第四章 免疫应答

ChapterⅣImmuneresponseimmuneresponseDefinitionimmuneresponseisabiologicalprocessmediatedbytheantibodyorcytokinesproducedbyimmunecellswhichwasactivatedafterantigenrecognition,thenproliferateanddifferentiateintoeffectorcells.

(免疫细胞识别抗原后活化、增殖、分化为效应细胞，并通过其所分泌的抗体或细胞因子表现出一定生物学效应的过程。)immuneresponseCharacteristics1.Selfandnonselfdiscrimination2.Specificity（特异性）3.Memory（记忆性）GENERALCHARACTERISTICSOFTHEANTIBODYRESPONSEA.Self/non-selfdiscrimination-Onecharacteristicfeatureofthespecificimmunesystemisthatitnormallydistinguishesbetweenselfandnon-selfandonlyreactsagainstnon-self.B.

Memory

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

-Athirdcharacteristicfeatureofthespecificimmunesystemisthatthereisahighdegreeofspecificityinitsreactions.Aresponsetoaparticularantigenisspecificforthatantigenorafewcloselyrelatedantigens.N.B.Thesearecharacteristicofallspecificimmuneresponses.

ImmuneresponseTypeMechanism(根据发挥效应的机理)humoralimmuneresponsecell-mediatedimmuneresponsIntroducedtimeofantigen(根据抗原进入体内的时间和次数)primaryimmuneresponseSecondaryimmuneresponseEffect(效应)Protectiveeffectself——norejectionNon-self——rejectionandeliminationDetrimentaleffectself——rejectionNon-self——norejectionoroverreactImmuneresponse损伤效应(免疫病理)自己——排己非己——不排异或高应答保护效应(免疫生理)自己——不排己非己——排异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细胞（ActivatedBcell）浆细胞(plasmacell)Forexample,onintroductionofantigen5(Ag5)intoaperson,morethan106

Bcellshavetheopportunitytointeractwithit.OnlyaveryfewBcells(e.g.B5)havereceptorsspecificforthisantigen.B5bindsAg5,internalizes,andprocessesandpresentsitonMHCclassIImoleculesonthesurfaceofthisBcell.ThelpercellswithspecificreceptorsforapeptidefromAg5inMHCclassIIbindtothiscomplexandstimulatethisBcelltoclonallyexpandanddifferentiateintomemoryBcellsandplasmacellswhichproducesolubleantibodytoAg5.Inaddition,directTcellinteractionwiththeBcellinducesclassswitching,whichdependingonthetypeofhelpercell(Th1vsTh2)andthecytokinesitsecretes,willresultinproductionofantibodyoftheIgG,IgAorIgEclasses.B细胞活化的双信号模型活性封闭没有Th细胞的帮助第1信号BIFN-γ,IL-4,IL-5第2信号ThB第1信号CD40CD40L

BBCRTCR外来抗原MHCIITh细胞因子CD40LBcellgrowthanddifferentiationTcellgrowthanddifferentiationReciprocalactivationofTandBcells12345HumoralimmunityWhenintroducedintoanindividualwhohasnotpreviouslyencounteredtheantigen,aprimaryimmuneresponsewilldevelopwithin4-5days.ThisresponseresultsinitiallyintheproductionofIgMandthenIgGorotherantibodyisotypes(同种型抗体)directedtowardtheantigen,andhasaduration（延续时间）andantibodyisotypeprofilewhichdependsonthethequantityofantigenintroducedanditsmodeofentry.2.PrimaryandmemoryresponsesTheantibodyproducedreactswithremainingantigen,formingcomplexesand/orprecipitateswhichareeliminatedbyphagocytes.Antibodyiscontinuallymadebyplasmacellsduringtheirshortlifespan(3-4days).Ifenoughantigenisintroducedinitially,therecouldberestimulationofantigenspecificBcells,subsequentdevelopmentofmoreplasmacellsandthusincreasedproductionofantibody.Eventually,whenalloftheantigenhasbeenremovedandnoneremainstostimulateBcells,theantibodyresponsewillreachitspeakandtheconcentrationofantibodyinthecirculationwillbegintodecreaseasaresultofthenormalrateofcatabolismoftheantibody.Atthetimeantigenisreintroduced,moreantigenspecificBcellsexistintheindividualcomparedwiththeperiodbeforeprimaryintroductionofantigen.Moreover,thesecellshavedifferentiatedtomoreresponsivememoryBcells.PrimaryandSecondaryHumoralResponse

(初次与再次体液免疫应答)再次应答初次应答初次免疫再次免疫天数0714212835421000001000010001001010抗原特异性血清抗体滴度（Log）IgGIgM抗体分子的类别转换mdg3VJg3DVJDPrimarytranscriptV-D-JmmRNAPrimarytranscriptV-D-Jg3mRNAmdLostgenesIgMmaturationIgGIgGIgMprimaryantigensecondaryantigenantibodyresponseprimaryresponsesecondaryresponsetime（Class-switching）FeaturesofmemoryresponseThus,asecondary(memoryoranamnestic)antibodyresponseoccurswhichischaracterizedbyamuchshorterlagperiodbeforesignificantlevelsofantibodyarefoundintheserum（rapid）bythepresenceofmanymoreplasmacellsbyahigherrateofantibodyproductionandthusamuchhigherserumconcentrationofantibodyusuallyoftheIgGclass.初次与再次免疫应答的特性初次应答再次应答应答B细胞静息B细胞Bm所需Ag浓度高低Ag类型TI-Ag或TD-AgTD-Ag延迟相4-7天1-3天高峰浓度较低较高Ig类别主要为IgMIgG、IgA等亲和力低高Althoughantibodiesproducedbyasinglecellanditsdaughtercellsareidentical(homogeneousormonoclonal同质的或单克隆的),theresponsetoagivenantigeninvolvesmanydifferentclonesofcellsandthus,overall,isveryheterogeneous(multiclonal).3.ResponsesareusuallymulticlonalConsideringthefactorsbelow，theresponsetoamicroorganismresultsinalargenumberofdifferentantibodies.thesizeofanantigenicdeterminant,thenumberofdeterminantsonamoleculeandthenumberofdifferentmoleculesonamicroorganism.Asingleantigenicdeterminantscaninducedifferentisotypes(classes)ofantibodywiththesamespecificityfortheantigen.Whyismulticlonal?DifferentantigenicdeterminantsonthesamemoleculeDifferentantigensAllofaboveindicatethattheimmunesystemiscapableofproducingmanydifferentantibodies,eventoasinglewell-defined(单一明确的)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.淋巴结的基本结构HEV髓质淋巴窦皮质淋巴窦毛细血管小梁输入淋巴管输出淋巴管静脉动脉髓索生发中心髓质被膜淋巴结

淋巴结被膜外侧有数条输入淋巴管，门处有动、静脉神经和输出淋巴管。实质分为皮质和髓质。靠近被膜的浅层皮质区有生发中心（左）。右图显示生发中心的显微结构浆细胞B记忆细胞暗区明区生发中心树突细胞初级淋巴小结早期生发中心生发中心

Ab1

Ab1

Ab1

Ab1

Ab1AffinityandAvidity（抗体与抗原之间的亲合力）IgMantibodiesareproducedfirstinanimmuneresponsefollowedbyaswitchtoIgGorotherantibodyclasses.EachcellinitiallyexpressesIgMantibodiesandafteractivationundergoesswitchingtoadifferentclassofantibodywithoutchangingitsspecificityforantigen.2.Classswitching

Howithappened?Thisclassswitchisdependenton

signalingbythebindingoftheCD154(CD40ligandonTh)toCD40onBcells.thecytokinesproducedbytheThelpercellinfluencetheconstantregiongenetowhichclassswitchingoccurs.CytokinesTh2cellsproducingIL-4induceBcellstoclassswitchtoIgE;IL-5,whichisalsoproducedbyTh2cells,inducesBcellstoclassswitchtoIgA;IFNγproducedbyTh1cellsinducesclassswitchingtoIgGI.Fig.ClassswitchingismediatedthroughTh/Bcellinteractionsandspecificcytokines.抗体分子的类别转换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经血液循环进入脾脏的T细胞分布于PALS的内侧，而B细胞则分布于PALS的边缘，与边缘血窦比邻。B细胞聚集的区域可见淋巴小结和生发中心。脾血窦的周边布满了巨噬细胞，它们能够吞噬血液中的细胞碎片以及外来微生物或者抗原。脾脏*白髓（whitepulp）

（1）动脉周围淋巴鞘（periarteriallymphaticsheath，PALS），围绕在动脉周围的弥散淋巴组织，主要由T细胞组成，相当于副皮质区。（2）淋巴小结，主要由B细胞组成，可发展成生发中心，常出现于PALS的外侧。*红髓（redpulp）占脾实质的2/3，分布于小梁周围及白髓之间。（1）脾索，（2）脾血窦，*功能滤血、免疫、造血、储血脾脏结构（Spleen）红髓静脉窦小梁被膜动脉周围淋巴鞘中央动脉生发中心动脉周围淋巴鞘

淋巴小结边缘区

被膜脾索边缘区静脉窦

动脉周围淋巴鞘脾脏的结构浆细胞B记忆细胞暗区明区生发中心树突细胞初级淋巴小结早期生发中心生发中心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,whereithasitsprimaryprotec­tiverole.Antigenintroducedintotissuesischanneledthroughthelymphatics（淋巴）tothelymphnodes,whereagain,Bcells,macrophagesordendriticcellstrap,processtheantigenandpresentittoTcellsforinitiationofspecificimmuneresponses.3.lymphaticsAntigenisalsopickedupbydendriticcells(Langerhanscells)inthedermis（真皮的树突状细胞）,processedandcarriedviathelymphaticstothedraininglymphnodes（回流淋巴结）whereitispresentedtoThelpercells.lymphaticsBandTcellsareconcentratedindifferentpartsofthelymphnodes（聚集在淋巴结的不同部位),theBcellsinfolliclesandtheTcellsintheparacorticalareas(副皮质区).ThecenterofeachfollicleisthegerminalcenterandismadeupofrapidlydividingBcells.lymphatics淋巴结的基本结构HEV髓质淋巴窦皮质淋巴窦毛细血管小梁输入淋巴管输出淋巴管静脉动脉髓索生发中心髓质被膜淋巴结

淋巴结被膜外侧有数条输入淋巴管，门处有动、静脉神经和输出淋巴管。实质分为皮质和髓质。靠近被膜的浅层皮质区有生发中心（左）。右图显示生发中心的显微结构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与TD抗原1212CD40/CD40LB1细胞B2细胞Th细胞TI-1抗原TD抗原CD4TheproductionofantibodytomostantigensrequirestheparticipationofTcells.Inparticular,Thcells.differentiateandproduceantibodies.Inaddition,Thcellsinduceswitchingoftheclassofantibodybeingproducedandaffinitymaturation.Toaccomplishthis,ThcellsproducecriticalcytokinesanddirectlyengagethecognateBcellandtriggeritsactivationthroughcellsurfacereceptors.Thymusdependent（T-D）antigeninduceBcellstoproliferatedifferentiateandproduceantibodiesinduceswitchingoftheclassofantibodyaffinitymaturationHelpwhat?producecriticalcytokinesdirectlyengagethecognateBcellandtriggeritsactivationthroughcellsurfacereceptorsHowtohelp?

ThisTcellcollaborationwithBcellsisnecessarysincebindingofmost(nonmultimeric非多聚体)antigenstoantigenreceptorsonmostBcellsprovidesonesignalthat,intheabsenceofasecondsignal,isananergicsignal,i.e.turnsofftheBcell.Whythecollaborationisnecessary?ThecytokinesproducedbytheThcellsandtheengagement(接合)ofcomplementarysurfacemoleculesa.k.a.membrane(m)IgMandmIgDprovidetheessentialsecondsignalstotheBcellresultinginitsactivation.ActivationofBcellsthroughTcellhelp.CapturedsolubleantigensareprocessedandpresentedtoThcellswhichprovidethe2ndsignalrequiredforBcellactivation.Antigencaptureprocessingpresentation1212CD40/CD40LB1细胞B2细胞Th细胞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细胞的辅助NoformationofBm无Bm细胞产生GenerateprimarilyIgMantibodiesoflowaffinity抗体类型-IgMWithoutclassswitchingandaffinitymaturation无类别转换和亲和力成熟初次免疫再次免疫天数0714212835421000001000010001001010抗原特异性血清抗体滴度（Log）IgMTI抗原诱导的体液免疫应答Type1antigensBacterialpolysaccharideshavetheability,athighenoughconcentration,toactivatethemajorityofBcellsindependentlyoftheirspecificantigenreceptors.TypesType1antigensBacterialpolysaccharides

Theydothisthroughamitogeniccomponentwhichbypassestheearlybiochemicalpathwaysinitiatedthroughtheantibodyreceptor.TheBcellfocusesthepoly-saccharideantigenandatsufficientlyhighconcentrationsdrivesitsactivation(Fig.).Types它们通过一个促有丝分裂的成分，绕过从抗体受体开始的早期生化途径进行活化。B细胞集中多糖抗原，并在足够高的浓度促使其活化。Type2antigensSomelinearantigensthatarenoteasilydegradedandhaveepitopesspacedappropriatelyonthemolecule,e.g.pneumococcuspolysaccharide,candirectlystimulateBcellsinaTcellindependentfashion.typeType2antigensSomelinearantigens

TheseantigenspersistonthesurfaceofsplenicmarginalzoneandlymphnodesubcapsularmacrophagesanddirectlystimulateBcellsthroughcross-linkingoftheirsurfacereceptors(这些抗原存在脾边缘区和淋巴结被膜下的巨噬细胞细胞表面，并通过其表面受体的交联，直接刺激B细胞).

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

LPS受体TI-1抗原

TI-2抗原信号转导信号转导B1细胞A.6InnateandadaptiveimmunityMajorfeaturesTimecomplementofthetwoimmunity(时间互补)Collaborationofthetwosystem