免疫學(xué)知識(shí)概述課件

TheOriginofImmuneConceptTheterm“Immunity” =>Latinword“Immunitas”=>Protectionfromlegalprosecution(Romansenators)

Biologicaldefinition=>Protectionfrominfectiousdiseases2. Theconceptofimmunity=>existedinancientGreek&Chinese=>theexperiencedview“天花”又名痘瘡中國(guó)從宋朝起用人痘接種預(yù)防天花TheOriginofImmuneConceptTh1Themedicalviewofimmunity=>EdwardJenner(1796) Observation=>MilkmaidsgenerallygetNoSmallpox

Hypothesis=>Pusfromvaccinia(cowpox) =>Protectmilkmaidsfromsmallpox

Test=>Inoculatematerialsfromcowpoxpus =>Protectayoungboyfromsmallpox

(Protectiveimmunity)ThevaccinationagainstsmallpoxExudatefromacowpoxpustuleonthehandofmilkmaidSarahNelmeswasinsertedintoscratchesonthearmsofJamesPhipps,May14,1796.Thevaccinationagainstsmallp2EdwardJennerEradicationofsmallpox200yearsafterJennerWHOannouncesmallpoxeradicated1965197019751980Countrieswithmorethanonesmallpoxcasepermonth30150EdwardJennerEradicationofsm34. Theconceptof“Immunity”developedgraduallyovertimethroughmanyscientificfindings:

=>RobertKoch(1905NobelLaureate)=>Infectious diseasescausedbymicroorganisms =>LouisPasteur=>Vaccinesagainstcholera&rabies =>Theseclinicalsuccesses=>Thesearchofunderlyingmechanismof“ProtectionofInfectiousDiseases” =>Thedevelopmentof“Immunology”Advancesintechnology(e.g.,Cellculture,MonoclonalAb,Flowcytometry,Geneticengineering…etc)havefacilitatedourunderstandingoftheimmunesystemanditsfunctions.

“DescriptiveScience”=>“ExperimentalScience”4. Theconceptof“Immunity”d4免疫（immunity)傳統(tǒng)概念指免除疫病、免除感染，指機(jī)體抗感染的防御能力。現(xiàn)代概念指機(jī)體對(duì)“自己”或“非己”的識(shí)別并排除“非己”的功能。免疫（immunity)5免疫的基本功能功能正常表現(xiàn)（有利）異常表現(xiàn)（有害）免疫防御immunedefence抗病原微生物的侵襲超敏反應(yīng)易受感染或免疫缺陷病免疫穩(wěn)定immunehomeostasis清除損傷、衰老、死亡細(xì)胞自身免疫性疾病免疫監(jiān)視immunesurveillance清除突變或畸變的惡性細(xì)胞惡性腫瘤免疫的基本功能功能正常表現(xiàn)（有利）異常表現(xiàn)（有害）免疫防御抗6免疫系統(tǒng)(immunesystem)：機(jī)體執(zhí)行免疫功能的組織、器官、細(xì)胞和分子構(gòu)成免疫系統(tǒng)。免疫系統(tǒng)(immunesystem)：機(jī)體執(zhí)行免疫功能的7Thefourkindsofpathogensthatcausehumandisease常見(jiàn)的病原微生物Thefourkindsofpathogensth8OverviewofimmuneresponsesOverviewofimmuneresponses9固有免疫（innateimmunity）是機(jī)體抵御病原微生物入侵的第一道防線，并啟動(dòng)和參與適應(yīng)性免疫應(yīng)答。 天然免疫（naturalimmunity)或非特異性免疫(nonspecificimmunity)，是個(gè)體出生時(shí)就具有的免疫力，通過(guò)遺傳獲得，是生物在長(zhǎng)期進(jìn)化過(guò)程中逐漸形成的，其針對(duì)外來(lái)異物的范圍廣，反應(yīng)迅速，其應(yīng)答模式和強(qiáng)度不因與病原微生物的反復(fù)接觸而改變。固有免疫應(yīng)答的作用時(shí)相：瞬時(shí)固有免疫應(yīng)答階段、早期固有免疫應(yīng)答階段、適應(yīng)性免疫應(yīng)答誘導(dǎo)階段固有免疫固有免疫應(yīng)答的作用時(shí)相：10固有免疫系統(tǒng)的組成屏障細(xì)胞分子皮膚黏膜屏障：物理、化學(xué)、微生物血-腦屏障、血-胸腺屏障血-胎屏障、氣-血屏障巨噬細(xì)胞、中性粒細(xì)胞、樹(shù)突狀細(xì)胞、γδT細(xì)胞、NK細(xì)胞、NKT細(xì)胞、B1細(xì)胞、肥大細(xì)胞、嗜堿性粒細(xì)胞和嗜酸性粒細(xì)胞等?？咕?、溶菌酶、急性期蛋白、補(bǔ)體、細(xì)胞因子和黏附分子、固有免疫系統(tǒng)的組成屏障皮膚黏膜屏障：物理、化學(xué)、微生物巨噬細(xì)11Epithelialbarrierspreventthe

entryofmicrobesEpithelialbarrierspreventth12固有免疫細(xì)胞

PhagocyteNKILLs（固有樣淋巴細(xì)胞）DCMCBasophilEosinophil

T細(xì)胞

NKT細(xì)胞

B1細(xì)胞Monocyte-macrophageNeutrophil固有免疫細(xì)胞PhagocyteT細(xì)胞Monocyt13肺部巨噬細(xì)胞吞噬大腸桿菌肺部巨噬細(xì)胞吞噬大腸桿菌14PhagocytosisbyinnateimmunityPhagocytosisbyinnateimmunit15LeukocyterecruitmenttositesofinflammationorDCLeukocyterecruitmenttosites16固有性免疫分子指體表分泌液以及血漿和其它體液中能夠識(shí)別或攻擊病原體的可溶性分子。抗菌肽antimicrobialpeptides溶菌酶lysozyme急性期蛋白(acutephaseproteins,APP)脂多糖結(jié)合蛋白（LBP）血清淀粉樣蛋白（SAP）甘露糖結(jié)合蛋白（MBP）C反應(yīng)蛋白等（CRP）補(bǔ)體細(xì)胞因子和黏附分子固有性免疫分子指體表分泌液以及血漿和其它體液中能夠識(shí)別或攻擊17ComplementactivationpathwaysComplementactivationpathways18ElieMechnikoff:ThePioneerofInnateImmunity1.TheDiscoveryofPhagocytes&Phagocytosis2.TheNobelLaureateinMedicine1908AdoptedfromNatureImmunology,July2008ThedevelopmentofmodernImmunologyin20thcenturymainlycentersonunderstandingtheAdaptiveImmuneSystem.ElieMechnikoff:ThePioneerof19CharlesA.Janeway,M.D.YaleUniv.The“Renaissance”ofinnateimmunityIn1989,Janeway=>Immunerecognitionofmicrobes=>Detectionofconservedmolecularpatterns,referredtoPAMPs(Pathogen-AssociatedMolecularPatterns)withfeatures:1.Invariantamongagivenclassofmicrobes.2.Haveessentialrolesinmicrobialphysiology.3.Recognizedbyreceptorsoftheinnateimmunesystem,calledPRRs(Pattern-RecognitionReceptors).4.InnateimmunityregulatesadaptiveimmunityCharlesA.Janeway,M.D.The“R20JulieA.Hoffmann,Ph.D.Strasbourg,FranceThe“Renaissance”ofinnateimmunityIn1996,Hoffmann’sgroupTollfunctionsasaPRRinDrosophilaJulieA.Hoffmann,Ph.D.The21Keyconceptsininnateimmunity1.Theinnateimmunesystemmainlyrecognizescommonstructuressharedbyclassesofmicrobes,=>PathogenAssociatedMolecularPatterns(PAMPs),e.g.,LPS,Peptidoglycan,MicrobialDNA&RNA.

2.HostreceptorsthatrecognizePAMPsarecalledPattern-RecognitionReceptors(PRRs),whichareencodedin“Germline”DNA=>limitedDiversity.

3.Innateimmunitynotonlyprovidethefirstlineofdefensesbutlinktotheprogramofadaptiveimmunity.4.PRRsmayalsorecognizecomponentsfrominjuredordeadhostcells=>AutoimmunediseasesKeyconceptsininnateimmunit22Pattern

Lipopolysaccharide(LPS)

Lipoteichoicacid

Bacteriallipopeptides

Peptidoglycan

Yeastandgram+bacteria

BacterialDNA(CpG)

Flagellin

Terminalmannose/fucose

ViralDNA(CpG)

ssRNA

dsRNAPathogen-

Associated

Molecular

Patterns

(PAMP)是病原微生物（尤其是原核生物）表面存在一些人體所沒(méi)有的，但可為許多相關(guān)微生物所共享、結(jié)構(gòu)恒定、進(jìn)化保守的分子結(jié)構(gòu)。PatternLipopolysaccharide(L23損傷相關(guān)分子模式（damage-associatedmolecularpatterns，DAMPs）機(jī)體自身細(xì)胞所釋放的內(nèi)源性分子，即內(nèi)源性危險(xiǎn)信號(hào)，來(lái)源于受損或壞死組織和某些激活的免疫細(xì)胞。主要有HMGB1、熱體克蛋白等。損傷相關(guān)分子模式機(jī)體自身細(xì)胞所釋放的內(nèi)源性分子，即內(nèi)源性危險(xiǎn)24PAMPvsDAMPSterileinflammationconservedmicrobialmotifsVSnon-microbialsignalsPAMPvsDAMPSterileinflammat25Toll-likeReceptorsToll-likeReceptors26LocationsofDifferentPRRsBodyfluids-SolublePRRsCellularPRRs-Cellsurface-Endosomes-CytosolLocationsofDifferentPRRsBod27SurfacereceptorsofmacrophagesMac-1、CR3Surfacereceptorsofmacrophag28PRR甘露聚糖凝集素（MBL）C反應(yīng)蛋白（CRP）脂多糖結(jié)合蛋白（LBP）可溶性：體液和血液細(xì)胞吞噬型：細(xì)胞膜甘露糖受體（MR）清道夫受體（SR）補(bǔ)體受體（CR）Fc受體（FcR）甲酰甲硫氨酰肽受體（fMLPR）信號(hào)轉(zhuǎn)導(dǎo)型細(xì)胞膜內(nèi)體、溶酶體細(xì)胞質(zhì)TLR1、2、4、5、6、10、11TLR3、7、8、9NLRs、RLRs、ALRs固有免疫細(xì)胞表面、內(nèi)體、溶酶體、細(xì)胞質(zhì)中、可識(shí)別一種或多種PAMPs或DAMPs的識(shí)別分子。DiversityofpatternrecognitionreceptorsPRR甘露聚糖凝集素（MBL）可溶性：體液和血液細(xì)胞吞噬型：29Toll-LikeReceptors(TLRs)Toll-LikeReceptors(TLRs)30MyD88-DependentandindependentSignalingMyD88-Dependentandindependen31NLRsarecytoplasmicbacterialsensorsthatactivateinflammasomesNLRsarecytoplasmicbacterial32免疫學(xué)知識(shí)概述課件331ViralPatternRecognitionReceptors:SignalingandConsequences1ViralPatternRecognitionRec34Interactionbetweeninnateand

&adaptiveimmunity1.Innateimmunity=>Agpresentation(byDendriticcells)2.Adaptiveimmunity=>Agrecognition(byT&Blymphocytes)Interactionbetweeninnateand35適應(yīng)性免疫（adaptiveimmunity）是機(jī)體獲得性、抗原特異性、抵抗病原微生物感染的高效防御機(jī)制。

獲得性免疫（acquiredimmunity)或特異性免疫(specificimmunity)，是個(gè)體出生后，在環(huán)境中受抗原刺激所產(chǎn)生的免疫力，針對(duì)特定抗原，有特異性、多樣性、記憶性和耐受性。1)特異性，對(duì)某個(gè)特定的異物性抗原能引起特異性免疫應(yīng)答；指抗原特異性。2)多樣性，機(jī)體可針對(duì)環(huán)境中多種多樣的抗原，分別建立起不同的特異性免疫應(yīng)答；多樣性是特異性產(chǎn)生的基礎(chǔ)。

3)記憶性，當(dāng)異物抗原再次入侵時(shí)，可產(chǎn)生快而強(qiáng)的再次免疫應(yīng)答效應(yīng)；記憶性淋巴細(xì)胞。

4)耐受性，正常情況下，免疫系統(tǒng)對(duì)自身成分有保護(hù)性的免疫耐受；

適應(yīng)性免疫是機(jī)體獲得性、抗原特異性、抵抗病原微生物感染的高效36抗原決定簇

Antigenicdeterminant，AD抗原分子表面具有特殊立體構(gòu)型和免疫活性的化學(xué)基團(tuán)稱(chēng)為抗原決定簇或抗原決定基。由于抗原決定簇通常位于抗原分子表面，因而又稱(chēng)為抗原表位(epitope)。

抗原決定簇＝抗原決定基＝抗原表位抗原決定簇決定抗原的特異性，即決定抗原與抗體發(fā)生特異性結(jié)合的能力（實(shí)際是抗原決定簇與抗體的結(jié)合）。AD的數(shù)目、性質(zhì)和空間構(gòu)象決定抗原特異性抗原以AD與相應(yīng)抗原受體及抗體特異性結(jié)合抗原決定簇

Antigenicdeterminant，A37

T細(xì)胞表位和B細(xì)胞表位T細(xì)胞表位：

TCR識(shí)別必須經(jīng)降解加工處理后才能被T細(xì)胞識(shí)別線性決定簇B細(xì)胞表位：

BCR識(shí)別或抗體識(shí)別并結(jié)合直接識(shí)別構(gòu)象決定簇或線性決定簇

T細(xì)胞表位和B細(xì)胞表位T細(xì)胞表位：38抗原提呈細(xì)胞

(antigen-presentingcell,APC)是指能攝取,加工處理抗原,并將抗原信息提呈給淋巴細(xì)胞的一類(lèi)免疫細(xì)胞，在機(jī)體免疫應(yīng)答過(guò)程中發(fā)揮重要作用。此類(lèi)細(xì)胞能輔助和調(diào)節(jié)T細(xì)胞、B細(xì)胞識(shí)別抗原并對(duì)其產(chǎn)生應(yīng)答，故又稱(chēng)為輔佐細(xì)胞(accessorycell)，簡(jiǎn)稱(chēng)A細(xì)胞?？乖岢始?xì)胞

(antigen-presentingcel39APC加工處理的抗原種類(lèi):

外源性抗原(exogenousantigen):通過(guò)吞噬或吞飲等作用被APC從細(xì)胞外攝入的抗原，以抗原肽-MHCII類(lèi)分子復(fù)合物形式提呈給CD4+T細(xì)胞。內(nèi)源性抗原(endogenousantigen):細(xì)胞內(nèi)合成的抗原，以抗原肽-MHCI類(lèi)分子復(fù)合物形式提呈給CD8+T細(xì)胞。APC加工處理的抗原種類(lèi):40外源性抗原加工，處理及提呈APC攝取的外源性抗原在內(nèi)體中降解成肽，與MHCⅡ類(lèi)分子(在內(nèi)質(zhì)網(wǎng)合成)結(jié)合后表達(dá)于細(xì)胞表面。外源性抗原加工中需要Ii鏈和HLA-DM分子的參與。Ii鏈與MHCⅡ類(lèi)分子的轉(zhuǎn)運(yùn)有關(guān)，并通過(guò)CLIP封閉MHCⅡ類(lèi)分子的肽結(jié)合部位，阻止MHC-Ⅱ類(lèi)分子在內(nèi)質(zhì)網(wǎng)中與內(nèi)源性抗原肽結(jié)合。HLA-DM分子促使CLIP從MHCⅡ類(lèi)分子肽結(jié)合區(qū)解離，有利抗原肽與MHCⅡ類(lèi)分子結(jié)合。外源性抗原加工，處理及提呈APC攝取的外源性抗原在內(nèi)體中降41內(nèi)源性抗原加工，處理及提呈內(nèi)源性抗原經(jīng)蛋白酶體降解成肽，通過(guò)抗原加工相關(guān)轉(zhuǎn)運(yùn)體(TAP1、TAP2)轉(zhuǎn)運(yùn)進(jìn)入內(nèi)質(zhì)網(wǎng)，與MHCⅠ類(lèi)分子(在內(nèi)質(zhì)網(wǎng)合成)結(jié)合成肽-MHCI類(lèi)復(fù)合物，通過(guò)高爾基體表達(dá)于細(xì)胞表面。TAP是內(nèi)質(zhì)網(wǎng)上的異源性二聚體，由TAP-1及TAP-2基因編碼胞漿中蛋白酶體（proteasomes,核心成分為低分子量多肽LMP細(xì)胞被病毒感染后出現(xiàn)的病毒蛋白，基因突變后產(chǎn)生的腫瘤抗原內(nèi)源性抗原加工，處理及提呈內(nèi)源性抗原經(jīng)蛋白酶體降解成肽，通過(guò)42脂類(lèi)抗原的CD1分子提呈

CD1分子：非經(jīng)典MHCI類(lèi)分子，30%同源性。提呈抗原：提呈糖脂或脂類(lèi)抗原，供CD1限制性T細(xì)胞識(shí)別CD1分子提呈微生物的脂質(zhì)抗原，脂質(zhì)抗原由CD1分子提呈后激活CD1限制性T細(xì)胞。脂類(lèi)抗原的CD1分子提呈CD1分子：非經(jīng)典MHCI類(lèi)分子43AdaptiveimmunityMaineffectors: AntibodyTcellreceptorsBBCRTTCRAdaptiveimmunityMaineffector44THEADAPTIVEIMMUNERESPONSEAntibody-MediatedImmunity(AMI)InvolvesBlymphocytes,plasmacellsandantibodiesHumoralimmunityNamederivesfromantibodiesfoundinbodyfluids(humors-oldmedicalterm)Cell-MediatedImmunity(CMI)InvolvesTlymphocytes,antigen-presentingcellsandMHC(majorhistocompatibilitycomplex)moleculesCellularimmunityTHEADAPTIVEIMMUNERESPONSEAn45Typesofadaptiveimmunity1.Humoralimmunity=>Moleculesinbodyfluid,e.g.Antibody(Ab)=>Keyplayer=>Bcells

=>Targetextracellularmicrobes&toxins2.Cell-mediatedimmunity=>Keyplayer=>Tcells=>regulateotherimmunecells=>Targetintracellularmicrobes,e.g.viruses,bacteriaForinnateimmunity,italsoincludesHumoral&CellularcomponentsforimmunedefenseTypesofadaptiveimmunity1.H461、抗原提呈與識(shí)別階段（感應(yīng)階段）：2、活化、增殖、分化階段（反應(yīng)階段）：

T細(xì)胞活化、增殖分化為效應(yīng)T細(xì)胞；

B細(xì)胞活化、增殖分化為漿細(xì)胞；部分細(xì)胞發(fā)育為記憶細(xì)胞。3、效應(yīng)階段：效應(yīng)T細(xì)胞對(duì)抗原的清除；漿細(xì)胞分泌抗體清除抗原。免疫應(yīng)答的三個(gè)階段1、抗原提呈與識(shí)別階段（感應(yīng)階段）：免疫應(yīng)答的三個(gè)階段47OverviewofadaptiveimmuneresponsesOverviewofadaptiveimmunere48CELL-MEDIATEDIMMUNITY(CMI)DirectedagainstintracellularmicroorganismsNon-phagocyticcellsandphagocyticcellsT-lymphocytes(Tcells)Differentiateintoeffectorcellsfollowingantigenpresentationbyantigenpresentingcells(APC’s)FunctionaltypesofTcellsHelper(CD4Tcells)TH1andTH2cellsCytotoxic(CD8Tcells)CELL-MEDIATEDIMMUNITY(CMI)Di49TcellsdevelopinthethymusTcellsdevelopinbonemarrow,butinordertomature,theyneedtomigratetothymus[=thymus-(T)-dependentlymphocytes]Thymusisaprimarylymphoidorganlocatedintheupperthorax(chest),justabovetheheart.Progenitor(precursor)Tcellsenterthethymus,wheretheymature(=produceTcellreceptors).MatureTcellsleavethethymusandenterthesecondarylymphoidtissues,wheretheybecomeactivatedafterexposuretoantigen.TcellsdevelopinbonemarrowandthenmigratetothymuswheretheymatureMatureTcellsenterthebloodstream,andafterinfectionaccumulateinthesecondarylymphoidtissueswheretheyareactivated.TcellsdevelopinthethymusT50TcelldevelopmentTcelldevelopment51TSCCD4RTEDNPre-TCRDPTCRCD4CD8TCRTCRCD8CD4SPTCRCD4CD4b-selectionPositiveselectionNegativeselectionFunctionalmaturationTCR-brearrangementTCR-arearrangementTCRCD8CD8SPCD8RTEDevelopmentofThymocytesDoublenegativeDoublepositiveSinglepositiveTSCCD4RTEDNPre-TCRDPTCRCD4CD852NotchSignalandT-lineageCommitment受體:Notch1-4；胸腺細(xì)胞表達(dá)Notch1-3；全部效應(yīng)由Notch1介導(dǎo)

配體：Dll1，3，4，Jagged1，2；胸腺上皮細(xì)胞表達(dá)全部配體；Dll4

可能為生理性配體

T系定向：始于DN1，完成于DN3；絕對(duì)依賴(lài)Notch1信號(hào)NotchSignalandT-lineageCom53TcellsundergofurtherdifferentiationinsecondarylymphoidtissuesafterencounterwithantigenOnlyasmallfractionofnaiveTcells(matureTcellsbeforetheyencounterantigen)survivesthepositiveandnegativeselection,andleavesthethymus.MaturenaiveTcellscanre-circulatebetweenbloodandlymphoidtissuesformanyyears(incontrasttoBcells,whichhaveshorterlifespan).Insecondarylymphoidtissues,TcellsaccumulateinTcellareas,wheretheybecomeactivatedbytheirspecificantigens.EncounterwithantigeninducesthefinalstageofTcelldevelopment:theirdifferentiationintoeffectorTcells.SomeeffectorTcellsstayinthelymphoidtissues(CD4-TH2cells),whileothersmigratetositeofinfection(CD8andCD4-TH1cells).Tcellsundergofurtherdiffer54T細(xì)胞受體復(fù)合物 由TCR和CD3組成。前者識(shí)別和結(jié)合抗原肽,后者將TCR獲得的抗原信號(hào)傳遞至細(xì)胞內(nèi)。T細(xì)胞對(duì)抗原的識(shí)別

APCT細(xì)胞T細(xì)胞受體復(fù)合物T細(xì)胞對(duì)抗原的識(shí)別APCT細(xì)胞55CDmoleculesassociatedwithreco-gnition,adhesionandactivationofTcell②③④⑤

︱MHC-Ⅰ

︱MHC-Ⅱ︱B7

︱CD40

︱

CD58

︱CD2①

CDmoleculesassociatedwithr56信號(hào)第一信號(hào)第二信號(hào)T細(xì)胞TCR和CD4/CD8CD28APCMHC-肽復(fù)合物B7(B7.1、B7.2)T細(xì)胞活化的雙信號(hào)刺激

第一信號(hào)：TCR對(duì)MHCII－抗原肽復(fù)合物的識(shí)別，CD3分子將第一信號(hào)傳遞到細(xì)胞內(nèi)。

第二信號(hào)：CD28識(shí)別專(zhuān)職APC上的B7分子,又稱(chēng)協(xié)同刺激信號(hào)。

信號(hào)第一信號(hào)第二信號(hào)T細(xì)胞TCR和CD28APCMHC-肽57免疫學(xué)知識(shí)概述課件58EffectorTcellsIncontrasttoterminallydifferentiatedBcells(plasmacells),thereareseveraltypesofterminallydifferentiatedeffectorTcells.CD8TcellsCytotoxicTcells(recognizeMHC classImolecules)CD4Tcells

TH1helpercells(activatemacrophages)TH2helpercells(inducedifferentiationofBcellsintoplasmacellsandproductionofantibodies)Activation(cytokines)(recognizeMHCIImolecules)EffectorTcellsIn59免疫學(xué)知識(shí)概述課件60Theimmunesystemismaintainedinacarefullyregulatedbalancebetweenthetwopolarisedcontrolarms,Th1(cellularimmunity)andTh2(humoralimmunity).Theimmunesystemismaintaine61Indiseasestatesthebalanceisskewed.multiplesclerosis,rheumatoidarthritisandtypeIdiabetes,haveaTh1bias,whereascancerpatientshaveaTh2bias.Indiseasestatesthebalance62Th1andTh2CellsDonotRepresentAllCD4+Cells免疫學(xué)知識(shí)概述課件63MoreThelpersubsetsTh3:TGFβ-producingCD4TcellsTr1:IL-10-producingCD4TcellsTh9:IL-9-producingCD4TcellsTfh:follicularhelperTcells,locatedinthefollicularregionsoflymphnodesandspleen,follicularTh1/Th2/Th17cellsMoreThelpersubsetsTh3:TGFβ64ANTIBODY-MEDIATED(HUMORAL)IMMUNITYDirectedagainstextracellularmicroorganismsandtoxinsB-lymphocytes(Bcells)DifferentiateintoplasmacellswhichproduceantibodiesFunctionasantigen-presentingcells(APC’s)ClassificationofAntibodies(Immunoglobulins)ImmunoglobulinM(IgM)ImmunoglobulinG(IgG)ImmunoglobulinA(IgA)ImmunoglobulinD(IgD)ImmunoglobulinE(IgE)ANTIBODY-MEDIATED(HUMORAL)IM65PaulEhrlich:Oneofthefathersofhumoraladaptiveimmunity1.TheDiscoveryofAntibodyfunctions2.TheNobelLaureateinMedicine1908AdoptedfromNatureImmunology,July2008PaulEhrlich:Oneofthefathe66

抗體的功能V區(qū)的功能

—識(shí)別并特異性結(jié)合抗原單體（IgG,IgE)—2價(jià)二聚體(分泌型IgA)—4價(jià)五聚體(IgM)—10價(jià)中和效應(yīng)—中和毒素和病毒與Ag結(jié)合—促吞噬細(xì)胞吞噬抗體的結(jié)合價(jià)實(shí)際意義 抗體的功能抗體的結(jié)合價(jià)實(shí)際意義67C區(qū)的功能

1.激活補(bǔ)體系統(tǒng)

Ab(IgM、IgG)+AgC1q

補(bǔ)體經(jīng)典途徑

IgG4、IgA和IgE的凝聚物

補(bǔ)體旁路途徑

2.介導(dǎo)免疫細(xì)胞活性

(1)調(diào)理作用（opsonization）：IgG+抗原(顆粒性)FcγR（單核、巨噬細(xì)胞及中性粒細(xì)胞）促吞噬細(xì)胞吞噬；

(2)ADCC：IgG+抗原(靶細(xì)胞)

FcγR（NK

細(xì)胞）

殺傷靶細(xì)胞；

(3)介導(dǎo)超敏反應(yīng)：Ⅰ型、Ⅱ型和Ⅲ型超敏反應(yīng)。

3.穿越胎盤(pán)和粘膜C區(qū)的功能68Antibody-DependentCellularCytotoxicity(ADCC)Antibody-DependentCellularCy69Th2與B細(xì)胞的相互作用，獲得第二信號(hào)：協(xié)同刺激信號(hào)CD40-CD40L活化的Th2細(xì)胞分泌細(xì)胞因子及表達(dá)CD40L，輔助B細(xì)胞活化CD79α/β2第二信號(hào)（Th細(xì)胞信號(hào)）——有二種方式（1）Th細(xì)胞-B細(xì)胞間接觸作用：CD40L-CD40等（2）Th細(xì)胞分泌細(xì)胞因子：IL-4、5、6等胸腺依賴(lài)性抗原（TD-Ag）Th2與B細(xì)胞的相互作用，獲得第二信號(hào)：協(xié)同刺激信號(hào)CD4070活化的B細(xì)胞增殖與分化

活化B細(xì)胞漿細(xì)胞產(chǎn)生抗體原始淋巴濾泡分裂增殖，形成 生發(fā)中心（一周左右）活化的B細(xì)胞增殖與分化71Specificity,Memory,andHomeostasisofAdaptiveImmunitySpecificity,Memory,andHomeo72體液免疫應(yīng)答一般規(guī)律體液免疫應(yīng)答一般規(guī)律73多克隆抗體(polyclonalantibody，PcAb)：采用傳統(tǒng)的免疫方法，將抗原物質(zhì)經(jīng)不同的途徑進(jìn)入動(dòng)物體內(nèi)，經(jīng)數(shù)次免疫后采取動(dòng)物血液，分離出血清，由此獲得的抗血清即為多克隆抗體。用天然的抗原物質(zhì)免疫動(dòng)物，刺激多個(gè)B細(xì)胞克隆所獲得的免疫血清（含多種特異性抗體）。單克隆抗體(MonoclonalAntibody，McAb):由一個(gè)B細(xì)胞分化增殖的子代細(xì)胞產(chǎn)生的針對(duì)單一抗原決定簇的抗體，稱(chēng)單克隆抗體。由一個(gè)B細(xì)胞克隆產(chǎn)生。識(shí)別一種抗原表位。高度均一（結(jié)構(gòu)、特異性）。雜交瘤技術(shù)制備?；蚬こ炭贵w：利用基因工程技術(shù)來(lái)制備的抗體分子稱(chēng)為基因工程抗體，是分子水平的抗體。多克隆抗體(polyclonalantibody，PcAb74抗體針對(duì)的靶分子作用機(jī)制治療疾病CD3阻斷T細(xì)胞功能預(yù)防腎移植排斥反應(yīng)CD25阻斷IL-2受體預(yù)防腎移植排斥反應(yīng)CD20(或偶聯(lián)核素)誘導(dǎo)腫瘤細(xì)胞凋亡non-Hidgkin’s淋巴瘤和RACD33(免疫毒素)誘導(dǎo)腫瘤細(xì)胞凋亡急性髓樣白血病CD52誘導(dǎo)腫瘤細(xì)胞凋亡慢性B淋巴細(xì)胞白血病，T細(xì)胞瘤Her2(CD340)抑制和殺傷腫瘤細(xì)胞轉(zhuǎn)移性乳腺癌EGFR抑制腫瘤血管形成轉(zhuǎn)移性結(jié)腸直腸癌和頭頸部腫瘤，非鱗癌、非小細(xì)胞肺癌，對(duì)化療反應(yīng)差的多形性膠質(zhì)細(xì)胞瘤CD41/CD61(gpIIbIIIa)抑制血小板凝聚預(yù)防冠狀動(dòng)脈血管形成術(shù)中血栓形成US和EU所批準(zhǔn)的治療性抗體抗體針對(duì)的靶分子作用機(jī)制治療疾病CD3阻斷T細(xì)胞功能預(yù)防腎移75抗體針對(duì)的靶分子作用機(jī)制治療疾病TNF阻斷TNF與受體結(jié)合RA、銀屑病性關(guān)節(jié)炎、克隆氏病、強(qiáng)直性脊椎炎CD11a抑制白細(xì)胞黏附斑狀牛皮癬VEGF抑制血管形成年齡相關(guān)性黃斑變性4整合蛋白抑制白細(xì)胞黏附多發(fā)性硬化癥IgE阻斷IgE與IgE受體結(jié)合，抑制肥大細(xì)胞、嗜堿性粒細(xì)胞釋放介質(zhì)持續(xù)性哮喘RSVgpF中和病毒預(yù)防兒童高危期RSV感染US和EU所批準(zhǔn)的治療性抗體抗體針對(duì)的靶分子作用機(jī)制治療疾病TNF阻斷TNF與受體結(jié)76

鼠源性單克隆抗體將逐漸被人源化抗體所替代：鼠源性單克隆抗體與人補(bǔ)體成分結(jié)合能力低，CDC作用相應(yīng)較弱，對(duì)腫瘤細(xì)胞的殺傷能力較弱；它與NK等免疫細(xì)胞表面Fc受體親和力弱，介導(dǎo)的ADCC作用較弱；鼠源抗體在人血循環(huán)中的半衰期短，它發(fā)揮ADCC與CDC作用的時(shí)間較短；鼠單克隆抗體具有免疫原性，宿主易產(chǎn)生抗抗體引起過(guò)敏反應(yīng)?？贵w人源化改造及人源抗體制備 鼠源性單克隆抗體將逐漸被人源化抗體所替代：鼠源性單克隆77

人-鼠嵌合抗體：應(yīng)用基因工程技術(shù)將小鼠單克隆抗體的恒定區(qū)用人源抗體恒定區(qū)代替而拼接成嵌合抗體。改型抗體如CDR移植、SDR移植：用鼠單克隆抗體的CDR、SDR移植到人源抗體可變區(qū)，替代人源抗體CDR、SDR。表面氨基酸殘基人源化抗體人源化的主要技術(shù)人-鼠嵌合抗體：應(yīng)用基因工程技術(shù)將小鼠單克隆抗體的恒定區(qū)用78提高抗體效應(yīng)功能偶聯(lián)細(xì)胞毒物質(zhì)雙特異性抗體抗體Fc突變改變抗體糖基化細(xì)胞內(nèi)抗體抗體融合蛋白提高抗體效應(yīng)功能提高抗體偶聯(lián)細(xì)胞毒物質(zhì)雙特異性抗體抗體Fc突變改變抗體糖基化79MjmacrophageIL-8Activated

TcellaADP56BC58B’CNH2COOHIL-2

Cytockinesarelow-molecular-weightregulatoryproteins

orglycoproteinssecretedbywhitebloodcellsandvariouscells(vascularendothelialcell,epidermiccellandfibroblast)inbodyinresponsetoanumberofstimuli.

CytokineMjmacrophageIL-8ActivatedTc80BiologicaleffectsBiologicaleffects81IL-1TNFGM-CSFM-CSFFGFPDGFVEGFIL-12IL-15IL-6LIFOSMChemokinesTGFIL-10IL-11IL-13sTNF-RIL-1raPRO-INFLAMMATORYANTI-INFLAMMATORYCytokineimbalanceduringinflammationIL-1GM-CSFFGFIL-12IL-6Chemokin82細(xì)胞因子的研究熱點(diǎn)1、新細(xì)胞因子的基因克隆化2、細(xì)胞因子受體的基因克隆化3、細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)機(jī)制4、新一代細(xì)胞因子：高活性，多功能，低毒副作用，長(zhǎng)半衰期，高穩(wěn)定性5、細(xì)胞因子作為生物應(yīng)答調(diào)節(jié)劑（BRM）的臨床應(yīng)用6、細(xì)胞因子表達(dá)調(diào)控7、細(xì)胞因子基因治療細(xì)胞因子的研究熱點(diǎn)83Infectionsoccurwhenthephysicalbarriersofepitheliumarebreached,orwhenpathogensadheretotheepitheliumPathogenreplicationRecruitmentofneutrophilsandmacrophagesInflammationPathogenadherencetoepitheliumPathogensarecarriedtothecl