第四章 免疫應(yīng)答

ChapterⅣImmuneresponseimmuneresponseDefinitionimmuneresponseisabiologicalprocessmediatedbytheantibodyorcytokinesproducedbyimmunecellswhichwasactivatedafterantigenrecognition,thenproliferateanddifferentiateintoeffectorcells.

(免疫細(xì)胞識(shí)別抗原后活化、增殖、分化為效應(yīng)細(xì)胞，并通過其所分泌的抗體或細(xì)胞因子表現(xiàn)出一定生物學(xué)效應(yīng)的過程。)immuneresponseCharacteristics1.Selfandnonselfdiscrimination2.Specificity（特異性）3.Memory（記憶性）GENERALCHARACTERISTICSOFTHEANTIBODYRESPONSEA.Self/non-selfdiscrimination-Onecharacteristicfeatureofthespecificimmunesystemisthatitnormallydistinguishesbetweenselfandnon-selfandonlyreactsagainstnon-self.B.

Memory

-Asecondfeatureofthespecificimmuneresponseisthatitdemonstratesmemory.Theimmunesystem"remembers"ifithasseenanantigenbeforeanditreactstosecondaryexposurestoanantigeninamannerdifferentthanafteraprimaryexposure.Generallyonlyanexposuretothesameantigenwillillicitthismemoryresponse.C.Specificity

-Athirdcharacteristicfeatureofthespecificimmunesystemisthatthereisahighdegreeofspecificityinitsreactions.Aresponsetoaparticularantigenisspecificforthatantigenorafewcloselyrelatedantigens.N.B.Thesearecharacteristicofallspecificimmuneresponses.

ImmuneresponseTypeMechanism(根據(jù)發(fā)揮效應(yīng)的機(jī)理)humoralimmuneresponsecell-mediatedimmuneresponsIntroducedtimeofantigen(根據(jù)抗原進(jìn)入體內(nèi)的時(shí)間和次數(shù))primaryimmuneresponseSecondaryimmuneresponseEffect(效應(yīng))Protectiveeffectself——norejectionNon-self——rejectionandeliminationDetrimentaleffectself——rejectionNon-self——norejectionoroverreactImmuneresponse損傷效應(yīng)(免疫病理)自己——排己非己——不排異或高應(yīng)答保護(hù)效應(yīng)(免疫生理)自己——不排己非己——排異SectionA.HumoralImmuneResponseSection1A1

thecellularbasisoftheantibodyresponseAntigenintroducedintoanindividualbindsspecificallytoBcellswithreceptorsforthatantigen.InthepresenceofTcellhelptheseBcellsclonallyexpand(proliferate)andsomedifferentiateintoplasmacellswhichmakeantibodyspecificfortheantigentriggeringtheresponse.SelectionandactivationofBcellsKeynotesOnfirstexposuretoantigen,aprimaryimmuneresponsedevelopsresultinginproductionofIgMantibodies.ThisisusuallyfollowedbyanIgGimmuneresponsewithin4-5days.ThisresponseisselflimitingandwillstopwhenantigenisnolongeravailabletostimulateBcells.Whenantigenisreintroduced,therearemoreantigenspecificBcellswhichhavedifferentiatedtomoreresponsivememoryBcells,resultinginamorerapidresponseandusuallyinIgGantibodyproduction.Primaryandmemory(secondary)responsesKeynotesAntibodiesproducedbyasinglecellarehomogeneous,buttheresponsetoagivenantigeninvolvesmanydifferentspecificantibodyproducingcellsandthus,overall,isveryheterogeneous(i.e.multiclonal).Moreover,theeffectivenessofanantibodyresponsetoamicroorganismmaydependonthisheterogeneity.ResponsesareusuallymulticlonalKeynotesSimilaroridenticalantigenicdeterminantsaresometimesfoundinassociationwithwidelydifferentmoleculesorcells.Thiscross-reactivityisimportant:(a)inprotectionagainstorganismswithcross-reactiveantigens;and(b)inautoimmunediseasesinducedbyinfectiousorganismsbearingantigenscross-reactivewithnormalselfantigens(e.g.streptococcalinfectionswhichpredisposetorheumaticfever).Cross-reactiveresponsesKeynotes1.

SelectionandactivationofBcells

Whenantigenisintroducedintoanindividual,Bcellswithreceptorsforthatantigenbindandinternalizeitintoanendosomalcompartment,andprocessandpresentitonMHCclassIImoleculestohelperTcells.MHCclassPeptidederivedfromcarrierproteinpresentedinMHCclassⅡ

SelectionandactivationofBcells

TheseBcellsaretriggeredtoproliferate,givingrisetoclonesoflargenumbersofdaughtercells.Someofthecellsoftheseexpandingclonesserveasmemorycells,othersdifferentiateandbecomeplasmacellswhichmakeandsecretelargequantitiesofspecificantibody.免疫球蛋白（ImmunoglobulinIg）活化B細(xì)胞（ActivatedBcell）漿細(xì)胞(plasmacell)Forexample,onintroductionofantigen5(Ag5)intoaperson,morethan106

Bcellshavetheopportunitytointeractwithit.OnlyaveryfewBcells(e.g.B5)havereceptorsspecificforthisantigen.B5bindsAg5,internalizes,andprocessesandpresentsitonMHCclassIImoleculesonthesurfaceofthisBcell.ThelpercellswithspecificreceptorsforapeptidefromAg5inMHCclassIIbindtothiscomplexandstimulatethisBcelltoclonallyexpandanddifferentiateintomemoryBcellsandplasmacellswhichproducesolubleantibodytoAg5.Inaddition,directTcellinteractionwiththeBcellinducesclassswitching,whichdependingonthetypeofhelpercell(Th1vsTh2)andthecytokinesitsecretes,willresultinproductionofantibodyoftheIgG,IgAorIgEclasses.B細(xì)胞活化的雙信號(hào)模型活性封閉沒有Th細(xì)胞的幫助第1信號(hào)BIFN-γ,IL-4,IL-5第2信號(hào)ThB第1信號(hào)CD40CD40L

BBCRTCR外來抗原MHCIITh細(xì)胞因子CD40LBcellgrowthanddifferentiationTcellgrowthanddifferentiationReciprocalactivationofTandBcells12345HumoralimmunityWhenintroducedintoanindividualwhohasnotpreviouslyencounteredtheantigen,aprimaryimmuneresponsewilldevelopwithin4-5days.ThisresponseresultsinitiallyintheproductionofIgMandthenIgGorotherantibodyisotypes(同種型抗體)directedtowardtheantigen,andhasaduration（延續(xù)時(shí)間）andantibodyisotypeprofilewhichdependsonthethequantityofantigenintroducedanditsmodeofentry.2.PrimaryandmemoryresponsesTheantibodyproducedreactswithremainingantigen,formingcomplexesand/orprecipitateswhichareeliminatedbyphagocytes.Antibodyiscontinuallymadebyplasmacellsduringtheirshortlifespan(3-4days).Ifenoughantigenisintroducedinitially,therecouldberestimulationofantigenspecificBcells,subsequentdevelopmentofmoreplasmacellsandthusincreasedproductionofantibody.Eventually,whenalloftheantigenhasbeenremovedandnoneremainstostimulateBcells,theantibodyresponsewillreachitspeakandtheconcentrationofantibodyinthecirculationwillbegintodecreaseasaresultofthenormalrateofcatabolismoftheantibody.Atthetimeantigenisreintroduced,moreantigenspecificBcellsexistintheindividualcomparedwiththeperiodbeforeprimaryintroductionofantigen.Moreover,thesecellshavedifferentiatedtomoreresponsivememoryBcells.PrimaryandSecondaryHumoralResponse

(初次與再次體液免疫應(yīng)答)再次應(yīng)答初次應(yīng)答初次免疫再次免疫天數(shù)0714212835421000001000010001001010抗原特異性血清抗體滴度（Log）IgGIgM抗體分子的類別轉(zhuǎn)換mdg3VJg3DVJDPrimarytranscriptV-D-JmmRNAPrimarytranscriptV-D-Jg3mRNAmdLostgenesIgMmaturationIgGIgGIgMprimaryantigensecondaryantigenantibodyresponseprimaryresponsesecondaryresponsetime（Class-switching）FeaturesofmemoryresponseThus,asecondary(memoryoranamnestic)antibodyresponseoccurswhichischaracterizedbyamuchshorterlagperiodbeforesignificantlevelsofantibodyarefoundintheserum（rapid）bythepresenceofmanymoreplasmacellsbyahigherrateofantibodyproductionandthusamuchhigherserumconcentrationofantibodyusuallyoftheIgGclass.初次與再次免疫應(yīng)答的特性初次應(yīng)答再次應(yīng)答應(yīng)答B(yǎng)細(xì)胞靜息B細(xì)胞Bm所需Ag濃度高低Ag類型TI-Ag或TD-AgTD-Ag延遲相4-7天1-3天高峰濃度較低較高Ig類別主要為IgMIgG、IgA等親和力低高Althoughantibodiesproducedbyasinglecellanditsdaughtercellsareidentical(homogeneousormonoclonal同質(zhì)的或單克隆的),theresponsetoagivenantigeninvolvesmanydifferentclonesofcellsandthus,overall,isveryheterogeneous(multiclonal).3.ResponsesareusuallymulticlonalConsideringthefactorsbelow，theresponsetoamicroorganismresultsinalargenumberofdifferentantibodies.thesizeofanantigenicdeterminant,thenumberofdeterminantsonamoleculeandthenumberofdifferentmoleculesonamicroorganism.Asingleantigenicdeterminantscaninducedifferentisotypes(classes)ofantibodywiththesamespecificityfortheantigen.Whyismulticlonal?DifferentantigenicdeterminantsonthesamemoleculeDifferentantigensAllofaboveindicatethattheimmunesystemiscapableofproducingmanydifferentantibodies,eventoasinglewell-defined(單一明確的)antigenicdeterminant.Thisheterogeneityisessentialformanyoftheprotectivefunctionsofantibodies.Occasionally,asimilaroridenticalantigenicdeterminantisfoundinassociationwithwidelydifferentmoleculesorcells.Thisistermedcross-reactivity.4.Cross-reactiveresponsesdefinition

Thedevelopmentofimmunitytooneorganismcould,insomeinstances,protectagainstinfectionbyanotherorganismwithcross-reactiveantigens.Theimportance(1)bothvirulentandavirulentstrainsoftheorganism;ortoxicmoleculesandtheirnon-toxicderivativeManyvaccinesareeffectivebecauseofsimilaroridenticaldeterminantsexpressedby:Theimportance(2)exampleProtectionvsbacterialtoxin——tetanustoxoid

vstetanustoxinProtectionvspathogenicpoliovirus——sabinattenuatedstrainofpoliovirusvspoliomyelitisInaddition,certainkindsofautoimmunediseasemaybeduetoinfectionbyorganismsbearingantigensthatarecross-reactivewithnormalselfantigens.Importance(3)detrimentalGroupAβ-hemolyticstreptococcalinfectionsmayleadtorheumaticfeverasaresultofthedevelopmentofantibodiestothestreptococcaldeterminants.Becauseofthesimilarityofthestreptococcalantigenstomoleculesinhearttissue,theantibodiesmaythenreactwithanddamagenotonlythemicroorganismbutalsoheartmusclecells.exampleA2

affinitymaturationandclassswitchingAntibodiesproducedinthesecondaryresponsehavehigheraffinityforantigenthanthoseproducedintheprimaryresponsedueto(a)morememorycellsafterantigenicchallenge,ofwhichthosewiththehighestaffinityantigenreceptorscompetesuccessfullyforlimitedamountsofantigen,and(b)pointmutationsintheDNAofthevariableregionsoftheantibodyL-andH-chains,whichresultinantibodieswithincreasedaffinityforantigen.KeynotesforaffinitymaturationIgMantibodiesareproducedfirstinanimmuneresponsefollowedbyaswitchtoIgG,IgAorIgE.Classswitchdependson(a)interactionofCD154onTcellswithCD40onBcellsand(b)thecytokinesproducedbytheThelpercell:IL-4inducesswitchtoIgE;IL-5toIgA;IFNγtoIgGl.KeynotesforclassswitchingAntibodiesproducedinthesecondaryresponseusuallyhavehigheraffinityfor(tighterbindingto)theantigenthanthoseproducedintheprimaryresponse.Thisispartlyduetoclonalselectionandthepresenceoflargerquantitiesof

memorycellsafterantigenicchallenge.1.AffinitymaturationInasecondaryresponsetherearemoreantigenbindingBcellsthanduringtheprimaryresponse,andthequantityofantigenmaybeinsufficienttostimulateallcellsthatcouldbindtheantigen.Thus,whenantigenislimited,thecellswiththehighestaffinityantigenreceptorswillcompetemostsuccessfullyfortheantigen.Thereason(A)Whyhavehigheraffinity?Inaddition,affinityalsoincreasesafterclassswitchingbecauseofincreasedpointmutationsintheDNAofthevariableregionsoftheantibodyL-andH-chains.Althoughsomeofthesemutationsresultinlossofbindingactivityoftheantibody,otherswillresultinantibodieswithincreasedaffinityfortheirantigen.Thereason(2)Bcellswiththeseantibodiesasreceptorswillcompetemoreeffectivelyforantigenandbemorelikelytobestimulatedtoproliferateanddifferentiate.Theresultingplasmacellsmakethehigheraffinityantibodyandoveralltheaffinityoftheantibody.populationtothatantigenincreases.Thisprocessmainlytakesplaceingerminalcentersinlymphoidtissues.淋巴結(jié)的基本結(jié)構(gòu)HEV髓質(zhì)淋巴竇皮質(zhì)淋巴竇毛細(xì)血管小梁輸入淋巴管輸出淋巴管靜脈動(dòng)脈髓索生發(fā)中心髓質(zhì)被膜淋巴結(jié)

淋巴結(jié)被膜外側(cè)有數(shù)條輸入淋巴管，門處有動(dòng)、靜脈神經(jīng)和輸出淋巴管。實(shí)質(zhì)分為皮質(zhì)和髓質(zhì)?？拷荒さ臏\層皮質(zhì)區(qū)有生發(fā)中心（左）。右圖顯示生發(fā)中心的顯微結(jié)構(gòu)漿細(xì)胞B記憶細(xì)胞暗區(qū)明區(qū)生發(fā)中心樹突細(xì)胞初級(jí)淋巴小結(jié)早期生發(fā)中心生發(fā)中心

Ab1

Ab1

Ab1

Ab1

Ab1AffinityandAvidity（抗體與抗原之間的親合力）IgMantibodiesareproducedfirstinanimmuneresponsefollowedbyaswitchtoIgGorotherantibodyclasses.EachcellinitiallyexpressesIgMantibodiesandafteractivationundergoesswitchingtoadifferentclassofantibodywithoutchangingitsspecificityforantigen.2.Classswitching

Howithappened?Thisclassswitchisdependenton

signalingbythebindingoftheCD154(CD40ligandonTh)toCD40onBcells.thecytokinesproducedbytheThelpercellinfluencetheconstantregiongenetowhichclassswitchingoccurs.CytokinesTh2cellsproducingIL-4induceBcellstoclassswitchtoIgE;IL-5,whichisalsoproducedbyTh2cells,inducesBcellstoclassswitchtoIgA;IFNγproducedbyTh1cellsinducesclassswitchingtoIgGI.Fig.ClassswitchingismediatedthroughTh/Bcellinteractionsandspecificcytokines.抗體分子的類別轉(zhuǎn)換mdg3VJg3DVJDPrimarytranscriptV-D-JmmRNAPrimarytranscriptV-D-Jg3mRNAmdLostgenesIgMmaturationIgGIgGIgMprimaryantigensecondaryantigenantibodyresponseprimaryresponsesecondaryresponsetime（Class-switching）A.3Antibodyresponsesindifferenttissues

BloodMucosalymphaticsAntigensintroducedintothebloodarepickedupbysplenicmacrophages,dendriticcellsandBcells.ThesecellsprocessandpresenttheantigenonMHCclassIImoleculestoThelpercells,whichinduceBcelldifferentiationandclassswitchtoIgG.Keynotes——AntibodyresponsesinbloodAntigenintroducedintomucosalareascontactBcellsunderlyingtheseareas,whichinturninteractwithTh2cellswhichinduceclassswitchto-IgAorIgE.DimericIgAbindstothepoly-Igreceptorsonepithelialcellsandistransportedtothelumen,whereitmediatesprotection.Keynotes——AntibodyresponsesinmucosaAntigenintroducedintotissuesischanneledthroughthelymphaticstolymphnodes,whereAPCsprocessandpresentittoTcellswhichprovidehelptoantigenspecificBcells.Keynotes——AntibodyresponsesinlymphaticsThelocalizationandmechanismofeliminationofantigendependtoalargeextentontherouteofitsintroduction.Whenintroducedintotheblood,antigensareeventuallytrappedinthespleen.Theantigenispickedupbysplenicmacrophagesanddendriticcellswhichprocessandpresentpiecesoftheantigen(antigenicdeterminants)onMHCclassIImolecules.ThelpercellsrecognizetheseMHC-peptidecomplexesandprovidehelptoBcellspresentingthesameantigen.TheseThelpercellsalsoinduceclassswitchingtoIgG.1.blood經(jīng)血液循環(huán)進(jìn)入脾臟的T細(xì)胞分布于PALS的內(nèi)側(cè)，而B細(xì)胞則分布于PALS的邊緣，與邊緣血竇比鄰。B細(xì)胞聚集的區(qū)域可見淋巴小結(jié)和生發(fā)中心。脾血竇的周邊布滿了巨噬細(xì)胞，它們能夠吞噬血液中的細(xì)胞碎片以及外來微生物或者抗原。脾臟*白髓（whitepulp）

（1）動(dòng)脈周圍淋巴鞘（periarteriallymphaticsheath，PALS），圍繞在動(dòng)脈周圍的彌散淋巴組織，主要由T細(xì)胞組成，相當(dāng)于副皮質(zhì)區(qū)。（2）淋巴小結(jié)，主要由B細(xì)胞組成，可發(fā)展成生發(fā)中心，常出現(xiàn)于PALS的外側(cè)。*紅髓（redpulp）占脾實(shí)質(zhì)的2/3，分布于小梁周圍及白髓之間。（1）脾索，（2）脾血竇，*功能濾血、免疫、造血、儲(chǔ)血脾臟結(jié)構(gòu)（Spleen）紅髓靜脈竇小梁被膜動(dòng)脈周圍淋巴鞘中央動(dòng)脈生發(fā)中心動(dòng)脈周圍淋巴鞘

淋巴小結(jié)邊緣區(qū)

被膜脾索邊緣區(qū)靜脈竇

動(dòng)脈周圍淋巴鞘脾臟的結(jié)構(gòu)漿細(xì)胞B記憶細(xì)胞暗區(qū)明區(qū)生發(fā)中心樹突細(xì)胞初級(jí)淋巴小結(jié)早期生發(fā)中心生發(fā)中心CA.CentralarterioleT.Tcellarea(PALS)B.IgM+BcellsMZ.MarginalzoneBlue.MetallophilicMacrophagesOrange.MarginalzoneMacrophagesRP.RedPulpCrossSectionofaMousespleenFollicleWhenintroducedintomucosalareas,theantigencomesintocontactwithlymphocytesunderlyingthemucosalareas,includingthoseinthetonsils,theappendixandPeyer'spatches.Asinthespleen,Bcellsinteractwithantigenthroughcell-surfaceantibodieswhichfunctionastheirantigen-specificreceptor.TcellsinteractwithantigenthatisprocessedandpresentedbyBcells,andahumoralimmuneresponseisstimulated.2.mucosaInthiscase,theThelpercellpopulationisaTh2cellthatusuallyinducesBcellclassswitchtoIgA,butsometimestoIgE.DimericIgAisreleasedfromplasmacells,bindstothepoly-Igreceptoronepithelialcellsandistransportedthroughthecelltothelumen,whereithasitsprimaryprotec-tiverole.Antigenintroducedintotissuesischanneledthroughthelymphatics（淋巴）tothelymphnodes,whereagain,Bcells,macrophagesordendriticcellstrap,processtheantigenandpresentittoTcellsforinitiationofspecificimmuneresponses.3.lymphaticsAntigenisalsopickedupbydendriticcells(Langerhanscells)inthedermis（真皮的樹突狀細(xì)胞）,processedandcarriedviathelymphaticstothedraininglymphnodes（回流淋巴結(jié)）whereitispresentedtoThelpercells.lymphaticsBandTcellsareconcentratedindifferentpartsofthelymphnodes（聚集在淋巴結(jié)的不同部位),theBcellsinfolliclesandtheTcellsintheparacorticalareas(副皮質(zhì)區(qū)).ThecenterofeachfollicleisthegerminalcenterandismadeupofrapidlydividingBcells.lymphatics淋巴結(jié)的基本結(jié)構(gòu)HEV髓質(zhì)淋巴竇皮質(zhì)淋巴竇毛細(xì)血管小梁輸入淋巴管輸出淋巴管靜脈動(dòng)脈髓索生發(fā)中心髓質(zhì)被膜淋巴結(jié)

淋巴結(jié)被膜外側(cè)有數(shù)條輸入淋巴管，門處有動(dòng)、靜脈神經(jīng)和輸出淋巴管。實(shí)質(zhì)分為皮質(zhì)和髓質(zhì)。靠近被膜的淺層皮質(zhì)區(qū)有生發(fā)中心（左）。右圖顯示生發(fā)中心的顯微結(jié)構(gòu)Virginlymphocytesfromtheprimarylymphoidtissuessuchasbonemarrowmigratetosecondarylymphoidtissues,i.e.thespleenandlymphnodes.Antigen-presentingcells(APCs),includingdendriticcellsandmononuclearphagocytes(monocytes),alsoderivefrombonemarrowstemcells.TheseAPCsentertissues,takeupantigenandtransportittothelymphoidtissuestobepresentedtoTcellsandBcells.Primedlymphocytesthenmigratefromthelymphoidtissuesandaccumulatepreferentiallyatsitesofinfectionandinflammation.A.4

Immunecomplexes

antigen/antibodycomplexes

ImmunecomplexesInvitroImmunecomplexesinvivoImmunecomplexesandtissuedamageCombinationofantibody(Ab)withamultideterminantantigen(Ag)resultsinalatticeofalternatingmoleculesofAgandAb,whichgrowsuntillargeprecipitatingaggregatesareformed(equivalence).InAbexcessorinAgexcess,lesslatticeformationoccursandsolublecomplexesform.Keynotes

ImmunecomplexesinvitroIntroductionofAginvivoresultsinanimmuneresponseinwhichthereisinitiallyAgexcess.Withindays,asAbisproduced,equivalenceisreachedandtheresultingimmunecomplexesareremovedbyphagocyticcells.AfterAgremoval,Bcellstimulationstops,andtheAbconcentrationintheserumdecreasesasaresultofnormalcatabolism.Keynotes

ImmunecomplexesinvivoPersistenceofAg(microbialorself)mayresultincontinualformationofimmunecomplexesthatwithan'overwhelmed'phagocyticsystemaredepositedintissuesresultingindamage(typeIIIhypersensitivity)mediatedmainlybycomplementandneutrophils.Keynotes

ImmunecomplexesandtissuedamageImmunogenshavemorethanoneantigenicdeterminantpermolecule(aremultideterminant).Immunizationwith,antigenthereforeresultsinmanyantibodypopulations,eachdirectedtowarddifferentdeterminantsontheprotein.SinceonemoleculeofAb(IgG)canreactwithtwomoleculesofAg,andonemoleculeofAgcanreactwithmanymoleculesofAb,alatticeorframeworkconsistingofalternatingmoleculesofAgandAbisproducedwhichprecipitates.1.ImmunecomplexesInvitroTheextenttowhichalatticeformsdependsontherelativeamountsofAgandAbpresent(Fig.）.AstheamountofAgaddedincreases,theamountofprecipitateandAbintheprecipitateincreases,untilamaximumisreached,andthendecreaseswithfurtheradditionofAg.ImmunecomplexesInvitro

WhenthereisbothsufficientAgandsufficientAb,thecombinationofAgandAbproceedsuntillargeaggregatesareformed,whichareinsolubleandprecipitate(equivalence).However,inAbexcessorinAgexcess,lesslatticeformationoccursandmoresolublecomplexesareformed.ImmunecomplexesInvitro

QuantityofantigenaddedThesameamountofAbtoaproteinwasaddedtoeachofaseriesoftubes(1-9),followedbytheadditionofincreasingamountsoftheproteinAgtoeachsuccessivetube.(A)ThezoneofAbexcess:(B)ZoneofequivalenceinwhichalloftheAgandAbareincorporatedintoaprecipitate;and(C)ThezoneofAgexcess.ImmunecomplexformationandprecipitationThesereactionsoccurinvivoduringanimmuneresponse.Initially,thereisAgexcessasnoAbtotheAgispresentatthetimeoffirstcontactwiththeAg.Withindayshowever,plasmacellsdevelop,producingAbtotheAgwhichcomplexwithit(Agexcess).AsmoreAbisproduced,equivalenceisreachedresultinginlargeAg-AbcomplexeswhichareremovedbyphagocyticcellsthroughinteractionwiththeirFcandcomplementreceptors.2.ImmunecomplexesinvivoPlasmacellscontinuetoproduceAbduringtheirshortlife,increasingtheAbconcentrationintheserum(Abexcess).However,asAghasbeenremoved,nofurtherrestimulationofBcellsoccursandnomoreplasmacellsdevelop.Thus,theAbconcentrationintheserumbeginstodecreaseasaresultofnormalcatabolism.ImmunecomplexesinvivoIftheAgpersists(e.g.withsomeinfectiousorganismssuchasStreptococcus}orisselfAg,immunecomplexesarecontinuallyformedandmaynotreadilyberemovedduetoan'overwhelmed'phagocyticsystem.3.ImmunecomplexesandtissuedamageThiscanleadtothedepositionofimmunecomplexesintissuesresultingindamagingreactions(typeIIIhypersensitivity).ImmunecomplexesandtissuedamagetissuedamageThecomplexesactivatecomplementandinduceanacuteinflammatoryresponse.DirectinteractionoftheimmunecomplexeswithFcandcomplementreceptorsontheneutrophilscausesthereleaseofproteolyticenzymeswhichdamagesurroundingtissues.A.5

TIvsTDantigen

Thymusdependent（T-D）antigenAntigenindependent(T-I)antigens

B1CD5+B2CD5-TI與TD抗原1212CD40/CD40LB1細(xì)胞B2細(xì)胞Th細(xì)胞TI-1抗原TD抗原CD4TheproductionofantibodytomostantigensrequirestheparticipationofTcells.Inparticular,Thcells.differentiateandproduceantibodies.Inaddition,Thcellsinduceswitchingoftheclassofantibodybeingproducedandaffinitymaturation.Toaccomplishthis,ThcellsproducecriticalcytokinesanddirectlyengagethecognateBcellandtriggeritsactivationthroughcellsurfacereceptors.Thymusdependent（T-D）antigeninduceBcellstoproliferatedifferentiateandproduceantibodiesinduceswitchingoftheclassofantibodyaffinitymaturationHelpwhat?producecriticalcytokinesdirectlyengagethecognateBcellandtriggeritsactivationthroughcellsurfacereceptorsHowtohelp?

ThisTcellcollaborationwithBcellsisnecessarysincebindingofmost(nonmultimeric非多聚體)antigenstoantigenreceptorsonmostBcellsprovidesonesignalthat,intheabsenceofasecondsignal,isananergicsignal,i.e.turnsofftheBcell.Whythecollaborationisnecessary?ThecytokinesproducedbytheThcellsandtheengagement(接合)ofcomplementarysurfacemoleculesa.k.a.membrane(m)IgMandmIgDprovidetheessentialsecondsignalstotheBcellresultinginitsactivation.ActivationofBcellsthroughTcellhelp.CapturedsolubleantigensareprocessedandpresentedtoThcellswhichprovidethe2ndsignalrequiredforBcellactivation.Antigencaptureprocessingpresentation1212CD40/CD40LB1細(xì)胞B2細(xì)胞Th細(xì)胞TI-1抗原TD抗原CD4Tcellsprovide

the2ndsignaltoBcellsvialigationofCD40byCD154(CD40ligand)butalsoviacytokinesAlthoughBcellresponsestomostantigensrequireTcellhelp,activationofBcellsbycertainantigensdoesnot.Forthemostpart,theseT-independent(T-I)antigensgenerateprimarilyIgMantibodiesoflowaffinitywhereasT-dependent(T-D)antigensgeneratemuchhigheraffinityantibodiesoftheotherclasses.Antigenindependent(T-I)antigens

definitionFeaturesofTI-AgDoesn’trequireTcellhelp不需Th細(xì)胞的輔助NoformationofBm無Bm細(xì)胞產(chǎn)生GenerateprimarilyIgMantibodiesoflowaffinity抗體類型-IgMWithoutclassswitchingandaffinitymaturation無類別轉(zhuǎn)換和親和力成熟初次免疫再次免疫天數(shù)0714212835421000001000010001001010抗原特異性血清抗體滴度（Log）IgMTI抗原誘導(dǎo)的體液免疫應(yīng)答Type1antigensBacterialpolysaccharideshavetheability,athighenoughconcentration,toactivatethemajorityofBcellsindependentlyoftheirspecificantigenreceptors.TypesType1antigensBacterialpolysaccharides

Theydothisthroughamitogeniccomponentwhichbypassestheearlybiochemicalpathwaysinitiatedthroughtheantibodyreceptor.TheBcellfocusesthepoly-saccharideantigenandatsufficientlyhighconcentrationsdrivesitsactivation(Fig.).Types它們通過一個(gè)促有絲分裂的成分，繞過從抗體受體開始的早期生化途徑進(jìn)行活化。B細(xì)胞集中多糖抗原，并在足夠高的濃度促使其活化。Type2antigensSomelinearantigensthatarenoteasilydegradedandhaveepitopesspacedappropriatelyonthemolecule,e.g.pneumococcuspolysaccharide,candirectlystimulateBcellsinaTcellindependentfashion.typeType2antigensSomelinearantigens

TheseantigenspersistonthesurfaceofsplenicmarginalzoneandlymphnodesubcapsularmacrophagesanddirectlystimulateBcellsthroughcross-linkingoftheirsurfacereceptors(這些抗原存在脾邊緣區(qū)和淋巴結(jié)被膜下的巨噬細(xì)胞細(xì)胞表面，并通過其表面受體的交聯(lián)，直接刺激B細(xì)胞).

AlthoughactivationisindependentofTcells,cytokinesproducedbyTcellscanamplifytheseresponses.type(a)TypeI(T-I)(b)TypeⅡ(T-I)(b)TypeII(T-I)Solubleantigen(signal1)Anergy(無反應(yīng)性)IL-1(2)ActivationofBcellsthroughTTcellindependentantigens.ActivationofBcellsthroughTcellindependentantigens.ActivationofBcellsthroughTTcellindependentantigens.SolubleantigeninteractionwiththeBcellantigenreceptor(antibody)resultsinanergy(signal1only).Signal2isprovidedbyamitogeniccomponentoftype1antigen(a)andviaautocrineactivityofIL-1fortypeⅡantigen(b)TI-1和TI-2抗原LPS

LPS受體TI-1抗原

TI-2抗原信號(hào)轉(zhuǎn)導(dǎo)信號(hào)轉(zhuǎn)導(dǎo)B1細(xì)胞A.6InnateandadaptiveimmunityMajorfeaturesTimecomplementofthetwoimmunity(時(shí)間互補(bǔ))Collaborationofthetwosystem