免疫應答概論課件

1、免疫應答概論免疫應答概論免疫應答概論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 MHCB and T Lymphocyte Antigen Recep

2、torsBDC2020/11/42免疫應答概論免疫應答概論免疫應答概論2 light chai2 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

3、 70fynlckgezVVCCCH1CH2CH3CH2CH3CH1CLCLVLVLVHVHedzIga/IgbIga/IgbBlk, Fyn or LynB and T Lymphocyte Antigen ReceptorsBDC2020/11/422 light chains ( or )2 ChainXPID: X-linked polyendocrinopathy, immune dysfunction and diarrheaXLAAD: “Autoimmunity Allergic Dysreg”Scurfin gene (Foxp3/JM2)Immunopathogenesis

4、: Th2 Cytokines, abnormal activation (Il-4,5,13)-Scurfy+Nude: No Autoimmunity-CD4+ into Nude: Disease-Bone Marrow into irradiated: No Disease-Require Antigen Stimulation for Disease-Mixed Chimera: No DiseaseBDC2020/11/43XPID: X-linked polyendocrinopaHuman Leukocyte Antigenhuman MHCcell-surface prote

5、insimportant in self vs. nonself distinctionpresent peptide antigens to T cellsCLASS I: A,B,CCLASS II: DR,DQ,DPHLAJ. Noble2020/11/44Human Leukocyte AntigenCLASS IThe 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 g

6、enesand pseudogenesFrequent Recombination Recombinationis RareTelomereCentromere Recombinationis Rare(0.7Mb)BDC2020/11/45The Human Leukocyte Antigen Coa3b2a1a2a1a2b1b2Binds 8-10mersExpressed on most Nucleated cellsPresents Cytosolic Proteins to CD8+ T cellsBinds 13-25mersExpressed on APCs, Macs, B c

7、ells, activated T cellsPresents Vesicular Proteins to CD4+ T cellsClass IClass IIHLA Class I and II Molecules Have a Distinct Structure and FunctionBDC2020/11/46a3b2a1a2a1a2b1b2Binds 8-10mers0501 02010301 0302 ciscisDQA1 DQB1transDQA1*0301/DQB1*0201DQA1*0501/DQB1*0302DQA1*0501/DQB1*0201DQA1*0301/DQB

8、1*0302MaternalPaternalCis and Trans- Class II DimerizationBDC2020/11/470501 0201030DQB1*0402Asp57Leu56 -chain-chainBDCBDC2020/11/48DQB1*0402Asp57Leu56 -chainHLA-Peptide: TCRCDR1CDR2CDR3CDR3CDR2CDR1NH3+COO-TCRalphaTCRbeta2 Helix1 HelixBDC2020/11/49HLA-Peptide: TCRCDR1CDR2CDR3CDCo-Stimulation TCellAPC

9、CTLA-4 -CD28 +CD154(CD40L)CD2CD58CD40B7(+)IL-1, IL-6, TNFIL-10TGF(-)TCR-MHCBDC2020/11/410Co-Stimulation TAPCCTLA-4 -CAbsence of Signal 2ActivationClonal Anergy or DeletionTCRMHCAPCToleranceT CellTCRMHCAPCSignal 1 + Signal 2B7T CellcytokinesCD28The 2-Signal Model of Lymphocyte ActivationBDC2020/11/41

10、1Absence of Signal 2ActivationCMHC/self-peptideCD4MHC/VbCD4CD4+ Vbx T cell APCActivated autoreactive CD4+TCR Vbx TH1 cell TCR VbxTCR Vbx(1) expansion of CD4+, autoreactive TH1 cells specific for autoantigens(2) migration and infiltration of these self reactive CD4+ TH1 cells into tissues and inducti

11、on of inflammation and autoimmunity(3) induction of regulatory 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 dia

12、betesL. Chess 20022020/11/412MHC/self-peptideCD4MHC/VbCD4CDTH1 CD4+ cellsTH2 CD4+ cells CD8 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 cellsApoptosisRes

13、ting CD4 T cellsIL-12/IFN-gIL-4NKT cells/ CD4+CD25+ cellsCD4+CD25- cells(- )(- )IL-10IFN-gL. Chess 20022020/11/413TH1 CD4+ cellsTH2 CD4+ cells CT cell activation is regulated by signals derived from the TCR /CD3/CD4 complex and the CD40L and CD28/CTLA-4 co-stimulatory molecules gedzzCD3MHC class II

14、a,b TCRhhPeptide antigenCD4+ T Cell Antigen Presenting Cell (APC)VaVbCaCbCD4Antigen specific TCR signalsCD40CD40LsignalCD28/CTLA-4CD80 (B7.1)/CD86 (B7.2)lckCo-stimulatory signals(- ) / +L. Chess 20022020/11/414T cell activation is regulatedgedVaCaCbVbzzp56 lck peptideCD3CD28CD40LFA-3LFA-1ICAM-1MHC I

15、IB7CD40LCD4CD45TCRCD2CD4+ T CellAPC/ B cellhhMolecular Interactions of Helper T Cells and APCB7CTLA-4VLA-1CollagenCD80/CD86L. Chess 20022020/11/415gedVaCaCbVbzzp56 lck peptidMHC/peptideTCRQa-1/VbActivated CD4+ T cellRestingCD4+ T cellDown-regulation of Activated CD4+ T CellsT cell activation induces

16、 expression of functional T cell surface molecules Regulatory CD8+ T cellTCR (anti-Qa-1/Vb) Activated CD8+ T cell(+)(-)TCRAPCTCRLate Activated CD4+ T cellVLA-1CollagenCD40LMigration of sites of inflammationInduction and activation of B cells APCsCD25L. Chess 20022020/11/416MHC/peptideTCRQa-1/VbActiv

17、atedActivated 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-4CD

18、40LCD8+ CTLFasLperforinb cell deathb islet cellsL. Chess 20022020/11/417Activated TH1 CD4+ T CellCD4+ Innate 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 Presenting Cell (APC)BDC2020/11/418Innate Immune System: Toll-likTh1 vs. Th2 CD4 T CellsTh1IL-12 for differentiationCytokines:Interferon-Interleukin-2Intracellular Pathogens CD8 CytotoxicityDelayed Type HypersensitivityMacrophage ActivationTh2IL-4 for differen