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抗微生物免疫-抗菌免疫

-抗病毒免疫2023/9/211抗微生物免疫2023/8/61感染免疫力感染灶的范圍x毒力免疫力疾病=感染與免疫之間的平衡關(guān)系與疾病機(jī)體抗感染機(jī)制-共性-個(gè)性:不同微生物的特性和致病機(jī)制不同抗感染免疫2023/9/212感染免疫力感染灶的范圍x毒力免疫力疾病=感染與免疫之間Spectrumof

virulence脊髓灰質(zhì)炎0.1-1%顯性感染風(fēng)疹50%顯性感染狂犬病100%顯性感染感染性疾病的“冰山”概念Theicebergconceptofinfectiousdisease無(wú)癥狀感染

典型臨床疾病表現(xiàn)輕度疾病lessseveredisease2023/9/213Spectrumofvirulence脊髓灰質(zhì)炎風(fēng)疹狂犬微生物的結(jié)構(gòu)與免疫應(yīng)答

-內(nèi)部抗原

-外部抗原

-與致病性的關(guān)系(進(jìn)入途徑、感染部位全身/淺表、靶細(xì)胞/組織)

-寄生的部位:細(xì)胞外;兼性細(xì)胞內(nèi);專性細(xì)胞內(nèi)寄生

-誘導(dǎo)產(chǎn)生免疫應(yīng)答的類型抗微生物感染免疫

-天然免疫

-特異性免疫細(xì)胞免疫應(yīng)答/體液免疫應(yīng)答 保護(hù)性免疫應(yīng)答 免疫損傷(超敏反應(yīng)、自身免疫應(yīng)答)2023/9/214微生物的結(jié)構(gòu)與免疫應(yīng)答2023/8/64微生物體積的大小不同細(xì)菌衣原體病毒體積微小2023/9/215微生物體積的大小不同細(xì)菌衣原體病毒體積微小2023/8/65Figure2-1不同免疫應(yīng)答的時(shí)間抗再次感染?抗再次感染?抗再次感染抗再次感染應(yīng)答的時(shí)間初次感染2023/9/216Figure2-1不同免疫應(yīng)答的時(shí)間抗再次感染?抗再次感染抗菌免疫ImmunitytoBacteria基本原則1)抗菌免疫機(jī)制與細(xì)菌表面結(jié)構(gòu)相關(guān)

細(xì)胞壁和細(xì)胞膜包括LPS -flagella(鞭毛) -fimbriae(菌毛) -capsules(莢膜)2023/9/217抗菌免疫2023/8/67細(xì)菌細(xì)胞表面結(jié)構(gòu):免疫系統(tǒng)作用的靶標(biāo)細(xì)胞壁結(jié)構(gòu)與細(xì)菌的抵抗力有關(guān)

結(jié)核桿菌細(xì)胞壁的抵抗力強(qiáng)細(xì)菌莢膜抗吞噬

鏈球菌、炭疽桿菌有毒株具有莢膜細(xì)菌細(xì)胞壁成分佐劑活性-激發(fā)炎性細(xì)胞因子

(LPS,capsule,arabinoglactan/glycolipids)2023/9/218細(xì)菌細(xì)胞表面結(jié)構(gòu):免疫系統(tǒng)作用的靶標(biāo)2023/8/68不同微生物具有不同的細(xì)胞壁結(jié)構(gòu)

-革蘭陽(yáng)性細(xì)菌(G+)

-革蘭陰性細(xì)菌(G-)

-分支桿菌(結(jié)核分支桿菌) -Spriochaetes(螺旋體)不同的細(xì)菌-細(xì)胞壁結(jié)構(gòu)不同

-致病性、致病機(jī)制不同

-抗感染免疫不同2023/9/219不同微生物具有不同的細(xì)胞壁結(jié)構(gòu)2023/8/69G+金葡菌G-大腸桿菌分枝桿菌螺旋體細(xì)菌細(xì)胞壁結(jié)構(gòu)2023/9/2110G+G-分枝桿菌螺旋體細(xì)菌細(xì)胞壁結(jié)構(gòu)2023/8/610G+金葡菌G-大腸桿菌革蘭陰性菌的脂質(zhì)外膜

-補(bǔ)體-裂解

-NK-殺傷

-陽(yáng)離子蛋白肽聚糖-細(xì)胞壁成分

-溶菌酶2023/9/2111G+G-革蘭陰性菌的脂質(zhì)外膜肽聚糖-細(xì)胞壁成分2023/8革蘭陰性菌的脂質(zhì)外膜(G-)-細(xì)胞壁成分

-補(bǔ)體-裂解

-NK-殺傷

-陽(yáng)離子蛋白肽聚糖-細(xì)胞壁成分

-溶菌酶鞭毛和菌毛

-抗體菌細(xì)胞

-吞噬細(xì)胞細(xì)胞表面結(jié)構(gòu)與免疫力研究抗菌免疫時(shí),需了解該菌結(jié)構(gòu)2023/9/2112革蘭陰性菌的脂質(zhì)外膜(G-)-細(xì)胞壁成分細(xì)胞表面結(jié)構(gòu)與免疫2)抗菌免疫機(jī)制與細(xì)菌致病性相關(guān)細(xì)菌的致病性①產(chǎn)生毒素,但不具侵襲力 毒素(Corynebacteriumdiphtheriae,VibrioCholerae)

免疫力:Neutralizationantibody/中和抗體

Anti-adhesionAb/抗黏附抗體②具有侵襲力,但不產(chǎn)生毒素酶類:擴(kuò)散因子(tissue-degradingenzymes)

免疫力:殺傷菌細(xì)胞③大多數(shù)細(xì)菌既產(chǎn)生毒素也具侵襲力2023/9/21132)抗菌免疫機(jī)制與細(xì)菌致病性相關(guān)2023/8/613Adhesion/黏附toxin產(chǎn)生毒素entryMultiplication繁殖AdhesionMultiplication繁殖Toxin產(chǎn)生毒素2023/9/2114Adhesion/黏附entryAdhesion2023/83)免疫機(jī)制與細(xì)菌賴于環(huán)境的生存能力相關(guān)①胞外菌:葡萄球菌、鏈球菌

②兼性胞內(nèi)寄生菌:結(jié)核分枝桿菌③專性胞內(nèi)寄生菌:衣原體、立克氏體病毒等

-存活絕對(duì)依賴細(xì)胞的內(nèi)環(huán)境2023/9/21153)免疫機(jī)制與細(xì)菌賴于環(huán)境的生存能力相關(guān)2023/8/61ExtracellularversusIntracellularpathogenExtracellularpathogencapableofreplicatingoutsideofthehostcellsdestroyedwhenphagocytoseddamagingtissuesastheyremainoutsidecellsinducingtheproductionofopsonizingantibodiesusuallycauseacutediseasesofrelativelyshortdurationIntracellularpathogencanmultiplywithinphagocytesfrequentlycausechronicdisease2023/9/2116ExtracellularversusIntracell17ExtracellularpathogenRespiratorytract,cutaneous,infections:

Streptococcusspp,Staphylococcusspp.Digestiontractinfections:

Salmonellaspp.,Shigellaspp.IntracellularpathogenRespiratory(pneumopathies:immunosuppresive;children):Chlamydia,Legionella,Mycobateria.Sex-transmitted:

ChlamydiatrachomatisCNS+othersites:

Listeriamonocytogenes;Pregnantwomen;immunosuppressivepatients2023/9/2117Extracellularpathogen2023/18EndosomesPhagosomeslysosomesPhagolysosomes軍團(tuán)菌衣原體李斯特菌志賀菌沙門菌結(jié)核菌胞內(nèi)寄生菌Cytosol:pH=7Phagosome:pH=6Phagolysosome:pH=52023/9/2118EndosomesPhagosomeslysosomesFigure10-4胞外寄生菌胞內(nèi)寄生菌感染部位病原體保護(hù)性免疫2023/9/2119Figure10-4胞外寄生菌胞內(nèi)寄生菌感染部位病原體保護(hù)呼吸道消化道眼皮膚生殖道4)人體解剖結(jié)構(gòu)與免疫

-無(wú)/有菌狀態(tài)的差異

-免疫因子/細(xì)胞的差異

-免疫應(yīng)答的特點(diǎn)/差異2023/9/2120呼吸道消化道眼皮膚生殖道4)人體解剖結(jié)構(gòu)與免疫2023/8AdenoidTonsilLymphnodesSpleenPeyer’spatches(smallintestine)AppendixLymphaticvesselsLymphnodeMassesofdefensivecellsBloodcapillaryLymphaticvesselTissuecellsInterstitialfluid淋巴系統(tǒng)2023/9/2121AdenoidTonsilLymphSpleenPeyer’INNATEIMMUNITYRecognitionoftraitssharedbybroadrangesofpathogens,usingasmallsetofreceptorsRapidresponseRecognitionoftraitsspecifictoparticularpathogens,usingavastarrayofreceptorsSlowerresponseACQUIREDIMMUNITYPathogens(microorganismsandviruses)Barrierdefenses:SkinMucousmembranesSecretionsInternaldefenses:PhagocyticcellsAntimicrobialproteinsInflammatoryresponseNaturalkillercellsHumoralresponse:Antibodiesdefendagainstinfectioninbodyfluids.Cell-mediatedresponse:Cytotoxiclymphocytesdefendagainstinfectioninbodycells.人體抗菌免疫的三道防線2023/9/2122INNATEIMMUNITYRecognitionof一般因素物理和化學(xué)屏障系統(tǒng)完整的皮膚和粘膜上皮細(xì)胞纖毛體液、胃酸、眼淚低pH(皮膚,陰道,etc.)發(fā)熱>37oC年齡嬰兒vs.幼兒vs.老人2.人體抗菌免疫的第一道防線2023/9/2123一般因素2.人體抗菌免疫的第一道防線2023/8/623LactobacillusacidophilusLactobacilluscaseiEnterococcusfaeciumSaccharomycescerevisiae營(yíng)養(yǎng)狀況激素孕婦感染HEV-死亡率遺傳因子宿主種屬的抗性共生菌

-colicins,occupyecologicalniche益生菌(“probiotic”organisms)

-lactobacillietc.酸奶-保加利亞乳酸桿菌嗜熱鏈救菌

雙岐桿菌嗜酸乳桿菌2023/9/2124LactobacillusLactobacillusEnSomeprotectivefactorsfound

inbodytissuesandfluids2023/9/2125SomeprotectivefactorsfoundAntimicrobialPeptidesandProteinsPeptidesandproteinsfunctionininnatedefensebyattackingmicrobesdirectlyorimpedingtheirreproductionAntimicrobialpeptides:"hostdefensepeptides"partofthe

innateimmuneresponse

foundamongallclassesoflife.Thesepeptidesarepotent,broadspectrum

antibiotics

whichdemonstratepotentialasnovelpotentialtherapeuticagents.-kill

Gramnegative

and

Grampositive

bacteria,envelopedviruses,fungiandeventransformedorcancerouscells.-enhanceimmunitybyfunctioningas

immunomodulatory.

Thecomplementsystem~30proteins -lysisofinvadingcells -helpstriggerinflammation2023/9/2126AntimicrobialPeptidesandProVariousstructuresofantimicrobialpeptidesThemodesofactionbyAntimicrobialpeptidesImmunomodulatory

functions:AlterhostgeneexpressionActaschemokinesand/orinduce

chemokine

productionInhibiting

LPS

inducedpro-inflammatory

cytokine

productionPromotingwoundhealingModulatingtheresponsesof

dendriticcells

andcellsoftheadaptiveimmuneresponse2023/9/2127VariousstructuresofantimicrFigure2-19趨化裂解調(diào)理補(bǔ)體的抗菌作用2023/9/2128Figure2-19趨化裂解調(diào)理補(bǔ)體2023/8/6283.人體抗菌免疫的第二道防線 識(shí)別細(xì)菌保守的“共有”成分天然免疫/固有免疫/InnateImmunity無(wú)記憶 同一微生物每次感染后的免疫應(yīng)答強(qiáng)度均相似無(wú)多樣性免疫分子的基因不會(huì)出現(xiàn)重組2023/9/21293.人體抗菌免疫的第二道防線天然免疫/固有免疫/InnOutcomeofInfectionInfectionwins deathInfectionloses live(innateplusadaptive)

StudiedintenselyBestoutcomeisInfectionskilledquickly(innateonly)

Notwellstudied

Howisitthatmostpeoplearenotperpetuallysick?(Innateimmunitysquelchingmostinfections)2023/9/2130OutcomeofInfectionInfection微生物存活數(shù)量天然免疫缺損小鼠天然免疫正常小鼠T、B細(xì)胞缺損小鼠天然免疫在微生物感染中的作用2023/9/2131微生物存活數(shù)量天然免疫天然免疫T、B細(xì)胞2023/8/631天然免疫識(shí)別的細(xì)菌細(xì)胞壁的表面成分G-bacteriaG+bacteria脂多糖脂蛋白孔蛋白穿孔素磷壁酸肽聚糖2023/9/2132天然免疫識(shí)別的細(xì)菌細(xì)胞壁的表面成分G-bacteriaG+物種演化中遺傳的古老廣譜抗微生物機(jī)制微生物的LPS,甘露糖等“pathogen-associatedmolecularpatterns”–PAMPs識(shí)別PAMPsreceptors:patternrecognitionreceptors(PRRs),onmembrane:Toll-likereceptors(TLRs),C-typelectinreceptors(CLRs),incytoplasm:Nod-likereceptors(NLRs);RIG-I-likereceptors(RLRs)“microbe-associatedmolecularpattern”-MAMPsMBLMannosebindinglectinMBLbelongstotheclassofcollectins

intheC-typelectinsuperfamilyC-typelectinreceptors(CLRs)CLR2023/9/2133物種演化中遺傳的古老廣譜MBLMannosebindingEXTRACELLULARFLUIDLipopolysaccharideFlagellinTLR4TLR5HelperproteinTLR9TLR3WHITEBLOODCELLVESICLECpGDNAdsRNAInflammatoryresponsesPAMPsPRRs2023/9/2134EXTRACELLULARLipopolysaccharid

不同Toll-likeReceptors識(shí)別不同微生物的產(chǎn)物2023/9/2135不同Toll-likeReceptors識(shí)別不同微生物的TLR9UnmethylatedCpGDNAdsRNATLR3TLR7ssRNATLR4TLR2TLR6TLR1TLR5LipoproteinsLipoarabinomannanLipoteichoicAcidsZymosan(Yeast)LPSFlagellinCD14MD2TLR11T.gondiProfilin識(shí)別細(xì)菌Toll-likeReceptors識(shí)別微生物的表面產(chǎn)物/結(jié)構(gòu)2023/9/2136TLR9UnmethylateddsRNATLR3TLR7TLR4TLR2TLR6TLR1TLR5TLR9PeptidoglycanLipoproteinsLipoarabinomannanLPS(Leptospira)LPS(Porphyromonas)GPI(T.Cruzi)Zymosan(Yeast)LPSLipoteichoicAcidsFlagellinUnmethylatedCpGDNAdsRNACD14TLR3TLR7ssRNAMD2TLR11識(shí)別病毒T.gondiProfilinToll-likeReceptors識(shí)別病毒2023/9/2137TLR4TLR2TLR6TLR1TLR5TLR9Peptid吞噬細(xì)胞表面具有識(shí)別微生物成分的多種受體2023/9/2138吞噬細(xì)胞表面具有識(shí)別微生物成分的多種受體2023/8/638PhagocytosisandkillingPrimarygranules:AntimicrobialpeptidesLysozyme(degradespeptidoglycan)Proteases(elastase,etc.)Secondarygranules:phagocyteoxidase?NewSciencePressLtd.2004MicrobesPHAGOCYTICCELLVacuoleLysosomecontainingenzymesPrimarygranuleslysosomeSecondarygranulesLysosomes:Digestiveenzymes2023/9/2139PhagocytosisandkillingPrimarPhagosytosisanddestructionofbacteriasuperoxidedismutase:superoxide(O2-),hydrogenperoxide(H2O2),andsingletoxygen,hydroxylradicalsmyeloperoxidase

(phagolysosome),hydrogenperoxide+chlorinehypochlorite(toxictobacteria)Oxygen-dependentbacteria-killingsubstance2023/9/2140PhagosytosisanddestructionoEffectorMoleculeFunctionCationicproteins(cathepsin)DamagetomicrobialmembranesLysozymeHydrolysesmucopeptidesinthecellwallLactoferrinDeprivespathogensofironHydrolyticenzymes(proteases)DigestskilledorganismsOxygenIndependentKillinginthePhago-lysosome2023/9/2141EffectorMoleculeFunctionCatio趨化吞噬2023/9/2142趨化吞噬2023/8/642Therearedifferenttypesofphagocyticcells:Neutrophils

engulfanddestroymicrobesMacrophages

arepartofthelymphaticsystemandarefoundthroughoutthebodyDendriticcellsstimulatedevelopmentofacquiredimmunityEosinophilsdischargedestructiveenzymes2023/9/2143NeutrophilphagocytosinganthraxbacilliTherearedifferenttypesofpFigure2-152023/9/2144Figure2-152023/8/644Figure2-5part1of2巨噬細(xì)胞表面表達(dá)多種受體細(xì)菌表面成分與巨噬細(xì)胞表面受體結(jié)合細(xì)菌與巨噬細(xì)胞表面受體結(jié)合后激發(fā)細(xì)胞因子/炎性因子的釋放巨噬細(xì)胞吞噬細(xì)菌2023/9/2145Figure2-5part1of2巨噬細(xì)胞表面表達(dá)IFN-g釋放NK細(xì)胞激活2023/9/2146inflammasome

Nod-likereceptors(NLRs)

IFN-g釋放2023/8/646inflammasome2023/9/2147Inflammasomeactivationanddiseases2023/8/647InflammasomeactivatInflammatoryResponsesInflammationisaprotectiveresponsethatinvolvesimmunecells,bloodvessels,andmolecularmediators,Mastcell,-containsmanygranulesrichinhistamineandheparin,promoteschangesinbloodvessels,apartoftheinflammatoryresponseIncreaselocalbloodsupplyandallowmorephagocytesandantimicrobialproteinstoentertissuesPus,afluidrichinWBC,deadmicrobes,andcelldebris,accumulatesatthesiteofinflammation2023/9/2148InflammatoryResponsesInflammaTNF?NewSciencePressLtd.2000ormastcell2023/9/2149TNF?NewSciencePressLtd.20Fig.43-8-1PathogenSplinterMacrophageMastcellChemicalsignalsCapillaryPhagocyticcellRedbloodcellsFluid2023/9/2150Fig.43-8-1PathogenSplinterMacInflammation:Neutrophilsvs.MonocytesAcuteinflammationisinitiallycharacterizedasrichinneutrophils;lateritismoremonocytes,controlledbychemokinesexpressedbytheendothelialcells.Neutrophils

arededicatedtokillingbacteriaandareshort-lived,oftendamagehosttissueasabyproduct.【interleukin-8

(IL-8),

interferongamma

(IFN-gamma),

chemokines:C3a,

C5a,LeukotrieneB4,】Monocytes

aremulti-potential,dependingoncytokinesignals: +IFN-g:assumeavigorouskillingphenotypesimilartoneutrophils +IL-10:assumeawound-healingtypephenotype(tocleanupafterinfectioniscleared) +GM-CSF:assumeadendriticcellphenotypeandpropagateadaptiveimmunepriming2023/9/2151Inflammation:Neutrophilsvs.Cytokinestorm

-sepsissyndromeBacterialsepticemialeadstoactivationofTLRsonmonocytesinthebloodSystemicreleaseofTNFandIL-1leadsto“inflammation”alloverthebodyShockfromlossofbloodpressure(vasodilationandleakageoffluidintotissues)TLRsalsoinducecoagulation(viatissuefactor)Thecombinationofeffectscanleadtomulti-organfailureanddeath2023/9/2152Cytokinestorm

-sepsissyndrom2023/9/2153通過(guò)多途徑控制感染2023/8/653通過(guò)多途徑控制感染TNFproductionInductionofSignalingCascadesNFActivationBIOLOGICALEFFECTSHowdomacrophagesdetectLPS?宿主抵抗LPS的機(jī)制2023/9/2154TNFproductionInductionofSigLBP和CD14是內(nèi)毒素的受體MacrophagesEndothelialcellsBiologicalActivitiesEarlierSignalingEvents?LBP-CD14Co-receptor(s)??2023/9/2155LBP和CD14是內(nèi)毒素的受體MacrophagesLPSBindingProtein/LPS結(jié)合蛋白(LBP)60-kDa血漿糖蛋白具有與LPS高親和力由肝細(xì)胞合成的急性期蛋白(肝功能不全-LPS清除?)正常血清量1~10ug/ml急性期血清含量>300ug/ml對(duì)少量LPS或革蘭陰性菌快速反應(yīng),運(yùn)輸至巨噬細(xì)胞LPS,上調(diào)IL-1,IL-6andTNF表達(dá).CD14-巨噬細(xì)胞表面

-可溶性CD14-上皮細(xì)胞-與LBP共同將LPS結(jié)合于細(xì)胞表面2023/9/2156LPSBindingProtein/LPS結(jié)合蛋白(特異性抗菌免疫2023/9/2157特異性抗菌免疫2023/8/657Figure2-1不同免疫應(yīng)答的時(shí)間抗再次感染抗再次感染應(yīng)答的時(shí)間特異性抗菌免疫2023/9/2158Figure2-1不同免疫應(yīng)答的時(shí)間抗再次感染抗再次感染應(yīng)巨噬細(xì)胞與淋巴細(xì)胞相互作用巨噬細(xì)胞淋巴細(xì)胞細(xì)菌Cytokinesaresecretedbymacrophagesanddendriticcellstorecruitandactivatelymphocytes2023/9/2159巨噬細(xì)胞與淋巴細(xì)胞相互作用巨噬細(xì)胞淋巴細(xì)胞細(xì)菌Cytok

Antigen-bindingsite

Antigen-bindingsiteAntigen-bindingsiteDisulfidebridge

VariableregionsConstantregionsTransmembraneregionPlasmamembraneLightchainHeavychainsTcellchainchainDisulfidebridgeCytoplasmofTcell(b)TcellreceptorCytoplasmofBcell(a)BcellreceptorBcellVVCCVVCCCCVVAsingleBcellorTcellhasabout100,000identicalantigenreceptors2023/9/2160Antigen-Antigen-AnFigure9-5T輔助細(xì)胞-B細(xì)胞激活,B細(xì)胞分化為漿細(xì)胞,分泌特異性抗體2023/9/2161Figure9-5T輔助細(xì)胞-B細(xì)胞激活,B細(xì)胞分化為漿Figure9-19part1of22023/9/2162Figure9-19part1of22023/8/Figure9-19part2of22023/9/2163Figure9-19part2of22023/8/特異性體液免疫-抗胞外菌特異性抗體-毒素--中和-菌細(xì)胞--調(diào)理抗體+吞噬細(xì)胞-菌細(xì)胞--裂解

抗體+補(bǔ)體-阻斷細(xì)菌黏附中和調(diào)理裂解2023/9/2164特異性體液免疫中和調(diào)理裂解2023/8/664抗黏附抗體阻斷細(xì)菌定居2023/9/2165抗黏附抗體2023/8/665Anti-ExtracellularBacteriaExtracellularBacteriaCapableofreplicatingoutsideofthehostcells.Theycausediseasebytwoprinciplemechanisms.InduceinflammationManyofthesebacteriaproducetoxins.EndotoxinsExotoxins2023/9/2166Anti-ExtracellularBacteriaExtInnateimmunitytoExtracellularBacteriaPhagocytosisbyneutrophils,monocytes,andthetissuemacrophages.Activationofthecomplementsystem(withoutantibody) ChemotaxisC3a,C5a, OpsonizationC3betc, lyticcomplexC5-9ChemotexistriggeredbyPAMPs,chemokine,C3a,C5aectCytokinesTNF,IL-1,andchemokine:MCP-1,MIP-1aNK–INF-gTheimmuneresponsesagainstextracellularbacteria -eliminatingthebacteria -neutralizingtheeffectsoftoxins.2023/9/2167InnateimmunitytoExtracellulHumoralimmunityistheprinciplespecificimmuneresponseagainstextracellularbacteria-StrongIgMresponsesarecausedbypolysaccharides.AntibodiesIgMandIgGagainstbacteriasurfaceantigensandtoxinsstimulatethreetypesofeffectormechanisms:-opsonizebacteriaandenhancephagocytosis-neutralizebacterialtoxins -inhibitbacterialenzymeactivities -limitthebacteriamobility-activatethecomplementsystem(lyticandopsonic) -IgA(local/mucosalimmunity)blockbacteriaadhesionPrincipalinjuriesofhostresponsestoextracellularbacteria:Inflammation&SepticshockSpecificImmunityExtracellularBacteria2023/9/2168Humoralimmunityistheprinci69IntracellularbacteriaNofusionLysozomePhagosomeFusionEntercytoplasmBacteriaMacrophageorneutrophilPhagolysosomes2023/9/2169IntracellularbacteriaNofus70EndosomesPhagosomeslysosomesPhagolysosomes軍團(tuán)菌衣原體李斯特菌志賀菌沙門菌結(jié)核菌Anti-IntracellularBacteriaCytosol:pH=7Phagosome:pH=6Phagolysosome:pH=52023/9/2170EndosomesPhagosomeslysosomes1.胞內(nèi)寄生菌對(duì)宿主細(xì)胞幾乎無(wú)/或無(wú)直接的毒性作用;但感染伴隨遲發(fā)型超敏反應(yīng)2.胞內(nèi)寄生菌能與宿主長(zhǎng)期共存,導(dǎo)致慢性感染;胞外菌引起急性感染3.胞內(nèi)寄生菌感染的病理與免疫損傷有關(guān),而胞外菌往往產(chǎn)生毒素直接造成組織損傷;4.T細(xì)胞是控制胞內(nèi)寄生菌感染主要免疫因素;胞內(nèi)寄生菌感染的特征2023/9/21711.胞內(nèi)寄生菌對(duì)宿主細(xì)胞幾乎無(wú)/或無(wú)直接的毒性作用;但感染伴Anti-IntracellularBacteriaIntercellularbacteriahavetheabilitytosurviveandevenreplicatewithinphagocytesImmuneresponsesforeliminationofintracellularbacteria-verydifferentfromtheresponsesagainstextracellularbacteria.InnateimmunitytointracellularBacteria-Intracellularbacteriaareresistanttodegradationwithinphagocytes.-IntracellularbacteriaactivateNKcells,eitherdirectlyorbystimulatingmacrophagesproductionofIL-12,apowerfulNKcell–activatingcytokine.2023/9/2172Anti-IntracellularBacteriaIntSpecificImmunitytoIntracellularBacteriaCell-mediatedimmuneresponseisthemajorspecificimmuneresponseagainstintracellularbacteria.Twotypesofcell-mediatedreactions:KillingofphagocytosedintracellularbacteriaasaresultofmacrophageactivationbyTcellderivedcytokines,particularlyIFN-gamma.LysisofinfectedcellsbyCTLs.Tissuedamagecausedbymacrophageactivationthatoccursinresponsetointracellularbacteria.2023/9/2173SpecificImmunitytoIntracell抗胞內(nèi)寄生菌的天然免疫和獲得性免疫活菌數(shù)感染清除感染控制活菌數(shù)活菌數(shù)感染后天數(shù)2023/9/2174抗胞內(nèi)寄生菌的天然免疫和獲得性免疫活菌數(shù)感染清除感染控制活菌Figure1-262023/9/2175Figure1-262023/8/675結(jié)核分枝桿菌的胞內(nèi)感染CD4Tcells控制結(jié)核感染ImmunitytotheintracellularbacteriainvolvesaDTHresponse激活的巨噬細(xì)胞包裹感染灶-結(jié)核球tubercle.巨噬細(xì)胞釋放的酶導(dǎo)致肺組織損傷2023/9/2176結(jié)核分枝桿菌的胞內(nèi)感染CD4Tcells控制結(jié)核感染2細(xì)菌 致病性 免疫機(jī)制

白喉?xiàng)U菌 非侵襲性毒素 中和抗體霍亂弧菌 非侵襲性毒素 中和抗體、阻斷細(xì)菌黏附奈瑟菌腦膜炎雙球菌 侵襲性 抗體、補(bǔ)體裂解、吞噬、調(diào)理金黃色葡萄球菌 局部侵襲性+毒素

抗體和補(bǔ)體的調(diào)理、吞噬、結(jié)核桿菌 侵襲性、激發(fā)免疫病理 巨噬細(xì)胞激活麻風(fēng)桿菌 侵襲性、激發(fā)免疫病理 巨噬細(xì)胞激活2023/9/2177細(xì)菌 致病性 免疫機(jī)制78EVASIONSTRATEGIES(1)2023/9/21ref78EVASIONSTRATEGIES(1)2023/79EVASIONSTRATEGIES(2)2023/9/21ref79EVASIONSTRATEGIES(2)2023/病毒基本結(jié)構(gòu):核酸+蛋白 核酸+蛋白+包膜(含脂質(zhì)和糖蛋白)抗病毒免疫2023/9/2180病毒基本結(jié)構(gòu):核酸+蛋白抗病毒免疫2023/8/680病毒復(fù)制周期吸附穿入脫衣殼生化合成裝配釋放出芽方式釋放細(xì)胞裂解釋放2023/9/2181病毒復(fù)制周期吸附穿入脫衣殼生化合成裝配釋放出芽方式釋放細(xì)Figure2-49病毒感染后體內(nèi)免疫應(yīng)答的動(dòng)態(tài)變化2023/9/2182Figure2-49病毒感染后體內(nèi)免疫應(yīng)答的動(dòng)態(tài)變化202干擾素細(xì)胞因子IFN-gCTL細(xì)胞增殖CTLT細(xì)胞增殖IFN-g,細(xì)胞因子抗體天然免疫獲得性免疫2023/9/2183干擾素天然免疫獲得性免疫2023/8/683屏障系統(tǒng)

-respiratoryepitheliumandskin,etc.2.體液

-stomachacid,tears,etc.3.干擾素4.NK細(xì)胞5.巨噬細(xì)胞抗病毒天然免疫2023/9/2184屏障系統(tǒng)抗病毒天然免疫2023/8/684干擾素Interferons(IFN) -第一個(gè)被發(fā)現(xiàn)的抗病毒因子

-免疫調(diào)節(jié)劑

-IFNalpha,beta,gamma

IFNalpha

20variants白細(xì)胞–病毒

IFNbeta

單個(gè)蛋白,纖維母細(xì)胞–病毒

IFNgamma單個(gè)蛋白,NK細(xì)胞,

T細(xì)胞–抗原,mitogensTypeITypeII2023/9/2185干擾素Interferons(IFN)TypeIType干擾素誘生劑

IFN-alphaandIFN-beta誘生劑:

virusinfection: -RNAviruses -DNAvirusesarepoorIFNinducers,withtheexceptionofpoxviruses. -doublestrandedRNA -LPS,andcomponentsfromsomebacteriaIFN-gamma誘生劑: -有絲分裂原mitogens -抗原antigen中草藥

2023/9/2186干擾素誘生劑2023/8/686Interferons

生物學(xué)活性

-anti-viralactivity抗病毒

-immunomodulateactivity免疫調(diào)節(jié)

-regulationofcellularproliferation

調(diào)節(jié)細(xì)胞增殖2023/9/2187Interferons2023/8/687IFNtypeI,II不同受體不同的激活途徑調(diào)控不同生物學(xué)活性Ⅰ型干擾素受體基因位于人染色體第21對(duì)染色體Ⅱ型干擾素受體基因位于第6對(duì)染色體2023/9/2188IFNtypeI,II2023/8/688IFN的抗病毒作用病毒病毒復(fù)制抑制病毒復(fù)制信號(hào)轉(zhuǎn)導(dǎo)IFN-aIFN-誘導(dǎo)蛋白誘導(dǎo)刺激胞核胞核IFN受體細(xì)胞建立抗病毒狀態(tài)病毒感染細(xì)胞2023/9/2189IFN的抗病毒作用病毒病毒復(fù)制抑制病毒復(fù)制信號(hào)轉(zhuǎn)導(dǎo)IFN干擾素通過(guò)作用于具有干擾素受體的細(xì)胞發(fā)揮抗病毒作用mRNA降解蛋白合成抑制抗病毒狀態(tài)病毒易感患者:干擾素產(chǎn)生能力?受體變異?信號(hào)轉(zhuǎn)導(dǎo)通路的改變/影響?2023/9/2190干擾素通過(guò)mRNA降解蛋白合成抑制抗病毒狀態(tài)病毒易感患者:2IFN的臨床應(yīng)用病毒感染乙型肝炎丙型肝炎疣-人乳頭瘤病毒/HPV呼吸道合胞病毒腫瘤毛細(xì)胞白血病(90%有效)濾泡性淋巴瘤宮頸癌(HPV)基底細(xì)胞癌(80-90%)卡波濟(jì)瘤(HHVtype8)Otherconditions -慢性

肉芽腫病毒(IFN-g) -多硬化癥2023/9/2191IFN的臨床應(yīng)用病毒感染腫瘤Otherconditions自然殺傷細(xì)胞(NKcell)病毒感染的靶細(xì)胞無(wú)TandB細(xì)胞標(biāo)志(noTCR)CD5(specificNKmarker)FcRIII(CD16)IL-2

作用使NK分化為lymphokine-activatedkiller(LAK)cells2023/9/2192自然殺傷細(xì)胞(NKcell)病毒感染的靶細(xì)胞無(wú)T2023/9/2193ComplementaryactivitiesofCTLs

andNKcells2023/8/693ComplementaryactiviNK細(xì)胞的效應(yīng)機(jī)制殺傷靶細(xì)胞的機(jī)制類似于Tccells殺傷靶細(xì)胞的活性為非MHC限制對(duì)NK細(xì)胞敏感的靶細(xì)胞

-MHCI表達(dá)下調(diào)

killerinhibitoryreceptors(KIR)onNKcellsrecognizeclassIMHCandpreventkillingNK細(xì)胞表面具有FcRIII(CD16)可識(shí)別IgG-coated靶細(xì)胞發(fā)揮ADCC活性殺傷靶細(xì)胞antibody-dependentcell-mediatedcytotoxicity2023/9/2194NK細(xì)胞的效應(yīng)機(jī)制殺傷靶細(xì)胞的機(jī)制類似于TccellsMacrophage/巨噬細(xì)胞細(xì)胞因子淋巴因子激活功能增強(qiáng)吞噬、殺傷呈遞抗原免疫調(diào)節(jié)2023/9/2195Macrophage/巨噬細(xì)胞細(xì)胞因子淋巴因子激活功能增強(qiáng)吞

抗病毒特異性免疫應(yīng)答病毒抗原呈遞途徑抗原呈遞細(xì)胞:專職性:樹(shù)突狀細(xì)胞、B細(xì)胞等

CD8+MHCI CD4+MHCII相同MHC分子的細(xì)胞才能呈遞抗原

(試驗(yàn)中的難點(diǎn))2023/9/2196抗原呈遞細(xì)胞:相同MHC分子的細(xì)胞才能呈遞抗原2023抗原的處理和呈遞病毒在細(xì)胞內(nèi),MHCclassI抗原呈遞途徑,Tc胞外細(xì)菌,MHCclassII抗原呈遞途徑,Th2,Ab胞內(nèi)寄生菌,MHCclassI+MHCclassII,Th1response MHCI/II特異性2023/9/2197抗原的處理和呈遞病毒在細(xì)胞內(nèi),MHCclassI抗原外源性抗原呈遞途徑2023/9/2198外源性抗原呈遞途徑2023/8/698內(nèi)源性抗原呈遞途徑2023/9/2199內(nèi)源性抗原呈遞途徑2023/8/699V.Brusic,2002內(nèi)質(zhì)網(wǎng)蛋白酶體蛋白抗原T殺傷細(xì)胞MHCI-抗原肽復(fù)合體2023/9/21100V.Brusic,2002內(nèi)質(zhì)網(wǎng)蛋白酶體蛋白抗原T殺傷T細(xì)胞受體(TCR)TCR識(shí)別抗原肽-MHC復(fù)合體T輔助細(xì)胞(Th)TCR識(shí)別

抗原肽-MHCclassII復(fù)合體T殺傷細(xì)胞(Tc)識(shí)別抗原肽-MHCclassI復(fù)合體MHCII-抗原肽復(fù)合體MHCI-抗原肽復(fù)合體2023/9/21101T細(xì)胞受體(TCR)TCR識(shí)別抗原肽-MHC復(fù)合體MH2023/9/211022023/8/6102Fig.43-17Antigen-presentingcellPeptideantigenCell-mediatedimmunity(attackoninfectedcells)ClassIIMHCmoleculeCD4TCR(Tcellreceptor)HelperTcellHumoralimmunity(secretionofantibodiesbyplasmacells)CytotoxicTcellCytokinesBcellBacterium++++2023/9/21103Fig.43-17Antigen-PeptideantiFig.43-19Antigen-presentingcellEndoplasmicreticulumofplasmacellSecretedantibodymoleculesBacteriumBcellPeptideantigenClassIIMHCmoleculeTCRCD4HelperTcellActivatedhelperTcellCytokinesCloneofmemoryBcellsCloneofplasmacells2μm+2023/9/21104Fig.43-19Antigen-presentingc保護(hù)性特異性免疫應(yīng)答中和抗體-中和游離的病毒,在再感染中發(fā)揮保護(hù)性作用2.細(xì)胞免疫應(yīng)答

-T輔助細(xì)胞:Th1/Th2 -細(xì)胞因子Cytokines(IFN-r) -T殺傷細(xì)胞CytotoxicT-cells

在清除病毒感染的靶細(xì)胞非常重要3.Ab-mediatedlysis(補(bǔ)體,NK細(xì)胞)

抗體介導(dǎo)的靶細(xì)胞裂解2023/9/21105保護(hù)性特異性免疫應(yīng)答中和抗體2023/8/6105保護(hù)性特異性免疫應(yīng)答中和抗體-中和游離的病毒,在再感染中發(fā)揮保護(hù)性作用2.細(xì)胞免疫應(yīng)答

-T輔助細(xì)胞:Th1/Th2 -細(xì)胞因子Cytokines(IFN-r) -T殺傷細(xì)胞CytotoxicT-cells

在清除病毒感染的靶細(xì)胞非常重要3.Ab-mediatedlysis(補(bǔ)體,NK細(xì)胞)

抗體介導(dǎo)的靶細(xì)胞裂解2023/9/21106保護(hù)性特異性免疫應(yīng)答中和抗體2023/8/6106Fig.43-21ViralneutralizationVirusOpsonizationBacteriavirusMacrophageActivationofcomplementsystemandporeformationComplementproteinsFormationofmembraneattackcomplexFlowofwaterandionsPoreForeigncell2023/9/21107Fig.43-21ViralneutralizationIgM感染早期診斷指標(biāo)2023/9/21108IgM感染早期診斷指標(biāo)2023/8/6108病毒高滴度低滴度2023/9/21109病毒高滴度低滴度2023/8/6109保護(hù)性特異性免疫應(yīng)答中和抗體-中和游離的病毒,在再感染中發(fā)揮保護(hù)性作用2.細(xì)胞免疫應(yīng)答

-T輔助細(xì)胞:Th1/Th2 -細(xì)胞因子Cytokines(IFN-r) -T殺傷細(xì)胞CytotoxicT-cells

在清除病毒感染的靶細(xì)胞非常重要3.Ab-mediatedlysis(補(bǔ)體,NK細(xì)胞)

抗體介導(dǎo)的靶細(xì)胞裂解2023/9/21110保護(hù)性特異性免疫應(yīng)答中和抗體2023/8/6110TCellsT細(xì)胞在病毒感染中起關(guān)鍵性的作用-T殺傷細(xì)胞CytotoxicTcells(CTLs)

殺傷病毒感染的細(xì)胞 阻斷病毒的擴(kuò)散-T輔助細(xì)胞HelperTcells

輔助CTLs的產(chǎn)生 輔助B細(xì)胞產(chǎn)生特異性抗體-Lymphokines T細(xì)胞產(chǎn)生的細(xì)胞因子,招募和激活巨噬細(xì)胞和NK細(xì)胞,作用于病毒感染的細(xì)胞2023/9/21111TCells2023/8/6111T輔助細(xì)胞2023/9/21112T輔助細(xì)胞2023/8/61122023/9/211132023/8/6113IgG2a(mu)IgG1(hu)IgG1(mu)IgG4(hu)2023/9/21114IgG2a(mu)IgG1(mu)2023/8/6114Figure9-72023/9/21115Figure9-72023/8/6115Th17TcelldevelopmentallydistinctfromTh1andTh2cellsandexcessiveamountsofthecellarethoughttoplayakeyroleinautoimmunedisease-Th17Tcellsserveaveryimportantfunctioninanti-microbialimmunityatepithelial/mucosalbarriers.-Th17cellsproducecytokines(suchasinterleukin22)whichstimulatesepithelialcellstoproduceanti-microbialproteinstoclearoutcertaintypesofmicrobe(suchasCandidaandStaphylococcus).-AlackofTh17cellsmayleavethehostsusceptibletoopportunisticinfections-Th17Tcellscancausesevereautoimmunediseases2023/9/21116Th17TcelldevelopmentallydiTc細(xì)胞的激活Pre-TccellTccellThelpercellClassIMHCClassIIMHCAPC1.CellexpressingclassIMHCpresentsantigen()

toapre-TccellIFNIL-22.Antigen-presentingcellpresentsantigeninassociationwith

classIIMHCtoThcell3.Thcellmakescytokines4.Pre-TccelldifferentiatestofunctionalTccell5.TcrecognizesantigenonclassIMHC-expressingtargetcell6.Targetcelliskilled2023/9/21117Tc細(xì)胞的激活Pre-TccellTccellTheMechanismofTcKillingTc

cellCa++PerforinmonomersPerforinpolymerizesPolyperforin

channelsTc

cellTargetcellGranzymesTarget

celllysisapoptosis2023/9/21118MechanismofTcKillingTccellTc殺傷靶細(xì)胞的過(guò)程Tccell1.Tcrecognizesantigenontargetcell

TargetcellTccell2.AlethalhitisdeliveredbytheTcusingagentssuchasperforinorgranzymeBTargetcellTccell3.TheTcdetaches

fromthetargetcellTargetcell4.Targetcelldies

byapoptosisTargetcell2023/9/21119Tc殺傷靶細(xì)胞的過(guò)程Tccell1.TcrecognT殺傷細(xì)胞殺傷病毒感染把細(xì)胞的過(guò)程T淋巴細(xì)胞?病毒感染的靶細(xì)胞?

2023/9/21120T殺傷細(xì)胞殺傷病毒感染把細(xì)胞的過(guò)程2023/8/61202023/9/211212023/8/6121細(xì)胞因子的特性由細(xì)胞和免疫細(xì)胞產(chǎn)生參與或調(diào)節(jié)免疫應(yīng)答分泌短暫和有限

-細(xì)胞不儲(chǔ)存,需要時(shí)產(chǎn)生

-刺激后基因轉(zhuǎn)錄合成

-mRNA半衰期短可由多種細(xì)胞產(chǎn)生,作用于多種細(xì)胞(pleiotropic)不同細(xì)胞因子可具有相似的作用(redundant)2023/9/21122細(xì)胞因子的特性由細(xì)胞和免疫細(xì)胞產(chǎn)生2023/8/61226.可影響其他細(xì)胞因子的合成

-系列反應(yīng)producecascades-促進(jìn)或抑制其它細(xì)胞因子的產(chǎn)生

-對(duì)免疫應(yīng)答起正/負(fù)調(diào)節(jié)作用影響其他細(xì)胞因子的功能

-拮抗,相加,協(xié)同與相應(yīng)受體結(jié)合并舉有高親和力9.細(xì)胞對(duì)細(xì)胞因子的應(yīng)答較慢,需要合成新的mRNA和蛋白質(zhì)2023/9/211236.可影響其他細(xì)胞因子的合成2023/8/6123細(xì)胞因子對(duì)免疫細(xì)胞的作用LymphocyteMacrophageBcellTcellNKLAKProliferation,Differentiation,Igsecretion

andselectionProliferation,Differentiation,CytokineproductionActivationofcellsofimmunesystemCytokineproductionIL1IL2IL4IL1IL2IL4IL5IL6IFNγcytokines2023/9/21124細(xì)胞因子對(duì)免疫細(xì)胞的作用LymphocyteMacropha細(xì)胞因子作用于不同器官Lympho

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