第13章免疫系統(tǒng)的細(xì)胞

性免獲得性免2014-6- 固有免疫應(yīng)答激活適應(yīng)性免疫應(yīng)2014-6- 第一固有免疫系InnateimmuneAdaptiveimmune2014-6- 第一 免人類淋2014-6- 初級(jí)淋巴與次級(jí)淋初級(jí)(中樞次級(jí)(周圍)淋2014-6- 2014-6-

ChangesintheThymuswith胸腺的重量自出生到上升 后胸腺逐漸萎IdentifyingCellUsingtheCDDN–CD4和CD8雙胸腺細(xì)胞DPCD4和CD8雙陽性胸腺細(xì)胞SP–CD4或CD8陽性胸腺細(xì)胞pTECs–原始胸腺上皮細(xì)胞cTECs–皮質(zhì)胸腺上皮細(xì)胞Over350CDTcells,CD4orCD8andBcells,NKcells,DendriticCells,CD1c(Human),CD11c脾臟是最大的次級(jí)淋巴。它由B細(xì)然細(xì)胞及紅細(xì)胞組成。 2014-6- 淋2014-6- Figure25-16MolecularBiologyoftheCell(?GarlandScienceLymphnodes:Small,bean-shapedstructuresthatproduceandstorecellsthatfightinfectionanddiseaseandarepartofthelymphaticsystem.Lymphnodesalsocontainlymph,theclearfluidthatcarriesthosecellstodifferentpartsofthebody.Whenthebodyisfightinginfection,lymphnodescan eenlargedandfeel第二節(jié)固有免疫系統(tǒng)的細(xì)2014-6- 一、固有免疫系統(tǒng)的細(xì)ProtectionbySkinandMucousPhagocyticRemovedebris(garbageMacrophages,Dendriticcells,Neutrophils,NaturalKillerLymphocytesthatkillvirallyinfectedcellsandeosinophils,basophils,mast巨噬細(xì)胞樹突狀細(xì)胞Dendritic

抗原遞呈細(xì)1、巨噬細(xì)胞LargerthanMadeinbonemarrowasmonocytes,calledmacrophagesoncetheyreachorgans.Monocytes:circulatingintheMacrophages:inthe 巨噬細(xì)胞消滅細(xì) 巨噬細(xì)胞攝入5個(gè)紅細(xì)2014-6- 5-to10-foldlargerthancontainmoreandcomplexorganelles,especiallyproducehigherlevelsofhydrolyticincreasedabilitytokillingestedincreasedsecretionofinfltoryincreasedabilitytoactivateT干擾素

巨噬細(xì)胞功2014-6- 2、樹突狀細(xì)胞

（MHCⅠ和MHCⅡ）2014-6-majorfunctionsofimmatureDCinhighphagocyticsenseofcaptureofforeignmatureDCmigrateintolymphoidhighcytokine-producingpresentationofAgtoT

NatureReviewsimmunology2014-6- 樹突狀細(xì)胞的功 內(nèi)吞作用活胞表面通過MHC分子遞呈這些片斷2014-6-

Theydis yalargevarietyofpatternrecognitionreceptors,includingTLRs,thatenablethecellstorecognizeandphagocytoseinvadingpathogensandtoeactivatedintheThedendriticcellscleavetheproteinsofthepathogensintopeptidefragments,whichthenbindtoMHCproteinsthatcarrythefragmentstothecell (pathogen-derivedpeptides,ascomplexeswithMHCproteins)Activateddendriticcellsalsodis special,cell-surfaceco-stimulatoryproteinsthathelpactivatetheTTheactivateddendriticcellsalsosecreteavarietyofcytokinesthatinfluencethetypeofresponsethattheTcellsmake,ensuringthatitisappropriatetofighttheparticularpathogen.2014-6- Toll樣受體（TLR是單跨膜非催化性蛋白質(zhì)，可識(shí)別微生物的具有保守結(jié)構(gòu)的TLR監(jiān)視與識(shí)別各種不同的疾病相關(guān)分子模式（PAMP），是機(jī)體抵2014-6- TLR在天然免疫中的識(shí)別作Theactivationofamacrophageby

(LPS).LPSbindstoLPS-bindingprotein(LBP)intheblood,andthecomplexbindstotheGPI-anchoredproteinCD14onthemacrophagesurface.TheternarycomplexthenactivatesToll-likereceptor4(TLR4),whichactivatesmultiple,downstream,intracellularsignalingpathways.2014-6- 人類TollTLR11-13TLR10

receptors,TLR）是參與非2014-6- TLR在獲得性免疫系統(tǒng)中的作2014-6- 3、自 細(xì)胞（NK 免疫調(diào)節(jié)NK細(xì) 腫瘤細(xì)2014-6- 4、粒細(xì)受T細(xì)胞分泌的細(xì)胞因子的刺激而活化Thereisonlyonenucleuspercell,butithasanirregularlobedshape2014-6-

Neutrophils(alsocalledpolymorphonuclearleucocytesbecauseoftheirmultilobednucleus)arethemostcommontypeofgranulocyte;theyphagocytoseanddestroymicroorganisms,especiallybacteria,andthushaveakeyroleininnateimmunitytobacterial 2014-6- V.Brinkmannetal.,Science303:1532–1535,NeutrophilsejecttheirchromatintotrapbacteriainastickyScanningelectronmicrographshowingrestingActivatedneutrophilshavemultiplesurfacerufflesandareassociatedwithfibrousstrands(arrow).ThestrandscontainDNAandhistonesandappeartobechromatinfromtheneutrophilnucleusthathasbeenejectedduringtheprocessofactivation.Thestickychromatincanentrapmanydifferentkindsofbacteria,including(lefttoright)Staphylococcusaureus,Salmonellaenterica,andShigellaflexneri.2014-6- parasitesandmodulateallergicinfltoryresponses.嗜堿性粒細(xì)胞（basophil）和肥大細(xì)2014-6- TypesofWhiteBloodThereare5differenttypesofNeutrophilskillEosinophilsAllergicParasiteBasophilsAllergicMonocyteseLymphocytesDirecttheimmune二、固有免疫的防御機(jī)皮膚及粘膜完整的皮形成一個(gè)抵抗微生物進(jìn)入機(jī)體的物理屏粘抑制許多微生物的進(jìn)入，但沒有完整的皮膚那么有粘在呼吸道和消化道內(nèi)抑制微生絨過濾鼻腔內(nèi)的微生物及灰纖與粘液一起，抑制和除去上呼吸道內(nèi)的微生物及灰淚眼淚可以沖淡和洗去刺激性物質(zhì)及微生唾洗去牙齒表面及口腔粘膜上的微生會(huì)厭軟微生物及灰塵進(jìn)尿洗去中的微生2014-6- 皮膚及粘膜－化學(xué)因胃在胃內(nèi)消滅細(xì)菌與眾酸性表阻礙許多微生物的生不飽和脂肪皮脂中的抗菌物溶菌抗菌物干擾補(bǔ)2014-6- Complementcomplements補(bǔ)體并非單一分子，而是存在于、組織液和細(xì)胞膜表 2014-6- 其它反吞噬作小噬細(xì)胞和巨噬細(xì)胞對(duì)外來微粒及消炎癥反鑒定及消滅微生物和修復(fù)組發(fā)抑制微生物的生長及加快機(jī)體的修復(fù)反2014-6- Ifcellsareunderattacktheyreleasehistamine.Histaminepluschemicalsfrompathogensmeanneutrophilsareattractedtothesiteofattack.PathogensareattachedtoantibodiesandneutrophilshaveantibodyFcreceptors.EnodcytosisofneutrophilLysosomesattachtopathogendigestedby吞噬作

Macrophagescanbeactivatedby:ComponentsofbacterialcellwallsparticulateAgbyTHcells(themostpotentoneisMediatorsofthe2014-6- 第三節(jié)適應(yīng)性免疫系統(tǒng)的細(xì) 高效，長時(shí)地免疫 ”物質(zhì)的免疫系統(tǒng)2014-6- AdaptiveTwoComponentsofAdaptiveImmuneSystemHumoral(humoralmediatedB-CellssmaCellsCellular(cellularmediatedCD8+T-CellsDirectCellularKillingCD4+T-CellsRecruitmentofotherimmunecells(infltoryresponse)BcellssecreteantibodiesthatneutralizetheTcellskillthe-infectedInbothcases,innateimmuneresponseshelpactivatetheadaptiveimmuneresponses適應(yīng)性免疫系統(tǒng)中的細(xì)抗原遞呈細(xì)BB淋巴細(xì)BT淋巴細(xì)T(ThT4CD4TcellsT細(xì)胞2014-6- 兩種主要的淋巴細(xì)胞發(fā)育模BandTcellsmaturethencirculateinthebloodandlymphB-cellsmatureinbonemarrowthenconcentrateinlymphnodesandspleenT-cellsmaturein2014-6- 巨噬巨噬樹突細(xì)B2014-6- 二、B巴細(xì)骨髓依賴性淋巴細(xì)胞（bonemarrow前B細(xì)胞(pro-Bcell)在哺乳動(dòng)物的骨髓中再2014-6- TandBRestingTandBcellslookverysimilar,Botharesmall,andcontainlittlecyto TandBcells distinguishablefromeachotheronlyaftertheyhavebeenactivatedbyantigen eeffectorThisrestinglymphocytecouldbeeitheraTcelloraBAneffectorBcell(asmacell)filledwithanextensive2014-6-ER,whichdistendedB細(xì)胞漿細(xì)B細(xì)Thereareasmallgroupofclonesofeachtypeof2014-6- Howcanadaptiveimmunesystemrespondtomillionsofdifferentforeigninahighlyspecificway?HumanBcellscanmakemorethan1012differentantibodymoleculesThehugevarietyiscausedbygenescodingforantibodychangingslightlyduringEachofBcellsmakeadifferentantibodyreactsspecificallywiththeantigenthatinducedtheirproduction.Clonalselection2014-6- ClonalselectionAnanimalfirstrandomlygeneratesavastdiversityoflymphocytesandthenselectsforactivationthoselymphocytesthatcanreactagainsttheforeignthattheanimalAseachlymphocytedevelopsinacentrallymphoidorgan,it escommittedtoreactwithaparticularantigenbeforeeverbeingexposedtotheantigen.2014-6- AttheclonestageantibodiesdonotleavetheB-cells,theabsareembeddedinthesmamembraneofthecell.Whentheabsinthemembranerecognise antigenonthesurfaceofthepathogentheB-celldividesrapidly.ThearepresentedtotheB-cellsby2014-6- Primaryimmuneresponsevs.SecondaryimmuneresponsePrimaryimmuneresponse,occurringonananimal’sfirstexposuretoanantigen.Secondaryimmuneresponse,thelagperiodisshorter,andtheresponseisgreaterandmoreSecondaryresponsereflectsantigen-specificimmunologicalmemoryforantigenA(theanimalmembered‖exposuretoantigenA).Whenthepathogen/infectioninfectsagainitisdestroyedbeforeanysymptomsshow.2014-6- AmodelforthecellularbasisofimmunologicalWhenstimulatedbytheirspecificantigen,naivecellsproliferateanddifferentiate.Most eeffectorcells,whichfunctionandthenusuallydie,whileothers memorycells.Duringasubsequentexposuretothesameantigen,thememorycellsrespondmorereadily,rapidly,andefficientlythandidthenaivecells:theyproliferateandgiverisetoeffectorcellsandtomorememorycells.2014-6- Howcanimmunesystemdistinguishbetweenselfandnon-selfImmunologicalclonaldeletion-cellsthatmightreactwithself-antigenareeliminatedClonalanergy-cellsareformedbutarenotactivatedagainstcertain2014-6- ImmunologicalToleranceEnsuresThatSelfAreNotNormallyAttacked2014-6- 體液免刺激后，經(jīng)一系列的分化、增殖成為漿細(xì)胞，漿細(xì)胞產(chǎn)生抗體，抗體進(jìn)入體2014-6-

在效應(yīng)器階段,激活的Th外源物質(zhì)上以防止 Antibody–shapedprotein,foundonthesurfaceofB-Cellsor intheblood,thatneutralizeantigenbybindingspecificallytoit‖AlsoknownasanWhenantigenstimulatestheproductionofhundredsofspeciesofantibodies,eachmadebyadifferentBcellclone.Suchresponsesaresaidtobe

InmonoclonalresponsesonlyasingleBisactivated.2014-6- B細(xì)胞發(fā)膜表面免疫球蛋白(surfacemembraneimmunoglobulin;(BCR)，可特2014-6- 特異抗ATypicalAntibodyHasTwoIdenticalAntigen-BindingSites

細(xì)胞）。B-細(xì)胞能產(chǎn)生針對(duì)某種特異Anindividualantibodymoleculealwayscontainsidenticallightchainsandidenticalheavychains:2014-6-

免疫球蛋白IgG結(jié)構(gòu) 幾種同型抗體及相應(yīng)的功抗特2014-6- Table25-1MolecularBiologyoftheCell(?GarlandScience2014-6- V是編碼可變區(qū)，有300個(gè)種類；D編碼高變區(qū),有15～20個(gè) 2014-6- Figure25-30MolecularBiologyoftheCell(?GarlandScienceTheorganizationoftheDNAsequencesthatencodetheconstantregionofanantibodyheavychain2014-6- Figure25-33MolecularBiologyoftheCell(?GarlandScienceTheV–Jjoiningprocessinvolvedinmakingahumanklightchain.Figure25-36MolecularBiologyoftheCell(?GarlandScience2014-6- Theroleof binationsignalsequencesinRAG-mediatedgenesegmentjoining2014-6- Figure25-38MolecularBiologyoftheCell(?GarlandScienceThehumanheavy-chainAnorderedclusterofC-regioncodingsequences,eachclusterencodingadifferentclassofheavychain.2014-6- SelectionofantibodylociduringBcelldevelopmentintheboneToproduceantibodieswithonlyonetypeofantigen-bindingsite,adeveloBcellmustuseonlyoneL-chainlocusandoneH-chainlocus.Twoseparatelociencodinglight-chainvariableregionsEachcellhassixlociencodingantibodychains:twoheavy-chainlociandfourlight-chainloci(onefromeach2014-6- Figure25-39MolecularBiologyoftheCell(?GarlandScience抗體的功2014-6- TheroleofIgEinhistaminesecretionbymastThesolubleIgEantibodiesbindtoFcreceptorproteinsonthemastcell2014-6- 抗體的免疫效2014-6- 抗原及其受 withproteins(lipoproteins)andpolysaccharides(glycolipids).Protein,lipidandpolysaccharidearepresentedtotheimmunesystem2014-6- 抗原理化性半抗原或不2014-6- 2014-6- 2014-6- Figure25-19aMolecularBiologyoftheCell(?GarlandScienceTheStrengthofanAntibody–AntigenInctionDependsonBoththeNumberandtheAffinityoftheAntigen-Binding2014-6- Figure25-28MolecularBiologyoftheCell(?GarlandScienceB細(xì)胞膜主要表面2014-6- B細(xì)胞被蛋白抗原和T輔助細(xì)胞活2014-6- Figure25-20MolecularBiologyoftheCell(?GarlandScienceHumoralMediated三、T巴細(xì) 2014-6- 細(xì)胞免2014-6- 或CTLs）,

掃描電鏡2014-6- Afteractivationthecelldividestoform:T-helpercells–secrete→helpBcells→stimulate CytotoxicTcells(killerT→KillbodycellsdisMemoryT→remaininT-輔助細(xì)T-輔助細(xì)胞,即Th（可幫助免疫系統(tǒng)其它細(xì)胞）T輔助細(xì)胞也分泌刺激B細(xì)胞和T細(xì)胞Cytokines,Interleukin,2014-6- THcells(usuallyCD4+):proliferateandvariousTH1response–producesacytokineprofilesupportsinfl tionandactivatesmainlyTcellsandTH2response–activatesmainlyBcellsimmuneresponsesthatdependuponantibodies.T-免 細(xì)胞（Tc細(xì)胞毒素(免疫 )T細(xì)胞 2014-6- T細(xì)胞遷移到淋，并被二次快速激活抑制性T抑制性T細(xì)胞(suppressorTcell)，Ts他們對(duì)2014-6- 電子顯微鏡下細(xì)胞毒T細(xì)胞與T細(xì)胞殺死的癌細(xì)C：免疫熒光顯微鏡下用抗-微管蛋白抗體染色后的T細(xì)胞和癌細(xì)2014-6- T胞抗原受體由細(xì)胞亞型特異性的細(xì)胞抗原受體的MatureT-cellshaveTcellreceptorswhichhaveaverysimilarstructuretoantibodiesandarespecificto1TheyareactivatedwhenthereceptorcomescontactwiththeAgwithanotherhostcell(e.g.onamacrophagemembraneoraninvadedbodycell)2014-6- antigen,TCRshaveonlysTwoIg-likes—onevariable(V)andoneconstant(C).Theantigen-bindingsiteisformedbyaVaandantigen,TCRshaveonlys

Theantigen-bindingsiteisformedbythehypervariableloopsofboththeVaand一個(gè)T細(xì)胞受體（TCR）2014-6- 2014-6- 抗原遞2014-6- 抗原遞呈需要組織相容性（MHC） patibilitycomplex，MHC）。2014-6- MHC人類MHC即為編碼HLA（humanleukocyte

responsegene,Irgene）也存在于2014-6- HLA編碼產(chǎn)I類抗原：HLA-A、HLA-B和HLA-C等31個(gè)座，廣泛表達(dá)在某些免疫細(xì)胞表面，如B細(xì)胞、單核/2014-6- HLA抗原多態(tài)位點(diǎn)多，目前已發(fā)現(xiàn)有229個(gè)，其中有128個(gè)功能共顯性表達(dá)，同一內(nèi)，每個(gè)位點(diǎn)的1對(duì)等位，有些位點(diǎn)有復(fù)等位，這是HLA高度多態(tài)性的最主要原因由于各個(gè)座位是隨機(jī)組合的，故人群中的型可108之多2014-6- 2014-6- CellularMediatedB-Cellshavedirectsurfacereceptors(immunoglobulins)forantigenT-CellsdonotpossesstheseT-CellsneedtohaveantigenpresentedtoAntigenispresentedtoT-Cellsby…AntigenPresentingCellsCellularMediatedAllB-Cells,DendriticPresentantigenfoundinsidethecellPresentantigenfoundoutsidethecellUseanMHCclassmoleculetopresentctwithCD8+T-ctwithCD4+T-CellularGeneral―cling‖Whentheyfindsome(viralprotein,normalcellulardebris)NeedtomakesureitisnotsomethingharmfulAttachthe‖toanMHC-IPresentthis‖toaCD8+T-抗原遞呈的途CD8+T細(xì)胞與MHC家細(xì)胞都表達(dá)MHC 2014-6- GeneralACD8+T-TwostrategiesbywhicheffectorcytotoxicTcellskilltheirtargetcells2014-6- ProfessionalProfessionalAPCshavetheabilitytotakeup(endocytosis)extracellularproteins(selforforeign)BreakdownthisproteinintopeptidesandattachittoanMHC-IImoleculePresentthepeptidetoaCD4+T-抗原遞呈的途CD4+T細(xì)胞與胞表達(dá)MHCII分2014-6- ProfessionalAPCCD4+Th1-CellProfessionalAPCCD4+Th2-Cells內(nèi)源性抗原