1、The Immune SystemInnateAntimicrobial PeptidesPhagocytes (Macrophages, PMNs, Monocytes, DCs)Alternative Complement SystemAcquired (Adaptive)-B Lymphocytes Antibody-T Lymphocytes Cytotoxicity “Help” Antibody Cytokine SecretionBDCThe Immune SystemInnateAcquire2 light chains ( or )2 heavy chains (5 isot

2、ypes: 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 70fynlckgezVVCCCH1CH2CH3CH2CH3CH1CLCLVLVLVHVHedzIga/IgbIga/IgbBlk, Fyn or LynB and T Lymp

3、hocyte Antigen ReceptorsBDC2 light chains ( or )2 ChainXPID: X-linked polyendocrinopathy, immune dysfunction and diarrheaXLAAD: “Autoimmunity Allergic Dysreg”Scurfin gene (Foxp3/JM2)Immunopathogenesis: Th2 Cytokines, abnormal activation (Il-4,5,13)-Scurfy+Nude: No Autoimmunity-CD4+ into Nude: Diseas

4、e-Bone Marrow into irradiated: No Disease-Require Antigen Stimulation for Disease-Mixed Chimera: No DiseaseBDCXPID: X-linked polyendocrinopaHuman Leukocyte Antigenhuman MHCcell-surface proteinsimportant in self vs. nonself distinctionpresent peptide antigens to T cellsCLASS I: A,B,CCLASS II: DR,DQ,D

5、PHLAJ. NobleHuman 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 genesand pseudogenesFrequent Recombination Recombinationis RareTelomereCentromere Recombinationis Rare(0.7Mb)BDCThe Human

6、 Leukocyte Antigen Coa3b2a1a2a1a2b1b2Binds 8-10mersExpressed 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 Stru

7、cture and FunctionBDCa3b2a1a2a1a2b1b2Binds 8-10mers0501 02010301 0302 ciscisDQA1 DQB1transDQA1*0301/DQB1*0201DQA1*0501/DQB1*0302DQA1*0501/DQB1*0201DQA1*0301/DQB1*0302MaternalPaternalCis and Trans- Class II DimerizationBDC0501 0201030DQB1*0402Asp57Leu56 -chain-chainBDCBDCDQB1*0402Asp57Leu56 -chainHLA

8、-Peptide: TCRCDR1CDR2CDR3CDR3CDR2CDR1NH3+COO-TCRalphaTCRbeta2 Helix1 HelixBDCHLA-Peptide: TCRCDR1CDR2CDR3CDCo-Stimulation TCellAPCCTLA-4 -CD28 +CD154(CD40L)CD2CD58CD40B7(+)IL-1, IL-6, TNFIL-10TGF(-)TCR-MHCBDCCo-Stimulation TAPCCTLA-4 -CAbsence of Signal 2ActivationClonal Anergy or DeletionTCRMHCAPCT

9、oleranceT CellTCRMHCAPCSignal 1 + Signal 2B7T CellcytokinesCD28The 2-Signal Model of Lymphocyte ActivationBDCAbsence 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 f

10、or autoantigens(2) migration and infiltration of these self reactive CD4+ TH1 cells into tissues and induction 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 medi

11、ated autoimmunity:A paradigm for the pathogenesis of rheumatoid arthritis, multiple sclerosis and type I diabetesL. Chess 2002MHC/self-peptideCD4MHC/VbCD4CDTH1 CD4+ cellsTH2 CD4+ cells CD8 or CD4 suppressor precursorCD8 or CD4 suppressor effectorActivated CD4 T cellspeptide/APC Regulatory immunityCD

12、4/CD8 interactions(- )(- )The Control of Activated CD4+ T Cells by Regulatory T cellsApoptosisResting CD4 T cellsIL-12/IFN-gIL-4NKT cells/ CD4+CD25+ cellsCD4+CD25- cells(- )(- )IL-10IFN-gL. Chess 2002TH1 CD4+ cellsTH2 CD4+ cells CT cell activation is regulated by signals derived from the TCR /CD3/CD

13、4 complex and the CD40L and CD28/CTLA-4 co-stimulatory molecules gedzzCD3MHC class II 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 2002T cell activati

14、on is regulatedgedVaCaCbVbzzp56 lck peptideCD3CD28CD40LFA-3LFA-1ICAM-1MHC IIB7CD40LCD4CD45TCRCD2CD4+ T CellAPC/ B cellhhMolecular Interactions of Helper T Cells and APCB7CTLA-4VLA-1CollagenCD80/CD86L. Chess 2002gedVaCaCbVbzzp56 lck peptidMHC/peptideTCRQa-1/VbActivated CD4+ T cellRestingCD4+ T cellDo

15、wn-regulation of Activated CD4+ T CellsT cell activation induces 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

16、cells APCsCD25L. Chess 2002MHC/peptideTCRQa-1/VbActivatedActivated 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?

17、Antibody mediated injuryDendritic cell/APCCD40LIL-4CD40LCD8+ CTLFasLperforinb cell deathb islet cellsL. Chess 2002Activated 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

18、1Anitgen Presenting Cell (APC)BDCInnate Immune System: Toll-likTh1 vs. Th2 CD4 T CellsTh1IL-12 for differentiationCytokines:Interferon-Interleukin-2Intracellular Pathogens CD8 CytotoxicityDelayed Type HypersensitivityMacrophage ActivationTh2IL-4 for differentiationCytokines:Inerluekin-4Interleukin-5Interluekin-13Extracellular PathogensB Cell activation & IgEImmunoglobu