Immune deficiency syndromes：免疫缺陷綜合征課件

ImmunedeficiencysyndromesKeriC.SmithMay28,2009ImmunedeficiencysyndromesKer1ImmunedeficienciesPrimaryHereditaryoracquiredCanbecategorizedbasedonclinicalpresentationCellmediated(Tcell)Antibodymediated(Bcell)Nonspecific(phagocytes,NKcells)ComplementactivationSecondaryImmunedeficiencyistheresultofanotherdiseaseImmunedeficienciesPrimary2MajorclinicalmanifestationsofimmunedisordersDisorderAssociatedDiseaseDeficiencyBcelldeficiency–deficiencyinAbmediatedimmunityRecurrentbacterialdisease(otitismedia,recurrentpneumoniaTLymphocytedeficiency–deficiencyincellmediatedimmunityIncreasedsusceptibilitytoviral,fungal,protozoalinfectionTandBlymphocytedeficiency–combineddeficiencyofAb-andcell-mediatedimmunityAcuteandchronicinfectionswithviral,bacterial,fungal,andprotozoalorganismsPhagocyticcelldeficiencySystemicinfectionswithbacteriaofusuallylowvirulence,infectionswithpyogenicbacteria,impairedpusformationandwouldhealingNKcelldeficiencyViralinfections,associatedwithseveralTcelldisordersandX-linkedlymphoproliferativesyndromesComplementcomponentdeficiencyBacterialinfections;autommunityMajorclinicalmanifestations3SevereCombinedImmunodeficiencyDisease(SCID)

LifethreateninginfectionssoonafterbirthWasting,FailuretothriveLackofThymicshadowLackofCD3+,CD4+,CD8+andlymphocyteresponsetoantigensSevereCombinedImmunodeficien4“TheBoyintheBubble”“TheBoyintheBubble”5PrimaryimmunodeficienciesSevereCombinedImmunodeficiencyDiseaseT-B+X-linkedSCID(40-50%ofcases)LackgchainforcommoncytokinereceptorAutosomalrecessiveSCIDMutationingenethatencodesJAK3tyrosinekinasePrimaryimmunodeficienciesSeve6XlinkedandautosomalrecessiveXlinkedandautosomalrecessi7PrimaryimmunodeficiencySevereCombinedImmunodeficiencyDiseaseT-B-Adenosinedeaminasedeficiency(20%ofcases)Missinghousekeepingenzymeinpurinesalvagepathway,autosomalrecessive,buildupoftoxicwastesaffectsBandTcellsPurinenucleosidephosphorylasedeficiencyPurinesalvagepathway,toxicwastesaffectneurologicsystemandTcells(thesepatientshaveautoimmunity?!)RecombinasedeficiencyRAG1and2requiredfortherearrangementofIggenesandTCR.Cellsarestuckinpre-Bandpre-Tstages.NKcellfunctionOKPrimaryimmunodeficiencySevere8PrimaryImmunodeficiencySevereCombinedImmunodeficiencyDiseaseT+B-Omennsyndrome“l(fā)eaky”SCIDwithpartialRAGactivity.Th2imbalanceandatendencytowardshyperIgEsyndromeT+B+BarelymphocytesyndromeFailuretoexpressHLAmoleculesZAP-70mutationUnabletosignalthroughTCRPrimaryImmunodeficiencySevere9FailuretostimulateTcellsFailuretostimulateTcells10MultisystemdisordersWiskott-AldrichSyndromeXlinkedmutationingeneencodingproteinthatinteractswithcytoskeletonBleeding,recurrentbacterialinfections,allergicreactionsAbnormalBandTcells,lowTcellcountCanbetreatedwithantibiotics,antivirals,bonemarrowtransplantAtaxiaTelangiectasiaMutationinATMgeneManifestsasstaggeringgaitwithabnormalvasculardilationIncreasedsusceptibilitytoinfection,lymphopenia,depressedIgandTcellresponseMultisystemdisordersWiskott-A11TreatmentforSCIDBonemarrow/placentalstemcelltransplantIvIgifnecessarySupportivecareGenetherapy,ifpossibleAvoidliveviralvaccines!CMV-/irradiated/lowWBCbloodtransfusionsTreatmentforSCIDBonemarrow/12Futureresearchdirections….CarefulconsiderationofpatientsDifferentvectors?MonitorpatientsforinsertionsitesStemcells?Futureresearchdirections….Ca13ImmunodeficienciesofTcellsandcell-mediatedimmunityPatientsaresusceptibletoviral,fungal,andprotozoalinfectionsOftenexhibitselectivedefectsinAbproductionCanbedifficulttodistinguishfromSCIDpatientsImmunodeficienciesofTcells14DiGeorgesyndromeCongenitalthymicaplasia–thymusdoesnotdevelopnormally(neitherdoesparathyroid)1:4000Resultsfromdeletioninchromosome22q11,butisnotinheritedFewtonomatureTcellsinperipherySymptoms:HypocalcemiaCongenitalcardiacdiseaseRecurrentorchronicinfectionswithviruses,bacteria,fungi,protozoaLackofimmuneresponseafterimmunizationwithTdependentantigensDiGeorgesyndromeCongenitalth15FormertreatmentofDiGeorgesyndromeFetalthymusgraft(<14weeksgestation)WhydidthisresultinfunctionalTcells?Donorfetalthymusprovidedthymicepithelialcells,andpatient’sTcellshadanenvironmenttomatureWhydidtheTcells“collaborate”poorlywithpatientAPC?PatientTcellsrecognizedtheMHCofthedonoras“self”,notthepatientMHC.FormertreatmentofDiGeorges16NudeMiceMousemodelforDiGeorgesyndromeNudeMiceMousemodelforDiGeo17TcelldeficiencieswithnormalperipheralTcellnumbersFunctional,ratherthannumericaldefectinTcellpopulationSusceptibletoopportunisticinfections,highincidenceofautoimmunediseaseAutosomalrecessiveDeficientexpressionin:ZAP-70tyrosinekinase(phenotypeincludesCD8deficiencyandSCID-likesymptomsCD3eCD3gTcelldeficiencieswithnorma18ALPSAutoimmuneLymphoproliferativeDisorderSystemicautoimmunedisease,susceptibleonlytochronicviralinfectionsIncreasedCD4-/CD8-Tcells,candevelopBcelllymphomasMostpatientshaveamutationingeneencodingforFas(CD95)ALPSAutoimmuneLymphoprolifera19ChronicMucocutaneousCandidiasisPoorlydefinedcollectionofsyndromescharacterizedbyCandidainfectionsofskinandmucousmembranesNormalBcellimmunity,andnormalTcellimmunity(toeverythingotherthanCandida)Maybeinherited,affectspredominantlychildrenChronicMucocutaneousCandidia20BcellorIg-associatedImmunodeficiencyMaybeassociatedwithdefectiveBcelldevelopment(absenceofallIgsubclasses)ordeficiencyinsubclassorclassofIgPatientssufferfromrecurrentorchronicinfectionsBcellorIg-associatedImmuno21Brunton’sagammaglobulinemiaX-linkedinfantileagmmaglobulinemia1:100,000Noticedininfantsat5-6monthsofageSeriousandrepeatedbacterialinfectionsDefectinBTKgenePre-BcellscannotdevelopintomatureBcellsTreatmentconsistsofIvIginjections,butchroniclungdiseaseisaproblemBrunton’sagammaglobulinemiaX-22TransientHypogammaglobulinemiaNormalnumberofBcellsinbloodTransientinabilitytoproduceIgGMaybeduetodeficiencyinnumberandfunctionofhelperTcellsDoesnotusuallypersistpast2yearsTransientHypogammaglobulinemi23CVIDCommonVariableImmunodeficiencyDiseaseOnset15-35years,decreasedserumIgA,IgG,lowtonormalIgMPneumonia,bronchiectasis,sinusitis,GIinfectionsMayalsohaveautoantibodies,SLE,higherincidenceofcancerCausedbyfailureofBcellstomaturetoAbsecretingcellsClassIIMHC6thchromosomeICOSgene(5%)TACIgene(15%)TreatmentwithIvIgCVIDCommonVariableImmunodefi24Immunedeficiencysyndromes：免疫缺陷綜合征課件25IgAdeficiency1:800incidenceLackofserumandmucosalIgAUsuallyasymptomaticGI,respiratorydiseaseAssociatedwithallergy,autoimmunityEtiologyunknown,butfamilialassociationsandlinkagewithCVIDBroadspectrumantibioticsIgAdeficiency1:800incidence26AssociationbetweenCVIDandIgADAssociationbetweenCVIDandI27PatientswithIgAdeficiencyareusuallytreatedwithbroad-spectrumantibiotics.WhyistheinjectionofIgAnotasuitabletreatmentinthesepatients?SerumsicknesswilloccurIgAisn’tagoodactivatorofcomplement,andthusisuselessagainstbacterialinfectionsInjectedIgAisunlikelytobesecretedatthemucosalimmunesurfacesA,B,andCAandCPatientswithIgAdeficiencya28TreatmentofIgdeficiencydisordersIvIgSupportivecare(antibiotics)Noliveviralvaccines!Complicationsincludemalignancies,autoimmunityTreatmentofIgdeficiencydis29HyperIgMsyndromeMostlymales,rarelyfemalesSevererespiratoryinfections,sinusitis,diagnosedage1-2VerylowserumIgG,IgE,IgA,andnormaltoelevatedIgMTcellimmunitycanweakenwithtimeAbnormalgerminalcenterformationComplicationsincludemalignancy,autoimmunityHyperIgMsyndromeMostlymales30ThemanycausesofHyperIgMThemanycausesofHyperIgM31Immunedeficiencysyndromes：免疫缺陷綜合征課件32Immunedeficiencysyndromes：免疫缺陷綜合征課件33Immunedeficiencysyndromes：免疫缺陷綜合征課件34DuncanSyndromeX-linkedlymphoproliferativediseaseOriginallyobservedin6maternallyrelatedmalesoftheDuncanfamilyTcellscan’tregulateBcellgrowthExposuretoEBVresultsinsevereinfectiousmononucleosisHighprobabilityoflymphomadevelopmentPoorprognosisDuncanSyndromeX-linkedlympho35PhagocyticdysfunctionsAffecttheinnateandacquiredresponsetopathogensDysfunctionin:ActionrequiredtophagocytizeMigrationandadhesionofphagocyticcellsPhagocyticdysfunctionsAffect36LADLeukocyteadhesiondeficiencyAutosomalrecessiveGroupofdisordersinwhichtheleukocyteinteractionwithvascularendotheliumisdisruptedbsubunitofintegrinsSelectinligandsConsequences:RecurrentsofttissuebacterialinfectionIncreasedbloodWBCcountsNopusformationoreffectivewoundhealingLADLeukocyteadhesiondeficien37BLADEarly1990’s–upto15%ofHolsteinbullsand6-8%ofcowswerecarriersformutatedCD18geneUpto20,000calves/yearpotentiallyaffectedScreeningfortheaffectedgenereducedincidenceBLADEarly1990’s–upto15%o38Chediak-HigashiSyndromeAutosomalrecessiveAbnormalgiantgranulesandorganellesinthecellDiminishedkillingofintracellularorganisms(lysosomesanddegranulation),leadingtomassiveinfiltrationoflymphocytesandmacrophagesinliver,spleen,lymphnodesStrepandStaphmainproblem–recurrentinfectionsPoorprognosisChediak-HigashiSyndromeAutoso39ChronicGranulomatousDiseaseX-linked,autosomalrecessiveSkin,lymphnode,lunginfectionsHighWBCinbloodPhagocytesunabletocompleterespiratoryburstTreatmentsincludeantibiotics,antifungals,IFNgChronicGranulomatousDiseaseX40SummaryofphagocyticdysfunctionSummaryofphagocyticdysfunct41ComplementAbnormalitiesDeficienciesinheritedinautosomalfashion,heterozygoteshave50%ofgivencomplementproteinComplementisrequiredfor:OpsonizationandkillingofbacteriaChemotaxisBcellactivationEliminationofAg-AbcomplexesComplementAbnormalitiesDefici42EarlycomplementproteindeficienciesC1,C2,C4orC3deficiencyPyogenicinfectionsAutoimmunity–SLEverycommonEarlycomplementproteindefic43LatecomplementproteindeficienciesC5-C9PreventsformationofmembraneattackcomplexGramnegativebacterialinfectionsLatecomplementproteindefici44Immunedeficiencysyndromes：免疫缺陷綜合征課件45DiagnosisofimmunedeficiencydisordersMedicalHistoryAgeatonsetLivevaccines?FamilyhistorySeverityofillnessPhysicalExamTonsils?OrganomegalyPalpatelymphnodesChartgrowthChestXrayDiagnosisofimmunedeficiency46LabtestsPhagocyteCellsurfacemarkersBacteriocidalassayChemotaxisandopsonizationassaysNKandMacrophage51CrreleaseassaysCytokinereleaseIgfunctionIsohemagluttininsDT,TTresponseAnti-pneumococcusIglevelsmolecular/DNAstudiesBcellfunctionCD27memorycellsNucleicacidenzymeassaysmolecular/DNAstudiesTcellfunctionDTHFlowcytometryforsubsetsPHA/AgstimulationTCRspectratypingLabtestsPhagocyteBcellfunct47AcquiredImmunodeficienciesSecondaryimmunedeficienciesthataretheconsequencesofotherdiseasesMalnutritionChemotherapeuticagentsDeliberateimmunosuppressionUntreatedautoimmunityOverwhelmingbacterialinfectionAcquiredImmunodeficienciesSec48HIVHIV49HIVbinding,replicationGp120bindsCD4CoreceptorbindingCCR5(macrophagetropic)CXCR4(lymphtropic)PenetrationofcellmembraneTranscriptionofRNAtoCDNA,remainsinlatentphaseActivatedTcells,viralreplicationandreleaseMacrophages,DCgenerallyserveasreservoirsHIVbinding,replicationGp12050ClinicalcourseofHIVinfectionAcuteinfectionAsymptomaticorflu-likeillnessDropincirculatingCD4cells,CTLsandAbincreaseSeroconversionChroniclatentphaseUpto15yearsLowlevelofviralreplication,graduallossofCD4cellsCrisisphaseCharacterizedbyunusualmalignancies,opportunisticinfections,neurologicsundromesActivationofvirallyinfectedTcellsbyAgresultsinstimulationofviraltransc