分子和细胞免疫进展0课件1.ppt

1、 Adaptive immunity-New T cell subsets,Th17 and TregsImmunity Antigen Antibody Section I.Some basic conceptions1233333 33534Immune system Immune responsen Immunity is the ability to respond to foreign substances(antigen),including microbes,as well as macromolecules such as proteins and polysaccharide

2、s,mediated by immune system,regardless of the physiologic or pathologic consequence of such a reaction 1.Immunity Antigen is used to indicate any molecule that can be specifically recognized by B cells or T cells,or both 2.AntigenAg B cells Ab T cells effective T cells Immunogenicity Immunoreactivit

3、yAntigenic determinantAntigen determinants(epitope)are small particular chemical groups existing in antigen which can be recognized by TCR/BCR or Ab.Polypeptide antigen-5-23 amino acid residuesPolysaccharide antigen-5-7 monosaccharides Nuclear acid antigen-6-8 nucleotidesConformational determinantsC

4、onformational determinants are formed by amino acid residues that arent in a sequence but become spatially juxtaposed in the folded protein.They are normally exist on the surface of antigen molecules.They are recognized by B cells or antibody.Sequential(or linear)determinantsEpitopes formed by sever

5、al adjacent amino acid residues are called linear determinants.They are exist on the surface of antigen molecules or inside molecules.They are mainly recognized by T cells,but some also can be recognized by B cells.Antibody：a type of glycoprotein molecule,also called immunoglobulin(Ig),producedby B

6、cells that bind antigens often with a high degree of specificity and affinity The basic structural unit of antibody is composed of two identical heavy chains and two identical light chains（1）Four polypeptide chains 2 identical heavy chains 2 identical light chains The 4 polypeptide chains are joined

7、 by inter-chain disulfide bonds(S-S bond)Two terminal ends “N”terminal end “C”terminal end Two regions variable regions constant regionn C-terminal endN-terminal end The basic structural unit Variable region(V)Hypervariable region(HVR)Framework region (FR)CDR1CDR2CDR3CDR1,CDR2,CDR3L:CDR128-35,CDR249

8、-56,CDR391-98 H:CDR1-29-31 CDR2-49-58 CDR3-95-102Hypervariable region(HVR)Framework region (FR)nCDR:complementarity determining regions The three short stretches in the V regions of Ig that contain most of the sequence differences among Igs are called CDR because these sequences form an antigen-bind

9、ing surface that is complementary to the three-dimensional structure of the bound antigenAg-binding sites The molecules,cells,tissues and organs that collectively function to provide immunity or protection against foreign substances 4.Immune systemImmune system immune organs or tissues bone marrow t

10、hymus spleen lymph nodes Immune cells:lymphocytes:T cells,B cells and NK cells phagocytes:macrophage immune molecules:antibody complement(补体）补体）cytokines :IL,IFN,TNF,CSF adhesive molecules:Integrin,selectin,Ig superfamily.Immune organs nCentral immune organs or primary lymphoid organs The site that

11、lymphocytes generate and mature into functional cells Bone marrow and Thymus nPeripheral immune organs or secondary lymphoid organs and tissues The sites that T and B lymphocytes reside in and respond to antigens spleen,lymph nodes,mucosal or cutaneous lymphoid tissues Central immune organ and perip

12、heral immune organ A collective and coordinated response to the introduction of foreign substances in an individual mediated by cells and moleculesI.Immune response:(1).immunological defense(2).immunological homeostasis(3).immunological surveillance 5.Function of ImmunityImmunodeficiency Immune resp

13、onse-Section IIInnate immunity and Adaptive immunity innate immunity and Adaptive immunityAgI.innate immunity(natural immunity or non-specific immunity)1.CharacteristicsnNatural Existence:Consists of cellular and biochemical defense mechanisms that are in place even before infectionnNonspecificty:re

14、spond rapidly to all infectionnNo memory:Respond in same way to repeated infections nReact only to microbes and not to noninfectious substance(2)CompositionnMechanical Barrier:skin,mucus blood-brain barriers,placental barriernCells:macrophages,Dendritic cells,NK cellsnChemical factors:complement cyt

15、okines lysozymeII.Adaptive immunity 1.characteristicsnInduction by exposure infectious agentnSpecificity:immune response are specific for distinct antigens nMemory:respond more vigorously to repeated exposures to same microbesnAble to recognize and react to a large number of microbial and nonmicrobi

16、al substancelatent periodSignificanceVaccination diagnosis 2.Compositionn Humoral immunity(HI)-mediated by antibody produced by B celln Cellular Mediated immunity(CMI)-mediated by T cell Humoral immunity(HI)HI is mediated by molecules in the blood and mucosal secretions,called antibodies,that are pr

17、oduced by B lymphocytes Antibody recognizes microbial antigens,neutralize the infectivity of the microbes,and target microbes for elimination by various effector mechanisms HI is the principal defense mechanisms against extrocellular microbes and their toxins Cellular Mediated immunity(CMI)nMediated

18、 by T cellsnPromote the destruction of microbes residing in phagocytes or killing of infected cells to eliminate reservoirs of infection nCMI is the principal defense mechanisms against introcellular microbes(virus and some bacteria in phagocytes)Cell-mediated ImmunityCD4+Th and CD8+CTL Section III.

19、CD4+T cell subsets-Th17 and TregsTwo traditional CD4 T cell subsets-Th1 and Th2Autoimmune diseasesTwo new CD4+Tcell subsets-Tregs and Th17nTh17：CD4+T cells which produce IL-17 play an important role in promoting chronic inflammation and autoimmune diseasesnTreg-regulatory T cell：A population of T ce

20、lls that regulates the activation of other T cells and is necessary to the maintain peripheral tolerance to self antigens.Inhibit autoimmunitynprevent transplant rejectionnInterfere with anti-cancer immunitynPotential in immune deficiencyConception:Tregs and Th17 Yin-yang balance Effect immune cells

21、 Regulatory Immune cells Th1,Th17TregsTh2 I.Discovery of Th17 subsetsTwo traditional CD4 T cell subsets-Th1 and Th21.A number of observations which could not be explained on the basis of the two Th1 and Th2 subtypes nMice deficient in IFN-or IFN-receptors have increased susceptibility to EAE and col

22、lagen-induced arthritis(CIA)nEAE was exacerbated in mice deficient in the Th1 polarizing cytokine,IL-12 Krakowski,M.,and Owens,T.,Interferon-gamma confers resistance to experimental allergic encephalomyelitis.Eur.J.Immunol.2019.26:1641-1646.Vermeire,K.,Heremans,H.,Vandeputte,M.,Huang,S.,Billiau,A.an

23、d Matthys,P.,Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice.J.Immunol.2019.158:5507-5513.experimental autoimmune encephalomyelitis(EAE)nHarrington,L.E.,Hatton,R.D.,Mangan,P.R.,Turner,H.,Murphy,T.L.,Murphy,K.M.,and Weaver,C.T.,Interleukin 17-producing CD4+effector T cells

24、 develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat.Immunol.2019.6:1123-1132.n nPark,H.,Li,Z.,Yang,X.O.,Chang,S.H.,Nurieva,R.,Wang,Y.H.,Wang,Y.-Chen Dong.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat.Immunol.2019.6:1133-1141.2

25、.IL-17-producing CD4+T cells was identified as a new subset by two groups in 2019Antigen-inducing Th17nPark,H.,et al Nat.Immunol.2019.6:1133-1141.EAEII.Characteristics of Th17 1.Induction of Th17 2.Cytokines produced by Th17：IL-17A,IL-17F,IL-6,IL-21,IL-22,TNF-Proinflammatory cytokines3.The transcrip

26、tional factor ROR-t directed development of IL-17-secreting T cellsThe transcriptional factor ROR-t directed development of IL-17-secreting T cells STATs:signal transducer and activator of transcriptionROR t:retinoid-related orphan receptor t4.IL-17 Receptor Macrophage and endothelial cells IL-17 Re

27、ceprornThe IL 17R family comprises five receptor subunits,IL 17RAIL 17RE.nDespite considerable sequence divergence,many of the genes encoding the IL 17R family members are linked,with clusters on human chromosome 3(for IL 17RB,IL 17RC,IL 17R D and IL 17RE)and mouse chromosomes 6(for IL 17RA,IL 17RC

28、and IL 17RE)and 14 (for IL 17RB and IL 17RD).nAll of the receptor subunits are single trans membrane domain containing proteins,ranging in size from 499 to 866 amino acids.nThese receptor subunits contain certain conserved structural motifs,including an extracellular fibronectin III like domain(FN)a

29、nd a cytoplasmic SEF/IL 17R(SEFIR)domain IL 17RA expression and complex formationnIL 17RA was initially identified as the receptor for mammalian IL 17A and vIL 17.IL 17RA also binds IL 17FnIL 17RA is expressed ubiquitously,with particularly high levels in haematopoietic tissues.nThis expression patt

30、ern is interesting,as the main responses to IL 17A occur in epithelial cells,endothelial cells and fibroblasts,although macrophages and DCs are also responsivep65p505.IL-17 mediated signal pathwaysInterleukin 17 receptor(IL 17R)signalingn IL 17RA engages the SEFIR domain containing adaptor ACT1 to m

31、ediate various downstream eventsnNF-KB pathway:ACT1 is required for recruitment of TNFR associated factor 6(TRAF6)and possibly TRAF3,which are essential upstream activators of the canonical nuclear factor B(NF B)pathway.nMAPK pathway:ACT1,but not TRAF6,is required for IL 17A induced stabilization of

32、 several target mRNAs,particularly those encoding chemokines and cytokines by p38 extracellular signal regulated kinase(ERK)might also be controlled by ACT1,at least indirectlynC/EBP:The CBAD is required for IL 17A mediated inducible nphosphorylation of C/EBP on threonine,which is mediated by glycog

33、en synthase kinase 3 (GSK3)Comparison of IL-17R and TLR signaling Potential drugs targeting IL-17 or IL-17RStrategies for therapeutic blockade of I l-17 signalingnAntibodies specific for individual ligands or the individual receptor subunits are the most straightforward approach.nSoluble IL 17R subu

34、nits,such as fusions to IgG Fc,have been evaluated in pre clinical models nsoluble peptides:Preventing receptor assembly by means of soluble peptides containing the pre ligand assembly domain(PLAD)III.Th17 and diseasesPromoting organ-specific autoimmunity and chronic inflammatory conditions 1.Organ-

35、specific autoimmune diseases Experimental allergic encephalomyelitis,EAE Rheumotoid arthritis（RA）ColitisAtherosclerosis2.Chronic infection IL-17 protect against bacterial infections Protective pulmonary immunity to M.tuberculosis 3.Tumor:?Th17 and IL-17 in atherosclerosisAtherosclerosis is pathologi

36、cal basis of Cardiovascular diseases Coronary artery disease(CAD)Unstable anginaMyocardial InfarctionCardiovascular diseases Cerebrovascular disease The most common forms AtherosclerosisBrain infarction 16.7 million deaths Atherosclerosis is a slowly progressing chronic disorder of large and medium-

37、sized arteriesWhen it causes thrombosis,it becomes clinically manifest-acute coronary syndrome：unstable angina pectorispectoris and acute myocardial infarctionan accumulation of lipids infiltration of immunocytes,macrophages,T cells and mast cellsvascular smooth muscle cells collagen.Atherosclerosis

38、AtherosclerosisTregTh17Atherosclerosis?Th17The different CD4+subsets have various roles in Atherosclerosis?AACS NCBCCD4IL-17SALevel of IL-17ANCSAACS050100150Levels of IL-17(pg/ml)NCSAACS0123Percent of Th17/CD4+Tcell(%)1.The circulating Th17 cells and IL-17 significantly increase in patients with ACS

39、 compared with normal control and stable angina NC：Normal controlSA：stable angina pectorisACS：Acute coronary syndrome-unstable angina acute myocardial infarction Th17IL-17Th17and IL-17 may be involved in atherosclerosis.2.Establishment of two atherosclerotic mice modelsRapid carotid model Standard m

40、odelplaque in A Aortic root plaque in carotid3.The dynamic change of Th17 subset in spleen during the development of atherosclerosis(1)0.5%C57ApoE-/-C57ApoE-/-8 weeksIL-17IFN-C57ApoE-/-3.The dynamic change of Th17 subset in spleen during the development of atherosclerosis(2)CarotidC57ApoE-/-C57ApoE-

41、/-16 weeks24 weeks3.0%IL-17IFN-IL-17IFN-4.4%Advanced plaque 4.The percentage of Th17 in spleen has a positive correlation to size of plaque8 weeks 16 weeks 24 weeksCD4+IL-17+(%)Plaque area(m2)Th175.Expression of IL-17 and its transcriptional factor ROR-t in arterial walls during formation of plaqueE

42、stablished plaque advanced plaque ROR-t IL-17b b-actinNo plaqueIL-17macrophageCD4+T cells5.IL-17 is expressed in both CD4+T cells and MacrophageTh17 and IL-17 are involved in the atherosclerosisNeutrolizing anti-IL-17 antibody or exogenous IL-17 was injected into ApoE-/-mice to confirm causative rol

43、e NeutrolizingNeutrolizing Rapid carotid model Standard modelNeutrolizingNeutrolizingplaque in aortic root plaque in plaque in carotid6.Blockage of endogenous IL-17 markedly suppresses the development of plaque in carotidModel 1CarotidN=10/groupGao,et al,J.Immuno,2019Anti-IL-17IsotypeLesions area(um

44、2)Anti-IL-17IsotypeHELesions area(um2)Anti-IL-17IsotypeUltrosound imaging 7.Blockage of IL-17 markedly suppresses the development of plaque in standard model Aortic root N=5/groupGao,et al,J.Immuno,2019Anti-IL-17IsotypeOROLesions area(um2)Anti-IL-17IsotypeModel 2OROSMCMacrophageControlIL-17 Gao,et a

45、l,J.Immuno 2019 8.Treatment of Exogenous IL-17 accelerates plaque formation in ApoE-/-micenTh17 is involved in atherosclerosisnIL-17 promotes the development of atherosclerosisnBlockade of endogenous IL-17 by neutrolizing antibody attenuates formation of plaque nQi Gao et al,A critical function of T

46、h17 proinflammatory cells in the development of atherosclerotic plaque in mice.J.Immunol.2019 Nov 15;185(10):5820-7.ConclusionIII.Th17 and diseasesPromoting organ-specific autoimmunity and chronic inflammatory conditions 1.Organ-specific autoimmune diseases Experimental allergic encephalomyelitis,EA

47、E-reference Rheumotoid arthritis（RA）Colitis Atherosclerosis2.Chronic infection IL-17 protect against bacterial infections Protective pulmonary immunity to M.tuberculosis CD4+T cell subsetsReference 1.Harrington,L.E.,Hatton,R.D.,Mangan,P.R.,Turner,H.,Murphy,T.L.,Murphy,K.M.,and Weaver,C.T.,Interleuki

48、n 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat.Immunol.2019.6:1123-1132.2.Park,H.,Li,Z.,Yang,X.O.,Chang,S.H.,Nurieva,R.,Wang,Y.H.,Wang,Y.-Chen Dong.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat.Immunol.2019.6:1133-1141.