9.黏膜免疫 研究生

黏膜免疫

MucosalImmune

2021/6/281黏膜免疫系統(tǒng)（mucosalimmunesystem）：

直接接觸病原體的解剖部位并能夠分泌粘液的上皮細胞所覆蓋，構(gòu)成黏膜免疫系統(tǒng)。

廣泛分布于呼吸道、胃腸道、泌尿生殖道黏膜下及一些外分泌腺體（唾液腺、淚腺、乳腺）處的淋巴組織。

執(zhí)行局部特異性免疫功能的主要場所。2021/6/282Themucosalimmunesystem.Thetissuesofthemucosalimmunesystemarethelymphoidorgansassociatedwiththeintestine,respiratorytract,andurogenitaltract,aswellastheoralcavityandpharynxandtheglandsassociatedwiththesetissues,suchasthesalivaryglandsandlachrymalglands.Thelactatingbreastisalsopartofthemucosalimmunesystem.黏膜免疫系統(tǒng)亦稱黏膜相關(guān)淋巴組織（mucosa-associatedlymphoidtissue,MALT）。2021/6/283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)黏膜免疫與疾病主要內(nèi)容2021/6/284小腸黏膜免疫系統(tǒng)的各種細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細胞小腸上皮細胞上皮內(nèi)淋巴細胞(IEL)絨毛共生菌粘液漿細胞隱窩杯狀細胞IgA巨噬細胞腸腺嗜酸細胞B細胞T細胞抗菌肽DC輸出淋巴管肥大細胞分立的淋巴濾泡派氏集合淋巴結(jié)濾泡T細胞腸系膜淋巴結(jié)Cross-sectionaldiagramofthemucousmembraneliningtheintestineshowinganoduleoflymphoidfolliclesthatconstitutesaPeyer’spatchinthesubmucosa.Theintestinallaminapropriacontainslooseclustersoflymphoidcellsanddiffusefollicles.黏膜免疫系統(tǒng)與免疫應(yīng)答（結(jié)構(gòu)和應(yīng)答特點）2021/6/285黏膜免疫系統(tǒng)的特點

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。

－啟用抗原攝取機制，如出現(xiàn)派氏集合淋巴結(jié)和M細胞。

效應(yīng)機制

－在無感染發(fā)生的情況下?lián)碛写罅炕罨腡細胞和記憶細胞。

－存在非特異性激活的“天然”效應(yīng)性T細胞和記憶性T細胞。

－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)

－可主動下調(diào)針對食物和其它共生性抗原的強勢免疫應(yīng)答。

－可激活抑制性巨噬細胞及誘導(dǎo)耐受的樹突狀細胞。*黏膜覆蓋面大；腸腔中充滿各種微生物；防御病原體的入侵，維持對共生菌的耐受。2021/6/286一、組成腸相關(guān)淋巴組織的固有免疫細胞二、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2021/6/287Mucosallymphoidtissueinthehumanintestine.2021/6/2882021/6/289Thelaminapropriaandepitheliumoftheintestinalmucosaarediscretelymphoidcompartments.組成腸相關(guān)淋巴組織的固有免疫細胞2021/6/2810

lntraepitheliallymphocytesexpressCCR9andtheintegrin

E:

7,whichbindstoE-cadherinonepithelialcells.TheyaremostlyCD8Tcells,someofwhichexpresstheconventional

:

formofCD8andotherstheCD8

:

homodimer.

CD8Tcellspredominateintheepithelium,whereasCD8Tcellspredominateinthelaminapropria.2021/6/2811ThelaminapropriacontainslgA-producingplasmacells,lymphocytes,effectorTcells,dendriticcells,macrophages,andmastcells.Tcellsinthelaminapropriaofthesmallintestineexpresstheintegrin

4:

7andthechemokinereceptorCCR9,whichattractsthemintothetissuefromthebloodstream.2021/6/2812黏膜淋巴細胞與上皮細胞相互作用：黏膜淋巴細胞：位于黏膜上皮細胞間和上皮細胞基底層一側(cè)的T淋巴細胞，包括固有類T淋巴細胞和NK細胞。分布部位特殊、功能發(fā)揮受控于上皮細胞表面各類MHC分子與其受體分子間的相互作用。除了經(jīng)典的MHCI類和II類分子，上皮細胞還表達范圍廣泛的各種非經(jīng)典MHC分子，包括TL、HLA-E、MIC-A/-B、MR1和進化上與之高度同源的CD1d分子，激活多種黏膜淋巴細胞。2021/6/2813TLMHCIIMHCITLMIC-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受體上皮細胞配體粘膜淋巴細胞分泌因子功能

TL:非經(jīng)典MHCI類分子胸腺白血病抗原；MIC:MHCI類鏈相關(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類分子；MAIT:MR1限制性粘膜相關(guān)恒定鏈T細胞;Pf:穿孔素；Gz:顆粒酶。KGF:角朊細胞生長因子。2021/6/2814物理免疫屏障功能上皮細胞分泌的粘液防止微生物接近上皮細胞上皮細胞產(chǎn)生的防御素具有抗菌活性上皮細胞表達的TLR和NLR顯示雙重免疫功能固有層中的DC和巨噬細胞具有炎癥反應(yīng)抑制作用和免疫調(diào)節(jié)作用腸道黏膜相關(guān)的固有免疫應(yīng)答2021/6/2815免疫屏障功能2021/6/2816腸腔固有層腸系膜粘膜上皮DCM細胞小腸上皮細胞上皮內(nèi)淋巴細胞(IEL)絨毛共生菌粘液漿細胞隱窩杯狀細胞IgA巨噬細胞腸腺嗜酸細胞B細胞T細胞抗菌肽DC輸出淋巴管肥大細胞分立的淋巴濾泡派氏集合淋巴結(jié)濾泡T細胞腸系膜淋巴結(jié)分泌的粘液防止微生物接近2021/6/2817腸腔固有層腸系膜粘膜上皮DCM細胞小腸上皮細胞上皮內(nèi)淋巴細胞(IEL)絨毛共生菌粘液漿細胞隱窩杯狀細胞IgA巨噬細胞腸腺嗜酸細胞B細胞T細胞抗菌肽DC輸出淋巴管肥大細胞分立的淋巴濾泡派氏集合淋巴結(jié)濾泡T細胞腸系膜淋巴結(jié)產(chǎn)生的防御素具有抗菌活性含有大量嗜酸顆粒分顆粒含有防御素、溶菌酶對腸道微生物有殺滅功能2021/6/2818Epithelialcellshaveacrucialroleininnatedefenseagainstpathogens.TLRsarepresentinintracellularvesiclesoronthebasolateralorapicalsurfacesofepithelialcells,wheretheyrecognizedifferentcomponentsofinvadingbacteria.NOD1andNOD2pattern-recognitionreceptorsarefoundinthecytoplasmandrecognizecellwallpeptidesfrombacteria.BothTLRsandNODsactivatetheNF

Bpathwayleadingtothegenerationofpro-inflammatoryresponsesbyepithelialcells.TheseincludetheproductionofchemokinessuchasCXCL8,CXCL1(GROa),CCL1,andCCL2,whichattractneutrophilsandmacrophages,andCCL20and-defensin,whichattractimmaturedendriticcellsinadditiontopossessingantimicrobialproperties.ThecytokinesIL-1andIL-6arealsoproducedandactivatemacrophagesandothercomponentsoftheacuteinflammatoryresponse表達的TLR和NLR顯示雙重免疫功能2021/6/2819Commensalbacteriacanpreventinflammatoryresponsesintheintestine.Thepro-inflammatorytranscriptionfactorNF

BpathwayisactivatedinepithelialcellsviatheligationofTLRsbypathogens(firsttwopanels).Commensalbacteriahavebeenfoundtoinhibitthispathwayandthuspreventinflammation.OnewayisbyactivationofthenuclearreceptorPPAR

,leadingtotheexportofNF

Bfromthenucleus(thirdpanel).AnotherisbyblockingthedegradationoftheinhibitorI

BandthusretainingNF

Binthecytoplasm(fourthpanel).2021/6/2820小腸上皮細胞及固有層中DC上PRR的表達和功能可降低針對腸腔共生微生物的炎癥反應(yīng)。能識別細菌鞭毛的PRR(NLR:表達于胞質(zhì)中；TLR：表達于小腸上皮細胞基底膜一側(cè))，對共生微生物的炎癥反應(yīng)只有當(dāng)微生物進入或穿越上皮細胞后才能產(chǎn)生。識別LPS的TLR4在小腸上皮細胞及固有層DC上的表達皆下調(diào)。能下調(diào)TLR信號轉(zhuǎn)導(dǎo)的胞內(nèi)調(diào)節(jié)蛋白（在固有層的DC中）可優(yōu)勢表達。TLRTLR4DCNLR

細菌PAMP小腸上皮層固有層DC具有炎癥反應(yīng)抑制作用2021/6/2821IEL參與構(gòu)筑黏膜防御屏障IEL對病原體的殺傷功能IEL的維穩(wěn)和保護功能的功能IEL殺傷入侵病毒和修復(fù)損傷組織2021/6/28222021/6/2823病毒食物抗原（谷朊肽）TCRMHCI類分子MIC-A/-BNKG2DLTCD8

CD8FasFasLGz(顆粒酶)Pf(穿孔素)

a型和b型粘膜上皮細胞間淋巴細胞（IEL）的主要功能A.a型IEL。左：病毒感染粘膜上皮細胞；中：受感染細胞通過MHCI類分子向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，通過分泌Pf和Gz，以及通過Fas/FasL途徑殺傷病毒感染的上皮細胞；B.b型IEL。左：發(fā)生應(yīng)急改變（感染、損傷、接觸毒性肽）的上皮細胞表達非經(jīng)典MHC分子MIC-A、MIC-B和胸腺白血病抗原(LT)；中：IEL表達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)急損傷的上皮細胞，機制同上。上皮細胞CD8IELABa型IELb型IEL2021/6/2824一、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)答的免疫細胞三、黏膜免疫中的抗體應(yīng)答四、黏膜免疫中T細胞介導(dǎo)的應(yīng)答黏膜免疫中的適應(yīng)性免疫應(yīng)答2021/6/2825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細胞散在性淋巴濾泡腸系膜淋巴結(jié)2021/6/2826派氏集合淋巴結(jié)（Peyer’s小結(jié)）2021/6/2827腸系膜淋巴結(jié)（腫大）腸系膜淋巴結(jié)2021/6/2828黏膜免疫系統(tǒng)含有大量效應(yīng)淋巴細胞黏膜免疫系統(tǒng)中獨特的樹突狀細胞黏膜固有層中T細胞的致敏和歸巢參與適應(yīng)性黏膜免疫應(yīng)答的免疫細胞2021/6/2829腸道中T細胞依賴的IgA抗體類別轉(zhuǎn)換機制派氏集合淋巴結(jié)圓丘狀隆起部位的DC獲取由M細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細胞并使之激活和分化成Th。Th與借助其BCR識別了抗原的B細胞發(fā)生相互作用，通過T-B間CD40L-CD40的結(jié)合，B細胞分化成產(chǎn)生IgA的漿細胞。該過程受DC產(chǎn)生的一氧化氮及TGF-

的促進。由此產(chǎn)生的漿細胞經(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)過上皮細胞胞吞轉(zhuǎn)換進入腸腔，與當(dāng)初致敏的腸腔抗原結(jié)合。CD40LCD40DC初始T激活的ThNOB漿母細胞TGF-

經(jīng)過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胞腸腔抗原IgAIgA分泌IgA漿細胞DCB7CD28M細胞2021/6/2830Captureofantigensfromtheintestinallumenbymononuclearcellsinthelaminapropria.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.Captureofantigensfromtheintestinallumen2021/6/2831參見圖9-7黏膜免疫系統(tǒng)中獨特的樹突狀細胞2021/6/2832CCR9CCL25

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細胞固有層上皮細胞TT上皮細胞小腸淋巴細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視黃醇脫氫酶(RALDH)，后者將維生素A轉(zhuǎn)化成視黃酸(RC)。RC誘導(dǎo)，已被抗原活化的效應(yīng)T細胞（及B細胞）表達趨化因子受體CCR9和整合素

4

7，并進入血循環(huán)。2021/6/2833CCR9CCL25

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細胞固有層上皮細胞TT上皮細胞小腸淋巴細胞的激活和歸巢分布在黏膜固有層中的后毛細血管微靜脈的內(nèi)皮細胞表達MadCAM-1(

4

7配體)，使CCR9+

4

7+T細胞停留于該處并穿越微靜脈到達固有層,并變更其表型為CCR9+

E

7+T。固有層上皮細胞表達CCL25(CCR9配體)和E-鈣粘素（

E

7配體），使效應(yīng)性淋巴細胞選擇性地歸巢和停于黏膜固有層。2021/6/28342021/6/2835Molecularcontrolofintestine-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.2021/6/2836分泌型IgA的特征影響分泌型IgA抗體類別轉(zhuǎn)換的因素分泌型IgA的轉(zhuǎn)運分泌型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2021/6/2837參見圖9-62021/6/28382021/6/2839分泌型IgA的特征影響分泌型IgA抗體類別轉(zhuǎn)換的因素分泌型IgA的轉(zhuǎn)運分泌型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2021/6/2840黏膜DC與炎癥反應(yīng)Th17與黏膜免疫屏障腸道蠕蟲感染與Th2型免疫應(yīng)答黏膜免疫中T細胞介導(dǎo)的應(yīng)答2021/6/28412021/6/2842對腸道蠕蟲感染的保護性應(yīng)答和病理性應(yīng)答大部分腸道蠕蟲即可啟動CD4T細胞介導(dǎo)的保護性應(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，屬保護性應(yīng)答；當(dāng)DC接觸抗原時產(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)的保護性應(yīng)答不能處于優(yōu)勢地位，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胞，用粘液阻止寄生蟲粘附，促其脫落。肥大細胞產(chǎn)生TNF,組胺等介質(zhì)，募集炎癥細胞,重塑粘膜。產(chǎn)生能固定補體的抗體IgG2a?；罨木奘杉毎云洚a(chǎn)物引起組織損傷，誘導(dǎo)組織重塑。IgE激活肥大細胞，介導(dǎo)ADCC。嗜酸粒細胞通過主要堿性蛋白

(MBP)殺傷寄生蟲。激活巨噬細胞招募和激活嗜酸粒細胞驅(qū)動

B

淋巴細胞產(chǎn)生IgE招募肥大細胞，抗蠕蟲驅(qū)動B淋巴細胞產(chǎn)生IgG2aIL-13IL-5IL-4IL-9IL-3IFN-

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

初始CD4T保護效應(yīng)宿主損傷2021/6/2843一、黏膜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、黏膜耐受的誘導(dǎo)黏膜免疫中的免疫耐受和免疫調(diào)節(jié)2021/6/2844黏膜DC---CD103+DCiTreg2021/6/2845正常腸道的大量共生菌不引發(fā)有害的免疫反應(yīng)腸道共生菌對維持人體的健康發(fā)揮著重要的作用。能夠促進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。通過競爭空間和營養(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胞，對維持黏膜的屏障功能有重要作用。共生菌和其產(chǎn)物對于免疫系統(tǒng)的發(fā)展和功能有重要作用。

2021/6/2846Localresponsestocommensals.Severallocalprocessesensurepeacefulcoexistencebetweenthemicrobiotaandthehost,allowingthecommensalorganismstoberecognizedbytheimmunesystemwithoutinducinginflammationoranimmuneresponsethatwouldeliminatethem.CommensalbacteriainthelumengainaccesstotheimmunesystemviaMcellsinPeyer'spatchesandisolatedfollicles(leftpanel).UptakeandpresentationofthesenoninvasiveorganismsbyrestingdendriticcellsgenerateslgA-switchedBcellsthatlocalizeinthelaminapropriaaslgA-producingplasmacells(rightpanel).ThesecretorylgAthatisproducedlimitstheaccessofcommensalstotheepitheliumandhelpspreventtheirpenetration.Thisisassistedfurtherbythepresenceofthicklayersofmucus,whichalsocontainmucinglycoproteinsthathaveantibacterialproperties.Inaddition,stimulationofpattern-recognitionreceptorsonepithelialcellsandlocalleukocytesinducestheproductionofantimicrobialpeptidessuchasdefensins.2021/6/2847A.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天后測定小鼠針對卵清蛋白的血清抗體和T細胞應(yīng)答水平。B.同一品系的對照小鼠，喂飼無關(guān)蛋白，而7天后注射的卵清蛋白屬首次免疫，誘導(dǎo)出的典型保護性免疫針對卵清蛋白。C.B組小鼠以無關(guān)蛋白喂飼后若注射同一無關(guān)蛋白，同樣可誘導(dǎo)針對該無關(guān)蛋白的粘膜耐受。特異應(yīng)答

＋＋＋－7d7d14d14dAB特異應(yīng)答黏膜耐受保護性免疫

－7d14dC特異應(yīng)答

黏膜

耐受黏膜耐受的誘導(dǎo)2021/6/2848一、病原體感染與宿主免疫反應(yīng)之間的消長

決定了感染的結(jié)局二、針對共生菌的免疫應(yīng)答與腸道疾病三、腸道中與免疫應(yīng)答相關(guān)的一些臨床疾病黏膜免疫與疾病2021/6/2849Mucosalinfectionsareoneofthebiggesthealthproblemsworldwide.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.2021/6/2850InfectionbyClostridiumdifficile.Treatmentwithantibioticscausesmassivedeathofthecommensalbacteriathatnormallycolonizethecolon.Thisallowspathogenicbacteriatoproliferateandtooccupyanecologicalnichethatisnormallyoccupiedbyharmlesscommensalbacteria.Clostridiumdifficileisanexampleofapathogenproducingtoxinsthatcancauseseverebloodydiarrheainpatientstreatedwithantibiotics.病原體感染與宿主免疫反應(yīng)之間的消長決定了感染的結(jié)局2021/6/2851Shigellaflexneri,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.2021/6/2852針對共生菌的免疫應(yīng)答與腸道疾病2021/6/2853Mucosaldendriticcellsregulatetheinductionoftoleranceandimmunityintheintestine.Undernormalconditions(leftpanels),dendriticcellsarepresentinthemucosaunderlyingtheepitheliumandcanacquireantigensfromfoodsorcommensalorganisms.Theytaketheseantigenstothedrainingmesentericlymphnode,wheretheypresentthemtonaiveCD4Tcells.Thereis,however,constitutiveproductionbyepithelialcellsandmesenchymalcellsofmoleculessuchasTGF-

,thymicstromallymphopoietin(TSLP),andprostaglandinE2(PGE2),whichmaintainthelocaldendriticcellsinaquiescentstatewithlowlevelsofco-stimulatorymolecules,sothatwhentheypresentantigentonaiveCD4Tcells,anti-inflammatoryorregulatoryTcellsaregenerated.Theserecirculatebacktotheintestinalwallandmaintaintolerancetotheharmlessantigens.Invasionbypathogensoramassive