FinalCaseStudy-CalStateLA-InstructionalWebServer最后的案例研究-加州大学洛杉矶-教学的Web服务器

FinalCaseStudyCase#4NancyLee,AndreaUstarez,LuisCastellonCSULACaseSummaryA3-year-oldgirlwasdiagnosedwithpneumonia,causedbyStreptococcuspneumoniae.Shehadfever,highrespiratoryrate,andlowbloodoxygensaturation.HerlymphnodeswereenlargedandachestX-rayshoweddiffusedconsolidationofthelowerlobeoftheleftlung.Shehadpneumoniabefore,whenshewas25monthsold.Shealsohad10episodesofotitismediathatrequiredantibiotictreatment.Herimmunoglobulinlevelsweremeasured:highlevelsofIgM,undetectablelevelsofIgA,andlowlevelsofIgG.ShewaspreviouslyvaccinatedagainsttetanusandHaemophilusinfluenzae,butshedidnotexpressspecificIgGagainstthetetanustoxoidorthepolyribosylphosphate(PAP)polysaccharideantigenofH.influenzae.ShehadbloodtypeAsoshewastestedforanti-antibodies.HerIgMtiterofanti-Bantibodieswaspositiveattheupperlimitofnormal,herIgGtiterwasundetectable.HerperipheralbloodlymphocyteswereanalyzedshowingnormalexpressionofCD40ligandonTcellsactivatedbyanti-CD3antibodies,andnormalexpressionofCD40onBcells.HerbloodcellscompletelyfailedtosecreteIgGandIgEafterstimulationwithanti-CD40antibody(tomimictheeffectsofengagementofCD40ligand)andinterleukin4(IL-4).

KeyInformationPointingtoDiagnosisCLINICALFeatures3yearsoldRecurrentinfectionsPneumonia25moago10episodesofotitismediaStreptococcuspneumoniafoundinbloodEnlargedlymphnodesinneckandarmpitsLABORATORYFeaturesHighIgM 470mg/dl(normal40-240mg/dl)LowIgG 40mg/dl(normal639-1344mg/dl)UndetectableIgAUponvaccinationnospecificIgGantibodiesTreatmentwintravenousantibioticshowedimprovementFailuretosecreteIgGandIgEafterstimulationNormalexpressionof:CD40LonTcellsCD40onBcellsTheDiagnosisforCase#4HIGM2-HyperIgMsyndrometype2(AIDdeficiency).DiagnosticTestsforActivation-inducedCytidineDeaminase(AID)DeficiencyCompletephysicalexamination.

enlargedlymphnodes(signoflymphnodehyperplasia)ImmunohistologicalExaminationLymphNodes.follicularhyperplasiaandenlargedgerminalcentersCompletebloodcount(CBC)andMeasurementofserumimmunoglobulinlevelsElevatedlevelofIgM,anddiminishedserumIgGandIgAlevelsFlowcytometrynormalexpressionofCD40andCD40ligandMolecularGeneticTesting:DNAAnalysisforAIDmutationsofautosomalrecessivegeneofconsanguineous(relatedbyblood)familiesAnalysisofCD40ligand,CD40,UracylN-glycosylasetoconfirmthedeficiencyandruleoutotherpossiblecauses.TherapyforHIGM2RegularinfusionsofIVIG(400-600mg/kgevery2to3weeksormonthly).IgGcollectedfrom100’s-1000’sofindividuals,filteredandpurified,givenintravenouslyinequaldosesover2-5consecutivedays.HIGM2ischaracterizedbynotshowingopportunisticinfections,sonoprophylaxisisneededunlikeinothersubtypesofHIGM.PrognosisforAIDDeficiencyHyperIgMsyndromeFairlygood,comparedtoothertypesofhyperIgMsyndrome.Raredisease:affectsonly1:2,000,000births/yearMostchildrencancontinuetolivenormal,healthylivesandsocializedespitethischronicdisorderprovidedthattheyreceiveadequatetreatment/therapyandappropriatetreatmentforinfections.Changesinlifestylethataffectstheentirefamilywillbemadethough:Frequentvisitstodoctors,specialistsforregularassessmentstolookoutforsignsoflongtermdamagetoorgans.LifelongimmunoglobulinreplacementtherapyAntibioticstoprotectandpreventfromfurtherinfectionsthattheimmunoglobulintreatmentisnoteffectiveagainstExtracareandprotectivemeasuresinallenvironments,especiallysociallyactiveenvironmentsHowwouldyoucommunicatediagnosisanddiseasetothepatientMrs.Tudor,afterevaluationofyourdaughterssymptomsandlaboratoryexamswehavediagnosedherwithAIDdeficiency.Thisconditionisduetoaninheritedgenemutationthataffectsyourdaughtersimmuneresponse.Sheisunabletomakedifferentantibodies,whichhelpherbodyfightoffinfections,andthatiswhyshegetssicksooften.Inordertohelpherbodygainbetterimmunitywecantreatherusingintravenousimmunoglobulintherapy.Thistherapyinvolvesinjectingimmunoglobulinintoherblood.Somecommonsideeffectsofthistherapyincludeheadaches,nausea,fever,malaise.Althoughnotverycommon,sideeffectscanalsoincludeanaphylacticreactions,asepticmeningitis,acuterenalfailure,stroke,myocardialinfarction.Howeverthetherapywillprovideyourdaughtersbodywiththeantibodiessheismissing,andhelpherfightoffinfections.TheoreticalImmunologicalBasisAIDdeficiencypreventsisotypeswitch(immunoglobulinclassswitch).AftertheBcellisactivated,AIDistranscribedandtranslated.Atthesametime,transcriptionoftheconstantregionoftheDNAcodingforIg’sistakingplace.Theisotypeswitchregionsarecytidine-rich,astheyarebeingtranscribed,AIDconvertscytidinetouridine.UridineisnotabasefoundinnormalDNAanditisextractedbyuracil-DNAglycosylase.ThedamagedDNAisrecognizedbyDNArepairendonuclease,whichreattachestwodifferentswitchsites.TheoreticalImmunologicalBasisAIDdeficiencyalsopreventssomatichypermutations–pointmutationsinthevariableregionofIg.ThesemutationsaltertheaffinityoftheantibodyforitsantigenReducedantigenbindingleadstonegativeselectionandcelldeathImprovedantigenbindingleadstopositiveselection,proliferationandfinallyplasmacelldevelopmentTheseBcellscannotundergoaffinitymaturationaftertheyareactivated,theyonlyproliferate.IgM+Bcellsstarttoaccumulateinlymphoidtissue,producinganenlargedspleenandlymphnodes.Activation-InducedCytidineDeaminase(AID)DeficiencyCausestheAutosomalRecessiveFormoftheHyper-IgMSyndrome(HIGM2).Revyet.al(2000).Cell.Researchobjectives:TotestthegeneticbasisoftheHIGM2syndromeandwhetherthehumanAIDgenedefectscouldcausetheHIGM2syndromeExperimentalsetup:IdentificationofgeneticbasisforHIgM2syndromebyperformingagenome-widesearchforsusceptibilitylociusingpolymorphicmicrosatellitemarkersinconsanguineousfamilies.Theystudied18HIGM2patientsfrom12familieswhofulfilledthediagnosticcriteriaofHIGM2.PerformedImmunologicalStudyofBcells,LinkageAnalysis,HuAIDGenesequencing,HuAIDGeneexpressionstudy,CloningandsequencingofV3-23-CµTranscripts,ImmunopathologyofLymphNodesandTonsils.Whatdidtheyfind:WidelyscatteredpointmutationsinhuAIDarealldefective.clearlydemonstrateacrucialroleofAIDinIgswitch,Igvariableregiongenesomaticmutationgeneration,andnormalgerminalcenterformation.Thepossiblecandidategene,humanAID(huAID)genehasastronglinkageandmapstochromosome12p13.(B)LocalizationofmutationsinthehuAIDgene.Ninedifferentmutationswerefoundinthecodingsequence(red)in18patientstested.MutationsinpatientsP1-P2-P3,P4-P5,andP16werelocalizedinthecytidinedeaminasecatalyticregion.InpatientsP1-P2-P3,afurtherheterozygousdeletionwasdetectedbySouthernblot(notshown).

Figure2.LocalizationandGeneticAnalysisofhuAIDMutationsinHIGM2PatientsFigure4.ImmunohistologicalExaminationofCervicalLymphNodecomparedtocontrolreactivelymphnodefromPatientP4HE=hematoxilin-eosinstaining(magnification×25).P4lymphnodeshowsfollicularhyperplasiawithg