抗感染免疫-臨床研究生-2015

抗微生物免疫-抗菌免疫

-抗病毒免疫復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院病原生物學(xué)系醫(yī)學(xué)分子病毒學(xué)教育部/衛(wèi)生部重點(diǎn)實(shí)驗(yàn)室復(fù)旦大學(xué)醫(yī)學(xué)院瞿滌54237524dqu@2023/4/31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-個性：不同微生物的特性和致病機(jī)制不同抗感染免疫2023/4/32Spectrumof

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無癥狀感染

典型臨床疾病表現(xiàn)輕度疾病lessseveredisease2023/4/33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）2023/4/34微生物體積的大小不同細(xì)菌衣原體病毒體積微小2023/4/35Figure2-1不同免疫應(yīng)答的時間抗再次感染？抗再次感染？抗再次感染抗再次感染應(yīng)答的時間初次感染2023/4/36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)2023/4/37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)2023/4/38不同微生物具有不同的細(xì)胞壁結(jié)構(gòu)

-革蘭陽性細(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2023/4/39G+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)2023/4/310G+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

-陽離子蛋白肽聚糖-細(xì)胞壁成分

-溶菌酶2023/4/311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，需了解該菌結(jié)構(gòu)2023/4/3122)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2023/4/313Adhesion/黏附toxin產(chǎn)生毒素entryMultiplication繁殖AdhesionMultiplication繁殖Toxin產(chǎn)生毒素2023/4/3143)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

-存活絕對依賴細(xì)胞的內(nèi)環(huán)境2023/4/315ExtracellularversusIntracellularpathogenExtracellularpathogencapableofreplicatingoutsideofthehostcellsdestroyedwhenphagocytoseddamagingtissuesastheyremainoutsidecellsinducingtheproductionofopsonizingantibodiesusuallycauseacutediseasesofrelativelyshortdurationIntracellularpathogencanmultiplywithinphagocytesfrequentlycausechronicdisease2023/4/31617ExtracellularpathogenRespiratorytract,cutaneous,infections:

Streptococcusspp,Staphylococcusspp.Digestiontractinfections:

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

ChlamydiatrachomatisCNS+othersites:

Listeriamonocytogenes;Pregnantwomen;immunosuppressivepatients2023/4/318EndosomesPhagosomeslysosomesPhagolysosomes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=52023/4/3Figure10-4胞外寄生菌胞內(nèi)寄生菌感染部位病原體保護(hù)性免疫2023/4/319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/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2023/4/320AdenoidTonsilLymphnodesSpleenPeyer’spatches(smallintestine)AppendixLymphaticvesselsLymphnodeMassesofdefensivecellsBloodcapillaryLymphaticvesselTissuecellsInterstitialfluid淋巴系統(tǒng)2023/4/321INNATEIMMUNITYRecognitionoftraitssharedbybroadrangesofpathogens,usingasmallsetofreceptorsRapidresponseRecognitionoftraitsspecifictoparticularpathogens,usingavastarrayofreceptorsSlowerresponseACQUIREDIMMUNITYPathogens(microorganismsandviruses)Barrierdefenses:SkinMucousmembranesSecretionsInternaldefenses:PhagocyticcellsAntimicrobialproteinsInflammatoryresponseNaturalkillercellsHumoralresponse:Antibodiesdefendagainstinfectioninbodyfluids.Cell-mediatedresponse:Cytotoxiclymphocytesdefendagainstinfectioninbodycells.人體抗菌免疫的三道防線2023/4/322一般因素物理和化學(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2023/4/323LactobacillusacidophilusLactobacilluscaseiEnterococcusfaeciumSaccharomycescerevisiae營養(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2023/4/324GroupNameMajorSourcesActivityagainst

EnzymesLysozymeSerum;leukocytesBacteria

Basicpeptidesandproteinsb-lysin

Phagocytin

Leukin

PlakinPlatelets

Neutrophils

NeutrophilsGrampositivebacteria

IronbindingproteinsTransferrinLactoferrinSerum,Leukocytes,milkBacteria

BasicaminesSpermine;spermidinePancreas,kidney,prostateGrampositivebacteria

ComplementcomponentsSerumBacteria,viruses,protozoa

PeroxideMyeloperoxidase;xanthineoxidaseNeutrophils,milkBacteria,viruses,protozoa

InterferonMostcellsbutnotneutrophilsViruses,intracellularparasites,activationofmacrophages

Someprotectivefactorsfound

inbodytissuesandfluids2023/4/325AntimicrobialPeptidesandProteinsPeptidesandproteinsfunctionininnatedefensebyattackingmicrobesdirectlyorimpedingtheirreproductionAntimicrobialpeptides："hostdefensepeptides"partofthe

innateimmuneresponse

foundamongallclassesoflife.Thesepeptidesarepotent,broadspectrum

antibiotics

whichdemonstratepotentialasnovelpotentialtherapeuticagents.-kill

Gramnegative

and

Grampositive

bacteria,envelopedviruses,fungiandeventransformedorcancerouscells.-enhanceimmunitybyfunctioningas

immunomodulatory.

Thecomplementsystem~30proteins -lysisofinvadingcells -helpstriggerinflammation2023/4/326VariousstructuresofantimicrobialpeptidesThemodesofactionbyAntimicrobialpeptidesImmunomodulatory

functions:AlterhostgeneexpressionActaschemokinesand/orinduce

chemokine

productionInhibiting

LPS

inducedpro-inflammatory

cytokine

productionPromotingwoundhealingModulatingtheresponsesof

dendriticcells

andcellsoftheadaptiveimmuneresponse2023/4/327Figure2-19趨化裂解調(diào)理補(bǔ)體的抗菌作用2023/4/3283.人體抗菌免疫的第二道防線 識別細(xì)菌保守的“共有”成分天然免疫/固有免疫/InnateImmunity無記憶 同一微生物每次感染后的免疫應(yīng)答強(qiáng)度均相似無多樣性免疫分子的基因不會出現(xiàn)重組2023/4/329OutcomeofInfectionInfectionwins deathInfectionloses live(innateplusadaptive)

StudiedintenselyBestoutcomeisInfectionskilledquickly(innateonly)

Notwellstudied

Howisitthatmostpeoplearenotperpetuallysick?(Innateimmunitysquelchingmostinfections)2023/4/330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2023/4/331天然免疫識別的細(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2023/4/332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)CLR2023/4/333EXTRACELLULARFLUIDLipopolysaccharideFlagellinTLR4TLR5HelperproteinTLR9TLR3WHITEBLOODCELLVESICLECpGDNAdsRNAInflammatoryresponsesPAMPsPRRs2023/4/334受體(PatternRecognitionReceptors)PPR配體(Pathogen-AssociatedMolecularPatterns)PAMPTLR1與TLR2形成異源二體TLR2PGN,someLPS,someLTA,lipoproteins,AraLAM/細(xì)菌TLR3dsRNA病毒TLR4Gram(-)LPS,Taxol,someLTA/細(xì)菌TLR5Flagellin/細(xì)菌TLR6與TLR2形成異源二體TLR7ImidazoquinolineTLR9BacterialDNA(CpG)/細(xì)菌TLR8,10Unknown

不同Toll-likeReceptors識別不同微生物的產(chǎn)物2023/4/335TLR9UnmethylatedCpGDNAdsRNATLR3TLR7ssRNATLR4TLR2TLR6TLR1TLR5LipoproteinsLipoarabinomannanLipoteichoicAcidsZymosan(Yeast)LPSFlagellinCD14MD2TLR11T.gondiProfilin識別細(xì)菌Toll-likeReceptors識別微生物的表面產(chǎn)物/結(jié)構(gòu)2023/4/336TLR4TLR2TLR6TLR1TLR5TLR9PeptidoglycanLipoproteinsLipoarabinomannanLPS(Leptospira)LPS(Porphyromonas)GPI(T.Cruzi)Zymosan(Yeast)LPSLipoteichoicAcidsFlagellinUnmethylatedCpGDNAdsRNACD14TLR3TLR7ssRNAMD2TLR11識別病毒T.gondiProfilinToll-likeReceptors識別病毒2023/4/337吞噬細(xì)胞表面具有識別微生物成分的多種受體2023/4/338PhagocytosisandkillingPrimarygranules:AntimicrobialpeptidesLysozyme(degradespeptidoglycan)Proteases(elastase,etc.)Secondarygranules:phagocyteoxidase?NewSciencePressLtd.2004MicrobesPHAGOCYTICCELLVacuoleLysosomecontainingenzymesPrimarygranuleslysosomeSecondarygranulesLysosomes:Digestiveenzymes2023/4/339Phagosytosisanddestructionofbacteriasuperoxidedismutase：superoxide(O2-),hydrogenperoxide(H2O2),andsingletoxygen,hydroxylradicalsmyeloperoxidase

（phagolysosome）,hydrogenperoxide+chlorinehypochlorite(toxictobacteria)Oxygen-dependentbacteria-killingsubstance2023/4/340EffectorMoleculeFunctionCationicproteins(cathepsin)DamagetomicrobialmembranesLysozymeHydrolysesmucopeptidesinthecellwallLactoferrinDeprivespathogensofironHydrolyticenzymes(proteases)DigestskilledorganismsOxygenIndependentKillinginthePhago-lysosome2023/4/341趨化吞噬2023/4/342Therearedifferenttypesofphagocyticcells:Neutrophils

engulfanddestroymicrobesMacrophages

arepartofthelymphaticsystemandarefoundthroughoutthebodyDendriticcellsstimulatedevelopmentofacquiredimmunityEosinophilsdischargedestructiveenzymes2023/4/343NeutrophilphagocytosinganthraxbacilliFigure2-152023/4/344Figure2-5part1of2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2023/4/345IFN-g釋放NK細(xì)胞激活2023/4/346inflammasome

Nod-likereceptors(NLRs)

2023/4/347InflammasomeactivationanddiseasesInflammatoryResponsesInflammationisaprotectiveresponsethatinvolvesimmunecells,bloodvessels,andmolecularmediators,Mastcell,-containsmanygranulesrichinhistamineandheparin,promoteschangesinbloodvessels,apartoftheinflammatoryresponseIncreaselocalbloodsupplyandallowmorephagocytesandantimicrobialproteinstoentertissuesPus,afluidrichinWBC,deadmicrobes,andcelldebris,accumulatesatthesiteofinflammation2023/4/348TNF?NewSciencePressLtd.2000ormastcell2023/4/349Fig.43-8-1PathogenSplinterMacrophageMastcellChemicalsignalsCapillaryPhagocyticcellRedbloodcellsFluid2023/4/350Inflammation: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:assumeadendriticcellphenotypeandpropagateadaptiveimmunepriming2023/4/351Cytokinestorm

-sepsissyndromeBacterialsepticemialeadstoactivationofTLRsonmonocytesinthebloodSystemicreleaseofTNFandIL-1leadsto“inflammation”alloverthebodyShockfromlossofbloodpressure(vasodilationandleakageoffluidintotissues)TLRsalsoinducecoagulation(viatissuefactor)Thecombinationofeffectscanleadtomulti-organfailureanddeath2023/4/3522023/4/353通過多途徑控制感染TNFproductionInductionofSignalingCascadesNFActivationBIOLOGICALEFFECTSHowdomacrophagesdetectLPS?宿主抵抗LPS的機(jī)制2023/4/354LBP和CD14是內(nèi)毒素的受體MacrophagesEndothelialcellsBiologicalActivitiesEarlierSignalingEvents?LBP-CD14Co-receptor(s)??2023/4/355LPSBindingProtein/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2023/4/356特異性抗菌免疫2023/4/357Figure2-1不同免疫應(yīng)答的時間抗再次感染抗再次感染應(yīng)答的時間特異性抗菌免疫2023/4/358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Cytokinesaresecretedbymacrophagesanddendriticcellstorecruitandactivatelymphocytes2023/4/359

Antigen-bindingsite

Antigen-bindingsiteAntigen-bindingsiteDisulfidebridge

VariableregionsConstantregionsTransmembraneregionPlasmamembraneLightchainHeavychainsTcellchainchainDisulfidebridgeCytoplasmofTcell(b)TcellreceptorCytoplasmofBcell(a)BcellreceptorBcellVVCCVVCCCCVVAsingleBcellorTcellhasabout100,000identicalantigenreceptors2023/4/360Figure9-5T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2023/4/361Figure9-19part1of22023/4/362Figure9-19part2of22023/4/363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2023/4/364抗黏附抗體阻斷細(xì)菌定居2023/4/365Anti-ExtracellularBacteriaExtracellularBacteriaCapableofreplicatingoutsideofthehostcells.Theycausediseasebytwoprinciplemechanisms.InduceinflammationManyofthesebacteriaproducetoxins.EndotoxinsExotoxins2023/4/366InnateimmunitytoExtracellularBacteriaPhagocytosisbyneutrophils,monocytes,andthetissuemacrophages.Activationofthecomplementsystem(withoutantibody) ChemotaxisC3a,C5a, OpsonizationC3betc, lyticcomplexC5-9ChemotexistriggeredbyPAMPs,chemokine,C3a,C5aectCytokinesTNF,IL-1,andchemokine:MCP-1,MIP-1aNK–INF-gTheimmuneresponsesagainstextracellularbacteria -eliminatingthebacteria -neutralizingtheeffectsoftoxins.2023/4/367Humoralimmunityistheprinciplespecificimmuneresponseagainstextracellularbacteria-StrongIgMresponsesarecausedbypolysaccharides.AntibodiesIgMandIgGagainstbacteriasurfaceantigensandtoxinsstimulatethreetypesofeffectormechanisms:-opsonizebacteriaandenhancephagocytosis-neutralizebacterialtoxins

-inhibitbacterialenzymeactivities

-limitthebacteriamobility-activatethecomplementsystem(lyticand

opsonic)

-IgA(local/mucosalimmunity)blockbacteriaadhesionPrincipalinjuriesofhostresponsestoextracellularbacteria:Inflammation&SepticshockSpecificImmunityExtracellularBacteria2023/4/36869IntracellularbacteriaNofusionLysozomePhagosomeFusionEntercytoplasmBacteriaMacrophageorneutrophilPhagolysosomes2023/4/370EndosomesPhagosomeslysosomesPhagolysosomes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=52023/4/31.胞內(nèi)寄生菌對宿主細(xì)胞幾乎無/或無直接的毒性作用；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2023/4/371Anti-IntracellularBacteriaIntercellularbacteriahavetheabilitytosurviveandevenreplicatewithinphagocytesImmuneresponsesforeliminationofintracellularbacteria-verydifferentfromtheresponsesagainstextracellularbacteria.InnateimmunitytointracellularBacteria-Intracellularbacteriaareresistanttodegradationwithinphagocytes.-IntracellularbacteriaactivateNKcells,eitherdirectlyorbystimulatingmacrophagesproductionofIL-12,apowerfulNKcell–activatingcytokine.2023/4/372SpecificImmunitytoIntracellularBacteriaCell-mediatedimmuneresponseisthemajorspecificimmuneresponseagainstintracellularbacteria.Twotypesofcell-mediatedreactions:KillingofphagocytosedintracellularbacteriaasaresultofmacrophageactivationbyTcellderivedcytokines,particularlyIFN-gamma.LysisofinfectedcellsbyCTLs.Tissuedamagecausedbymacrophageactivationthatoccursinresponsetointracellularbacteria.2023/4/373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)2023/4/374Figure1-262023/4/375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2023/4/376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2023/4/37778DefenseMicrobialstrategyMechanismExampleBindtocellAdhesinsNeisseriaWash-outInhibitciliaryactivityCiliotoxic/CiliostaticmoleculeBordetellaStreptococcusIngestionandkillingbyphagocyteDisruptChemotaxiscytotoxicLeucocidinsStaphylococcus

InhibitphagocytosisCapsuleStreptococcus

Inhibitlysosomalfusion

InhibitorymoleculeMycobacterium

MultiplyUnknownListeriaEVASIONSTRATEGIES(1)2023/4/3ref79DefenceMicrobialstrategyMechanismExampleRestrictFe-Lactoferrin

TransferrinCompeteSiderophore

Mycobacterium

EscherichiaActivatecomplementInterferewith

alternativepathwayFullysialylatedsurfaceNeisseria

InactivateElastasePseudomonas

Antigenprojects

beyondsurfaceActivationoccursatthewrongsiteGram-negatives

Interferewith

complement-

mediated

phagocytosis

C3breceptorcompetition,

microbeandphagocyteStreptococcusEVASIONSTRATEGIES(2)2023/4/3ref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2023/4/380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2023/4/381Figure2-49病毒感染后體內(nèi)免疫應(yīng)答的動態(tài)變化2023/4/382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2023/4/383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2023/4/384干擾素Interferons(IFN) -第一個被發(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

單個蛋白，纖維母細(xì)胞–病毒

IFNgamma單個蛋白，NK細(xì)胞，

T細(xì)胞–抗原，mitogensTypeITypeII2023/4/385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

2023/4/386Interferons

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2023/4/387IFNtypeI,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對染色體Ⅱ型干擾素受體基因位于第6對染色體2023/4/388IFN的抗病毒作用病毒病毒復(fù)制抑制病毒復(fù)制信號轉(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2023/4/389干擾素通過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？信號轉(zhuǎn)導(dǎo)通路的改變/影響？2023/4/390IFN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2023/4/391自然殺傷細(xì)胞(NKcell)病毒感染的靶細(xì)胞無TandB細(xì)胞標(biāo)志(noTCR)CD5（specificNKmarker）FcRIII(CD16)IL-2

作用使NK分化為lymphokine-activatedkiller(LAK)cells2023/4/3922023/4/393ComplementaryactivitiesofCTLs

andNKcellsNK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)可識別IgG-coated靶細(xì)胞發(fā)揮ADCC活性殺傷靶細(xì)胞antibody-dependentcell-mediatedcytotoxicity2023/4/394Macrophage/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)2023/4/395

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))2023/4/396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2023/4/397外源性抗原呈遞途徑2023/4/398內(nèi)源性抗原呈遞途徑2023/4/399V.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2023/4/3100T細(xì)胞受體(TCR)TCR識別抗原肽-MHC復(fù)合體T輔助細(xì)胞(Th)TCR識別

抗原肽-MHCclassII復(fù)合體T殺傷細(xì)胞(Tc)識別抗原肽-MHCclassI復(fù)合體MHCII-抗原肽復(fù)合體MHCI-抗原肽復(fù)合體2023/4/31012023/4/3102Fig.43-17Antigen-presentingcellPeptideantigenCell-mediatedimmunity(attackoninfectedcells)ClassIIMHCmoleculeCD4TCR(Tcellreceptor)HelperTcellHumoralimmunity(secretionofantibodiesbyplasmacells)CytotoxicTcellCytokinesBcellBacterium++++2023/4/3103Fig.43-19Antigen-presentingcellEndoplasmicreticulumofplasmacellSecretedantibodymoleculesBacteriumBcellPeptideantigenClassIIMHCmoleculeTCRCD4HelperTcellActivatedhelperTcellCytokinesCloneofmemoryBcellsCloneofplasmacells2μm+2023/4/3104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2023/4/3105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2023/4/3106Fig.43-21ViralneutralizationVirusOpsonizationBacteriavirusMacrophageActivationofcomplementsystemandporeformationComplementproteinsFormationofmembraneattackcomplexFlowofwaterandionsPoreForeigncell2023/4/3107IgM感染早期診斷指標(biāo)2023/4/3108病毒高滴度低滴度2023/4/3109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2023/4/3110TCellsT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2023/4/3111T輔助細(xì)胞2023/4/31122023/4/3113IgG2a(mu)IgG1(hu)IgG1(mu)IgG4(hu)2023/4/3114Figure9-72023/4/3115Th17TcelldevelopmentallydistinctfromTh1andTh2cellsandexcessiveamountsofthecellarethoughttoplayakeyroleinautoimmunedisease-Th17Tcellsserveaveryimportantfunctioninanti-microbialimmunityatepithelial/mucosalbarriers.-Th17cellsproducecytokines(suchasinterleukin22)whichstimulatesepithelialcellstoproduceanti-microbialproteinstoclearoutcertaintypesofmicrobe(suchasCandidaandStaphylococcus).-AlackofTh17cellsmayleavethehostsusceptibletoopportunisticinfections-Th17Tcellscancausesevereautoimmunediseases2023/4/3116Tc細(xì)胞的激活Pre-TccellTccellThelpercellClassIMHCClassIIMHCAPC1.CellexpressingclassIMHCpresentsantigen()

toapre-TccellIFNIL-22.Antigen-presentingcellpresentsantigeninassociationwith

classIIMHCtoThcell3.Thcellmakescytokines4.Pre-TccelldifferentiatestofunctionalTccell5.TcrecognizesantigenonclassIMHC-expressingtargetcell6.Targetcelliskilled2023/4/3117MechanismofTcKillingTc

cellCa++PerforinmonomersPerforinpolymerizesPolyperforin

channelsTc

cellTargetcellGranzymesTarget

celllysisapoptosis2023/4/3118Tc殺傷靶細(xì)胞的過程Tccell1.Tcrecognizesantigenontargetcell

TargetcellTccell2.AlethalhitisdeliveredbytheTcusingagentssuchasperforinorgranzymeBTargetcellTccell3.TheTcdetaches

fromthetargetcellTargetcell4.Targetcelldies

byapoptosisTargetcell2023/4/3119T殺傷細(xì)胞殺傷病毒感染把細(xì)胞的過程T淋巴細(xì)胞？病毒感染的靶細(xì)胞？

2023/4/31202023/4/3121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)胞不儲存，需要時產(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)2023/4/31226.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)胞對細(xì)胞因子的應(yīng)答較慢，需要合成新的mRNA和蛋白質(zhì)2023/4/3123細(xì)胞因子對免疫細(xì)胞的作用LymphocyteMacrophageBcellTcellNKLAKProliferation,Differentiation,Igsecretion

andselectionProliferation,Dif