Atypical_Manifestation_of_LRBA_Deficiency_with.5

炎性肠病(克罗恩,溃疡性结肠炎)的基础研究,临床治疗,国外现状,进展

AtypicalManifestationofLRBADeficiencywithPredominantIBD-likePhenotype

lu,MD, NinaKathrinSerwas,MSc,*AydanKansu,MD, ElisangelaSantos-Valente,MD,*ZarifeKulog

ArzuDemir,MD, Aytac¸Yaman,MD, LauraYanethGamezDiaz,MSc, RehaArtan,MD,§ErsinSayar,MD,kArzuEnsari,MD,¶BodoGrimbacher,MD, andKaanBoztug,MD*,**

Background:In ammatoryboweldiseases(IBDs)denoteaheterogeneousgroupofdisordersassociatedwithanimbalanceofgutmicrobiomeandthe

immunesystem.ImportanceoftheimmunesysteminthegutisendorsedbythepresenceofIBD-likesymptomsinseveralprimaryimmunode ciencies.Afractionofearly-onsetIBDspresentingwithmoreseverediseasecourseandincompleteresponsetoconventionaltreatmentisassumedtobeinheritedinaMendelianfashion,asexempli edbytherecentdiscoveryofinterleukin(IL)-10(receptor)de ciency.

Methods:Weanalyzedapatientborntoconsanguineousparentssufferingfromsevereintestinalmanifestationssince6monthsofageandlater

diagnosedasIBD.Eventually,shedevelopedautoimmunemanifestationsincludingthyroiditisandtypeIdiabetesattheageof6and9years,http://www.wendangwang.combinedsingle-nucleotidepolymorphismarray-basedhomozygositymappingandexomesequencingwasperformedtoidentifytheunderlyinggeneticdefect.ProteinstructuralpredictionswerecalculatedusingI-TASSER.Immunoblotwasperformedtoassessproteinexpression.FlowcytometricanalysiswasappliedtoinvestigateB-cellsubpopulations.

Results:Weidenti edahomozygousmissensemutation(p.Ile2824Pro)inlipopolysaccharide-responsiveandbeige-likeanchor(LRBA)affectingthe

C-terminalWD40domainoftheprotein.IncontrasttopreviouslypublishedLRBA-de cientpatients,themutantproteinwasexpressedatsimilarlevelstohealthycontrols.ImmunophenotypingoftheindexpatientrevealednormalB-cellsubpopulationsexceptincreasedCD21lowBcells.

Conclusions:WedescribeapatientwithanovelmissensemutationinLRBAwhopresentedwithIBD-likesymptomsatearlyage,illustratingthat

LRBAde ciencyshouldbeconsideredinthedifferentialdiagnosisforIBD(-like)diseaseevenintheabsenceofovertimmunode ciency.(In ammBowelDis2015;21:40–47)

KeyWords:LRBA,in ammatoryboweldisease,autoimmunity,exomesequencing

T

hegastrointestinaltractrepresentsthelargestinterfaceoftheorganismwiththeenvironmentandisconstantlyconfrontedwithforeignantigensandbacteria,whichmayeliciteitherbene cial

Supplementaldigitalcontentisavailableforthisarticle.DirectURLcitationsappearintheprintedtextandareprovidedintheHTMLandPDFversionsofthisarticleonthejournal’sWebsite(http://www.wendangwang.com).

ReceivedforpublicationAugust15,2014;AcceptedOctober2,2014.

Fromthe*CeMMResearchCenterforMolecularMedicineoftheAustrianAcademyofSciences,Vienna,Austria; DepartmentofPediatricGastroenterology,AnkaraUniversity,Ankara,Turkey; CenterforChronicImmunode ciency,Univer-sityMedicalCenterFreiburg,Freiburg,Germany;§DepartmentofPediatricGastro-enterology,AkdenizUniversity,Antalya,Turkey;kKonyaTrainingandResearchHospital,Konya,Turkey;¶DepartmentofPathology,AnkaraUniversity,Ankara,Turkey;and**DepartmentofPediatricsandAdolescentMedicine,MedicalUniver-sityofVienna,Vienna,Austria.

SupportedbyfundingfromtheAustrianScienceFund(FWF)grantnumberP24999andtheFWFSTARTprizetoK.Boztug(Y595-B13)andbytheGermanFederalMinistryofEducationandResearch(BMBF01EO1303)toB.Grimbacher.WethankEssiEmingerandElisabethSalzerfortechnicalsupport.

Theauthorshavenocon ictsofinteresttodisclose.

Reprints:KaanBoztug,MD,CeMMResearchCenterforMolecularMedicineoftheAustrianAcademyofSciences,Vienna;DepartmentofPediatricsandAdolescentMedicine,MedicalUniversityofViennaLazarettgasse14AKHBT25.3,A-1090Vienna,Austria(e-mail:kboztug@cemm.oeaw.ac.at).

Copyright©2014Crohn’s&ColitisFoundationofAmerica,Inc.DOI10.1097/MIB.0000000000000266Publishedonline4December2014.

orpathogeniceffects.Whethertheoutcomeisbene cialisdeter-minedbyavarietyofsystems,includingtheimmunesystem(re-viewedinRef.1).Effectorfunctionsoftheimmunesysteminthegutaretightlyregulatedasinadequateactivationmayhavedestruc-tiveeffectsonthebowel(reviewedinRef.2).In ammatoryboweldiseases(IBDs)representagroupofdiseasesresultingfrompath-ologicallyincreasedactivationofhostdefensesystemsleadingtoseverein ammationanddiarrhea(reviewedinRef.3).Conversely,primaryimmunode ciencydisordersincludingcommonvariableimmunode ciencies(CVIDs)arealsoassociatedwithIBD-likemanifestations.4IthasbeenhypothesizedthatforIBDs,diseaseonsetisbothpartiallyenvironmentallyandpartiallygeneticallydriven(reviewedinRef.5).Recentstudieshaveidenti edmono-geneticcausesofIBD,whichmayexplainearlydiseaseonsetinparticularcaseswheretherelativecontributionofhostgeneticswillarguablybethehighest(reviewedinRef.6).Forinstance,muta-tionsaffectingtheinterleukin(IL)10(receptor),7,8ADAM17,9XIAP,10andTTC7A11geneshaverecentlybeenidenti edasmono-geniccausesofveryearly-onsetIBD(onsetbefore6yrofage12).Thediagnosisinthesecasesisdif cultduetotheunusualpheno-typeandlackofspeci claboratorysignsofintestinalin ammation(reviewedRef.6).Alargeproportionofpatientswithveryearly-orearly-onsetIBD(symptomsbefore10yrofage13)remain

In ammBowelDis Volume21,Number1,January2015

40

|http://www.wendangwang.com

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