免疫学-黏膜免疫

1、黏膜免疫MucosalImmune黏膜免疫系统与免疫应答黏膜免疫系统中的固有免疫应答黏膜免疫系统中的适应性免疫应答黏膜免疫中的免疫耐受和免疫调节粘膜免疫与疾病直接接触病原体的解剖部位并能够分泌粘液的上皮细胞所覆盖,构成粘膜免疫系统(mucosalimmunesystem)。包括启动和行使免疫应答的粘膜下固有层中各种散在的免疫细胞和一些器官化的淋巴组织，还包括与此相关的多种内分泌腺体：胰腺、眼结膜和泪腺、唾液腺以及乳腺。因而黏膜免疫系统亦称黏膜相关淋巴组织(mucosa-associatedlymphoidtissue,MALT）。Mucosaltissuesofthehumanbodyresp

2、iratorytractThemucosalimmunesystem.Thetissuesofthemucosalimmunesystemarethelymphoidorgansassociatedwiththeintestine,respiratorytract,andurogenitaltract,aswellastheoralcavityandpharynxandtheglandsassociatedwiththesetissues,suchasthesalivaryglandsandlachrymalglands.Thelactatingbreastisalsopartofthemuc

3、osalimmunesystem.黏膜免疫系统与免疫应答一、黏膜免疫系统的结构特点二、黏膜免疫系统的应答特点黏膜免疫系统的结构特点IntestinallumenFollicleInductivesiteVilliPrimary*follicleMusclelayervPeyserspatchcenterCioss-sectionaldiagramofthemucousmembianelmmgtheintestineshowmganoduleoflymphoidfolliclesthatconstitutesaPeyer5spatchinthesubmucosaThemtestinallanun

4、apropriacontainslooseclustersoflymphoidcellsanddiffusefollicles.绒毛共生菌O.M细胞小肠上皮细胞0,DC001隐窝T细胞浆细胞DC曰淋錨)滤泡T细胞B细胞抗菌肽WJolo上皮内淋巴细胞(IEL)000000IQ严细胞粘液lgA耀皮固有层肠系膜小肠黏膜免疫系统的各种细胞成分和器官化的淋巴组织粘膜免疫系统的特点解剖特征一粘膜上皮和淋巴组织间因相互作用而联系紧密。一由散在的淋巴组织和器官化的结构（如派氏集合淋巴结.分立的淋巴滤泡和扁桃体）共同组成。一启用特化的抗原摄取机制，如出现派氏集合淋巴结和M细胞。效应机制一在无感染发生的情况下拥有

5、大量活化的T细胞和记忆细胞。一存在非特异性激活的“天然”效应性T细胞和记忆性T细胞。大量启用分泌型IgA抗体。一涉及各种共生微生物菌丛。免疫调节一可主动下调针对食物和其它共生性抗原的强势免疫应答。一可激活抑制性巨噬细胞及诱导耐受的树突状细胞。黏膜免疫中的固有免疫应答一、组成肠相关淋巴组织的固有免疫细胞二、肠道粘膜相关的固有免疫应答三、上皮内淋巴细胞杀伤入侵病毒和修复损伤组织组成肠相关淋巴组织的固有免疫细胞BMcellsinthesmallintestine.Y也5縱nusrm卑他図:eishnesrdltoweraryrg阳&9(:绑wrmWlhaepcriiohsc曲rd对納畑伪elwrfi

6、&兀ewrclrtodtrwobesarexosiWntfrt刃卜絆删ItcPeodissues.w*eethhreWMottoCC$ICIrwny兀iw曲ren炳哄血知Me如y52H2.JW9.Thelaminapropriaandepitheliumoftheintestinalmucosaarediscretelymphoidcompartments.ThelaminapropriacontainsaheterogenousmixtureofIgA-producingplasmacells,lymphocyteswithamemoryphenotype,conventionalCD4an

7、dCD8effectorTcells,dendriticcells,macrophages,andmastcells.Tcellsinthelaminapropriaofthesmallintestineexpresstheintegrina4:|J7andthechemokinereceptorCCR9,whkhanractsthemintothetissuefromthebloodstream.IntraepitheliallymphocytesexpressCCR9andtheintegrinaE：P7,whichbindstoE-cadherinonepithelialcells.Th

8、eyaremostlyCD8Tcells,someofwhichexpresstheconventionala:BformofCD8andotherstheCD8a:ahomodimer.CD4Tcellspredominateinthelaminapropria,whereasCD8Tcellspredominateintheepithelium.上细皮胞配体受体粘淋细膜巴胞分;因泌子BCRTCRaB金门弟r亠loiOlQIPPloiojotoo|ooooBMHCIMR1CD8aaNKG2DTCRapTCRapNKNKTMAITTGF卩IFN-yJL-4PfzGz,FasLIFN-yJL-4

9、?TLCD8apTCRaBCD94/NKG2ATCRa卩CD8aaCD8aaTCR/5TCRapCD8TDid/:-GalCelTCRy6CD8aaAIL-6,KGFTNF-aATNF-a,PfzGzzIFN-yFasL功能调卫W2毒性巖，炎症毒性TL：非经典MHCI类分子胸腺白血病抗原；MIC:MHCI类链相关分子；CDld/a-GalCel:分化抗原CDld分子提呈的ex半乳糖神经酰胺；MR1：MHC相关I类分子；MAIT:MR1限制性粘膜相关恒定链T细胞;Pf：穿孔秦；Gz：颗粒酶。KGF：角反细胞生长因子。粘膜淋巴细胞及其与上皮细胞相互作用的分子机制图中所示粘膜淋巴细胞主要指位于粘膜上

10、皮细胞间和上皮细胞基底层T1的T淋巴细胞，包括固有类T淋巴细胞和NK细胞。此类细胞不仅分布部位特殊r而且功能发挥皆受控于上皮细胞表面各类MHC分子与其受体分子间的相互作用。有意义的是,除了经典的MHCI类和II类分子，上皮细胞还表达范围广泛的各种非经典MHC分子，包括TL、HLA-E.MIC-A/-B.MR1和进化上与之高度同源的CDld分子，激活多种粘膜淋巴细胞。肠道粘膜相关的固有免疫应答肠道上皮细胞的免疫屏障功能肠道上皮细胞分泌的粘液防止微生物接近上皮细胞A肠道上皮细胞产生的防御素和细胞園子具有抗菌活性A肠道上皮细胞耒达的TLR和NLR显示双重免疫功能固有层中的DC和巨噬细胞具有炎症反应抑

11、制作用和免疫调节作用MechanicalChemicalMicrobiologicalSkinGutLungsEyes/nose/oralcavityEpithelialcellsjoinedbytightjunctionsplefensinsLamellarbodiesCathelicidina-delensins(cryptdins)Reglll(lecticidins)Cathelicidina-defensinsCathelicidinHistatinsp-defensinsNormalmicrobiotaManybarrierspreventpathogensfromcrossing

12、epitheliaandcolonizingtissuesSurfaceepitheliaprovidemechanical,chemical,andmicrobiologicalbarrierstoinfection.细菌PAMPNLR小肠黏膜中固有免疫应答的调控机制小肠上皮细胞及固有层中DCPRR的表达和功能可降低针对肠腔共生微生物的炎症反应。上端：能识别细菌鞭毛的PRR仅作为NLR表达于胞质中和作为TLR表达于小肠上皮细胞基底膜一侧，因而PRR对共生微生物的炎症反应只有当微生物进入或穿越上皮细胞后才能产生。右下端：识别LPS的TLR4在小肠上皮细胞及固有层DC上的表达皆下调。而且固有层D

13、C中TLR信号并不诱导炎症基因的表达，因为其中能下调TLR信号转导的胞内调节蛋白可优势表达。BacteriaarerecognizedbyTLRsoncellsurfaceorinIntracellularvesiclesBacteriaortheirproductsdirectlyenteringthecytosolarerecognizedbyNOD1andNOD2CCL1CCL2CCL20defensinsTLRs,NOD1,andNOD2activateNFkB,inducingtheepithelialcelltoexpressinflammatorycytokines,chemok

14、ines,andothermediatorsTheserecruitandactivateneutrophils,macrophages,anddendriticcellsEpithelialcellshaveacrucialroleininnatedefenseagainstpathogens.TLRsarepresentinintracellularvesiclesoronthebasolateralorapicalsurfacesofepithelialcells,wheretheyrecognizedifferentcomponentsofinvadingbacteria.NODIan

15、dNOD2patternrecognitionreceptorsarefoundinthecytoplasmandrecognizecellwallpeptidesfrombacteria.BothTLRsandNODsactivatetheNFkBpathwayleadingtothegenerationofpro-inflammatoryresponsesbyepithelialcells.TheseincludetheproductionofchemokinessuchasCXCL8ZCXCL1(GROa),CCL1,andCCL2Zwhichattractneutrophilsandm

16、acrophages,andCCL20anddefensin,whichattractimmaturedendriticcellsinadditiontopossessingantimicrobialproperties.ThecytokinesIL-1andIL-6arealsoproducedandactivatemacrophagesandothercomponentsoftheacuteinflammatoryresponse.TheepithelialcellsalsoexpressMIC-AandMIC-Bandotherstress-relatednonclassicalMHCm

17、olecules,whichcanberecognizedbycellsoftheinnateimmunesystem.IkB,inhibitorofNFkB.PPfiRySomecommensalbacteriablockgenetranscriptionbyactivatingPPAR7,whichpreventsNFkBfrombindingtoitstargetpromoters,thuscausingNFkBtobeexportedfromthenucleusCommensalbacteriacanpreventinflammatoryresponsesintheintestine.

18、Thepro-inflammatorytranscriptionfactorNFkBpathwayisactivatedinepithelialcellsviatheliga廿onofTLRsbypathogens(firsttwopanels).Commensalbacteriahavebeenfoundtoinhibitthispathwayandthuspreventinflammation.OnewayisbyactivationofthenuclearreceptorPPARy,leadingtotheexportofNFkBfromthenucleus(thirdpanel).An

19、otherisbyblockingthedegradationoftheinhibitorIkBandthusretainingNFkBinthecytoplasm(fourthpanel).IEL杀伤入侵病毒和修复损伤组织AIEL参与构筑粘膜防御屏障AIEL对病原体的杀伤功能AIEL的维稳和保护功能的功能Intestinallymphocytesarefoundinorganizedtissueswhereimmuneresponsesareinduced,andscatteredthroughouttheintestine,wheretheycarryouteffectorfunction

20、sScatteredlymphoidceltsOrganizedlymphoidtissuestomesentericlymphnodeGut-associatedlymphoidtissuesandlymphocytepopulationsTheintestinalmucosaofthesmallintestineismadeupoffinger-likeprocesses(villi)coveredbyathinlayerofepithelialcells(red)thatareresponsiblefordigestionoffoodandabsorptionofnutrients.Th

21、eseepithelialcellsarereplacedcontinuallybynewcellsthatderivefromstemcellsinthecrypts.Thetissuelayerundertyingtheepitheliumiscalledthelaminapropria,andwillbecoloredpaleyellowthroughoutthischapter.Lymphocytesarefoundinseveraldiscretecompartmentsintheintestine,withtheorganizedlymphoidtissuessuchasPeyer

22、spatchesandisolatedlymphoidfollictesformingwhatisknownasthegut-associatedlymphoidtissues(GALT).Thesetissueslieinthewalloftheintestineitself,separatedfromthecontentsoftheintestinallumenbythesinglelayerofepitheliumThedraininglymphnodesforthegutarethemesentericlymphnodes(seeFig.12.12),whichareconnected

23、toPeyerspatchesandtheintestinalmucosabylymphaticvesselsandarethelargestlymphnodesinthebody.Together,theseorganizedtissuesarethesitesofantigenpresentationtoTcellsandBcellsandareresponsiblefortheinductionphaseofimmuneresponsesPeyerspatchesandmesentericlymphnodescontaindiscretecellareas(blue)andB-cellf

24、ollicles(yellow).whiletheisolatedfolliclescomprisemainlyBcells.Manylymphocytesarefoundscatteredthroughoutthemucosaoutsidetheorganizedfymphoidtissues:theseareeffectorcellseffectorTcellsandantitx)dy-secretingplasmacells.EffectorlymphocytesarefoundbothintheepitheliumandinthelaminapropriaLymphaticsalsod

25、rainfromthelaminapropriatothemesentericlymphnodes.病毒食物抗原*（谷阮肽）TCR0MHCI类分子1?MIC-A/-B亍NKG2D-fLTOTITCACD8ELa型IELnrr上皮细胞CD8aaCD8apFasFasLGz（颗粒酶）Pf（穿孔素）03ooa型和b型粘膜上皮细胞间淋巴细胞（IEL）的主要功能A.a型EL。左：病毒感染粘膜上皮细胞；中：受感染细胞通过MHCI类分子向CD8IEL展示病毒抗原肽，激活IEL；右：激活的IEL行使典型的CTL功能，通过分泌Pf和Gz,以及通过Fas/FasL途径杀伤病毒感染的上皮细胞；B.b型IEL。左：发

26、生应急改变（感染、损伤、接触毒性肽）的上皮细胞表达非经典MHC分子MICAMIC-B和胸腺白血病抗原（LT）；中：IE康达NKG2D和CD8分子，分别与MIC-A/-B以及LT结合，IEL被激活；右：激活的IEL杀伤受到应急损伤的上皮细胞，机制同上。黏膜免疫系统中的适应性免疫应答一、黏膜免疫系统器官化的淋巴组织二、参与适应性黏膜免疫应答的免疫细胞三、黏膜免疫中的抗体应答四、黏膜免疫中T细胞介导的应答黏膜免疫系统器官化的淋巴组织A派氏集合淋巴结与M细胞A散在性淋巴滤泡A肠系膜淋巴结Antigenistakenupbydendriticcells,whichactivateTcellsUptake

27、andtransportotantigensbyMcellsThefirstthreepanelsshowuptakeviaMcellsinthefollicle-associatedepitheliumofPeyerpatchesThesehaveconvolutedbasalmembranesthatformpocketswithintheepitheliallayecallowingclosecontactwithlymphocytesandothercellsThisfavorsthelocaltransportofantigensthathavebeentakenupfromthei

28、ntestinebytheMcellsandtheirdeliverytodendriticcellsforantigenpresentation.ThemicrographofpartofaPeyerspatchontherightshowsepithelialcells(darkblue),someofwhichareMcellsthatformpocketswhereTcells(red)andBcells(green)accumulate.Thecellshavebeenstainedwithfluorescentlylabeledantibodiesspecificforindivi

29、dualcelltypesMicrographfromBrandtzaeg,eta/.:Immunol.Today1999,20:141-151.参与适应性黏膜免疫应答的免疫细胞黏膜免疫系统含有大量效应淋巴细胞A黏膜免疫系统中独特的树突状细胞A黏膜固有层中T细胞的致敏和归巢McellPeyefspatchBcellDendriticIntraepitheliallymphocytesIntestinalepitheliacellDendriticcell.、Afferent摭黑、严phalicVillusMucus/oblelcellCommensalbacteriaf豎MastcellPan

30、ethAntimicrobialcellspeptidesWophagePlaCGllIntestinallumenMucosalepitheliumLaminapropriaMesentaryLaminapropriaThegastrointestinalimmunesystemA,SchernaticdiagramofthecellularcomponentsofthemucosslimmunesysteminthentGstirB,FtotomKXOrephofmucosalymphodtissueinthehumanintestneSmiiarggreoatesoi2mphodtiss

31、uearefoundthroughoutxhegastrointestinaliract.NonspecifictransportacrossepitheliumMcellFcRn-dependenttransportApoptosis-dependenttransferCaptureofantigensfromtheintestinallumenbymononuclearcellsinthelaminapropriaFirstpanel:solubleantigenssuchasfoodproteinsmightbetransporteddirectlyacrossorbetweenente

32、rocytes,ortheremightbeMcellsinthesurfaceepitheliumoutsidePeyerspatchesSecondpanel:enterocytescancaptureandinternalizeantigen:antibodycomplexesbymeansoftheFeRnontheirsurfaceandtransportthemacrosstheepitheliumbytranscytosisAtthebasalfaceoftheepithelium,laminapropriadendriticcellsexpressingFeRnandother

33、Fereceptorspickupandinternalizethecomplexes.Thirdpanel:anenterocyteinfectedwithanintracellularpathogenundergoesapoptosisanditsremainsarephagocytosedbythedendriticcellFourthpanel:mononuclearcellshavebeenseenextendingprocessesbetweenthecellsoftheepitheliumwithoutdisturbingitsintegrity.Thecellprocessco

34、uldpickupandinternalizeantigenfromthegutlumenandthenretract.Themicrographshowsmononuclearcells,whichmaybedendriticcellsormacrophages,(stainedgreenwithafluorescenttagontheCD11cmolecule)inthelaminapropriaofavillusofmousesmallintestine.Theepitheliumisnotstainedandappearsblack,butitsluminal(outer)surfac

35、eisshownbythewhiteline.Acellprocesshassqueezedbetweentwoepithelialcellsanditstipispresentinthelumenoftheintestine.Magnificat!onx200.MicrographfromNiess,J.H.,eta/.:Science2005,307:254-2584A給:Antigen参见图97%bAntigenTcell和抵|ifny|IL17|CD11b+CX3CRI+dendriticcellTGF-I3RACD103+CX3CRI-dondriticcellFoxp3+M7Tre

36、gcellDCsintheintestinalmucosaThereareseveraldifferenisubsetsofDCsconstitutivelypresentintheintestinalmucosathataredefinedbycellsurfacemoleculesandfunction.Twosuchsubsetsareshownthatarealsopresentinothermucosaltissues.A,Antigen-samphngDCsextenddendriticprocessesbetweenintestinalepithelialcellsintothe

37、lumen10sampleantigensandthenmigratetomesentericlymphnodes,wheretheyinitiateactivationanddifferentiationofproinflammatoryeffectorTcells.TheseDCsexpresstheCD11bintegrinchainandtheCX3CRIchemokinereceptor.B,OtherDCspresentinthelaminapropria,whichexpresstheintegrinCD103,presentantigenstonaiveTcellsandind

38、ucetheirdifferentiationofregulatoryTcells.inpartbysecretingTGF-pandretinoicacid(RA).TheregulatoryfunctionoftheseDCsdeperidsonfactorssecretedbyintestinalepithelialcells.SkinGastrointestinalRespiratorytractVenuleMicrobeEpitheliumConnectivetissueCell-freeantigenDendriticcell-Xassociated._antigen/JAntig

39、enthat（砾Mentersblood亠ULymphatic二streamvesselTocirculationandspleenSpleenTolymphnodeLymphRoutesofantigenentryMicrobiolantigenscommonlyenterthroughtheskinandgastrointestinalandrespiratorytracts,wheretheyarecapturedbydendriticcellsandtronsportedtoregionallymphnodes.Antigonsthatenterthebloodstreamarecap

40、turedbyAPCsinthosploen.LymphnodecollectsantigenfromepitheliumandconnectivetissueBlood-borneantigensarecapturedbyantigenpresentingcellsinthespleen固有层肠系膜M细胞0觀DC固有层肠系膜淋巴结CCR9CCR9MadCAM-1微静脉a407T騙TSLPRCaEp7E钙粘素肠系膜淋巴舌和派氏集合淋巴结中的DC,在胸腺基质淋巴生成素仃SLP）和其它因子的作用下表达视黄醇脱氢酸（RALDH）,后者将维生素A转化成视黄酸（RC）,在RC的作用下,已被抗原活化的效应

41、T细胞（及B细胞）被激发，诱导性表达趋化因子受体CCR9和整合素/4卩7,并进入血循环。小肠淋巴细胞的激活和归巢由于分布在粘膜固有层中的后毛细血管微静脉的内皮细胞表达MadCAMJ（a.437配体）f使CCR9+a4|37T细胞停留于该处并穿越微静脉到达回有层,并变更其表型为CCR99E附T。而固有层上皮细胞表达CCL25（CCR9配休）和E钙粘素（aE卩7配体厂使效应性淋巴细胞选择性地归里和停留于粘膜固有层。Gut-homingeffectorTcellsbindMAdCAM-1onendotheliumGutepithelialcellsexpresschemokinesspecificf

42、orgut-homingTcellsBloodendothelium2CCL28CCR10vessel/o/Q辭CCR9a4：B7MAdCAM-1E-cadherin/互LaminapropriaLargexJ/H。0oointestine1.A(%Molecularcontrolofintestine-specifichomingoflymphocytesLeftpanel:TandBlymphocytesprimedbyantigeninthePeyerspatchesormesentericlymphnodesarriveaseffectorlymphocytesinthebloodst

43、reamsupplyingtheintestinalwall).Thelymphocytesexpresstheintegrina4:p7,whichbindsspecificallytoMAdCAMexpressedselectivelyontheendotheliumofbloodvesselsinmucosaltissuesThisprovidestheadhesionsignalneededfortheemigrationofcellsintothelaminapropriaRightpanel:ifprimedinthesmallintestine,theeffectorlympho

44、cytesalsoexpressthechemokinereceptorCCR9,whichallowsthemtorespondtoCCL25(greencircles)producedbyepithelialcellsofthesmallintestine;thisenhancesselectiverecruitmentEffectorlymphocytesthathavebeenprimedinthelargeintestinedonotexpressCCR9butdoexpressCCR10.ThismayrespondtoCCL28(bluecircles)producedbycol

45、onepithelialcellstofulfillasimilarfunction.Lymphocytesthatwillentertheepitheliallayerstopexpressingthea4:p7integrinandinsteadexpresstheaE:07integrinThereceptorforthisisE-cadherinontheepithelialcellsTheseinteractionsmayhelpkeeplymphocytesintheepitheliumoncetheyhaveenteredit.0VitaminAGutepithelialbarr

46、ierBlooda4|37CCR9Effector、TorBcellRetinoicacidNaiveTorBcellLaminapropriavenuleLaminapropriaTorplasmaPeyerspatchormesentericlymphnodeIDendriticcellaTSLP,otherfactorsPoMadCAMCCL25HomingpropertiesofintestinallymphocytesThegut-homingpropertiesofeffectorlymphocytesareimprintedinthlymphoidtissueswhereThey

47、haveundergonedifferentiationfromnaiveprecursors.DCsingut-associatedlymphoidtissues,ineludingPeyer*spatchesandmesentericlymphnodes,areinducedbythymicstromallymphopoiotin(TSLP)andotherfactors10expressretinaldehydedehydrogenase(RALDH),whichconvertsdietaryvitaminAintoretinoicacidWhennaiveBorTcellsareact

48、ivatedbyantigeninGALT,theyareexposedtoretinoicacidproducedbytheDCs,andthisinducestheexpressionofthechemokinereceptorCCR9andtheintegrin047ontheplasmacellsandeffectorTcellsThatarisefromthenaivelymphocytes.TheeffectorlymphocytesenterthecirculationandhomebackintoihogutlaminapropriabecausethechemokineCCL

49、25(theligandforCCR9)andtheadhesionmoleculeMadCAM(theligandfora4p7laredisplayedonlaminapropriavenularendothelialcells黏膜免疫中的抗体应答分泌型IgA的特征影响分泌型IgA抗体类别转换的因素分泌型IgA的转运尸分泌型IgA的意义分泌型IgM可以代偿有缺陷的IgA肠腔抗原DC淋巴滤帀激活的ThNOQloTYYY)00.00D0B7-CD2DCIgACD40LCD40浆母细胞派氏集合总般固有层肠道中T细胞依赖的IgA抗体类别转换机制派氏集合淋巴结圆丘状隆起部位的DC获取由M细胞提交的肠

50、腔抗原并迁移至滤泡区近旁后f将抗原提呈给初始CD4T细胞并使之激活和分化成Th。Th与借助其BCR识别了抗原的B细胞发生相互作用r通过TB间CD40L-CD40的结合，B细胞分化成产生IgA的浆细胞。该过程受DC产生的一氧化氮及TGF书的促进。由此产生的浆细胞经由血循环再归槽至固有层，所分泌的高亲和力IgA抗体，经过上皮细胞胞吞转换进入肠腔,与当初致敏的肠腔抗原结合。二dcuPOQ2OPoc*.cMgi3o5c5532_2-3sa-AusqO25OJ5P_O*Mad-UOPU9O9PU._Q。aqp-爼3o$-aJpua3-83?asfl-UQarl4U.2puaJydaLLu.a8gpnuu

51、.MO=Ma5SU*OCaoxuN3aa-uPM*dPL*,l*QKXOMcaNctooxaa一unu&$JKl-2IMPOq=c02ArE,Egp_EA*L-a04-gU0Hr?3?WQ3xux.*QOduotusp6KJ02?vcccXE?2-zss辛u.eJLKuo=uQrArrA*Jt-8-,0900=8CDooc?-8PO0=fruH?o-PL”nE2m8o*oc-xuwsr85W-TQ8cfr0cczEA2qpS9WC&WOX6rt=spo-QAnoeclluEpotsu?8Co0063002oaAO5ovvCCON*0motQ-oJoQwope二2X1QQQ32Esodc-cv5

52、0S5Q0-COCOQOMYc-.DdouoIna22CIM42.M0a-naoiluQC2Oea-o-e_dodeUJe-lIjoleQs叟Q.=Q0eulse-d6a)0$CT-pu6=0寸05O0QO一=8hrP2eov0=匸PUOQ=0H+0QOGeN0-o-ossnon乏0uoplue-rocE3uJchainAIgA-producinplasmacellEndocytosedDimericIgAcomplexofIgAandpoly-lgIgA-secretingplasmacellsintheintestine.IheabundanceoflgA-p(odudbgptesmace

53、fe(greenlrcolonmucosacomparedwithIgG-secretingcells(red)idshownbyimmunofluorescencestaimrIgAtnatsbengsecretedcanbeseenasgreencytoplasmthecryp!epithelialcells.(HomBmzsegP.The/nocasafrmoibYiesystem初0its的Me?“彻tfwmamnwy応TheJojrndOOfcShigellaflexneri,acauseofbacterialdysentery,infectsintestinalepithelial

54、cells,triggeringactivationoftheNFkBpathwayShigellaflexneribindstoMcellsandistranslocatedbeneaththegutepithelium(firstpanel)Thebacteriainfectintestinalepithelialcellsfromtheirbasalsurfaceandarereleasedintothecytoplasm(secondpanel)Muramyltripeptidescontainingdiaminopimelicacidinthecellwallsoftheshigel

55、laebindtoandoligomerizetheproteinNODI.OligomerizedNODIbindstheserine/threoninekinaseRIPK2,whichtriggersactivationoftheNFkBpathway,leadingtothetranscriptionofgenesforchemokinesandcytokines(thirdpanel).ActivatedepithelialcellsreleasethechemokineCXCL8,whichactsasaneutrophilchemoattractant(fourthpanel).

56、IkB,inhibitorofNFkB;IkKzIkBkinaseInfectionofmucosaltissuesVirustransportedtolymphnodes004+TcellLJondriticcollDeathofmucosalmemoryCO4十TcellsInfectionestablishedinlymphoidtissues,e.g.lymphnodeSpreadofinfectionthroughoutthebodyViremiaImmuneresponseAntl-HIVHIVspoclcantibodiesCTLsPartialcontrolofviralrep

57、licationClinicallatencyEstablishmentofchronicinfection;virusconcontmtedinlymphoidtissues;low-levelvirusproductionOthermicrobialInfections；cytokinesIncreasedviralreplicationAIDSDestructionoflymphoidtissue;depletionofCD4*Tcells肠道中与免疫应答相关的一些临床疾病炎症性肠炎乳糜泻A食物过敏（I型超敏反应）微生物的持续感染与肿瘤Inthepresenceofcommensalba

58、cteria,productionofPGE2,TGF-(i,andTSLPinhibitsdendriticcellmaturationMucosafUWUWVVlo二rvvwuumAo(WUWUWloInvasivemicroorganismspenetrateepitheliumtoactivatedendriticcellsMucosaxZMesentericlymphnodeActivateddendriticcellsexpressstrongcostimulatoryligandsandinduceCD4TcellstodifferentiateintoeffectorTM1,T

59、H17tandcellsImmaturedendriticcellsgiveweakco-stimulatorysignalsandinduceCD4TcellstodifferentiateintoregulatoryTcellsMucosaldendriticcellsregulatetheinductionoftoleranceandimmunityintheintestineUndernormalconditions(leftpanels),dendriticcellsarepresentinthemucosaunderlyingtheepitheliumandcanacquirean

60、tigensfromfoodsorcommensalorganisms.Theytaketheseantigenstothedrainingmesentericlymphnode,wheretheypresentthemtonaiveCD4Tcells.Thereis,however,constitutiveproductionbyepithelialcellsandmesenchymalcellsofmoleculessuchasTGF-p,thymicstromallymphopoietin(TSLP)ZandprostaglandinE2(PGE2),whichmaintainthelo