自身免疫病專題培訓(xùn)專家講座

自身免疫病

Autoimmunedisease魯林榮浙江大學(xué)免疫學(xué)研究所Lu.Linrong@/llr

自身免疫病專題培訓(xùn)第1頁自身免疫病專題培訓(xùn)第2頁課件與相關(guān)閱讀自身免疫病專題培訓(xùn)第3頁?Autoimmunity:immuneresponseagainstself-antigens(components)?Autoimmunedisease,AID:Diseasesinducedbyinappropriateresponseoftheimmunesystemagainstself-components?Generalprinciples:-Significanthealthburden,5%ofpopulation(USA)-Multiplefactorscontributetoautoimmunity,-Includinggeneticpredisposition（遺傳傾向）,infections-Fundamentalproblemisthefailureofself-tolerance?Problems:Failuretoidentifytargetantigens,heterogeneous（異質(zhì)性）disease

manifestations,diseaseusuallypresentslongafterinitiationDefinition自身免疫病專題培訓(xùn)第4頁CharactersofAID

1

Hightiterauto-antibodyinserumand/orself-reactiveTcellsagainstself-components.2Damagetoorgansandtissuedestructioncausedbyauto-antibody&self-reactiveTcells.3

Repeat,Chronic,Persistent,Progress4

Animalmodelreplicationandtransferable.5

Inheritedtendency,femalesusceptible.6Noobviousreasons.自身免疫病專題培訓(xùn)第5頁Organ-specificvsSystemicAutoimmuneDiseasesFormostoftheAIDs,Thereisamajoraffectedorganbutalsoaffectothers自身免疫病專題培訓(xùn)第6頁Broadlyseparatedbythetypeofeffectormechanism(similartohypersensitivityclassificationscheme)?Threeclasses:–TypeII:Antibodyagainstcell-surfaceantigenormatrixantigens–TypeIII:Immune-complexdisease–TypeIV:Tcell-mediateddiseaseClassificationofAutoimmuneDiseases自身免疫病專題培訓(xùn)第7頁Antibody-mediatedDiseasesI-TissueInjuryTypeIITypeIII自身免疫病專題培訓(xùn)第8頁Antibody-mediatedDiseasesII-w/otissueinjuryAcetylcholine:乙酰膽堿重癥肌無力自身免疫病專題培訓(xùn)第9頁TypeIIAntibody-mediatedDiseases貧血血小板降低尋常型天皰瘡血管炎肺出血腎炎綜合征急性風(fēng)濕熱重癥肌無力甲狀腺亢進(jìn)胰島素耐受糖尿病惡性貧血自身免疫病專題培訓(xùn)第10頁Graves’Disease甲狀腺亢進(jìn)自身免疫病專題培訓(xùn)第11頁Graves’Disease：AntibodymediatedDisease自身免疫病專題培訓(xùn)第12頁Inthisdisease,autoantibodiestotheAcetylcholinereceptor（乙酰膽堿受體）

blockneuromusculartransmissionfromcholinergicneuronsbyblockingthebindingofacetylcholineandbycausingdownregulation(degradation)ofits'receptor.Progressiveweakeningofskeletalmuscles,manifestedbydifficultyinchewing,swallowingandbreathing,andeventuallydeathfromrespiratoryfailure.MyastheniaGravis（重癥肌無力）自身免疫病專題培訓(xùn)第13頁TypeIII：Immune-Complexmediateddiseases腎小球腎炎自身免疫病專題培訓(xùn)第14頁Immune-ComplexFormationandDepositionDepositiontoKidney,JointandvascularLesions自身免疫病專題培訓(xùn)第15頁?“redwolf”:reddishfacialrashonthecheeks?Antibodiestoavastarrayoftissues,RBCs,platelets,leukocytes

?Antibodiesagainstseveralnuclearantigens(MostlynativeDS-DNAandhistones)

?Thediseaseattacksmanyorgansandcausesfever,jointpainanddamagetothecentralnervoussystem,heartandkidneys.?Kidneylesion–causesthemostmortalityfromSLE?Women:men=10:1?Agedbetween20-40yrsSystemiclupuserythematosus(SLE)自身免疫病專題培訓(xùn)第16頁Rheumatoidfactors(agroupofautoantibodies,IgM)reactwithdeterminantsintheFcregionofIgGRheumatoidfactorsbindtocirculatingIgG,formingIgM-IgGcomplexesthataredepositedinthejoints.Immunecomplexesthenactivatecomplementcascade.Majorsymptoms:chronicinflammationofjointsMostaffectingwomenfrom40-60yrsoldRheumatoidarthritis自身免疫病專題培訓(xùn)第17頁TypeIVTcell-mediatedDiseases–DirectTcellcytotoxicityviaCD8+CTL–Self-destructionoftissuecellsinducedbycytokines,eg,TNFa–Recruitmentandactivationofmacrophagesleadingtobystandertissuedestruction自身免疫病專題培訓(xùn)第18頁TypeIVTcell-mediatedDiseases麩質(zhì)過敏癥自身免疫病專題培訓(xùn)第19頁?Tcellresponsetoantigensexpressedinthe-cellsoftheislets(Proinsulin/Insulin,GAD,I-A2)?TcellresponseisTh1“l(fā)ike”,makesg-IFNandhelpsrecruitatissue/celldestructionresponse?>90%isletdestructionneededforthediseasetobeexpressed

?Patientsalsohaveauto-antibodiestoisletantigensTypeIDiabetesTcell-directedattackagainstthe-cellsofthepancreaticislet自身免疫病專題培訓(xùn)第20頁胰高血糖素生長抑素自身免疫病專題培訓(xùn)第21頁Tetramerflowstudy:revealthepresenceofproIns–andGAD-reactiveCD4TcellsinPBMCofT1Dpatients自身免疫病專題培訓(xùn)第22頁?Involvesdemyelinization（脫髓鞘）

ofcentralnervoussystemtissue?Symptomsmaybemild,suchasnumbnessinthelimbs,orsevere,suchasparalysisorlossofvision.?T-cellmediatedautoimmunedisease?CauseofMS:notwellunderstood

–Failureofclonaldeletion,fromneuro-antigensensitization–Molecularmimicrytoaneuro-epitopefollowingvirusinfectionMultiplesclerosis(MS)自身免疫病專題培訓(xùn)第23頁Multiplesclerosis(MS)自身免疫病專題培訓(xùn)第24頁Whydoautoimmunediseaseoccur?Answer:Failureinself-tolerance

自身免疫病專題培訓(xùn)第25頁TypesofToleranceCentralTolerance–happensduringlymphocytedevelopment.NegativeselectionorclonaldeletionofTandBcellsthathavereceptorsforself-antigens.SelectedonthymicepithelialMHCagainsthighlyreactiveclonesagainstselfantigen.95%ofimmaturelymphocytedieinthymus/bonemarrow.PeripheralTolerance-occursintheperipheryafterlymphocytedevelopment.

Ignorance:lowdoseorimmunologicallyprivilegedsites;Anergy:Lackofco-stimulatorymoleculesduringTcellactivation;

ClonalcontractionandAICD:BothLPRFasdeficient,GldFasLdeficienthaveautoimmunephenotypes.Cannotregulatedurationofresponse

Suppression:specificimmuneregulationthroughregulatoryT cells,

Consequences:

apoptosis,anergy,inactivation自身免疫病專題培訓(xùn)第26頁CentralTcellToleranceachievedbyNegativeselection

TcellsthatarestronglyactivatedbyselfMHCplusselfpeptidesneedtobeeliminatedinthethymus.(Highaffinity)自身免疫病專題培訓(xùn)第27頁P(yáng)eripheraltolerancethroughdifferentmechanisms自身免疫病專題培訓(xùn)第28頁OverviewofAutoimmunity自身免疫病專題培訓(xùn)第29頁InformativeSingle-genemodelsofautoimmunityAIRE(APECED）：NegativeselectionFas/FasL(ALPS):peripheraldeletionofTandBcellsFoxP3(IPEX):TregCTLA-4(mouseKO):anergy;TregIL2,IL-2R(mouseKO):TregManyotherreportedBUT：notseemstobethebasisofmostautoimmunediseases自身免疫病專題培訓(xùn)第30頁Autoimmunityissocomplicated,howcanwefigureouthowithappens?Answer:Usegenetics–GeneticReasons2)Animalmodels–GeneticReasonsandenvironmenttrigger自身免疫病專題培訓(xùn)第31頁Geneticbasisofautoimmunity?Geneticpredispositionofautoimmunediseases–Increasedincidenceintwins–Identificationofdisease-associatedgenesbybreedingandgenomicapproaches?Multiplegenesareassociatedwithautoimmunity–singlemutationcausesautoimmunity-rare?MHCgenes–Majorgeneticassociationwithautoimmunediseases

–Disease-associatedallelesmaybefoundinnormalindividuals?Non-MHCgenes–Manylociidentifiedbygenomicmethods,animalstudies–Mutationsincomplementgenespredisposetolupus自身免疫病專題培訓(xùn)第32頁HLA(orMHC)isthestrongestgeneticfactorforsusceptibilitytoautoimmunediseaseRelated:DifferentsusceptibilitiesofAIsfordifferentmousestrains自身免疫病專題培訓(xùn)第33頁P(yáng)opulationStudyFamilyStudyHLAandsusceptibilitytoautoimmunedisease自身免疫病專題培訓(xùn)第34頁HLAandsusceptibilitytoautoimmunediseaseHowHLAconfersusceptibilityand/orprotectionCapacitytopresentantigensandtoinducepositiveselectionbutnotnegativeselection(central)SomeHLAsaremorepotentinpresentingself-antigens(peripheral)3.Linkedtoothernon-MHCdiseasecausinggenes(indirect)Otherunknownreasons自身免疫病專題培訓(xùn)第35頁Non-MHCgenesassociatedwithautoimmunediseaseinHUMANS?Singlegenedisorders:AIRE,FoxP3,Fas/FasL,CTLA-4,CD25(IL-2R)?PTPN22:phosphatase,polymorphisminLupus,Type1Diabetes,RheumatoidArthritis,mechanismofaction??NOD2:intracellulartollreceptor,Microbialsensorinintestinalepithelialcells,polymorphismassociatedwith~25%ofCrohn’sdiseaseandUveitis(eyeautoimmunity)?ATG16:autophagygene,associatedinIBD(resistancetomicrobes?)?IL-23R:receptorforTh17-inducingcytokine,affectTh17responses?ComplementgenesinLupus自身免疫病專題培訓(xùn)第36頁自身免疫病專題培訓(xùn)第37頁自身免疫病專題培訓(xùn)第38頁Susceptibilitylociassociatedwithautoimmunity自身免疫病專題培訓(xùn)第39頁GWAS(GenomeWideAssociationStudy)SNParrayMassivesequencingGenomewide,FastBecomingCost-effective自身免疫病專題培訓(xùn)第40頁GWAS–T1Dasanexample自身免疫病專題培訓(xùn)第41頁GWASDiagramBrowser自身免疫病專題培訓(xùn)第42頁ExploreDiseasemechanisms(geneticandenvironmental)TestTreatmentdrugorstrategySpontanuousDiseasemodels:?NODmouse-modeloftype1diabetes?NZBxNZWmouse-modelofLupus?KBxNmouse-modelofrheumatoidArthritisInducibleDiseasemodels：?EAE-inducedmodelofmultiplesclerosiswherebydiseaseisinducedbyinjectingproteinsofthemyelinsheathwithadjuvantKnock-outs:?Knockoutsthatgetautoimmunity?CombinedKoswithspontanuous/induciblemodelsNextstep:Animalmodelsofautoimmunity自身免疫病專題培訓(xùn)第43頁EAE–mousemodelofhumanmultiplesclerosis自身免疫病專題培訓(xùn)第44頁EAE–mousemodelofhumanmultiplesclerosisDaysMeanDiseaseScoreAnti-NKG2A/C/EFab2MechanismTreatmentThakkerPetalJILuLetalImmunity自身免疫病專題培訓(xùn)第45頁NODmicerepresentspontaneousdiabetes自身免疫病專題培訓(xùn)第46頁B7.1/B7.2KO’sgetworsediabetesintheNODbackground–decreaseinTreg自身免疫病專題培訓(xùn)第47頁DevelopmentofautoimmunediseaseCause：Lossofself-toleranceWhattriggersautoimmunediseases?自身免疫病專題培訓(xùn)第48頁P(yáng)roposedmechanismsfortriggeringautoimmunityAlteredantigenorantigenpresentationViralInfection自身免疫病專題培訓(xùn)第49頁Alteredantigenorantigenpresentation-ReleaseofsequesteredantigensMyelinbasicprotein(MBP):Sequesteredfromimmunesystembyblood-brainbarrierSpermantigens.EyeHeart-muscleantigensPhysicalaccidentOrinfection自身免疫病專題培訓(xùn)第50頁AlteredantigenorantigenpresentationInappropriateexpressionofclassIIMHCmoleculesonnon-APCs*HighexpressionofMHCIandIIonthepancreaticbetacellsofindividualswithinsulin-dependentdiabetesmellitus(IDDM).*ExpressionofMHCIIonthyroidacinar(腺泡)cells(inGraves’disease).*IFN-γfromtraumaorviralinfection.自身免疫病專題培訓(xùn)第51頁Infectionsandautoimmunity?Infectionstriggerautoimmunereactions–Clinicalprodromes（先驅(qū)癥狀）,animalmodels–Autoimmunitydevelopsafterinfection(i.e.theautoimmunediseaseisprecipitatedbyinfectionbutisnotdirectlycausedbytheinfection)?Someautoimmunediseasesarereducedorpreventedbyinfections–Increasingincidenceoftype1diabetes,multiplesclerosisindevelopedcountries;experimental-NODmice:mechanismunknown–The“hygienehypothesis”(originallyproposedtodescribeeffectsofinfectionsonasthma)自身免疫病專題培訓(xùn)第52頁ViralinfectionsandautoimmunediseaseBystanderactivationMolecularMimicry自身免疫病專題培訓(xùn)第53頁AutoreactiveTcellscanbeactivatedthroughamechanismofmolecularmimicrythatinvolvescross-reactiverecognitionofaviralantigenthathassimilaritytoselfantigen.Molecularmimicry自身免疫病專題培訓(xùn)第54頁Epitopemimicry(humanandmicrobialproteins)ProteinA.A.PositionA.A.SequenceCMVIE279~88PDPLGRPDEDHLA-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自身免疫病專題培訓(xùn)第55頁HelicobacterpyloriandgastricautoimmunityH.pyloriinducestheexpansionofH.pylori-specificTh1cellsthatcross-reactwithH+,K+-ATPaseepitopes.H.pylori-H+,K+-ATPasecross-reactiveTh1cellscouldmediatedestructionofgastricmucosa.幽門螺旋桿菌自身免疫病專題培訓(xùn)第56頁(1)MicrobialinfectionstimulatesToll-likereceptors(TLRs)andotherpattern-recognitionreceptorsonantigen-presentingcells(APCs),leadingtotheproductionofpro-inflammatorymediators,whichinturncanleadtotissuedamage.(2)SelfantigenthatisreleasedfromdamagedtissuecanbetakenupbyactivatedAPCs,processedandpresentedtoautoreactiveTcells.(3)Alternatively,aninfectioncanleadtomicrobialsuperantigen-inducedactivationofasubsetofTcells,someofwhichcouldbespecificforselfantigen.BystanderActivation自身免疫病專題培訓(xùn)第57頁FurthertissuedestructionbyactivatedTcellsandinflammatorymediatorscausesthereleaseofmoreselfantigenfromtissues.Bd|TheT-cellresponsecanthenspreadtoinvolveTcellsspecificforotherselfantigensinaprocessknownasepitopespreading.Epitopespreading自身免疫病專題培訓(xùn)第58頁Epitopespreadingresponsiblefortherelapseofdisease自身免疫病專題培訓(xùn)第59頁GutmicrobiotaandautoimmunediseaseGutBacteriaAffectMultipleSclerosis自身免疫病專題培訓(xùn)第60頁Gutmicrobiotaandautoimmunedisease自身免疫病專題培訓(xùn)第61頁Endocrinefactors?Mostautoimmunediseasedonotoccurwithequalfrequencyinmalesandfemales.ForexampleGraves‘a(chǎn)ndHashimoto'sare4-5times,andSLE10times,morecommoninfemaleswhileAnkylosingSpondylitisis3-4×morefrequentinmales.Thesedifferencesarebelievedtobetheresultofhormonalinfluences.?Asecondwelldocumentedhormonaleffectisthemarkedreductionindiseaseseverityseeninmanyautoimmuneconditionsduringpregnancy.Rheumatoidarthritisisperhapstheclassicexampleofthiseffect.Insomecasesthereisalsoarapidexacerbation(rebound)aftergivingbirth.自身免疫病專題培訓(xùn)第62頁Whatwouldbetheidealwaytotreatautoimmunedisease?Answer:removeonlytheantigen-specificresponseReality:Unabletoremovetheantigen-specificresponseingeneralMainstayoftreatment:anti-inflammatories(corticosteroid)andglobalimmunosuppression(cyclosporine)ifsymptomsaresevereenoughtowarrantitTreatmentofAutoimmuneDiseases自身免疫病專題培訓(xùn)第63頁Corticosteroid自身免疫病專題培訓(xùn)第64頁Corticosteroid環(huán)氧合酶膜聯(lián)蛋白前列腺素

白三烯自身免疫病專題培訓(xùn)第65頁Cyclosporin自身免疫病專題培訓(xùn)第66頁Cyclosporin自身免疫病專題培訓(xùn)第67頁ImmuneTherapyofAutoimmunediseases自身免疫病專題培訓(xùn)第68頁Therapeuticapproachesforimmunedisorders自身免疫病專題培訓(xùn)第69頁TherapeuticsbasedontheB7:CD28/CTLA-4family1.Costimulatoryblockade自身免疫病專題培訓(xùn)第70頁TherapeuticsbasedontheB7:CD28/CTLA-4family2.Inhibitingtheinhibitor–anti-tumorimmunetherapy自身免疫病專題培訓(xùn)第71頁Anti-CD11aantibody(efalizumab)inhibitsthemigrationofdendriticcellsandTcellsintopsoriaskinlesions自身免疫病專題培訓(xùn)第72頁Anti-CD3mAbTreatmentforAutoimmunity自身免疫病專題培訓(xùn)第73頁Suppressionofautoimmunitywithanti-CD3自身免疫病專題培訓(xùn)第74頁ResultsofHeroldanti-CD3PhaseI/IItrialinType1Diabetes自身免疫病專題培訓(xùn)第75頁?TumorNecrosisFactor-α(TNF-α)?TNFαisamultifunctionalpro-inflammatorymediatora)Inductionoffurthercytokineproductionb)Activationorexpressionofadhesionmoleculesc)Growthstimulation?OverproductionofTNFαisassociatedwithawiderangeofpathologicalconditions.?Efforttofindwaystodown-regulateproductionorinhibititseffects.TNFα自身免疫病專題培訓(xùn)第76頁Crohn’sDisease(CD)?InflammatoryBowelDisease(IBD)?Chronicinflammationofareasofthegastrointestinaltract.?Canaffectalllayersofthebowelwallwithpossibleabscessesandfistulas（膿腫和瘺）

(~30%ofpatients).?CommonsymptomsAbdominalpainDiarrheaWeightLossLossofappetiteFever&FatigueExcruciatinglypainful–mayrequiremorphineIncreasedriskofcolorectalcancerUnknowncauseNoknowncure

Difficulttotreat.自身免疫病專題培訓(xùn)第77頁?Imbalanceofpro-andanti-inflammatorymediators?EnhancedTh1response(IFNγ,TNFα)?TNFαisapro-inflammatory