慢性活動(dòng)性EBV感染患者全外顯子測(cè)序分析及Caspase-8在其肝組織中的表達(dá)慢性活動(dòng)性EBV感染患者全外顯子測(cè)序分析及Caspase-8在其肝組織中的表達(dá)

摘要：

慢性活動(dòng)性EBV感染（CAEBV）是一種罕見的EB病毒相關(guān)淋巴增生性疾病，其嚴(yán)重程度和發(fā)展緩慢導(dǎo)致其難以診斷和治療。本研究的目的是通過(guò)全外顯子測(cè)序分析CAEBV患者的遺傳變異和識(shí)別和檢測(cè)可能的治療靶點(diǎn)。我們對(duì)兩個(gè)CAEBV患者的外顯子組進(jìn)行了深度測(cè)序，并將結(jié)果與基因組1000計(jì)劃的數(shù)據(jù)庫(kù)進(jìn)行比較。我們確定卡斯帕賽-8（Caspase-8）基因的缺失是CAEBV患者的常見遺傳缺陷之一。為了驗(yàn)證Caspase-8在CAEBV病理生理中的作用，我們檢測(cè)了CAEBV患者肝臟中Caspase-8及相關(guān)通路的表達(dá)。結(jié)果顯示，Caspase-8在CAEBV患者的肝臟中表達(dá)顯著降低。同時(shí)，肝組織中NF-κB和免疫相關(guān)轉(zhuǎn)錄因子的表達(dá)水平明顯增加，表明Caspase-8缺失可導(dǎo)致炎癥和免疫反應(yīng)的變化。

關(guān)鍵詞：

慢性活動(dòng)性EBV感染；全外顯子測(cè)序；卡斯帕賽-8；肝臟組織；炎癥免疫反應(yīng)

Abstract:

ChronicactiveEpstein-Barrvirusinfection(CAEBV)isarareEBV-associatedlymphoproliferativedisorder,characterizedbyitsseverityandslowdevelopment,makingitdifficulttodiagnoseandtreat.TheaimofthisstudywastoanalyzethegeneticvariationsofCAEBVpatientsthroughwholeexomesequencing,andidentifyanddetectpotentialtherapeutictargets.WeperformeddeepsequencingoftheexomesoftwoCAEBVpatientsandcomparedtheresultswiththedatabaseofthe1000GenomesProject.OurresultsrevealedthedeletionoftheCaspase-8geneasoneofthecommongeneticdefectsinCAEBVpatients.TovalidatetheroleofCaspase-8inCAEBVpathophysiology,weexaminedtheexpressionofCaspase-8andrelatedpathwaysinthelivertissueofCAEBVpatients.OurresultsshowedasignificantdecreaseinCaspase-8expressioninthelivertissueofCAEBVpatients.Moreover,theexpressionlevelsofNF-κBandimmune-relatedtranscriptionfactorsinthelivertissueweresignificantlyincreased,indicatingthatCaspase-8deficiencycouldleadtochangesininflammationandimmuneresponses.

Keywords:

ChronicactiveEpstein-Barrvirusinfection;wholeexomesequencing;Caspase-8;livertissue;inflammationandimmuneresponseChronicactiveEpstein-Barrvirus(CAEBV)infectionisararebutseriousconditionthatischaracterizedbypersistentanduncontrolledviralreplication,chronicinflammation,andimmunedysregulation.WhilethepathogenesisofCAEBVisnotfullyunderstood,thereisevidencethatgeneticfactorsmayplayaroleindiseasedevelopmentandprogression.

Inthisstudy,weperformedwholeexomesequencingoflivertissuesamplesfromCAEBVpatientstoinvestigatepotentialgeneticmutationsthatmaycontributetodiseasepathogenesis.OuranalysisidentifiedasignificantdecreaseintheexpressionoftheCaspase-8geneinthelivertissueofCAEBVpatientscomparedtohealthycontrols.

Caspase-8isakeyregulatorofapoptosis,orprogrammedcelldeath,andhasbeenshowntoplayaroleincontrollingimmuneresponsesandinflammation.ThedecreasedexpressionofCaspase-8inCAEBVpatientssuggeststhatalterationsinapoptosisandimmuneregulationmaycontributetodiseasepathogenesis.

Inaddition,ouranalysisrevealedasignificantincreaseintheexpressionofNF-κBandimmune-relatedtranscriptionfactorsinthelivertissueofCAEBVpatients.NF-κBisatranscriptionfactorthatregulatestheexpressionofgenesinvolvedinimmuneresponsesandinflammation.TheupregulationofNF-κBandotherimmune-relatedtranscriptionfactorsinCAEBVpatientssuggeststhatdysregulationofimmuneresponsesandinflammationmaybeakeyfeatureofdiseasepathogenesis.

Overall,ourstudyhighlightsthepotentialroleofCaspase-8deficiencyinthedevelopmentandprogressionofCAEBV.Additionally,ourfindingssuggestthatalterationsinimmuneresponsesandinflammationmayplayakeyroleindiseasepathogenesis,andmayrepresentpotentialtargetsfortherapeuticinterventioninCAEBVpatientsInconclusion,CAEBVisarareandpotentiallylethaldisorderthatremainspoorlyunderstood.OurstudyshedslightontheroleofCaspase-8deficiencyinthepathogenesisofthisdisease,andsuggestspotentialavenuesfortherapeuticintervention.Specifically,ourfindingssuggestthattargetingdysregulatedimmuneresponsesandinflammationmayrepresentapromisingapproachtotreatingCAEBVpatients.

However,manyquestionsremainunanswered.Forexample,itisunclearhowCaspase-8deficiencyleadstothedysregulationofimmuneresponsesandinflammationseeninCAEBVpatients.Additionally,itisnotyetclearwhetherothergeneticorenvironmentalfactorscontributetothedevelopmentandprogressionofthisdisease.

FurtherresearchisneededtobetterunderstandtheunderlyingmechanismsofCAEBVandtodevelopeffectivetherapiesforthisrareandlife-threateningdisorder.Nevertheless,ourstudyrepresentsanimportantstepforwardinourunderstandingofthisdiseaseanditspotentialtreatmentoptionsThediagnosisandtreatmentofCAEBVposeasignificantchallengetohealthcareproviders.Inmanycases,thediseaseisnotrecognizeduntilithasprogressedtoanadvancedstage,makingearlyidentificationandinterventioncritical.PhysiciansshouldconsiderthepossibilityofCAEBVinpatientswhopresentwithpersistentfevers,abnormallymphocytecounts,andothersymptomsassociatedwithmononucleosis.

TreatmentoptionsforCAEBVarelimited,andnosingletherapyhasproventobeuniversallyeffective.Immunomodulatoryagents,suchascorticosteroidsandcyclosporine,havebeenusedtosuppresstheimmuneresponseandreduceinflammation.Antiviraltherapywithdrugssuchasacyclovirandvalacyclovirmaybeeffectiveinreducingsymptomsinsomepatients,buttheirefficacyisvariable.Hematopoieticstemcelltransplantation(HSCT),whichinvolvestheinfusionofhealthyblood-formingstemcellsintothebodytoreplacedamagedordiseasedcells,hasshownpromiseasapotentialcureforCAEBV.However,therisksandtoxicitiesassociatedwiththisprocedure,aswellasthelimitedavailabilityofsuitabledonors,makeitachallengingtreatmentoption.

Inconclusion,CAEBVisarareandpotentiallylife-threateningillnessthatposessignificantdiagnosticandtherapeuticchallenges.AdvancesinourunderstandingoftheunderlyingmechanismsofCAEBV,aswellastheidentificationofpotentialtherapeutictargets,offerhopeforfuturetreatments.Furtherresearchisneededtoimprovethediagnosisandtreatmentofthisdisease,andtooptimizeoutcomesforaffectedpatients.Healthcareprovidersshouldremainvigilantintheireffortstorecognizeandmanagethis