1、The Immune System Innate Antimicrobial Peptides Phagocytes(Macrophages,PMNs,Monocytes,DCs)Alternative Complement System Acquired(Adaptive)-B Lymphocytes Antibody-T Lymphocytes Cytotoxicity “Help”Antibody Cytokine SecretionBDC2 light chains(or)2 heavy chains(5 isotypes:IgG,M,A,D,E)2 Binding sites(Div
2、alent)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 CH1CH2CH3CH2CH3CH1CLCLVLVLVHVHe e z zIg/IgIg/IgBlk,Fyn or LynB and T Lymphocyte Antigen ReceptorsBDCXPID:X-linked p
3、olyendocrinopathy,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-CD4+into Nude:Disease-Bone Marrow into irradiated:No Disease-Require Antigen Stimulation for Diseas
4、e-Mixed Chimera:No DiseaseBDCHuman Leukocyte Antigenhuman MHCcell-surface proteinsimportant in self vs.nonself distinctionpresent peptide antigens to T cellsCLASS I:A,B,CCLASS II:DR,DQ,DPHLAJ.NobleThe Human Leukocyte Antigen Complex (6p21.31)DP DQ DR B C AClass II (1.1 Mb)Class IIIClass I (2.2Mb)Com
5、plement and CytokinesClass I-like genesand pseudogenesFrequent Recombination Recombinationis RareTelomereCentromere Recombinationis Rare(0.7Mb)BDC 3 211 2211221122Binds 8-10mersExpressed on most Nucleated cellsPresents Cytosolic Proteins to CD8+T cellsBinds 13-25mersExpressed on APCs,Macs,B cells,ac
6、tivated T cellsPresents Vesicular Proteins to CD4+T cellsClass IClass IIHLA Class I and II Molecules Have a Distinct Structure and FunctionBDC0501 02010301 0302 ciscisDQA1 DQB1transDQA1*0301/DQB1*0201DQA1*0501/DQB1*0302DQA1*0501/DQB1*0201DQA1*0301/DQB1*0302MaternalPaternalCis and Trans-Class II Dime
7、rizationBDCDQB1*0402Asp57 Leu56 -chain-chainBDCBDCHLA-Peptide:TCRCDR1CDR2CDR3CDR3CDR2CDR1NH3+COO-TCRalphaTCRbeta2 Helix1 HelixBDCCo-Stimulation TCellAPCCTLA-4-CD28+CD154(CD40L)CD2CD58CD40B7(+)IL-1,IL-6,TNFIL-10TGF(-)TCR-MHCBDCAbsence of Signal 2ActivationClonal Anergy or DeletionTCRMHCAPCToleranceT
8、CellTCRMHCAPCSignal 1+Signal 2B7T CellcytokinesCD28The 2-Signal Model of Lymphocyte ActivationBDCMHC/self-peptideCD4MHC/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
9、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 mediated autoimmunity:A paradigm for the pathogenesis of
10、rheumatoid arthritis,multiple sclerosis and type I diabetesL.Chess 2002TH1 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 cellsApopt
11、osisResting CD4 T cellsIL-12/IFN-IL-4NKT cells/CD4+CD25+cellsCD4+CD25-cells(-)(-)IL-10IFN-L.Chess 2002T 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 A
12、ntigen Presenting Cell(APC)V V C C CD4Antigen specific TCR signalsCD40CD40LsignalCD28/CTLA-4CD80(B7.1)/CD86(B7.2)lckCo-stimulatory signals(-)/+L.Chess 2002 e e V C C V z zz zp56 lck peptideCD3CD28CD40LFA-3LFA-1ICAM-1MHC IIB7CD40LCD4CD45TCRCD2CD4+T CellAPC/B cellh h h hMolecular Interactions of Helpe
13、r T Cells and APCB7CTLA-4VLA-1CollagenCD80/CD86L.Chess 2002MHC/peptideTCRQa-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(+)(-)TCRA
14、PCTCRLate Activated CD4+T cellVLA-1CollagenCD40LMigration of sites of inflammationInduction and activation of B cells APCsCD25L.Chess 2002Activated 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?an
15、ti-insulin,GAD ab anti-MogIL-4Immunopathophysiology of Diabetes?Antibody mediated injuryDendritic cell/APCCD40LIL-4CD40LCD8+CTLFasLperforin cell death islet cellsL.Chess 2002Innate Immune System:Toll-like receptor activation of APC T CellCD28B7TCR-MHCLPSToll Like Receptor(pattern Recognition R)IL-1,
16、6,12“Signal 3”Signal 2Signal 1Anitgen Presenting Cell(APC)BDCTh1 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-5In
17、terluekin-13 Extracellular Pathogens B Cell activation&IgEImmunoglobulin Eosinophil responsesBDCTr: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 ActivatedBDCAvidinDQDQDQ“Tetramer”for T Cell AnalysisDQPEPTIDEBDC此课件下载可自行编辑修改，供参考！感谢您的支持，我们努力做得更好！
