFA-1ICAM-1MHC IIB7CD40LCD4CD45TCRCD2CD4+T CellAPC/B cellh h h hMolecular Interactions of Helper T Cells and APCB7CTLA-4VLA-1CollagenCD80/CD86L.Chess 20022020/11/415MHC/pept
13、ideTCRQa-1/V Activated CD4+T cellRestingCD4+T cellDown-regulation of Activated CD4+T CellsT cell activation induces expression of functional T cell surface molecules Regulatory CD8+T cellTCR(anti-Qa-1/V)Activated CD8+T cell(+)(-)TCRAPCTCRLate Activated CD4+T cellVLA-1CollagenCD40LMigration of sites
14、of inflammationInduction and activation of B cells APCsCD25L.Chess 20022020/11/416Activated TH1 CD4+T CellCD4+Cell(TH2)CD4+Cell(TH0)DR3,DR4,DQ8/insulin peptide CD2Macrophage/dendritic cellFc R IFN-IL-12CD40LCD40,TCRIL-1,TNF,LT,NO,PGE-2B Cell?anti-insulin,GAD ab anti-MogIL-4Immunopathophysiology of D
15、iabetes?Antibody mediated injuryDendritic cell/APCCD40LIL-4CD40LCD8+CTLFasLperforin cell death islet cellsL.Chess 20022020/11/417Innate Immune System:Toll-like receptor activation of APC T CellCD28B7TCR-MHCLPSToll Like Receptor(pattern Recognition R)IL-1,6,12“Signal 3”Signal 2Signal 1Anitgen Present
16、ing Cell(APC)BDC2020/11/418Th1 vs.Th2 CD4 T Cells IL-12 for differentiation Cytokines:Interferon-Interleukin-2 Intracellular Pathogens CD8 Cytotoxicity Delayed Type Hypersensitivity Macrophage Activation IL-4 for differentiation Cytokines:Inerluekin-4Interleukin-5Interluekin-13 Extracellular Pathoge
17、ns B Cell activation&IgEImmunoglobulin Eosinophil responsesBDC2020/11/419Tr:T Regulatory CellsReview:Roncarolo Curr Opinion Immunol 2000CD4+CD45RBloTGF,IL10Colitis by CD45RBhiTh3TGF,+/-IL10,IL4EAE,glomeruloneph,MG,clone DMTR1IL10,normalTGF,no IL4IBD by CD45RBhi,Respond IL-15CD4+CD25+(?=TR1)CTLA4Thymectomy autoimmuneConstituitive CTLA4Other CD4+IL2,IFNMBP EAE modelCD8+Oral tolerance intestineCD4-CD8-TCRFasSkin AllograftGamma/DeltaGut,Nasal InsulinNKTIL4,IL10,IFN,TGFCD1 ActivatedBDC2020/11/420
