临床免疫学-抗感染免疫-临床研究生-课件

抗微生物免疫-抗菌免疫

-抗病毒免疫2023/10/61抗微生物免疫2023/10/61感染免疫力感染灶的范围x毒力免疫力疾病=感染与免疫之间的平衡关系与疾病机体抗感染机制-共性-个性：不同微生物的特性和致病机制不同抗感染免疫2023/10/62感染免疫力感染灶的范围x毒力免疫力疾病=感染与免疫之间Spectrumof

virulence脊髓灰质炎0.1-1%显性感染风疹50%显性感染狂犬病100%显性感染感染性疾病的“冰山”概念Theicebergconceptofinfectiousdisease无症状感染

典型临床疾病表现轻度疾病lessseveredisease2023/10/63Spectrumofvirulence脊髓灰质炎风疹狂犬微生物的结构与免疫应答

-内部抗原

-外部抗原

-与致病性的关系（进入途径、感染部位全身/浅表、靶细胞/组织）

-寄生的部位：细胞外；兼性细胞内；专性细胞内寄生

-诱导产生免疫应答的类型抗微生物感染免疫

-天然免疫

-特异性免疫细胞免疫应答/体液免疫应答 保护性免疫应答 免疫损伤（超敏反应、自身免疫应答）2023/10/64微生物的结构与免疫应答2023/10/64微生物体积的大小不同细菌衣原体病毒体积微小2023/10/65微生物体积的大小不同细菌衣原体病毒体积微小2023/10/6Figure2-1不同免疫应答的时间抗再次感染？抗再次感染？抗再次感染抗再次感染应答的时间初次感染2023/10/66Figure2-1不同免疫应答的时间抗再次感染？抗再次感染抗菌免疫ImmunitytoBacteria基本原则1)抗菌免疫机制与细菌表面结构相关

细胞壁和细胞膜包括LPS -flagella(鞭毛) -fimbriae(菌毛) -capsules(荚膜)2023/10/67抗菌免疫2023/10/67细菌细胞表面结构：免疫系统作用的靶标细胞壁结构与细菌的抵抗力有关

结核杆菌细胞壁的抵抗力强细菌荚膜抗吞噬

链球菌、炭疽杆菌有毒株具有荚膜细菌细胞壁成分佐剂活性-激发炎性细胞因子

(LPS,capsule,arabinoglactan/glycolipids)2023/10/68细菌细胞表面结构：免疫系统作用的靶标2023/10/68不同微生物具有不同的细胞壁结构

-革兰阳性细菌（G+）

-革兰阴性细菌（G-）

-分支杆菌(结核分支杆菌) -Spriochaetes（螺旋体）不同的细菌-细胞壁结构不同

-致病性、致病机制不同

-抗感染免疫不同2023/10/69不同微生物具有不同的细胞壁结构2023/10/69G+金葡菌G-大肠杆菌分枝杆菌螺旋体细菌细胞壁结构2023/10/610G+G-分枝杆菌螺旋体细菌细胞壁结构2023/10/610G+金葡菌G-大肠杆菌革兰阴性菌的脂质外膜

-补体-裂解

-NK-杀伤

-阳离子蛋白肽聚糖-细胞壁成分

-溶菌酶2023/10/611G+G-革兰阴性菌的脂质外膜肽聚糖-细胞壁成分2023/1革兰阴性菌的脂质外膜（G-）-细胞壁成分

-补体-裂解

-NK-杀伤

-阳离子蛋白肽聚糖-细胞壁成分

-溶菌酶鞭毛和菌毛

-抗体菌细胞

-吞噬细胞细胞表面结构与免疫力研究抗菌免疫时，需了解该菌结构2023/10/612革兰阴性菌的脂质外膜（G-）-细胞壁成分细胞表面结构与免疫2)抗菌免疫机制与细菌致病性相关细菌的致病性①产生毒素,但不具侵袭力 毒素(Corynebacteriumdiphtheriae,VibrioCholerae)

免疫力：Neutralizationantibody/中和抗体

Anti-adhesionAb/抗黏附抗体②具有侵袭力,但不产生毒素酶类：扩散因子(tissue-degradingenzymes)

免疫力：杀伤菌细胞③大多数细菌既产生毒素也具侵袭力2023/10/6132)抗菌免疫机制与细菌致病性相关2023/10/613Adhesion/黏附toxin产生毒素entryMultiplication繁殖AdhesionMultiplication繁殖Toxin产生毒素2023/10/614Adhesion/黏附entryAdhesion2023/13)免疫机制与细菌赖于环境的生存能力相关①胞外菌：葡萄球菌、链球菌

②兼性胞内寄生菌：结核分枝杆菌③专性胞内寄生菌：衣原体、立克氏体病毒等

-存活绝对依赖细胞的内环境2023/10/6153)免疫机制与细菌赖于环境的生存能力相关2023/10/6ExtracellularversusIntracellularpathogenExtracellularpathogencapableofreplicatingoutsideofthehostcellsdestroyedwhenphagocytoseddamagingtissuesastheyremainoutsidecellsinducingtheproductionofopsonizingantibodiesusuallycauseacutediseasesofrelativelyshortdurationIntracellularpathogencanmultiplywithinphagocytesfrequentlycausechronicdisease2023/10/616ExtracellularversusIntracell17ExtracellularpathogenRespiratorytract,cutaneous,infections:

Streptococcusspp,Staphylococcusspp.Digestiontractinfections:

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

ChlamydiatrachomatisCNS+othersites:

Listeriamonocytogenes;Pregnantwomen;immunosuppressivepatients2023/10/617Extracellularpathogen2023/18EndosomesPhagosomeslysosomesPhagolysosomes军团菌衣原体李斯特菌志贺菌沙门菌结核菌胞内寄生菌Cytosol:pH=7Phagosome:pH=6Phagolysosome:pH=52023/10/618EndosomesPhagosomeslysosomesFigure10-4胞外寄生菌胞内寄生菌感染部位病原体保护性免疫2023/10/619Figure10-4胞外寄生菌胞内寄生菌感染部位病原体保护呼吸道消化道眼皮肤生殖道4)人体解剖结构与免疫

-无/有菌状态的差异

-免疫因子/细胞的差异

-免疫应答的特点/差异2023/10/620呼吸道消化道眼皮肤生殖道4)人体解剖结构与免疫2023/1AdenoidTonsilLymphnodesSpleenPeyer’spatches(smallintestine)AppendixLymphaticvesselsLymphnodeMassesofdefensivecellsBloodcapillaryLymphaticvesselTissuecellsInterstitialfluid淋巴系统2023/10/621AdenoidTonsilLymphSpleenPeyer’INNATEIMMUNITYRecognitionoftraitssharedbybroadrangesofpathogens,usingasmallsetofreceptorsRapidresponseRecognitionoftraitsspecifictoparticularpathogens,usingavastarrayofreceptorsSlowerresponseACQUIREDIMMUNITYPathogens(microorganismsandviruses)Barrierdefenses:SkinMucousmembranesSecretionsInternaldefenses:PhagocyticcellsAntimicrobialproteinsInflammatoryresponseNaturalkillercellsHumoralresponse:Antibodiesdefendagainstinfectioninbodyfluids.Cell-mediatedresponse:Cytotoxiclymphocytesdefendagainstinfectioninbodycells.人体抗菌免疫的三道防线2023/10/622INNATEIMMUNITYRecognitionof一般因素物理和化学屏障系统完整的皮肤和粘膜上皮细胞纤毛体液、胃酸、眼泪低pH(皮肤,阴道,etc.)发热>37ºC年龄婴儿vs.幼儿vs.老人2.人体抗菌免疫的第一道防线2023/10/623一般因素2.人体抗菌免疫的第一道防线2023/10/62LactobacillusacidophilusLactobacilluscaseiEnterococcusfaeciumSaccharomycescerevisiae营养状况激素孕妇感染HEV-死亡率遗传因子宿主种属的抗性共生菌

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

-lactobacillietc.酸奶-保加利亚乳酸杆菌嗜热链救菌

双岐杆菌嗜酸乳杆菌2023/10/624LactobacillusLactobacillusEnSomeprotectivefactorsfound

inbodytissuesandfluids2023/10/625SomeprotectivefactorsfoundAntimicrobialPeptidesandProteinsPeptidesandproteinsfunctionininnatedefensebyattackingmicrobesdirectlyorimpedingtheirreproductionAntimicrobialpeptides："hostdefensepeptides"partofthe

innateimmuneresponse

foundamongallclassesoflife.Thesepeptidesarepotent,broadspectrum

antibiotics

whichdemonstratepotentialasnovelpotentialtherapeuticagents.-kill

Gramnegative

and

Grampositive

bacteria,envelopedviruses,fungiandeventransformedorcancerouscells.-enhanceimmunitybyfunctioningas

immunomodulatory.

Thecomplementsystem~30proteins -lysisofinvadingcells -helpstriggerinflammation2023/10/626AntimicrobialPeptidesandProVariousstructuresofantimicrobialpeptidesThemodesofactionbyAntimicrobialpeptidesImmunomodulatory

functions:AlterhostgeneexpressionActaschemokinesand/orinduce

chemokine

productionInhibiting

LPS

inducedpro-inflammatory

cytokine

productionPromotingwoundhealingModulatingtheresponsesof

dendriticcells

andcellsoftheadaptiveimmuneresponse2023/10/627VariousstructuresofantimicrFigure2-19趋化裂解调理补体的抗菌作用2023/10/628Figure2-19趋化裂解调理补体2023/10/6283.人体抗菌免疫的第二道防线 识别细菌保守的“共有”成分天然免疫/固有免疫/InnateImmunity无记忆 同一微生物每次感染后的免疫应答强度均相似无多样性免疫分子的基因不会出现重组2023/10/6293.人体抗菌免疫的第二道防线天然免疫/固有免疫/InnOutcomeofInfectionInfectionwins deathInfectionloses live(innateplusadaptive)

StudiedintenselyBestoutcomeisInfectionskilledquickly(innateonly)

Notwellstudied

Howisitthatmostpeoplearenotperpetuallysick?(Innateimmunitysquelchingmostinfections)2023/10/630OutcomeofInfectionInfection微生物存活数量天然免疫缺损小鼠天然免疫正常小鼠T、B细胞缺损小鼠天然免疫在微生物感染中的作用2023/10/631微生物存活数量天然免疫天然免疫T、B细胞2023/10/63天然免疫识别的细菌细胞壁的表面成分G-bacteriaG+bacteria脂多糖脂蛋白孔蛋白穿孔素磷壁酸肽聚糖2023/10/632天然免疫识别的细菌细胞壁的表面成分G-bacteriaG+物种演化中遗传的古老广谱抗微生物机制微生物的LPS,甘露糖等“pathogen-associatedmolecularpatterns”–PAMPs识别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)CLR2023/10/633物种演化中遗传的古老广谱MBLMannosebindingEXTRACELLULARFLUIDLipopolysaccharideFlagellinTLR4TLR5HelperproteinTLR9TLR3WHITEBLOODCELLVESICLECpGDNAdsRNAInflammatoryresponsesPAMPsPRRs2023/10/634EXTRACELLULARLipopolysaccharid

不同Toll-likeReceptors识别不同微生物的产物2023/10/635不同Toll-likeReceptors识别不同微生物的TLR9UnmethylatedCpGDNAdsRNATLR3TLR7ssRNATLR4TLR2TLR6TLR1TLR5LipoproteinsLipoarabinomannanLipoteichoicAcidsZymosan(Yeast)LPSFlagellinCD14MD2TLR11T.gondiProfilin识别细菌Toll-likeReceptors识别微生物的表面产物/结构2023/10/636TLR9UnmethylateddsRNATLR3TLR7TLR4TLR2TLR6TLR1TLR5TLR9PeptidoglycanLipoproteinsLipoarabinomannanLPS(Leptospira)LPS(Porphyromonas)GPI(T.Cruzi)Zymosan(Yeast)LPSLipoteichoicAcidsFlagellinUnmethylatedCpGDNAdsRNACD14TLR3TLR7ssRNAMD2TLR11识别病毒T.gondiProfilinToll-likeReceptors识别病毒2023/10/637TLR4TLR2TLR6TLR1TLR5TLR9Peptid吞噬细胞表面具有识别微生物成分的多种受体2023/10/638吞噬细胞表面具有识别微生物成分的多种受体2023/10/63PhagocytosisandkillingPrimarygranules:AntimicrobialpeptidesLysozyme(degradespeptidoglycan)Proteases(elastase,etc.)Secondarygranules:phagocyteoxidase©NewSciencePressLtd.2004MicrobesPHAGOCYTICCELLVacuoleLysosomecontainingenzymesPrimarygranuleslysosomeSecondarygranulesLysosomes:Digestiveenzymes2023/10/639PhagocytosisandkillingPrimarPhagosytosisanddestructionofbacteriasuperoxidedismutase：superoxide(O2-),hydrogenperoxide(H2O2),andsingletoxygen,hydroxylradicalsmyeloperoxidase

（phagolysosome）,hydrogenperoxide+chlorinehypochlorite(toxictobacteria)Oxygen-dependentbacteria-killingsubstance2023/10/640PhagosytosisanddestructionoEffectorMoleculeFunctionCationicproteins(cathepsin)DamagetomicrobialmembranesLysozymeHydrolysesmucopeptidesinthecellwallLactoferrinDeprivespathogensofironHydrolyticenzymes(proteases)DigestskilledorganismsOxygenIndependentKillinginthePhago-lysosome2023/10/641EffectorMoleculeFunctionCatio趋化吞噬2023/10/642趋化吞噬2023/10/642Therearedifferenttypesofphagocyticcells:Neutrophils

engulfanddestroymicrobesMacrophages

arepartofthelymphaticsystemandarefoundthroughoutthebodyDendriticcellsstimulatedevelopmentofacquiredimmunityEosinophilsdischargedestructiveenzymes2023/10/643NeutrophilphagocytosinganthraxbacilliTherearedifferenttypesofpFigure2-152023/10/644Figure2-152023/10/644Figure2-5part1of2巨噬细胞表面表达多种受体细菌表面成分与巨噬细胞表面受体结合细菌与巨噬细胞表面受体结合后激发细胞因子/炎性因子的释放巨噬细胞吞噬细菌2023/10/645Figure2-5part1of2巨噬细胞表面表达IFN-g释放NK细胞激活2023/10/646inflammasome

Nod-likereceptors(NLRs)

IFN-g释放2023/10/646inflammasom2023/10/647Inflammasomeactivationanddiseases2023/10/647InflammasomeactivaInflammatoryResponsesInflammationisaprotectiveresponsethatinvolvesimmunecells,bloodvessels,andmolecularmediators,Mastcell,-containsmanygranulesrichinhistamineandheparin,promoteschangesinbloodvessels,apartoftheinflammatoryresponseIncreaselocalbloodsupplyandallowmorephagocytesandantimicrobialproteinstoentertissuesPus,afluidrichinWBC,deadmicrobes,andcelldebris,accumulatesatthesiteofinflammation2023/10/648InflammatoryResponsesInflammaTNF©NewSciencePressLtd.2000ormastcell2023/10/649TNF©NewSciencePressLtd.20Fig.43-8-1PathogenSplinterMacrophageMastcellChemicalsignalsCapillaryPhagocyticcellRedbloodcellsFluid2023/10/650Fig.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:assumeadendriticcellphenotypeandpropagateadaptiveimmunepriming2023/10/651Inflammation:Neutrophilsvs.Cytokinestorm

-sepsissyndromeBacterialsepticemialeadstoactivationofTLRsonmonocytesinthebloodSystemicreleaseofTNFandIL-1leadsto“inflammation”alloverthebodyShockfromlossofbloodpressure(vasodilationandleakageoffluidintotissues)TLRsalsoinducecoagulation(viatissuefactor)Thecombinationofeffectscanleadtomulti-organfailureanddeath2023/10/652Cytokinestorm

-sepsissyndrom2023/10/653通过多途径控制感染2023/10/653通过多途径控制感染TNFproductionInductionofSignalingCascadesNFActivationBIOLOGICALEFFECTSHowdomacrophagesdetectLPS?宿主抵抗LPS的机制2023/10/654TNFproductionInductionofSigLBP和CD14是内毒素的受体MacrophagesEndothelialcellsBiologicalActivitiesEarlierSignalingEvents?LBP-CD14Co-receptor(s)??2023/10/655LBP和CD14是内毒素的受体MacrophagesLPSBindingProtein/LPS结合蛋白(LBP)60-kDa血浆糖蛋白具有与LPS高亲和力由肝细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对少量LPS或革兰阴性菌快速反应，运输至巨噬细胞LPS,上调IL-1,IL-6andTNF表达.CD14-巨噬细胞表面

-可溶性CD14-上皮细胞-与LBP共同将LPS结合于细胞表面2023/10/656LPSBindingProtein/LPS结合蛋白(特异性抗菌免疫2023/10/657特异性抗菌免疫2023/10/657Figure2-1不同免疫应答的时间抗再次感染抗再次感染应答的时间特异性抗菌免疫2023/10/658Figure2-1不同免疫应答的时间抗再次感染抗再次感染应巨噬细胞与淋巴细胞相互作用巨噬细胞淋巴细胞细菌Cytokinesaresecretedbymacrophagesanddendriticcellstorecruitandactivatelymphocytes2023/10/659巨噬细胞与淋巴细胞相互作用巨噬细胞淋巴细胞细菌Cytok

Antigen-bindingsite

Antigen-bindingsiteAntigen-bindingsiteDisulfidebridge

VariableregionsConstantregionsTransmembraneregionPlasmamembraneLightchainHeavychainsTcellchainchainDisulfidebridgeCytoplasmofTcell(b)TcellreceptorCytoplasmofBcell(a)BcellreceptorBcellVVCCVVCCCCVVAsingleBcellorTcellhasabout100,000identicalantigenreceptors2023/10/660Antigen-Antigen-AnFigure9-5T辅助细胞-B细胞激活，B细胞分化为浆细胞，分泌特异性抗体2023/10/661Figure9-5T辅助细胞-B细胞激活，B细胞分化为浆Figure9-19part1of22023/10/662Figure9-19part1of22023/10Figure9-19part2of22023/10/663Figure9-19part2of22023/10特异性体液免疫-抗胞外菌特异性抗体-毒素--中和-菌细胞--调理抗体+吞噬细胞-菌细胞--裂解

抗体+补体-阻断细菌黏附中和调理裂解2023/10/664特异性体液免疫中和调理裂解2023/10/664抗黏附抗体阻断细菌定居2023/10/665抗黏附抗体2023/10/665Anti-ExtracellularBacteriaExtracellularBacteriaCapableofreplicatingoutsideofthehostcells.Theycausediseasebytwoprinciplemechanisms.InduceinflammationManyofthesebacteriaproducetoxins.EndotoxinsExotoxins2023/10/666Anti-ExtracellularBacteriaExtInnateimmunitytoExtracellularBacteriaPhagocytosisbyneutrophils,monocytes,andthetissuemacrophages.Activationofthecomplementsystem(withoutantibody) ChemotaxisC3a,C5a, OpsonizationC3betc, lyticcomplexC5-9ChemotexistriggeredbyPAMPs,chemokine,C3a,C5aectCytokinesTNF,IL-1,andchemokine:MCP-1,MIP-1aNK–INF-gTheimmuneresponsesagainstextracellularbacteria -eliminatingthebacteria -neutralizingtheeffectsoftoxins.2023/10/667InnateimmunitytoExtracellulHumoralimmunityistheprinciplespecificimmuneresponseagainstextracellularbacteria-StrongIgMresponsesarecausedbypolysaccharides.AntibodiesIgMandIgGagainstbacteriasurfaceantigensandtoxinsstimulatethreetypesofeffectormechanisms:-opsonizebacteriaandenhancephagocytosis-neutralizebacterialtoxins -inhibitbacterialenzymeactivities -limitthebacteriamobility-activatethecomplementsystem(lyticandopsonic) -IgA(local/mucosalimmunity)blockbacteriaadhesionPrincipalinjuriesofhostresponsestoextracellularbacteria:Inflammation&SepticshockSpecificImmunityExtracellularBacteria2023/10/668Humoralimmunityistheprinci69IntracellularbacteriaNofusionLysozomePhagosomeFusionEntercytoplasmBacteriaMacrophageorneutrophilPhagolysosomes2023/10/669IntracellularbacteriaNofus70EndosomesPhagosomeslysosomesPhagolysosomes军团菌衣原体李斯特菌志贺菌沙门菌结核菌Anti-IntracellularBacteriaCytosol:pH=7Phagosome:pH=6Phagolysosome:pH=52023/10/670EndosomesPhagosomeslysosomes1.胞内寄生菌对宿主细胞几乎无/或无直接的毒性作用；但感染伴随迟发型超敏反应2.胞内寄生菌能与宿主长期共存，导致慢性感染；胞外菌引起急性感染3.胞内寄生菌感染的病理与免疫损伤有关，而胞外菌往往产生毒素直接造成组织损伤；4.T细胞是控制胞内寄生菌感染主要免疫因素；胞内寄生菌感染的特征2023/10/6711.胞内寄生菌对宿主细胞几乎无/或无直接的毒性作用；但感染伴Anti-IntracellularBacteriaIntercellularbacteriahavetheabilitytosurviveandevenreplicatewithinphagocytesImmuneresponsesforeliminationofintracellularbacteria-verydifferentfromtheresponsesagainstextracellularbacteria.InnateimmunitytointracellularBacteria-Intracellularbacteriaareresistanttodegradationwithinphagocytes.-IntracellularbacteriaactivateNKcells,eitherdirectlyorbystimulatingmacrophagesproductionofIL-12,apowerfulNKcell–activatingcytokine.2023/10/672Anti-IntracellularBacteriaIntSpecificImmunitytoIntracellularBacteriaCell-mediatedimmuneresponseisthemajorspecificimmuneresponseagainstintracellularbacteria.Twotypesofcell-mediatedreactions:KillingofphagocytosedintracellularbacteriaasaresultofmacrophageactivationbyTcellderivedcytokines,particularlyIFN-gamma.LysisofinfectedcellsbyCTLs.Tissuedamagecausedbymacrophageactivationthatoccursinresponsetointracellularbacteria.2023/10/673SpecificImmunitytoIntracell抗胞内寄生菌的天然免疫和获得性免疫活菌数感染清除感染控制活菌数活菌数感染后天数2023/10/674抗胞内寄生菌的天然免疫和获得性免疫活菌数感染清除感染控制活菌Figure1-262023/10/675Figure1-262023/10/675结核分枝杆菌的胞内感染CD4Tcells控制结核感染ImmunitytotheintracellularbacteriainvolvesaDTHresponse激活的巨噬细胞包裹感染灶-结核球tubercle.巨噬细胞释放的酶导致肺组织损伤2023/10/676结核分枝杆菌的胞内感染CD4Tcells控制结核感染2细菌 致病性 免疫机制

白喉杆菌 非侵袭性毒素 中和抗体霍乱弧菌 非侵袭性毒素 中和抗体、阻断细菌黏附奈瑟菌脑膜炎双球菌 侵袭性 抗体、补体裂解、吞噬、调理金黄色葡萄球菌 局部侵袭性+毒素

抗体和补体的调理、吞噬、结核杆菌 侵袭性、激发免疫病理 巨噬细胞激活麻风杆菌 侵袭性、激发免疫病理 巨噬细胞激活2023/10/677细菌 致病性 免疫机制78EVASIONSTRATEGIES(1)2023/10/6ref78EVASIONSTRATEGIES(1)2023/79EVASIONSTRATEGIES(2)2023/10/6ref79EVASIONSTRATEGIES(2)2023/病毒基本结构：核酸+蛋白 核酸+蛋白+包膜（含脂质和糖蛋白）抗病毒免疫2023/10/680病毒基本结构：核酸+蛋白抗病毒免疫2023/10/680病毒复制周期吸附穿入脱衣壳生化合成装配释放出芽方式释放细胞裂解释放2023/10/681病毒复制周期吸附穿入脱衣壳生化合成装配释放出芽方式释放细Figure2-49病毒感染后体内免疫应答的动态变化2023/10/682Figure2-49病毒感染后体内免疫应答的动态变化202干扰素细胞因子IFN-gCTL细胞增殖CTLT细胞增殖IFN-g，细胞因子抗体天然免疫获得性免疫2023/10/683干扰素天然免疫获得性免疫2023/10/683屏障系统

-respiratoryepitheliumandskin,etc.2.体液

-stomachacid,tears,etc.3.干扰素4.NK细胞5.巨噬细胞抗病毒天然免疫2023/10/684屏障系统抗病毒天然免疫2023/10/684干扰素Interferons(IFN) -第一个被发现的抗病毒因子

-免疫调节剂

-IFNalpha，beta，gamma

IFNalpha

20variants白细胞–病毒

IFNbeta

单个蛋白，纤维母细胞–病毒

IFNgamma单个蛋白，NK细胞，

T细胞–抗原，mitogensTypeITypeII2023/10/685干扰素Interferons(IFN)TypeIType干扰素诱生剂

IFN-alphaandIFN-beta诱生剂：

virusinfection: -RNAviruses -DNAvirusesarepoorIFNinducers,withtheexceptionofpoxviruses. -doublestrandedRNA -LPS,andcomponentsfromsomebacteriaIFN-gamma诱生剂: -有丝分裂原mitogens -抗原antigen中草药

2023/10/686干扰素诱生剂2023/10/686Interferons

生物学活性

-anti-viralactivity抗病毒

-immunomodulateactivity免疫调节

-regulationofcellularproliferation

调节细胞增殖2023/10/687Interferons2023/10/687IFNtypeI,II不同受体不同的激活途径调控不同生物学活性Ⅰ型干扰素受体基因位于人染色体第21对染色体Ⅱ型干扰素受体基因位于第6对染色体2023/10/688IFNtypeI,II2023/10/688IFN的抗病毒作用病毒病毒复制抑制病毒复制信号转导IFN-aIFN-诱导蛋白诱导刺激胞核胞核IFN受体细胞建立抗病毒状态病毒感染细胞2023/10/689IFN的抗病毒作用病毒病毒复制抑制病毒复制信号转导IFN干扰素通过作用于具有干扰素受体的细胞发挥抗病毒作用mRNA降解蛋白合成抑制抗病毒状态病毒易感患者：干扰素产生能力？受体变异？信号转导通路的改变/影响？2023/10/690干扰素通过mRNA降解蛋白合成抑制抗病毒状态病毒易感患者：2IFN的临床应用病毒感染乙型肝炎丙型肝炎疣-人乳头瘤病毒/HPV呼吸道合胞病毒肿瘤毛细胞白血病(90%有效)滤泡性淋巴瘤宫颈癌(HPV)基底细胞癌(80-90%)卡波济瘤(HHVtype8)Otherconditions -慢性

肉芽肿病毒(IFN-g) -多硬化症2023/10/691IFN的临床应用病毒感染肿瘤Otherconditions自然杀伤细胞(NKcell)病毒感染的靶细胞无TandB细胞标志(noTCR)CD5（specificNKmarker）FcRIII(CD16)IL-2

作用使NK分化为lymphokine-activatedkiller(LAK)cells2023/10/692自然杀伤细胞(NKcell)病毒感染的靶细胞无T2023/10/693ComplementaryactivitiesofCTLs

andNKcells2023/10/693ComplementaryactivNK细胞的效应机制杀伤靶细胞的机制类似于Tccells杀伤靶细胞的活性为非MHC限制对NK细胞敏感的靶细胞

-MHCI表达下调

killerinhibitoryreceptors(KIR)onNKcellsrecognizeclassIMHCandpreventkillingNK细胞表面具有FcRIII(CD16)可识别IgG-coated靶细胞发挥ADCC活性杀伤靶细胞antibody-dependentcell-mediatedcytotoxicity2023/10/694NK细胞的效应机制杀伤靶细胞的机制类似于TccellsMacrophage/巨噬细胞细胞因子淋巴因子激活功能增强吞噬、杀伤呈递抗原免疫调节2023/10/695Macrophage/巨噬细胞细胞因子淋巴因子激活功能增强吞

抗病毒特异性免疫应答病毒抗原呈递途径抗原呈递细胞:专职性：树突状细胞、B细胞等

CD8+MHCI CD4+MHCII相同MHC分子的细胞才能呈递抗原

(试验中的难点)2023/10/696抗原呈递细胞:相同MHC分子的细胞才能呈递抗原2023抗原的处理和呈递病毒在细胞内,MHCclassI抗原呈递途径,Tc胞外细菌,MHCclassII抗原呈递途径,Th2,Ab胞内寄生菌,MHCclassI+MHCclassII,Th1response MHCI/II特异性2023/10/697抗原的处理和呈递病毒在细胞内,MHCclassI抗原外源性抗原呈递途径2023/10/698外源性抗原呈递途径2023/10/698内源性抗原呈递途径2023/10/699内源性抗原呈递途径2023/10/699V.Brusic,2002内质网蛋白酶体蛋白抗原T杀伤细胞MHCI-抗原肽复合体2023/10/6100V.Brusic,2002内质网蛋白酶体蛋白抗原T杀伤T细胞受体(TCR)TCR识别抗原肽-MHC复合体T辅助细胞(Th)TCR识别

抗原肽-MHCclassII复合体T杀伤细胞(Tc)识别抗原肽-MHCclassI复合体MHCII-抗原肽复合体MHCI-抗原肽复合体2023/10/6101T细胞受体(TCR)TCR识别抗原肽-MHC复合体MH2023/10/61022023/10/6102Fig.43-17Antigen-presentingcellPeptideantigenCell-mediatedimmunity(attackoninfectedcells)ClassIIMHCmoleculeCD4TCR(Tcellreceptor)HelperTcellHumoralimmunity(secretionofantibodiesbyplasmacells)CytotoxicTcellCytokinesBcellBacterium++++2023/10/6103Fig.43-17Antigen-PeptideantiFig.43-19Antigen-presentingcellEndoplasmicreticulumofplasmacellSecretedantibodymoleculesBacteriumBcellPeptideantigenClassIIMHCmoleculeTCRCD4HelperTcellActivatedhelperTcellCytokinesCloneofmemoryBcellsCloneofplasmacells2µm+2023/10/6104Fig.43-19Antigen-presentingc保护性特异性免疫应答中和抗体-中和游离的病毒，在再感染中发挥保护性作用2.细胞免疫应答

-T辅助细胞：Th1/Th2 -细胞因子Cytokines(IFN-r) -T杀伤细胞CytotoxicT-cells

在清除病毒感染的靶细胞非常重要3.Ab-mediatedlysis(补体,NK细胞)

抗体介导的靶细胞裂解2023/10/6105保护性特异性免疫应答中和抗体2023/10/6105保护性特异性免疫应答中和抗体-中和游离的病毒，在再感染中发挥保护性作用2.细胞免疫应答

-T辅助细胞：Th1/Th2 -细胞因子Cytokines(IFN-r) -T杀伤细胞CytotoxicT-cells

在清除病毒感染的靶细胞非常重要3.Ab-mediatedlysis(补体,NK细胞)

抗体介导的靶细胞裂解2023/10/6106保护性特异性免疫应答中和抗体2023/10/6106Fig.43-21ViralneutralizationVirusOpsonizationBacteriavirusMacrophageActivationofcomplementsystemandporeformationComplementproteinsFormationofmembraneattackcomplexFlowofwaterandionsPoreForeigncell2023/10/6107Fig.43-21ViralneutralizationIgM感染早期诊断指标2023/10/6108IgM感染早期诊断指标2023/10/6108病毒高滴度低滴度2023/10/6109病毒高滴度低滴度2023/10/6109保护性特异性免疫应答中和抗体-中和游离的病毒，在再感染中发挥保护性作用2.细胞免疫应答

-T辅助细胞：Th1/Th2 -细胞因子Cytokines(IFN-r) -T杀伤细胞CytotoxicT-cells

在清除病毒感染的靶细胞非常重要3.Ab-mediatedlysis(补体,NK细胞)

抗体介导的靶细胞裂解2023/10/6110保护性特异性免疫应答中和抗体2023/10/6110TCellsT细胞在病毒感染中起关键性的作用-T杀伤细胞CytotoxicTcells(CTLs)

杀伤病毒感染的细胞 阻断病毒的扩散-T辅助细胞HelperTcells

辅助CTLs的产生 辅助B细胞产生特异性抗体-Lymphokines T细胞产生的细胞因子，招募和激活巨噬细胞和NK细胞，作用于病毒感染的细胞2023/10/6111TCells2023/10/6111T辅助细胞2023/10/6112T辅助细胞2023/10/61122023/10/61132023/10/6113IgG2a(mu)IgG1(hu)IgG1(mu)IgG4(hu)2023/10/6114IgG2a(mu)IgG1(mu)2023/10/6114Figure9-72023/10/6115Figure9-72023/10/6115Th17TcelldevelopmentallydistinctfromTh1andTh2cellsandexcessiveamountsofthecellarethoughttoplayakeyroleinautoimmunedisease-Th17Tcellsserveaveryimportantfunctioninanti-microbialimmunityatepithelial/mucosalbarriers.-Th17cellsproducecytokines(suchasinterleukin22)whichstimulatesepithelialcellstoproduceanti-microbialproteinstoclearoutcertaintypesofmicrobe(suchasCandidaandStaphylococcus).-AlackofTh17cellsmayleavethehostsusceptibletoopportunisticinfections-Th17Tcellscancausesevereautoimmunediseases2023/10/6116Th17TcelldevelopmentallydiTc细胞的激活Pre-TccellTccellThelpercellClassIMHCClassIIMHCAPC1.CellexpressingclassIMHCpresentsantigen()

toapre-TccellIFNIL-22.Antigen-presentingcellpresentsantigeninassociationwith

classIIMHCtoThcell3.Thcellmakescytokines4.Pre-TccelldifferentiatestofunctionalTccell5.TcrecognizesantigenonclassIMHC-expressingtargetcell6.Targetcelliskilled2023/10/6117Tc细胞的激活Pre-TccellTccellTheMechanismofTcKillingTc

cellCa++PerforinmonomersPerforinpolymerizesPolyperforin

channelsTc

cellTargetcellGranzymesTarget

celllysisapoptosis2023/10/6118MechanismofTcKillingTccellTc杀伤靶细胞的过程Tccell1.Tcrecognizesantigenontargetcell

TargetcellTccell2.AlethalhitisdeliveredbytheTcusingagentssuchasperforinorgranzymeBTargetcellTccell3.TheTcdetaches

fromthetargetcellTargetcell4.Targetcelldies

byapoptosisTargetcell2023/10/6119Tc杀伤靶细胞的过程Tccell1.TcrecognT杀伤细胞杀伤病毒感染把细胞的过程T淋巴细胞？病毒感染的靶细胞？

2023/10/6120T杀伤细胞杀伤病毒感染把细胞的过程2023/10/61202023/10/61212023/10/6121细胞因子的特性由细胞和免疫细胞产生参与或调节免疫应答分泌短暂和有限

-细胞不储存，需要时产生

-刺激后基因转录合成

-mRNA半衰期短可由多种细胞产生，作用于多种细胞(pleiotropic)不同细胞因子可具有相似的作用(redundant)2023/10/6122细胞因子的特性由细胞和免疫细胞产生2023/10/61226.可影响其他细胞因子的合成

-系列反应producecascades-促进或抑制其它细胞因子的产生

-对免疫应答起正/负调节作用影响其他细胞因子的功能

-拮抗,相加,协同与相应受体结合并举有高亲和力9.细胞对细胞因子的应答较慢，需要合成新的mRNA和蛋白质2023/10/61236.可影响其他细胞因子的合成2023/10/6123细胞因子对免疫细胞的作用LymphocyteMacrophageBcellTcellNKLAKProliferation,Differentiation,Igsecretion

andselectionProliferation,Differentiation,CytokineproductionActivationofcellsofimmunesystemCytokineproductionIL1IL2IL4IL1IL2IL4IL5IL6IFNγcytokines2023/10/6124细胞因子对免疫细胞的作用LymphocyteMacropha细胞因子作用于不同器官Lymphocyte