黏膜免疫

MucosalImmune黏膜免疫系統(tǒng)與免疫應(yīng)答黏膜免疫系統(tǒng)中的固有免疫應(yīng)答黏膜免疫系統(tǒng)中的適應(yīng)性免疫應(yīng)答黏膜免疫中的免疫耐受和免疫調(diào)節(jié)粘膜免疫與疾病Themucosalimmunesystem.Thetissuesofthemucosalimmunesystemarethelymphoidorgansassociatedwiththeintestine,respiratorytract,andurogenitaltract,aswellastheoralcavityandpharynxandtheglandsassociatedwiththesetissues,suchasthesalivaryglandsandlachrymalglands.Thelactatingbreastisalsopartofthemucosalimmunesystem.

直接接觸病原體的解剖部位并能夠分泌粘液的上皮細(xì)胞所覆蓋，構(gòu)成粘膜免疫系統(tǒng)（mucosalimmunesystem）。包括啟動(dòng)和行使免疫應(yīng)答的粘膜下固有層中各種散在的免疫細(xì)胞和一些器官化的淋巴組織，還包括與此相關(guān)的多種內(nèi)分泌腺體：胰腺、眼結(jié)膜和淚腺、唾液腺以及乳腺。因而黏膜免疫系統(tǒng)亦稱(chēng)黏膜相關(guān)淋巴組織（mucosa-associatedlymphoidtissue,MALT）。一、黏膜免疫系統(tǒng)的結(jié)構(gòu)特點(diǎn)二、黏膜免疫系統(tǒng)的應(yīng)答特點(diǎn)黏膜免疫系統(tǒng)與免疫應(yīng)答黏膜免疫系統(tǒng)的結(jié)構(gòu)特點(diǎn)Cross-sectionaldiagramofthemucousmembraneliningtheintestineshowinganoduleoflymphoidfolliclesthatconstitutesaPeyer’spatchinthesubmucosa.Theintestinallaminapropriacontainslooseclustersoflymphoidcellsanddiffusefollicles.小腸黏膜免疫系統(tǒng)的各種細(xì)胞成分和器官化的淋巴組織腸腔固有層腸系膜粘膜上皮DCM細(xì)胞小腸上皮細(xì)胞

上皮內(nèi)淋巴細(xì)胞

(IEL)絨毛共生菌粘液漿細(xì)胞隱窩杯狀細(xì)胞IgA巨噬細(xì)胞腸腺嗜酸細(xì)胞B細(xì)胞T細(xì)胞抗菌肽DC輸出淋巴管肥大細(xì)胞分立的淋巴濾泡派氏集合淋巴結(jié)濾泡T細(xì)胞腸系膜淋巴結(jié)粘膜免疫系統(tǒng)的特點(diǎn)

解剖特征

－粘膜上皮和淋巴組織間因相互作用而聯(lián)系緊密。

－由散在的淋巴組織和器官化的結(jié)構(gòu)（如派氏集合淋巴結(jié)、

分立的淋巴濾泡和扁桃體）共同組成。

－啟用特化的抗原攝取機(jī)制，如出現(xiàn)派氏集合淋巴結(jié)和M細(xì)胞。

效應(yīng)機(jī)制

－在無(wú)感染發(fā)生的情況下?lián)碛写罅炕罨腡細(xì)胞和記憶細(xì)胞。

－存在非特異性激活的“天然”效應(yīng)性T細(xì)胞和記憶性T細(xì)胞。

－大量啟用分泌型IgA抗體。

－涉及各種共生微生物菌叢。

免疫調(diào)節(jié)

－可主動(dòng)下調(diào)針對(duì)食物和其它共生性抗原的強(qiáng)勢(shì)免疫應(yīng)答。

－可激活抑制性巨噬細(xì)胞及誘導(dǎo)耐受的樹(shù)突狀細(xì)胞。一、組成腸相關(guān)淋巴組織的固有免疫細(xì)胞二、腸道粘膜相關(guān)的固有免疫應(yīng)答三、上皮內(nèi)淋巴細(xì)胞殺傷入侵病毒和修復(fù)損傷組織黏膜免疫中的固有免疫應(yīng)答Thelaminapropriaandepitheliumoftheintestinalmucosaarediscretelymphoidcompartments.ThelaminapropriacontainsaheterogeneousmixtureoflgA-producingplasmacells,lymphocyteswitha'memory'phenotype,conventionalCD4andCD8effectorTcells,dendriticcells,macrophages,andmastcells.Tcellsinthelaminapropriaofthesmallintestineexpresstheintegrin

4:

7andthechemokinereceptorCCR9,whichattractsthemintothetissuefromthebloodstream.lntraepitheliallymphocytesexpressCCR9andtheintegrinE:

7,whichbindstoE-cadherinonepithelialcells.TheyaremostlyCD8Tcells,someofwhichexpresstheconventionala:BformofCD8andotherstheCD8a:ahomodimer.CD4Tcellspredominateinthelaminapropria,whereasCD8Tcellspredominateintheepithelium.組成腸相關(guān)淋巴組織的固有免疫細(xì)胞

粘膜淋巴細(xì)胞及其與上皮細(xì)胞相互作用的分子機(jī)制圖中所示粘膜淋巴細(xì)胞主要指位于粘膜上皮細(xì)胞間和上皮細(xì)胞基底層一側(cè)的T淋巴細(xì)胞，包括固有類(lèi)T淋巴細(xì)胞和NK細(xì)胞。此類(lèi)細(xì)胞不僅分布部位特殊，而且功能發(fā)揮皆受控于上皮細(xì)胞表面各類(lèi)MHC分子與其受體分子間的相互作用。有意義的是，除了經(jīng)典的MHCI類(lèi)和II類(lèi)分子，上皮細(xì)胞還表達(dá)范圍廣泛的各種非經(jīng)典MHC分子，包括TL、HLA-E、MIC-A/-B、MR1和進(jìn)化上與之高度同源的CD1d分子，激活多種粘膜淋巴細(xì)胞。TLMHCIIMHCITLMIC-MIC-HLA-ECD1d/MR1

A/-BA/-B

-GalCelCD8

CD4CD8

CD8

NKG2DCD94/TCR

TCR

TCR

TCR

TCRNKG2ATCR

TCR

TCR

TCR

NKNKTMAITCD8

CD4TCD8TCD8

TGF-

IFN-

,IL-4Pf,Gz,FasLIL-6,KGFTNF-

,Pf,Gz,IFN-

,IL-4?TNF-

IFN-FasL

調(diào)節(jié)Th1/Th2毒性炎癥,修復(fù)，炎癥毒性Th1/Th2？功能毒性抗炎功能？BCRB受體上皮細(xì)胞配體粘膜淋巴細(xì)胞分泌因子功能TL:非經(jīng)典MHCI類(lèi)分子胸腺白血病抗原；MIC:MHCI類(lèi)鏈相關(guān)分子；CD1d/a-GalCel:分化抗原CD1d分子提呈的

半乳糖神經(jīng)酰胺；MR1:MHC相關(guān)I類(lèi)分子；MAIT:MR1限制性粘膜相關(guān)恒定鏈T細(xì)胞;Pf:穿孔素；Gz:顆粒酶。KGF:角朊細(xì)胞生長(zhǎng)因子。腸道上皮細(xì)胞的免疫屏障功能腸道上皮細(xì)胞分泌的粘液防止微生物接近上皮細(xì)胞腸道上皮細(xì)胞產(chǎn)生的防御素和細(xì)胞因子具有抗菌活性腸道上皮細(xì)胞表達(dá)的TLR和NLR顯示雙重免疫功能固有層中的DC和巨噬細(xì)胞具有炎癥反應(yīng)抑制作用和免疫調(diào)節(jié)作用腸道粘膜相關(guān)的固有免疫應(yīng)答Manybarrierspreventpathogensfromcrossingepitheliaandcolonizingtissues.Surfaceepitheliaprovidemechanical,chemical,andmicrobiologicalbarrierstoinfection.小腸黏膜中固有免疫應(yīng)答的調(diào)控機(jī)制小腸上皮細(xì)胞及固有層中DC上PRR的表達(dá)和功能可降低針對(duì)腸腔共生微生物的炎癥反應(yīng)。上端：能識(shí)別細(xì)菌鞭毛的PRR僅作為NLR表達(dá)于胞質(zhì)中和作為T(mén)LR表達(dá)于小腸上皮細(xì)胞基底膜一側(cè)，因而PRR對(duì)共生微生物的炎癥反應(yīng)只有當(dāng)微生物進(jìn)入或穿越上皮細(xì)胞后才能產(chǎn)生。右下端：識(shí)別LPS的TLR4在小腸上皮細(xì)胞及固有層DC上的表達(dá)皆下調(diào)。而且固有層DC中TLR信號(hào)并不誘導(dǎo)炎癥基因的表達(dá)，因?yàn)槠渲心芟抡{(diào)TLR信號(hào)轉(zhuǎn)導(dǎo)的胞內(nèi)調(diào)節(jié)蛋白可優(yōu)勢(shì)表達(dá)。TLRTLR4DCNLR

細(xì)菌PAMP小腸上皮層固有層Epithelialcellshaveacrucialroleininnatedefenseagainstpathogens.TLRsarepresentinintracellularvesiclesoronthebasolateralorapicalsurfacesofepithelialcells,wheretheyrecognizedifferentcomponentsofinvadingbacteria.NOD1andNOD2pattern-recognitionreceptorsarefoundinthecytoplasmandrecognizecellwallpeptidesfrombacteria.BothTLRsandNODsactivatetheNF

Bpathwayleadingtothegenerationofpro-inflammatoryresponsesbyepithelialcells.TheseincludetheproductionofchemokinessuchasCXCL8,CXCL1(GROa),CCL1,andCCL2,whichattractneutrophilsandmacrophages,andCCL20and-defensin,whichattractimmaturedendriticcellsinadditiontopossessingantimicrobialproperties.ThecytokinesIL-1andIL-6arealsoproducedandactivatemacrophagesandothercomponentsoftheacuteinflammatoryresponse.TheepithelialcellsalsoexpressMIC-AandMIC-Bandotherstress-relatednonclassicalMHCmolecules,whichcanberecognizedbycellsoftheinnateimmunesystem.I

B,inhibitorofNF

B.Commensalbacteriacanpreventinflammatoryresponsesintheintestine.Thepro-inflammatorytranscriptionfactorNF

BpathwayisactivatedinepithelialcellsviatheligationofTLRsbypathogens(firsttwopanels).Commensalbacteriahavebeenfoundtoinhibitthispathwayandthuspreventinflammation.OnewayisbyactivationofthenuclearreceptorPPAR

,leadingtotheexportofNF

Bfromthenucleus(thirdpanel).AnotherisbyblockingthedegradationoftheinhibitorI

BandthusretainingNF

Binthecytoplasm(fourthpanel).IEL參與構(gòu)筑粘膜防御屏障IEL對(duì)病原體的殺傷功能IEL的維穩(wěn)和保護(hù)功能的功能IEL殺傷入侵病毒和修復(fù)損傷組織病毒食物抗原（谷朊肽）TCRMHCI類(lèi)分子MIC-A/-BNKG2DLTCD8

CD8FasFasLGz(顆粒酶)Pf(穿孔素)

a型和b型粘膜上皮細(xì)胞間淋巴細(xì)胞（IEL）的主要功能A.a型IEL。左：病毒感染粘膜上皮細(xì)胞；中：受感染細(xì)胞通過(guò)MHCI類(lèi)分子向CD8IEL展示病毒抗原肽，激活I(lǐng)EL；右：激活的IEL行使典型的CTL功能，通過(guò)分泌Pf和Gz，以及通過(guò)Fas/FasL途徑殺傷病毒感染的上皮細(xì)胞；B.b型IEL。左：發(fā)生應(yīng)急改變（感染、損傷、接觸毒性肽）的上皮細(xì)胞表達(dá)非經(jīng)典MHC分子MIC-A、MIC-B和胸腺白血病抗原(LT)；中：IEL表達(dá)NKG2D和CD8分子，分別與MIC-A/-B以及LT結(jié)合，IEL被激活；右：激活的IEL殺傷受到應(yīng)急損傷的上皮細(xì)胞，機(jī)制同上。上皮細(xì)胞CD8IELABa型IELb型IEL一、黏膜免疫系統(tǒng)器官化的淋巴組織二、參與適應(yīng)性黏膜免疫應(yīng)答的免疫細(xì)胞三、黏膜免疫中的抗體應(yīng)答四、黏膜免疫中T細(xì)胞介導(dǎo)的應(yīng)答黏膜免疫系統(tǒng)中的適應(yīng)性免疫應(yīng)答黏膜免疫系統(tǒng)器官化的淋巴組織派氏集合淋巴結(jié)與M細(xì)胞散在性淋巴濾泡腸系膜淋巴結(jié)UptakeandtransportofantigensbyMcells.ThefirstthreepanelsshowuptakeviaMcellsinthefollicle-associatedepitheliumofPeyer'spatches.Thesehaveconvolutedbasalmembranesthatform'pockets'withintheepitheliallayer,allowingclosecontactwithlymphocytesandothercells.ThisfavorsthelocaltransportofantigensthathavebeentakenupfromtheintestinebytheMcellsandtheirdeliverytodendriticcellsforantigenpresentation.ThemicrographofpartofaPeyer'spatchontherightshowsepithelialcells(darkblue),someofwhichareMcellsthatformpocketswhereTcells(red)andBcells(green)accumulate.Thecellshavebeenstainedwithfluorescentlylabeledantibodiesspecificforindividualcelltypes.MicrographfromBrandtzaeg,P.,eta/.:lmmunol.Today1999,20:141-151.黏膜免疫系統(tǒng)含有大量效應(yīng)淋巴細(xì)胞黏膜免疫系統(tǒng)中獨(dú)特的樹(shù)突狀細(xì)胞黏膜固有層中T細(xì)胞的致敏和歸巢參與適應(yīng)性黏膜免疫應(yīng)答的免疫細(xì)胞Captureofantigensfromtheintestinallumenbymononuclearcellsinthelaminapropria.Firstpanel:solubleantigenssuchasfoodproteinsmightbetransporteddirectlyacrossorbetweenenterocytes,ortheremightbeMcellsinthesurfaceepitheliumoutsidePeyer'spatches.Secondpanel:enterocytescancaptureandinternalizeantigen:antibodycomplexesbymeansoftheFeRnontheirsurfaceandtransportthemacrosstheepitheliumbytranscytosis.Atthebasalfaceoftheepithelium,laminapropriadendriticcellsexpressingFeRnandotherFereceptorspickupandinternalizethecomplexes.Thirdpanel:anenterocyteinfectedwithanintracellularpathogenundergoesapoptosisanditsremainsarephagocytosedbythedendriticcell.Fourthpanel:mononuclearcellshavebeenseenextendingprocessesbetweenthecellsoftheepitheliumwithoutdisturbingitsintegrity.Thecellprocesscouldpickupandinternalizeantigenfromthegutlumenandthenretract.Themicrographshowsmononuclearcells,whichmaybedendriticcellsormacrophages,(stainedgreenwithafluorescenttagontheCD11cmolecule)inthelaminapropriaofavillusofmousesmallintestine.Theepitheliumisnotstainedandappearsblack,butitsluminal(outer)surfaceisshownbythewhiteline.Acellprocesshassqueezedbetweentwoepithelialcellsanditstipispresentinthelumenoftheintestine.Magnificationx200.MicrographfromNiess,J.H.,eta/.:Science2005,307:254-258.參見(jiàn)圖9-7CCR9CCL25

4

7DCCCR9

4

7TSLPRCT腸系膜淋巴結(jié)微靜脈MadCAM-1E-鈣粘素

E

7固有層腸系膜M細(xì)胞固有層上皮細(xì)胞TT上皮細(xì)胞小腸淋巴細(xì)胞的激活和歸巢腸系膜淋巴結(jié)和派氏集合淋巴結(jié)中的DC，在胸腺基質(zhì)淋巴生成素(TSLP)和其它因子的作用下表達(dá)視黃醇脫氫酶(RALDH)，后者將維生素A轉(zhuǎn)化成視黃酸(RC)，在RC的作用下，已被抗原活化的效應(yīng)T細(xì)胞（及B細(xì)胞）被激發(fā)，誘導(dǎo)性表達(dá)趨化因子受體CCR9和整合素

4

7，并進(jìn)入血循環(huán)。由于分布在粘膜固有層中的后毛細(xì)血管微靜脈的內(nèi)皮細(xì)胞表達(dá)MadCAM-1(

4

7配體)，使CCR9+

4

7+T細(xì)胞停留于該處并穿越微靜脈到達(dá)固有層,并變更其表型為CCR9+

E

7+T。而固有層上皮細(xì)胞表達(dá)CCL25(CCR9配體)和E-鈣粘素（

E

7配體），使效應(yīng)性淋巴細(xì)胞選擇性地歸巢和停留于粘膜固有層。Molecularcontrolofintestine-specifichomingoflymphocytes.Leftpanel:TandBlymphocytesprimedbyantigeninthePeyer'spatchesormesentericlymphnodesarriveaseffectorlymphocytesinthebloodstreamsupplyingtheintestinalwall).Thelymphocytesexpresstheintegrin

4:

7,whichbindsspecificallytoMAdCAM-1expressedselectivelyontheendotheliumofbloodvesselsinmucosaltissues.Thisprovidestheadhesionsignalneededfortheemigrationofcellsintothelaminapropria.Rightpanel:ifprimedinthesmallintestine,theeffectorlymphocytesalsoexpressthechemokinereceptorCCR9,whichallowsthemtorespondtoCCL25(greencircles)producedbyepithelialcellsofthesmallintestine;thisenhancesselectiverecruitment.EffectorlymphocytesthathavebeenprimedinthelargeintestinedonotexpressCCR9butdoexpressCCR10.ThismayrespondtoCCL28(bluecircles)producedbycolonepithelialcellstofulfillasimilarfunction.Lymphocytesthatwillentertheepitheliallayerstopexpressingthe

4:

7integrinandinsteadexpressthe

E:

7integrin.ThereceptorforthisisE-cadherinontheepithelialcells.Theseinteractionsmayhelpkeeplymphocytesintheepitheliumoncetheyhaveenteredit.分泌型IgA的特征影響分泌型IgA抗體類(lèi)別轉(zhuǎn)換的因素分泌型IgA的轉(zhuǎn)運(yùn)分泌型IgA的意義分泌型IgM可以代償有缺陷的IgA

黏膜免疫中的抗體應(yīng)答腸道中T細(xì)胞依賴的IgA抗體類(lèi)別轉(zhuǎn)換機(jī)制派氏集合淋巴結(jié)圓丘狀隆起部位的DC獲取由M細(xì)胞提交的腸腔抗原并遷移至濾泡區(qū)近旁后，將抗原提呈給初始CD4T細(xì)胞并使之激活和分化成Th。Th與借助其BCR識(shí)別了抗原的B細(xì)胞發(fā)生相互作用，通過(guò)T-B間CD40L-CD40的結(jié)合，B細(xì)胞分化成產(chǎn)生IgA的漿細(xì)胞。該過(guò)程受DC產(chǎn)生的一氧化氮及TGF-

的促進(jìn)。由此產(chǎn)生的漿細(xì)胞經(jīng)由血循環(huán)再歸槽至固有層，所分泌的高親和力IgA抗體，經(jīng)過(guò)上皮細(xì)胞胞吞轉(zhuǎn)換進(jìn)入腸腔，與當(dāng)初致敏的腸腔抗原結(jié)合。CD40LCD40DC初始T激活的ThNOB漿母細(xì)胞TGF-

經(jīng)過(guò)血流派氏集合淋巴結(jié)淋巴濾泡固有層腸腔基底膜上皮細(xì)胞腸腔抗原IgAIgA分泌IgA漿細(xì)胞DCB7CD28M細(xì)胞參見(jiàn)圖9-6粘膜DC與炎癥反應(yīng)Th17與粘膜免疫屏障腸道蠕蟲(chóng)感染與Th2型免疫應(yīng)答黏膜免疫中T細(xì)胞介導(dǎo)的應(yīng)答Pathologicalresponsestointestinalhelminths.IftheCD4T-cellresponsetoahelminthparasiteispolarizedtoproducepredominantlyTH1effectorTcells(forexample,bytheproductionofIL-12bydendriticcells),itdoesnotclearthepathogen.IfnotbalancedbyaprotectiveTH2response,theTH1responseleadstopersistentinfectionandchronicintestinalpathology.M1macrophage,classicallyactivatedmacrophage.Protectiveresponsestointestinalhelminths.MostintestinalhelminthsinducebothprotectiveandpathologicalimmuneresponsesbyCD4Tcells.TH2responsestendtobeprotective,creatinganunfriendlyenvironmentfortheparasite,andleadingtoitsexpulsionandthegenerationofprotectiveimmunity(seethetextfordetails).M2macrophage,alternativelyactivatedmacrophage.對(duì)腸道蠕蟲(chóng)感染的保護(hù)性應(yīng)答和病理性應(yīng)答大部分腸道蠕蟲(chóng)即可啟動(dòng)CD4T細(xì)胞介導(dǎo)的保護(hù)性應(yīng)答也可誘導(dǎo)病理性應(yīng)答。其中Th2相關(guān)應(yīng)答有利于清除寄生蟲(chóng)，屬保護(hù)性應(yīng)答；當(dāng)DC接觸抗原時(shí)產(chǎn)生IL-12，則產(chǎn)生Th1型應(yīng)答。通常兩種應(yīng)答并存，若Th2介導(dǎo)的保護(hù)性應(yīng)答不能處于優(yōu)勢(shì)地位，Th1型應(yīng)答將使感染持續(xù)，并造成小腸的慢性病理性損傷。置換被寄生的上皮細(xì)胞，用粘液阻止寄生蟲(chóng)粘附，促其脫落。肥大細(xì)胞產(chǎn)生TNF,組胺等介質(zhì)，募集炎癥細(xì)胞,重塑粘膜。產(chǎn)生能固定補(bǔ)體的抗體IgG2a?；罨木奘杉?xì)胞以其產(chǎn)物引起組織損傷，誘導(dǎo)組織重塑。IgE武裝肥大細(xì)胞，介導(dǎo)ADCC。嗜堿粒細(xì)胞通過(guò)主要堿性蛋白

(MBP)殺傷寄生蟲(chóng)。激活巨噬細(xì)胞招募和激活嗜酸粒細(xì)胞驅(qū)動(dòng)

B

淋巴細(xì)胞產(chǎn)生IgE招募肥大細(xì)胞，抗蠕蟲(chóng)驅(qū)動(dòng)B淋巴細(xì)胞產(chǎn)生IgG2aIL-13IL-5IL-4IL-9IL-3IFN-

誘導(dǎo)上皮細(xì)胞修復(fù),分泌粘液.................................................................Th-2Th-1DC

初始CD4T保護(hù)效應(yīng)宿主損傷一、粘膜DC與免疫耐受二、正常腸道的大量共生菌不引發(fā)有害的免疫反應(yīng)三、粘膜耐受的誘導(dǎo)黏膜免疫中的免疫耐受和免疫調(diào)節(jié)正常腸道的大量共生菌不引發(fā)有害的免疫反應(yīng)腸道共生菌對(duì)維持人體的健康發(fā)揮著重要的作用。能夠促進(jìn)食物如纖維素的代謝；能分解毒素；能產(chǎn)生重要的輔助因子如維生素K1和短鏈脂肪酸。通過(guò)競(jìng)爭(zhēng)空間和營(yíng)養(yǎng)成份可以抑制病原體在腸道的繁殖和入侵共生菌能夠直接作用于黏膜上皮細(xì)胞，對(duì)維持黏膜的屏障功能有重要作用。共生菌和其產(chǎn)物對(duì)于免疫系統(tǒng)的發(fā)展和功能有重要作用。

Localresponsestocommensals.Severallocalprocessesensurepeacefulcoexistencebetweenthemicrobiotaandthehost,allowingthecommensalorganismstoberecognizedbytheimmunesystemwithoutinducinginflammationoranimmuneresponsethatwouldeliminatethem.CommensalbacteriainthelumengainaccesstotheimmunesystemviaMcellsinPeyer'spatchesandisolatedfollicles(leftpanel).UptakeandpresentationofthesenoninvasiveorganismsbyrestingdendriticcellsgenerateslgA-switchedBcellsthatlocalizeinthelaminapropriaaslgA-producingplasmacells(rightpanel).ThesecretorylgAthatisproducedlimitstheaccessofcommensalstotheepitheliumandhelpspreventtheirpenetration.Thisisassistedfurtherbythepresenceofthicklayersofmucus,whichalsocontainmucinglycoproteinsthathaveantibacterialproperties.Inaddition,stimulationofpattern-recognitionreceptorsonepithelialcellsandlocalleukocytesinducestheproductionofantimicrobialpeptidessuchasdefensins.1mmuneprimingandtolerancearedifferentoutcomesofintestinalexposuretoantigen.Leftpanel,theintestinalimmunesystemgeneratesprotectiveimmunityagainstantigensthatareathreattothehost,suchaspathogenicorganismsandtheirproducts.lgAantibodiesareproducedlocally,serumlgGandlgAaremade,andtheappropriateeffectorTcellsareactivatedintheintestineandelsewhere.Whentheantigensuppressed.Thisphenomenonisknownas'oraltolerance'andisshownintheright-handpanels,whereithasbeeninducedbyfeedingaproteinsuchasovalbumintoanormalmouse.First,micearefedeitherovalbuminoradifferentproteinasacontrol.Sevendayslater,themiceareimmunizedsubcutaneouslywithovalbuminandanadjuvant;2weekslater,systemicimmuneresponsessuchasserumantibodiesandT-cellfunctionaremeasured.Micefedovalbuminhavealowerovalbumin-specificsystemicimmuneresponsethanthosefedthecontrolprotein.Inthecaseofcommensalbacteria,thereisevidenceoflocallgAantibodyproduction,butnoprimarysystemicantibodyresponses,andeffectorTcellsarenotactivatedineithersite.ProfoundtoleranceofT-cellresponsesisretainedthereafter,butthesystemicimmunesystemremainsignorantofcommensalsunlesstheygainaccesstothecirculation,whenaprimarysystemicimmuneresponsewillresult.isencounteredagain,thereiseffectivememory,ensuringrapidprotection.Harmlessantigenssuchasfoodproteinsorantigensfromcommensalbacteriainducetolerance,eitherlocally,orbothlocallyandsystemically.Theylackthedangersignalsneededtoactivatelocalantigen-presentingcells,ordonotinvadesufficientlytocauseinflammation.Inthecaseoffoodproteins,thereislittleornolocallgAantibodyproductionorprimarysystemicantibodyresponse,norareeffectorTcellsactivated.Subsequentlocalandsystemicimmuneresponsestochallengearealsospecifically粘膜耐受的誘導(dǎo)A.健康小鼠飼以卵清蛋白，7天后，用同一抗原加佐劑作皮下免疫，14天后測(cè)定小鼠針對(duì)卵清蛋白的血清抗體和T細(xì)胞應(yīng)答水平。B.同一品系的對(duì)照小鼠，喂飼無(wú)關(guān)蛋白，而7天后注射的卵清蛋白屬首次免疫，誘導(dǎo)出的典型保護(hù)性免疫針對(duì)卵清蛋白。C.B組小鼠以無(wú)關(guān)蛋白喂飼后若注射同一無(wú)關(guān)蛋白，同樣可誘導(dǎo)針對(duì)該無(wú)關(guān)蛋白的粘膜耐受。特異應(yīng)答

＋＋＋－7d7d14d14dAB特異應(yīng)答粘膜耐受保護(hù)性免疫

－7d14dC特異應(yīng)答

粘膜免疫一、病原體感染與宿主免疫反應(yīng)之間的消長(zhǎng)

決定了感染的結(jié)局二、針對(duì)共生菌的免疫應(yīng)答與腸道疾病三、腸道中與免疫應(yīng)答相關(guān)的一些臨床疾病粘膜免疫與疾病Intestinalpathogensandinfectiousdiseaseinhumans.Manyspeciesofbacteria,viruses,andparasitescancausediseaseinthehumanintestine.Mucosalinfectionsareoneofthebiggesthealthproblemsworldwide.Mostofthepathogensthatcausethedeathsoflargenumbersofpeoplearethoseofmucosalsurfacesorenterthebodythroughtheseroutes.Respiratoryinfectionsarecausedbynumerousbacteria(suchasStreptococcuspneumoniaeandHaemophilusinfluenzae,whichcausepneumonia,andBordetellapertussis,thecauseofwhoopingcough)andviruses(suchasinfluenzaandrespiratorysyncytialvirus).Diarrhealdiseasesarecausedbybothbacteria(suchasthecholerabacteriumCholeravibrio)andviruses(suchasrotaviruses).Thehumanimmunodeficiencyvirus(HIV)thatcausesAIDSentersthroughthemucosaoftheurogenitaltractorissecretedintobreastmilkandispassedfrommothertochildinthisway.ThebacteriumMycobacteriumtuberculosis,whichcausestuberculosis,alsoentersthroughtherespiratorytract.Measlesmanifestsitselfasasystemicdisease,butitoriginallyentersviatheoral/respiratoryroute.HepatitisBisalsoasexuallytransmittedvirus.Finally,parasiticwormsinhabitingtheintestinecausechronicdebilitatingdiseaseandprematuredeath.Mostofthesedeaths,especiallythosefromacuterespiratoryanddiarrhealdiseases,occurinchildrenunder5yearsoldinthedevelopingworld,andtherearestillnoeffectivevaccinesagainstmanyofthesepathogens.Numbersshownarethemostrecentestimatedfiguresavailable(TheGlobalBurdenofDisease:2004Update.WorldHealthOrganization,2008).*Doesnotincludedeathsfromlivercancerorcirrhosisresultingfromchronicinfection.1nfectionbyClostridiumdifficile.Treatmentwithantibioticscausesmassivedeathofthecommensalbacteriathatnormallycolonizethecolon.Thisallowspathogenicbacteriatoproliferateandtooccupyanecologicalnichethatisnormallyoccupiedbyharmlesscommensalbacteria.Clostridiumdifficileisanexampleofapathogenproducingtoxinsthatcancauseseverebloodydiarrheainpatientstreatedwithantibiotics.病原體感染與宿主免疫反應(yīng)之間的消長(zhǎng)決定了感染的結(jié)局Shigellaflexneri,acauseofbacterialdysentery,infectsintestinalepithelialcells,triggeringactivationoftheNF

Bpathway.ShigellaflexneribindstoMcellsandistranslocatedbeneaththegutepithelium(firstpanel).Thebacteriainfectintestinalepithelialcellsfromtheirbasalsurfaceandarereleasedintothecytoplasm(secondpanel).MuramyltripeptidescontainingdiaminopimelicacidinthecellwallsoftheshigellaebindtoandoligomerizetheproteinNOD1.OligomerizedNOD1bindstheserine/threoninekinaseRIPK2,whichtriggersactivationoftheNF

Bpathway,leadingtothetranscriptionofgenesforchemokinesandcytokines(thirdpanel).ActivatedepithelialcellsreleasethechemokineCXCL8,whichactsasaneutrophilchemoattractant(fourthpanel).I

B,inhibitorofNF

B;I

K,I

Bkinase.炎癥性腸炎乳糜瀉食物過(guò)敏（I型超敏反應(yīng)）微生物的持續(xù)感染與腫瘤腸道中與免疫應(yīng)答相關(guān)的一些臨床疾病Mucosaldendriticcellsregulatetheinductionoftoleranceandimmunityintheintestine.Undernormalconditions(leftpanels),dendriticcellsarepresentinthemucosaunderlyingtheepitheliumandcanacquireantigensfromfoodsorcommensalorganisms.Theytaketheseantigenstothedrainingmesentericlymphnode,wheretheypresentthemtonaiveCD4Tcells.Thereis,however,constitutiveproductionbyepithelialcellsandmesenchymalcellsofmoleculessuchasTGF-

,thymicstromallymphopoietin(TSLP),andprostaglandinE2(PGE2),whichmaintainthelocaldendriticcellsinaquiescentstatewithlowlevelsofco-stimulatorymolecules,sothatwhentheypresentantigentonaiveCD4Tcells,anti-inflammatoryorregulatoryTcellsaregenerated.Theserecirculatebacktotheintestinalwallandmaintaintolerancetotheharmlessantigens.Invasionbypathogensoramassiveinfluxofcommensalbacteria(rightpanels)overcomesthesehomeostaticmechanisms,resultinginfullactivationoflocaldendriticcellsandtheirexpressionofco-stimulatorymoleculesandpro-inflammatorycytokinessuchasIL-12.PresentationofantigentonaiveCD4Tcellsinthemes