粘膜免疫簡(jiǎn)介課件

MucosalImmunity

黏膜免疫Innateresponsescritical先天反應(yīng)的關(guān)鍵Specificimmunityonlyinvoked激活ifinnate固有responseisovercome克服、攻下特異性免疫只有先天免疫被攻克的情況下才被激活Humoral體液Cellmediated細(xì)胞介導(dǎo)FunctionsofMucus

粘液的功能屏障多孔質(zhì)凝膠陷阱粘稠液體凝膠結(jié)合溶膠InnateDefenceatMucosalSurfaces粘膜表面的固有免疫

Mechanical-

Epithelialbarriertrefoils+Mucus Coughing,sneezing,vomiting, Cilia,peristalsis

Humoral-

Stomachacid(pH<1) Mucin(antibacterial,antiviral) Enzymes Defensins(antibacterialpeptides) Polyamines(spermine,spermidine)

Cellular-

Macrophages,mastcells,eosinophils物理方式-上皮屏障三葉草+粘液咳嗽，打噴嚏，嘔吐，纖毛，蠕動(dòng)體液-胃酸（pH值<1）酶

粘蛋白（抗菌，抗病毒）防御素（抗菌肽）多胺（精胺，精胺）細(xì)胞-巨噬細(xì)胞，肥大細(xì)胞，嗜酸性粒細(xì)胞ImportanceofMucosalImmunity

黏膜免疫的重要性Protectionvspathogens保護(hù)VS病原體Preventionofhypersensitivitytofoods,commensalsetc

預(yù)防食物過敏，共生等Immunopathologyofdisease(Crohn’sdisease,coeliacdisease,lunginflam)病的免疫病理學(xué)（Crohn氏病，腹腔疾病，肺炎）Vaccinedevelopment疫苗開發(fā)Lymphocytedevelopment淋巴細(xì)胞發(fā)育DeathsduetoInfectiousDisease大多數(shù)病原通過粘膜屏障入侵AntigenicChallengeinIntestine龐大的表面積-400m2(x200skin)

持續(xù)不斷的抗原攻擊：Foodproteins-25-30kg/yearCommensalbacteria->1014/mlincolonPathogenicbacteria,viruses,parasitesUniqueAspectsofMucosalImmuneSystem1

粘膜免疫系統(tǒng)的獨(dú)特之處1TissuesessentialforlifeSize,range,frequencyofAgexposureAnatomy解剖Lymphoepithelialinteractions淋巴相互作用Uniqueadhesionmolecules(a4b7+MADCAM-1)andchemokines(VIP)獨(dú)特的粘附分子（a4b7+的MAdCAM-1）和趨化因子（VIP）Distinctsitesforantigenuptakeandpriming不同位置對(duì)抗原的攝取和啟動(dòng)SmallIntestinalStructure小腸結(jié)構(gòu)Villi絨毛CryptsPeyer’sPatchesFollicleAssociatedEpithelium“Dome”卵泡關(guān)聯(lián)上皮“半球”PPVilliFollicleAssociatedEpithelium囊泡關(guān)聯(lián)上皮FAE濾泡相關(guān)上皮Follicle囊泡UniqueAspectsofMucosalImmuneSystem2粘膜免疫系統(tǒng)2的獨(dú)特之處Uniqueantigenpresentationmechanisms獨(dú)特的抗原提呈機(jī)制McellsDistinctDCpopulations不同的DC群Distinctiveeffectormechanisms獨(dú)特的效應(yīng)機(jī)制IgAantibodyActivated/memory活化/記憶Tcells+++Extrathymic胸腺外TcellsDominantdownregulatoryenvironment主導(dǎo)下的監(jiān)管環(huán)境Inhibitorymacrophages,DC抑制巨噬細(xì)胞，DCEpithelial上皮products,VIP血管活性腸肽IL10,TGFb,PGE2MCellsAntigenTheMCell“Pocket形成囊”TheMCell“Pocket”TheCommonMucosalImmuneSystemPrimingofamucosalimmuneresponserequiresmucosalimmunisationOtherroutesofimmunisationdoNOTprimemucosalimmunityThisisbecauseonlymucosallyprimedlymphocytesacquirea4b7integrin

ImmunisationviaonemucosaltissuecanprimeothersHumoralImmunityinMucosalTissuesIgA:IgM:IgG

40:3:1IgAPlasmaCellsinGutTransportofIgARequiresPolyIgReceptorNormalPolyIgRKOHepatobiliaryTransportofIgAOccursonlyinsomespecies-notman?DimericIgAinLPdrainsfromintestineinportalveinstoliverDimericIgAinliversinusoidsbindstopolyIgRonendothelialcell-transportedacrossintobileassecretoryIgABile+sIgAdrainsintosmallintestineAllowseliminationofimmunecomplexesSelectiveIgAdeficiencycommon(1:500)FunctionsofIgA3-4gIgAproduceddaily->>anyotherIgMostisexcretedMostarenormal-IgMmaytakeoverImmuneApparatusof

IntestinalMucosaLaminapropriaandepitheliumaredistinctcompartmentsofimmunesystemLaminaPropriaTCellsMajorityareCD4+(CD4+:CD8+=2:1)Mostarea4b7+“memory”TcellsProliferatepoorlytostimulationviaTcR–CD2importantcostimulatorProducecytokines–gIFN,IL4,IL5,IL10?Effectororanergic/regulatoryTcellsExpressreceptorsforinflammatorychemokines(CCR5,CXCR3,CXCR4)MayregulateotherTcellsviaIL10IntraepithelialLymphocytesLargestpopulationofTcellsinbody(10-15%epcells)ClosetoantigenMemory/activatedphenotype-CCR9+Numbersincreaseinresponsetolocalantigen,indiseaseEffectorcells????IntraepithelialLymphocytes

AllTcells->85%CD8+

gdTcellsmaybefrequent>70%incertainspeciesorneonatal/germfreeExpressspecificaEb7

integrin–ligandEcadherinonenterocytesUnresponsivetoTcRstimulationManyextrathymicallyderivedIntraepithelialLymphocytes5-10%CD4+-abTcR+85%CD8+CD8ab+

abTcR+CD8aa+

abTcR+SomeextrathymicgdTcR+ExtrathymicCD3+IELProportionsofsubsetsdependsonage,environmentetcConventionalTcellsPrimedinPPCryptopatchesDCTcRIL7RckitSmalllymphoidaggregatesinsmallintestineofrodentsand?manCPCryptopatches~1000insmallintestine-~1500cells

ContainDC,butnomatureTorBcellsExpressreceptorsforhaemopoieticcytokines,rag-1andrag-2ContainTcellprecursors

ExtrathymicsiteofintestinalTcelldevelopmentRegulationofMucosalImmuneResponses

HarmlessAntigenFoodproteins,commensalbacteria

OralTolerance

HarmfulAntigenInvasivebacteria,viruses,toxins

ProtectiveImmunityRegulationofMucosalImmuneResponses

Mostantigensenteringmucosaearenotpathogenic-foods,aerosols,commensals

ProtectiveimmunityessentialforlifeHarmlessantigensinducetolerance

BreakdownintolerancediseaseIBD-bacteriaCoeliacdisease-glutenAsthma,hayfever-pollenetc