胃腸道黏膜先天性免疫應(yīng)答課件

胃腸道黏膜先天性免疫應(yīng)答劉占舉M.D.,Ph.D

鄭州大學(xué)第二附屬醫(yī)院消化內(nèi)科InnateImmunityingutmucosa胃腸道黏膜先天性免疫應(yīng)答劉占舉M.D.,Ph.D

鄭1介紹胃腸道先天性免疫防御機(jī)制。了解胃腸道先天免疫系統(tǒng)如何識別腸道病原微生物。病原體識別信號系統(tǒng)。病原微生物感染引起腸道黏膜炎癥應(yīng)答。Lectureaims介紹胃腸道先天性免疫防御機(jī)制。Lectureaims2消化道是外界抗原或病原微生物進(jìn)入體內(nèi)的門戶。有生理性和生物學(xué)屏障阻擋著這些抗原的侵入，并保持著腸道粘膜組織“內(nèi)環(huán)境”的穩(wěn)定。1年內(nèi)有30kg食物蛋白通過腸道；每天有130～190g抗原被吸收進(jìn)入機(jī)體。每克糞便1012個微生物，這些微生物抗原可通過腸道粘膜吸收進(jìn)入機(jī)體引起免疫反應(yīng)。消化道是外界抗原或病原微生物進(jìn)入體內(nèi)的門戶。有生理性和生物學(xué)3消化道也是免疫器官，有許多免疫細(xì)胞參與了腸道粘膜免疫應(yīng)答。當(dāng)食物或細(xì)菌抗原接觸胃腸道后，抗原成分被腸粘膜Peyer’spatches表面的M細(xì)胞吸收，引起一系列的免疫反應(yīng)，出現(xiàn)免疫耐受，即對食物抗原不應(yīng)答；否則引起食物過敏反應(yīng)或炎癥應(yīng)答。消化道也是免疫器官，有許多免疫細(xì)胞參與了腸道粘膜免疫應(yīng)答。當(dāng)4GastricmucosalprotectivefactorsGastricmucosalprotectivefac5胃腸道黏膜先天性免疫應(yīng)答課件6病原微生物進(jìn)入體內(nèi)后識別免疫應(yīng)答（先天性、獲得性）清除免疫病理（過敏、感染、炎癥）病原微生物進(jìn)入體內(nèi)后7PathogenicinfectionImmuneresponseInnateimmunity(nonspecific)先天性與獲得性免疫應(yīng)答Adaptiveimmunity(Agspecific)InflammationMemoryofinfection獲得性免疫應(yīng)答：Ag特異性防御機(jī)制，抗原刺激數(shù)天后形成免疫保護(hù)，以排除體內(nèi)特異性抗原。終生伴隨。先天性免疫應(yīng)答：Ag非特異性防御機(jī)制，遇到任何抗原后迅速或數(shù)小時(shí)后形成，以清除病原體，是機(jī)體先天固有的。PathogenicinfectionImmuneres8先天性免疫組成

-生理性屏障 -補(bǔ)體系統(tǒng) -細(xì)胞組成 -細(xì)胞因子、炎癥反應(yīng)

病原體識別

-Pathogen-associatedmolecularpatterns(PAMPs) -Patternrecognitionreceptors(PRRs) -Toll-likereceptors(TLR) -NF-kBactivation -TLRsignaling -Nodproteins病原識別及炎癥反應(yīng)異常引起的疾病

-NodandCrohn’sdisease-Celiacdisease-Bacterialinfection先天性免疫應(yīng)答先天性免疫組成先天性免疫應(yīng)答9CellstypesinvolvedininnateimmunityNeutrophilsMonocytes/MacrophagesNKcellsDendriticcellsFunctionsKillingbyPhagocytosisReactiveoxygenspeciesAntimicrobialpeptidesExtracellulartrapsKillingbyPhagocytosisInflammationmediatorsReactiveoxygenspeciesCompltproteinsAgpresentationAgpresentationCostimulatorysignalsCytokinesLysisofviralinfectedcellsActivationofmacrophagesMastcellsPromoteinflammationbyreleasingHistamineLeukotriensProstaglandinCellsCellstypesinvolvedininnate10Innateimmunity:cytokines細(xì)胞因子是免疫細(xì)胞遇到抗原刺激后分泌的小分子可溶性蛋白，是調(diào)節(jié)先天性和獲得性免疫應(yīng)答的化學(xué)信使。調(diào)節(jié)先天性免疫應(yīng)答的細(xì)胞因子：MonocytesMacrophagesDendriticcellsTNF-aIL-1Chemokines(ex:IL-8)Innateimmunity:cytokines細(xì)胞因子11SequentialstepsofPathogeneliminationPlasmaNormalcapillaryEndothelialcellsNoinjuryorinfectionMastcellsNeutrophilsMonocytesTandBLymphocytesEosinophilsBasophilsResidentMacrophagesPlasmaNormalcapillaryMastcellsNeutrophilsMonocytesTandBLymphocytesEosinophilsBasophilsComplement,BacterialpeptidesfMet-Leu-Phe(fMLP)PlasmaNormalcapillaryNeutrophilsMonocytesTandBLymphocytesEosinophilsBasophilsChemotaxisPathogenrecognitionPhagocytosisandcytokinesInflammationSequentialstepsofPathogene12PlasmaNormalcapillaryNeutrophilsMonocytesTandBLymphocytesEosinophilsBasophilsChemotaxisPathogenrecognitionPhagocytosisandcytokinesInflammationSequentialstepsofPathogeneliminationMediatorsofinflammation(Histamine,cytokines,chemokines…)DilatingcapillaryduringinflammationNeutrophilsMonocytesLymphocytesEosinophilsComplementClottingfactorsAb…KillingmechanismsMACMembraneattackcomplexPhagocytosisPlasmaNormalcapillaryNeutroph13白細(xì)胞向血管腔外遷徙Cell2000白細(xì)胞向血管腔外遷徙Cell200014Inflammation:transmigrationofneutrophilsE-selectinP-SelectinICAM-1Inflammation:transmigrationo15問題：先天性免疫系統(tǒng)如何識別病原微生物抗原？？問題：先天性免疫系統(tǒng)如何識16先天性快速（小時(shí)內(nèi)） 慢（3-5天）細(xì)胞表面特異性識別受體受體特異性識別抗原決定簇吞噬細(xì)胞（中性粒細(xì)胞、巨噬細(xì)胞）炎癥介質(zhì)（噬堿性粒細(xì)胞、肥大細(xì)胞、噬酸性粒細(xì)胞）NK細(xì)胞補(bǔ)體細(xì)胞因子APC（巨噬細(xì)胞、DC）Ag特異性B細(xì)胞

Ag特異性T細(xì)胞Ab、CTL、細(xì)胞因子大多抗原決定簇來自病原體的多肽BCR、TCR識別抗原????????????獲得性先天性快速（小時(shí)內(nèi)） 17先天性免疫系統(tǒng)對病原體的識別系統(tǒng)Pathogen-associatedmolecularpatterns(PAMPs，病原相關(guān)分子模式)Patternrecognitionreceptors(PRRs，模式識別受體)Toll-likereceptors(TLR)NF-KBactivationTLRsignalingNodproteins先天性免疫系統(tǒng)對病原體的識別系統(tǒng)18病原相關(guān)的分子模式：PAMP模式識別受體：PRRPathogen-AssociatedMolecularPatterns(PAMPS)PathogenRecognitionReceptor(PRR)Macrophage病原相關(guān)的分子模式：PAMPPathogen-Associa19PAMPs主要特點(diǎn)：微生物(非機(jī)體細(xì)胞)產(chǎn)生，以確保先天免疫系統(tǒng)識別自身和非自身抗原。PAMP是微生物生存所必需的。PAMP是很穩(wěn)定的，僅有限的PRR可以識別之。PAMPS:PAMPs主要特點(diǎn)：PAMPS:20G-菌的LPSG+（少部分G-）菌細(xì)胞壁肽糖類抗原G+菌細(xì)胞壁磷脂壁酸、微生物糖蛋白、糖脂質(zhì)蛋白細(xì)菌鞭毛蛋白flagellin菌毛蛋白pilin細(xì)菌和病毒的核酸物質(zhì)細(xì)菌的N-甲酰蛋氨酸dsRNA霉菌的糖脂蛋白微生物膜表面的磷脂酰膽堿PAMP組成PAMPS:G-菌的LPSPAMP組成PAMPS:21PatternRecognitionReceptorsToll-likereceptors(TLRs):I型轉(zhuǎn)膜蛋白首先在黑腹果蠅中發(fā)現(xiàn)后來在哺乳類動物、魚、雞、植物中發(fā)現(xiàn)，可能來自一個起源。命名來自黑腹果蠅的基因Toll。1996年，發(fā)現(xiàn)Toll是蒼蠅識別真菌感染基因。1997年發(fā)現(xiàn)Toll表達(dá)在哺乳類細(xì)胞。Leucine-richrepeats(LRRs)Toll/IL-1Rcdomain(TIRdomain)PatternRecognitionReceptorsT22PatternRecognitionReceptors(PRRs)：TLR2classesofPRRs:-EndocyticPRRs -SignalingPRRsPatternRecognitionReceptors23PRRsEndocyticPRRs:在吞噬細(xì)胞表面，促使細(xì)胞對病原微生物的吞噬。PRRsEndocyticPRRs:在吞噬細(xì)胞表面，促使24SignalingPRRs:與微生物結(jié)合，促使細(xì)胞因子分泌，引起先天性和獲得性免疫應(yīng)答。SignalingPRRs:與微生物結(jié)合，促使細(xì)胞因子分25TLR識別微生物抗原成分TLR識別微生物抗原成分26TLR分布(Viral)Uracil-richsingle-strandedviralRNA(ex:HIV)Unmethylatedcytosine-guaninedinucleotidesequences(CpGDNA)foundinbacterialandviralgenomes細(xì)胞膜TLR分布(Viral)Uracil-richsingle27TLR信號傳導(dǎo)Pathogen-AssociatedMolecularPatterns(PAMPS)PathogenRecognitionReceptor(PRR)MacrophageUpregulationofcytokinegenesInflammationNucleusTLRactivationAdaptorproteinsNF-KBactivation(Transcriptionfactor)InflammationTLR信號傳導(dǎo)Pathogen-AssociatedPath28TLR信號誘導(dǎo)NF-KB激活Toll-likereceptorLeucine-richrepeats(LRRs)Toll/IL-1Rcdomain(TIRdomain)Adaptorprotein:MyD88Toll/IL-1Rcdomain(TIRdomain)DeathdomainDeathdomainIRAK:IL-1associatedkinaseNucleusNF-kBTRAF6IKKsPathogenrecognitionTLRactivationTLR信號誘導(dǎo)NF-KB激活Toll-likerecept29TLR信號傳導(dǎo)TLR信號傳導(dǎo)30TLR在免疫細(xì)胞表面表達(dá)TLR在免疫細(xì)胞表面表達(dá)31先天性免疫與獲得性免疫聯(lián)系先天性免疫與獲得性免疫聯(lián)系32表達(dá)TLR通過TLR識別PAMP(除隱窩上皮)Nod蛋白Commensalbacteria:腸道營養(yǎng)必需菌促使腸道發(fā)育阻止腸道病原微生物的感染Mucosalepithelium:IntestineandcommensalbacteriaIntestinalcrypt表達(dá)TLRCommensalbacteria:腸道營養(yǎng)33腸腔內(nèi)抗原進(jìn)入體內(nèi)的途徑腸腔內(nèi)抗原進(jìn)入體內(nèi)的途徑34NF-KBNodShigellaInflammationDisruptionofepitheliumintegrityGM-CSFCXCL1CYR-61…IL-8ICAM-1…微生物抗原誘導(dǎo)上皮細(xì)胞Nod激活、促使炎癥應(yīng)答NeutrophilsNod蛋白:表達(dá)的IEC、MfNod1（Card4）、Nod2（Card15）細(xì)胞內(nèi)識別細(xì)菌抗原NF-KBNodShigellaInflammationGM35Nod分子Caspase-activatingandrecruitmentdomainLeucine-richrepeatNucleotidebindingsiteMicrobialmotifsensingOligomerizationnecessaryforsignaltransductionHomophilicinteractionswithotherproteinscontainingthesedomains(apoptosis/inflammation)Nod分子Caspase-activatingandre36Nod1和Nod2識別細(xì)菌肽糖類抗原Gram-Gram+Nod1和Nod2識別細(xì)菌肽糖類抗原Gram-Gram+37Nod誘導(dǎo)NF-kB激活Nod:Nucleotide-bindingoligomerizationdomainRICK:RIP-likeCARD-containingdomainInflammationRusselRK.etal.,ADConline,2004;89;598-603Nod誘導(dǎo)NF-kB激活Nod:Nucleotide-bi38病原微生物識別異常導(dǎo)致炎癥疾病發(fā)生NodandCrohn’sdisease：MutantNod2isapredisposingriskfactorforCD,whichislikelytoactinsynergywithotherfactorsbothgeneticandenvironmental,incausingthedisease.病原微生物識別異常導(dǎo)致炎癥疾病發(fā)生NodandCrohn39克羅恩病克羅恩病40NOD2突變與Crohn’