醫(yī)學(xué)免疫學(xué)-免疫相關(guān)疾病

免疫相關(guān)疾病ImmuneOrgans(GALT):gut-associatedlymphoidtissue;Adenoids：腺樣體：Tonsils:扁桃體ImmuneCellsImmune

cellsarederivedfromHSCsBasophilsMast

cellsEosinophilsDendritic

cellsNeutrophilsMonocytesBlymphocytesNaturalkillecellTLymphocytesDendriticcellImmuneResponseTheimmuneresponseishowyourbodyrecognizesanddefendsitselfagainstbacteria,viruses,andsubstancesthatappearforeignandharmfultothebody.FromInnateImmunitytoAdaptiveImmunityOverviewofanimmuneresponseinvivoInfectionDCpickupantigentransporttoLN（atsametimeTBcellsarecirculatingandmigratetoLN）TBcellactivationDifferentiation,AbproductionTcellsantibodycirculatebacktoinfectionsiteEffectorfunction,memorycellalsoresidenceintissueInnatevs.adaptiveimmunityInnateimmunityFirstlineofdefense(presentinallindividualsatalltimes)Immediate(0–4hours)Non-specificDoesnotgeneratelastingprotectiveimmunityAdaptiveimmuneresponse(late:>96hours)Isinitiatedifinnateimmuneresponseisnotadequate(>4days)Antigen-specificimmunityGenerateslastingprotectiveimmunity(e.g.Antibodies,memoryT-cells)TheAdaptiveImmuneSystemPrimarylymphoidorgansSecondarylymphoidorgansIntracellularinfectionExtracellularinfectionAgVDJAgVDJPre-BPre-TTcellBcellMemoryTEffectorTMemoryBPlasmacellStemcellCellsoftheadaptiveimmunesystemDendriticcells(mostimportantAPCcell)B-cellsHumoralimmuneresponseProduceantibodiesAPCcellsT-cellsCell-mediatedimmuneresponseCytotoxicTcells(CD8)HelperTcells(CD4)MemorycellsImmunodeficienciesDefectsinthedevelopmentandfunctionsoftheimmunesystem.Resultinincreasedsusceptibilitytoinfectionsandinanincreasedincidenceofcertaincancers.Disorderscausedbydefectiveimmunityarecalledimmunodeficiencydiseases.ClassificationPrimaryorcongenitalimmunodeficienciesPresentatbirthResultfromgeneticabnormalitiesinoneormorecomponentsoftheimmunesystemSecondary

oracquiredimmunodeficienciesLaterinlifeResultfrominfections,malnutrition,ortreatmentsthatcauselossorinadequatefunctionofvariouscomponentsoftheimmunesystemMostcommonisacquiredimmunodeficiencysyndrome,orAIDS分類(lèi)：

1、按發(fā)病原因分：原發(fā)性免疫缺陷病（PIDD）

繼發(fā)性免疫缺陷?。⊿IDD）

2、按免疫系統(tǒng)累及范圍分：

非特異性IDD:吞噬細(xì)胞功能缺陷（占6%）

補(bǔ)體成分缺陷或異常（占4%）

特異性IDD：

體液免疫缺陷?。ㄕ?0%）

細(xì)胞免疫缺陷?。ㄕ?0%）

聯(lián)合型免疫缺陷病（占30%）

免疫缺陷病的一般特征：

（一）感染

（二）易發(fā)惡性腫瘤

（三）伴發(fā)自身免疫病

（四）多系統(tǒng)受累和癥狀多變性

（五）遺傳傾向性

（六）發(fā)病年齡

分類(lèi)：

1、以體液免疫缺陷為主的PIDD

2、以細(xì)胞免疫缺陷為主的PIDD

3、聯(lián)合型免疫缺陷病

4、非特異性免疫缺陷病以體液免疫缺陷為主的PIDD

病因：原發(fā)性B細(xì)胞發(fā)育不足、分化受阻或Th細(xì)胞的功能異常。

抗體缺陷的種類(lèi)：

①全部Ig缺陷

②選擇性的缺乏某類(lèi)或某亞類(lèi)Ig

③血清總Ig含量正?；蛏缘停禺愋钥贵w反應(yīng)低下BCR

Signaling

IBCR

Signaling

II2ndSignalforBcellactivationPlasmacellAntibodymediatedeffecterfunctionIgGandIgMmediatedAntigenneutralizationcomplementactivationADCCIgE

mediatedMastcelldegranulationAntigenNeutralization：BlockuptakeFCRmediatedphagocytosiscomplementactivationActivationofthecomplementsystemwillleadtoinstantlysisoftargetbacteriacellADCCIgE

mediatedMastcelldegranulation體液免疫缺陷的特點(diǎn)：1，對(duì)細(xì)菌尤其是對(duì)胞外菌感染的易感性增加2，對(duì)腸道病毒和某些腸道寄生蟲(chóng)易感性增加3，生長(zhǎng)發(fā)育遲緩，但不嚴(yán)重4，伴有自身免疫病，惡性腫瘤發(fā)生率升高5，免疫學(xué)特征為外周血B細(xì)胞數(shù)量減少，血清免疫球蛋白降低或缺失，Th功能降低或Tr細(xì)胞功能亢進(jìn)（1）X-性聯(lián)低丙球血癥（Bruton?。?/p>

特征：血循環(huán)中缺乏B細(xì)胞及丙球

（X-連鎖隱性遺傳病，多為男性發(fā)?。?/p>

發(fā)病機(jī)制：前B細(xì)胞分化、發(fā)育障礙，與Bruton酪氨酸蛋白激酶(BtK)基因突變有關(guān)，BtK基因位于Xq22上

臨床表現(xiàn)：出生后6~8個(gè)月起病，反復(fù)持久的胞外菌感染。20%病人伴自身免疫病

免疫學(xué)檢查：血清中總Ig明顯低下，各類(lèi)Ig均低，外周血的B細(xì)胞和漿A細(xì)胞缺乏。

治療：肌注丙球，感染時(shí)加抗生素。

X-linkedagammaglobulinemiaMutationinthebtkgeneBruton'sagammaglobulinemiatyrosinekinase(btk).FailureinBcelldevelopmentMalesaremoreaffected2）選擇性IgA缺陷

主要特征：血清IgA缺乏而其他Ig均正常。

發(fā)病機(jī)制：不清。

發(fā)病環(huán)節(jié)：B細(xì)胞在發(fā)育后階段停滯

（表達(dá)SmIgA的B細(xì)胞向漿細(xì)胞分化發(fā)育過(guò)程受阻）

臨床癥狀：表現(xiàn)不一。

50%以上可無(wú)臨床癥狀或輕度感染

常伴類(lèi)風(fēng)關(guān)、SLE等病。

治療：無(wú)滿意的方法，預(yù)后良好。

鼓勵(lì)母乳喂養(yǎng)。（2）伴IgM增高的免疫球蛋白缺陷或X－性聯(lián)高IgM綜合征

主要特征：血清IgM增高而其他免疫球蛋白低下。

發(fā)病機(jī)制：B細(xì)胞抗體類(lèi)別轉(zhuǎn)換機(jī)制缺陷所致，與T細(xì)胞CD40L基因缺失有關(guān)。也有人認(rèn)為與胚胎期風(fēng)疹病毒感染有關(guān)。

臨床癥狀：反復(fù)發(fā)生化膿性細(xì)菌感染

治療：無(wú)有效的治療方法IgM增高的免疫缺陷癥（性聯(lián)高IgM血癥.XLHM)原發(fā)性B細(xì)胞免疫缺陷2、以細(xì)胞免疫缺陷為主的的PIDD少見(jiàn)（5~10%）

特點(diǎn)：①對(duì)胞內(nèi)菌易感性增高；

②生長(zhǎng)發(fā)育延遲，多早年夭折；

③惡性腫瘤發(fā)病率高；

④免疫學(xué)特征是外周血細(xì)胞數(shù)量減少、患者皮膚DTH反應(yīng)陰性以及移植排斥反應(yīng)低下

⑤常伴B細(xì)胞功能降低

TCRsignalingThdifferentiationgovernedbysignalIII(cytokines)SignalISignalIISignalIIIOtherrequirementsforTcellmediatedresponse

–

CytokinesignalassignalIIIOtherrequirementsforTcellmediatedresponse

–

2.

CytokinesignalassignalIIIDifferentThcellsexertsdifferenteffecterfunctionsCD4

Tcellmediateimmunity–effecterfunctionsCTLsAPCvstargetcellsOverallprocessofCTL-mediatedtargetcellkilling:PolarizedreleaseofeffectormoleculesCTLsFasL-/-Perforin-/-Granzyme-/-FADD-FLICECaspaseDNAseApoptosisCTLmolecules

ActionsontargetcellsTCR pMHCrecognitionFasligand Inducedapoptosis(Fas)Perforin FormholesintargetcellmembraneGranzyme Serineprotease,activatecaspaseCTLskilltargetcellsbyinducingapoptosisTCRMHCFasLFasCTLTargetPerferineGranzymeMemorycellsOverviewNaiveEffectorMemoryTime(days)Tcellresponse7140AgClonalexpansionEffector/memoryTcellAPC12（1）DiGeorge綜合征（先天性胸腺發(fā)育不全或Ⅲ、Ⅳ咽囊綜合征）

特征：胸腺缺如或發(fā)育不良導(dǎo)致的T細(xì)胞功能缺陷

發(fā)病機(jī)制：非遺傳性，與酒精中毒有關(guān)

胚胎發(fā)育12周左右，Ⅲ、Ⅳ咽囊發(fā)育障礙，導(dǎo)致起源于該部位的相應(yīng)器官組織（胸腺、甲狀旁腺、人中、主動(dòng)脈弓等）發(fā)育不全。

臨床表現(xiàn)：細(xì)胞免疫功能低下；

伴甲狀旁腺功能不全；

其他先天性發(fā)育異常如短人中、心臟血管畸形等。

反復(fù)發(fā)生胞內(nèi)菌感染

實(shí)驗(yàn)室檢查：外周血中T細(xì)胞數(shù)減少；淋巴細(xì)胞對(duì)PHA、ConA刺激缺乏增殖反應(yīng)；皮膚DTH陰性。

治療：胚胎胸腺移植DiGeorge綜合征（2）T細(xì)胞表面分子缺陷①TCR缺失：αβTCR缺失會(huì)嚴(yán)重影響免疫功能；②CD3分子突變：γ、ε、ZAP70③協(xié)同刺激信號(hào)表達(dá)缺失：如B7分子家族；④細(xì)胞因子產(chǎn)生缺失：如IL-2、IFN-

等；⑤細(xì)胞因子受體表達(dá)缺乏：如IL-1R、IL-2R等3、聯(lián)合型免疫缺陷病

概念：指T細(xì)胞和B細(xì)胞同時(shí)受累或功能缺陷。

機(jī)制：淋巴干細(xì)胞發(fā)育的不同環(huán)節(jié)上受阻

分類(lèi)：重癥聯(lián)合免疫缺陷病（SCID）；

伴酶缺失的免疫缺陷病；

伴其他嚴(yán)重缺陷的免疫缺陷病。

（1）重癥聯(lián)合免疫缺陷病

（severecombinedimmunodeficiencydisease,SCID）概念：是一組細(xì)胞免疫和體液免疫功能同時(shí)喪失的遺傳性綜合征。表現(xiàn)為出生后6個(gè)月內(nèi)發(fā)復(fù)發(fā)生多種病原微生物感染，包括細(xì)菌、病毒、真菌等感染。多數(shù)1歲內(nèi)死亡。

①常染色體隱性遺傳的SCID

（瑞士型SCID）

機(jī)制：淋巴干細(xì)胞發(fā)生缺陷

②HLAⅡ類(lèi)分子表達(dá)缺陷的SCID（Barelymphocytesyndrome光禿淋巴細(xì)胞綜合征）

機(jī)制：Ⅱ類(lèi)轉(zhuǎn)錄活化子（CⅡTA）基因缺失

HLAⅡ類(lèi)基因轉(zhuǎn)錄障礙APC表面HLAⅡ類(lèi)分子表達(dá)降低抗原提呈功能障礙

③X-性連瑣隱性遺傳SCID（Gitfin型SCID）

機(jī)制：IL-2R

鏈?zhǔn)枪灿脕喕?IL-2R

鏈基因發(fā)生突變（該基因位于X染色體）

IL-2R、IL-4R、IL-7R缺陷T、B成熟受阻。Causedbydeficiencyincommongammachain(γc):TheCytokinereceptorcommongammachain(γc)(orCD132)isacytokinereceptorsub-unitthatiscommontothereceptorcomplexesforatleastsixdifferentinterleukinreceptors:IL-2,IL-4,IL-7,IL-9,IL-15andinterleukin-21receptor.DavidVetterThetransplantoperationwentwell,andforafewmonthshopewashighthatDavidwouldbeabletoleavethebubble.However,afewmonthsaftertheoperation,Davidbecamesickforthefirsttimeinhislife;hestartedhavingdiarrhea,fever,andseverevomitingfromintestinalbleeding.ThesesymptomsweresoseverethatDavidhadtobetakenoutofthebubblefortreatment.Inresponsetoadirectquestionfromhisfatheronwhetherhewishedtobetakenoutofthebubble,Davidreplied,"Daddy,Iwillagreetoanythingtofeelbetter."Outofthebubble,hecontinuedtogetworseandsankintoacoma;hismotherwasabletotouchhisskinforthefirstandlasttimebeforehedied.Hedied15dayslateronFebruary22,1984ofBurkitt'slymphomaattheageof12.Katherine'sbonemarrowcontainedtracesofadormantvirus,Epstein-Barr,whichhadbeenundetectableinthepre-transplantscreening.OnceinsideofDavid'sbody,thevirusspreadandproducedhundredsofcanceroustumors,whichwererevealedintheautopsy.DavidhadalwayswantedtotryCoca-Cola,afterseeingitinmanycommercialsandhearingaboutitfromotherchildren,butthesterilizationprocessrequiredtoinsertitintothebubbleruinedthetaste.Afterheexitedthebubble,herequestedaCoke.Hismothersaid"[i]twasoneofthefirstthingsheaskedforwhenhewastakenoutofhisbubblebeforehedied.Butthedoctorsdecidedheshouldn'thaveoneinhisfrailcondition.”AcquiredImmunodeficiencycanbecausedby:獲得性免疫缺陷綜合征（Acquired

immunedeficiencysyndrome,AIDS）

AIDS是因人類(lèi)免疫缺陷病毒(HumanImmunodeficiencyVirus,HIV)侵入機(jī)體引起細(xì)胞免疫嚴(yán)重缺陷，導(dǎo)致以機(jī)會(huì)性感染、惡性腫瘤和神經(jīng)系統(tǒng)病變?yōu)樘卣鞯呐R床綜合征。HIVandAIDS

aninfectiousagent1979-5例卡氏肺囊蟲(chóng)肺炎Withgiemsastainathighmagnification,thefaintbluishdot-likeintracysticbodiesofPneumocystiscariniiinlungareseeninthiscytologicpreparationfromabronchoalveolarlavage在洛杉磯1967-1978僅有兩例卡氏肺囊蟲(chóng)肺炎都為同性戀者>42million臨床表現(xiàn)艾滋病卡波氏肉瘤

口腔念球菌病

艾滋病的惡液質(zhì)OralCandidiasis(thrush霉菌性口炎)BeingthatHIVreducesimmunologicactivity,theintraoralenvironmentisaprimetargetforchronicsecondaryinfectionsandinflammatoryprocesses,includingOHL,whichisduetotheEpstein-BarrvirusunderimmunosuppressedconditionsKaposi’ssarcoma(KS)Kaposi’ssarcoma(shown)isararecancerofthebloodvesselsthatisassociatedwithHIV.Itmanifestsasbluish-redoval-shapedpatchesthatmayeventuallybecomethickened.Lesionsmayappearsinglyorinclusters.Figure9-22OpportunisticinfectionsandmalignancieskillHIVpatients臨床分期ProgressionofAIDSInfectionviremia(increaseofthevirusloadinblood)immuneresponsetoHIV:generationofTccellsandantibodytoHIV(seroconversion)temporaryreductionofvirus-infectedCD4Tcells(duetoHIV-inducedapoptosisandTcellattack)partialrecoveryofCD4TcellnumbergradualdecreaseofCD4Tcellnumberover2-15years(clinicallatencyisaperiodofactiveinfectionandCD4Tcellrenewal)

AIDS(CD4Tcellcount<200)CCR51.CD4isaprimaryreceptorusedbyHIV-1togainentryintohostTcells.2.HIV-1attachestoCD4withaproteininitsviralenvelopeknownasgp120.ThebindingtoCD4createsashiftintheconformationofgp120allowingHIV-1tobindtoothersurfacereceptorsonthehostcell,thechemokinereceptors

CCR5.Followingastructuralchangeinanotherviralprotein(gp41),HIVinsertsaintothehostcellthatallowstheoutermembraneofthevirustofusewiththecellmembrane.3.HIVinfectionleadstoaprogressivereductioninthenumberofTcellspossessingCD4receptors.Therefore,medicalprofessionalsrefertotheCD4counttodecidewhentobegintreatmentforHIV-infectedpatients.Normalbloodvaluesare500-1200x106/L.HAART:HighactiveantiretroviraldrugtherapyINTRODUCTIONTOALLERGY

Hypersensitivity:Initially,humanbeingcontactsAg(allergy)andbecomessensitization.Thenthebodyhasahighresponsetosameallergywhenitcontactswiththeminsecondtime(throughskin,mucosalorblood).GELLANDCOOMB’S

CLASSIFICATIONOFTHEHYPERSENSITIVIYSTATES

TYPE1-IgEAbmediatedimmediatereactionTYPE2-IgG,MmediatedAbresponseTYPE3-ImmunecomplexTYPE4-Delayedtypehypersensitivity

GeneralmechanismunderlyingatypeIhypersensitivereaction.Whenasubstanceiscapableofproducingallergicsymptoms,itisknownasanallergen.Immunoprophylaxis&immunotherapySkintesttoidentifyallergenandavoidtheoffendingallergenImmunesystemasa“simplified”systemAntigenRecognitionImmuneCellActivationImmuneResponseImmuneRegulationSensorGeneratorReactorRegulatorAntigensx1018

TumorAgAuto-AgMHCMicrobesEffectors

CytolysisCytokinesAntibodyPhagocytosisA“coolingsystem”topreventover-heatedimmuneresponse(Immunetolerance)

Immunetoleranceor'immunologicaltolerance'istheprocessbywhichtheimmunesystemdoesnotattackanantigen.Centraltolerance

isthemechanismbywhichnewlydevelopingTcellsandBcellsarerenderednon-reactivetoselfduringtheirdevelopmentinthymusandbonemarrow.MechanismsPositiveselection:

DuringpositiveselectionDouble-PositiveTcellsthatcanrecognizeselfMHC‘sareselectedforproliferation,andthoseTcellsthatdonotrecognizeselfMHCdieviaApoptosis.

PositiveselectionalsoassuresTCR

torecognizepeptide/MHCcomplexandalsogowiththeappropriateCD4orCD8.Forexample,TCR‘sspecificforMHCIIneedtoretainCD4,andloseCD8.Ifthereverseoccurs,theywilldieviaapoptosis.ThesameistruefortheTcellsthatarespecificforMHCI,whichneedtoretainCD8,andloseCD4.ThymocytesarepositiveselectedbyMHC/selfpeptidesNegativeselection:

TcellsthatarestronglyactivatedbyselfMHCplusselfpeptidesneedtobeeliminatedinthethymus.complex.Iftheyescapethiselimination,theymaysubsequentlyreactagainstselfantigens,andcauseAutoimmunedisease.

CentralToleranceisachievedbynegativeselectionDownloadedfrom:StudentConsult(on1June200601:58PM)?2005Elsevier

Peripheraltolerance

Someantigensarenotexpressedinthymusorbonemarrow,whichleadstothepossibilitytotriggerimmuneresponse.Negativeselectionisincomplete:Middletolowaffinityself-reactiveclonesarereleasedtoperipheralandcanbeactivatedundercertainconditions(injury,infection,inflammation……).Thecentraltolerancestorysoundsgreat,butwhywestillneedperipheraltoleranceagain?APCTCRTcellCD28

ActivatedTcellsAPCTCRFunctionalunresponsivenessNormalTcellresponseAnergyApoptosis(activation-inducedcelldeath)APCDeletionAPC

BlockinactivationSuppressionRegulatoryTcellPeripheralTcelltoleranceOffsignalsActivatedTcellPeripheralTcelltoleranceActivation-inducedCellDeath(AICD)Thedeathreceptor(Fas)pathwayDefectinFasorFasLtriggersAutoimmunityFasNormalFasLAutoimmunityandlymphoproliferativediseaseFasLFas+Fas-CD4+FoxP3+TregsPeripheralTcelltoleranceFirstObservation:

CD4+CD25-cellsinduceautoimmunediseaseCD25-PEPeripheralTcelltoleranceLackofCD4+FoxP3+TregsleadstoAIdiseaseinFoxP3-/-orScurfyMiceAlexanderY.RudenskyUniversityofWashingtonShimonSakaguchiKyotoUniversity，RIKENPeripheralTcelltoleranceAutoimmunityOriginsHorrorautotoxicus:Literally,thehorrorofself-toxicity.AtermcoinedbytheGermanimmunologistPaulEhrlich(1854-1915)todescribethebody'sinnateaversiontoimmunologicalself-destruction.AutoimmunityBasicallymeansimmunitytoselfAconditionthatoccurswhentheimmunesystemmistakenlyattacksanddestroyshealthybodytissue.在正常人和動(dòng)物體內(nèi)存在多種自身反應(yīng)性T細(xì)胞(autoreactiveTcell，ART)、自身反應(yīng)性B細(xì)胞(ARB)和自身抗體，它們并非是異常現(xiàn)象，而是屬于正常的免疫應(yīng)答。天然自身抗體(naturalautoantibody，NAA)：指在正常機(jī)體內(nèi)含有一些自身抗體，它們的效價(jià)低，不足以引起自身組織損傷，但可邦助清除衰老蛻變的自身成分。一、概念自身免疫：機(jī)體免疫系統(tǒng)識(shí)別自身成分，產(chǎn)生針對(duì)自身成分的抗體或細(xì)胞免疫的現(xiàn)象，稱(chēng)為自身免疫。自身免疫?。好庖哒{(diào)節(jié)功能紊亂，引起過(guò)度的自身免疫反應(yīng)，造成器質(zhì)性損害和功能障礙者。自身免疫病的本質(zhì)是自身抗體、自身反應(yīng)性淋巴細(xì)胞針對(duì)自身抗原的超敏反應(yīng)。1、器官特異性AID由于針對(duì)器官特異性抗原產(chǎn)生免疫應(yīng)答，患者的病變局限于某一特定的器官?；颊叩牟∽円?jiàn)于多種器官和組織。2、器官非特異性AID（全身性）

毒性彌漫性甲狀腺腫（Graves?。┰l(fā)性腎上腺皮質(zhì)萎縮（Addison?。┞詽冃越Y(jié)腸炎胰島素依賴(lài)型糖尿病（IDDM)

重癥肌無(wú)力（MS）自身免疫病的分類(lèi)器官特異性非器官特異性（系統(tǒng)性）

類(lèi)風(fēng)濕性關(guān)節(jié)炎(RA)

系統(tǒng)性紅斑狼瘡（SLE）CausesofAutoimmunity1.ReleaseofsequesteredantigensMyelinbasicprotein(MBP):sequesteredfromimmunesystembyblood-brainbarrierSpermantigens.EyeHeart-muscleantigensPhysicalaccidentOrinfection2.InappropriateexpressionofclassIIMHCmoleculesonnon-APCs*HighexpressionofMHCIandIIonthepancreaticbetacellsofindividualswithinsulin-dependentdiabetesmellitus(IDDM).*ExpressionofMHCIIonthyroidacinarcells(inGraves’disease).*IFN-γfromtraumaorviralinfection.3.Viralinfectionsandautoimmunedisease*MolecularMimicry*Bystanderactivation*PolyclonalactivationAutoreactiveTcellscanbeactivatedthroughamechanismofmolecularmimicrythatinvolvescrossreactiverecognitionofaviralantigenthathassimilaritytoselfantigen.molecularmimicry微生物和人組織蛋白的相似分子片段蛋白質(zhì)分子氨基酸片段氨基酸序列CMVIE279~88PDPLGRPDEDHLA-DR60~69VTELGRPDAEPolioV.VP270~79STTKESRGTT乙酰膽堿受體176~185TVIKESRGTK乳頭瘤V.E276~85SLHLESLKDS胰島素受體66~75VYGLESLKDLHIVP24160~167GVETTTPS人IgG頂恒定區(qū)466~473

GVETTTPS麻疹V.P313~20LECIRALK促腎上腺皮質(zhì)激素18~25LECIRACK(1)MicrobialinfectionstimulatesToll-likereceptors(TLRs)andotherpattern-recognitionreceptorsonantigen-presentingcells(APCs),leadingtotheproductionofpro-inflammatorymediators,whichinturncanleadtotissuedamage.(2)SelfantigenthatisreleasedfromdamagedtissuecanbetakenupbyactivatedAPCs,processedandpresentedtoautoreactiveTcells.(3)Alternatively,aninfectioncanleadtomicrobialsuperantigen-inducedactivationofasubsetofTcells,someofwhichcouldbespecificforselfantigen.多克隆激活作用某些病毒(EB病毒、HIV)、細(xì)菌內(nèi)毒素、

超抗抗原均可成為多克隆激活劑。4.表位擴(kuò)展

epitopespreading抗原決定簇可分為優(yōu)勢(shì)決定簇和隱蔽決定簇。前者在接觸抗原初始階段誘發(fā)免疫應(yīng)答后者在后續(xù)階段誘發(fā)免疫應(yīng)答在自身免疫病的發(fā)生過(guò)程中，這種細(xì)胞會(huì)不斷識(shí)別自身抗原的隱蔽決定簇，這一現(xiàn)象稱(chēng)為表位擴(kuò)展。由于針對(duì)自身抗原隱蔽決定簇的T細(xì)胞克隆可能逃避胸腺的陰性選擇，而成為自身反應(yīng)性T細(xì)胞。表位擴(kuò)展參與SLE、RA、多發(fā)性硬化和胰島素依賴(lài)性糖尿病的發(fā)生。FurthertissuedestructionbyactivatedTcellsandinflammatorymediatorscausesthereleaseofmoreselfantigenfromtissues.Bd|TheT-cellresponsecanthenspreadtoinvolveTcellsspecificforotherselfantigensinaprocessknownasepitopespreading.調(diào)節(jié)性T細(xì)胞亞群異常調(diào)節(jié)性T細(xì)胞是一具有免疫調(diào)節(jié)（或免疫抑制）作用的細(xì)胞群，能夠主動(dòng)抑制自身反應(yīng)性T細(xì)胞的活化，維持自身免疫耐受，防止自身免疫病的發(fā)生。

兩類(lèi)調(diào)節(jié)性T細(xì)胞抗原和多種刺激因子共刺激

IFN-

TNF-

CCR5CXCR3IL-4IL-5IL-13CCR3,4,8Th1Th2IL-4pMHCTh

0初始

TIL-4RStat6

IL4Gata3IFNGIFN-

RIL-12IL-12RpMHCTCRStat4Stat1

IFNGT-betIL4IL-23IL-23RStat3

IL17IFNG,IL4IL-17IL-17FTh17IL-23IL-12IL-4IFN

細(xì)胞免疫體液免疫炎癥反應(yīng)IL-17RORtIL-17:TheAutoimmunityCytokine?IL-17KOmice–lesssusceptibletoautoimmunity–especiallyMSandRATh1/Th2細(xì)胞亞群平衡的異常Th1細(xì)胞因子主要參與器官特異性自身免疫病，如胰島素依賴(lài)型糖尿病(T1D)、多發(fā)性硬化(MS)、甲狀腺疾病及葡萄膜炎等；Th2細(xì)胞因子在系統(tǒng)性紅斑狼瘡(SLE)和過(guò)敏性疾病中占優(yōu)勢(shì)。ImmumoregulatoryfunctionofTh1/Th2*Th1和Th2互為抑制細(xì)胞，從而調(diào)節(jié)機(jī)體的細(xì)胞免疫和體液免疫應(yīng)答；協(xié)同刺激分子異常表達(dá)B7分子高水平表達(dá)B7分子的胰島β細(xì)胞可激活T細(xì)胞CTLA-4不僅對(duì)T細(xì)胞活化起負(fù)向調(diào)節(jié)作用，還可介導(dǎo)自身免疫耐受，所以CTLA-4可能與T細(xì)胞介導(dǎo)的自身免疫性疾病有關(guān)。如CILA-4基因多態(tài)性與Grave’s病、T1D、自身免疫性甲狀腺炎、重癥肌無(wú)力、Addison綜合征等有關(guān)。

SinglegenemutationsandautoimmunityMutation/knockoutPhenotypeofknockout;humandiseaseMechanismCTLA-4Multi-organlymphocyteInfiltrate,lymphoproliferationRoleofCTLA-4InTcellanergyFas/FasLAnti-DNAAb,nephritis;ALPSDeletionofmatureTandBcellsIL-2/IL-2Ra,bIBD,hemolyticanemia,anti-DNAAbTcelldeletion,TregdevelopmentAIREPolyendocrinopathy,retinitis;APS-1RoleofAIREinthymicexpressionofselfantigensFoxP3Systemicautoimmunity;IPEXRoleingenerationofregulatoryTcells胸腺基質(zhì)細(xì)胞的AIRE（forautoimmuneregulator)基因作用AIRE調(diào)控自身抗原肽表達(dá)，誘導(dǎo)陰性選擇發(fā)生，清除自身反應(yīng)性T細(xì)胞當(dāng)無(wú)AIRE時(shí)，沒(méi)有自身抗原肽表達(dá)，不能誘導(dǎo)陰性選擇發(fā)生，自身反應(yīng)性T細(xì)胞不能清除。自身免疫反應(yīng)引起組織損傷的機(jī)制

器官特異性自身免疫病常由II型和IV型超敏反應(yīng)引起，而非器官特異性自身免疫病通常由III型超敏反應(yīng)引起。(一)自身抗體對(duì)細(xì)胞的溶解作用Ⅱ型補(bǔ)體依賴(lài)的細(xì)胞毒作用、ADCC、(甲抗)

(二)IC（ImmunoComplex）對(duì)組織的損傷作用III型(三)致敏T細(xì)胞對(duì)組織的損傷作用Ⅳ型自身抗原吸附的外來(lái)半抗原

吸附的抗原抗體復(fù)合物細(xì)胞膜抗原

誘導(dǎo)產(chǎn)生IgGIgM同種異型抗原MF吞噬、CDC、ADCC

靶細(xì)胞殺傷結(jié)合Ⅱ型超敏反應(yīng)發(fā)生機(jī)制示意圖IgGIgM

增強(qiáng)吞噬作用炎癥趨化作用過(guò)敏毒素作用

III型超敏反應(yīng) C3bC567C3aC5a激活補(bǔ)體血管內(nèi)皮間隙增大血管通透性增高中性粒細(xì)胞浸潤(rùn)吞噬免疫復(fù)合物并釋放溶酶體酶纖維素樣壞死血管炎組織消化誘導(dǎo)抗原再次接觸T細(xì)胞致敏CD8+T細(xì)胞局部組織損傷單個(gè)核細(xì)胞活化、浸潤(rùn)殺傷靶細(xì)胞趨化因子、IFN-γTNF-βIL-2IL-3GM-CSFⅣ超敏反應(yīng)的發(fā)生機(jī)制示意圖CD4T細(xì)胞Systemiclupuserythematosus(SLE)?“redwolf”:reddishfacialrashonthecheeks?Women:men=10:1?Agedbetween20-40yrs?AntibodiestoavastarrayoftissuessuchasDNA,histones,RBCs,platelets,leukocytesandclottingfactors.Systemiclupuserythematosus(SLE)?Thediseaseattacksmanyorgansandcausesfever,jointpainan