lessons from characterization and treatment of the autoinflammatory syndromes 2017 ivona aksentijevich资料.pdf

该【lessons from characterization and treatment of the autoinflammatory syndromes 2017 ivona aksentijevich资料 】是由【四婆子】上传分享，文档一共【8】页，该文档可以免费在线阅读，需要了解更多关于【lessons from characterization and treatment of the autoinflammatory syndromes 2017 ivona aksentijevich资料 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。:haploinsufficiencyofA20,otulipenia,asevereformofpyrin-associateddisease,,wediscussthebiologicalrationalefortreatmentwithcytokineinhibitorsandcolchicineinrespectiveconditionsandtheuseofinterleukin-,1,otulipenia,pyrininflammasome,,basedonlinkageofmolecules,includinginflammasomes,theprotea-type,,cytokinereceptorsorinhibitors,andarangeDeubiquitinases(DUBs)areenzymesthatreverseofdifferentenzymes[1].herapiestheeffectsofubiquitinationbyhydrolyzingareefficaciousinmostpatients,inparticularinter--1(IL-1)inhibition[2].NonbiologicaldrugsalterationsaffectingDUBshavebeenassociatedsuchastheJAK-,humancancers,andneuro-Abetterunderstandingofthemolecularmechan-degenerativediseases[4].Thispastyearsawtheismsassociatedwithautoinflammationwillprovidepublicationofthreearticlesthatlinkeddefectsinafoundationfordevelopingmoreaffordableandeffectivetreatmentsforthesechroniclife-,NationalHumanGenomeResearchInstitute,Bethesda,Maryland,USAandbNIHRNationalInstituteforHealthResearch–LeedsMusculoskeletalBiomedicalResearchUnitUBIQUTINATINATION-ASSOCIATED(NIHR-LMBRU)andLeedsInstituteofRheumaticandMusculoskeletalMedicine(LIRMM),eTrustBrennerBuilding,’sAUTOINFLAMMATORYDISEASESUniversityHospital,Leeds,UKPosttranslationalmodificationbyubiquitinationCorrespondencetoDrIvonaAksentijevich,NHGRI/NIH,-5235,9000RockvillePike,Bethesda,MD20892,:+1ofmanybiologicalprocesses,includingimmune3014968365;fax:+**********;e-mail:******@[3].Ubiquitin(Ub)chainsareassembledCurrOpinRheumatol2017,29:187–194inresponsetotheactivationofinnateimmuneDOI:-8711Copyright?2017WoltersKluwerHealth,?2017WoltersKluwerHealth,-associatedmutationaffectstheOTUdomainKEYPOINTSofA20andtheycreatetruncatedproteinswith,otulipeniasuggestsanewcategoryofhumanmutantcellsdisplayedelevatedlevelsofK63ubiq-inflammatorydiseases,diseasesofdysregulateduitinatedIKK/NEMO,RIPK1,andTNFR1,().Patients’primarycellsshowedconstitutiveMEFVmutationsareassociatedwithaspectrumofautoinflammatoryphenotypesincludingFMFandaactivationofNF-kBandtheNLRP3inflammasomesevereformofneutrophilicdermatosis(PAAND).[12,13]andhaveexcessiveproductionofproinflam-matorycytokinesincludingIL-1,IL-6,IL-9,IL-17,Pyrinmayfunctionasaninnateimmune‘guard’toTNF,IP-10/CXCL10,,namelyIL-,attenuatessystemicinflammationin,haploinsufficiencyofA20(HA20),1-mediatedmonogenicStill’---monvar-iants,neartheTNFAIP3gene,havebeenassociatedwithsusceptibilitytomanyautoimmunediseasestwoDUBstomonogenicsystemicinflammatory[14–16].Giventhepotentanti-inflammatoryfunc--celllymphomas,whichsuggestedthatZhouetal.[5&&]describedsixfamilieswithdomi-ene[17].nantlyinheritedloss-of-function(LOF)mutationsGerm-runcatingmutationsinTNFAIP3haveinA20,encodedbytheTNFAIP3gene,-onsetfevers,athral-MicelackingA20(Tnfaip3à/àmice)[18]exhibitgia/arthritis,apthousstomatitis,genitalulcers,aninflammationandperinataldeath,-specificablationsofA20giveriseresembleBehcet’sdisease,[19].TheinflammatorytohavefeaturesofsystemiclupuserythematosusphenotypeisparticularlysevereinA20-deficient(SLE),,humanandmurinemodelandidiopathicthrombocytopenicpurpura(ITP).studiesdemonstratevariableandcell-(GWASs)[6,7].Subsequently,twofamiliesofJapaneseancestryhavebeenreported[8,9].InOTULIPENIA/OTULIN-RELATEDadditiontoconstitutivesymptoms,twopatientsAUTOINFLAMMATORYSYNDROMEhadsevereintestinalinflammation,andwereTheseconddiseaserelatedtoadysregulationininitiallydiagnosedwithentero-Behcet’sdisease[9].deubiquitinationiscausedbyrecessivelyinheritedA20isanubiquitin-editingenzymethatplaysaLOFmutationsinthelinear(Met1)DUBOTULINkeyroleinthenegativeregulationofproinflamma-(alsoknownasgumby).OTULINisahighlycon-torysignalingpathwaysincludingnuclearfactor-kBservedcysteineproteasewithfunctiontospecifi-(NF-kB)[10,11].ThisinhibitoryfunctioniscarriedcallyhydrolyzelinearUbchainsthatareassembledoutbytwooppositeyetsynergisticactivities,ovar-plexiantumor(OTU)domain-mediatedDUBandzinc(LUBAC)[20–22].Met1Ubchainsplayanimport-finger(ZnF)domain-mediatedubiquitin-ligaseantroleinthepropagationofsignalsinNF-kB,,uponsimulationwithtumorNOD2,andMitogen-ActivatedProtein-kinasesnecrosisfactor(TNF),A20deubiqiuitinatesK63Ubmediatedinflammatorypathways[23].TheLUBACplexconsistsofthecatalyticsubunitHOIL-conjugateK48UbchainsonRIPK1totargetthis1-interactingprotein(HOIP)(RNF31):HOIL-1(RBCK1)andSHARPINVolume29Number2March2017Copyright?2017WoltersKluwerHealth,-UbK63-UbA20OTULINK63-UbPLinear-UbIKKγA20XIKKαIKKβXOTULINK48-UbHaploinsuf?ciencyofA20PPOtulipeniaκαHeterozygousmutations,LOFIBIκBαBi-allelicmutations,LOFDefectiveK63DUBactivityDefectivelinearDUBactivityIncreasedNF-κBactivity,IncreasedNF-κBactivityIncreasedNLRP3Targetgenes:herapiesNF-(HA20)-kBpathwayisregulatedbothbyK63(Lys63)-linkedandlinear(Met1)--(IkB)andtargetsIkBforubiquitin–proteasomesystem(UPS)--kBsignaling,bycleavingK63andlinearUBchainsfromtargetmolecules,RIPK1,-[12,13].TNFR1,TNFreceptor1;TRADD,TNFR1-associateddeathdomainprotein;RIPK1,thedeathdomain-containingproteinkinasereceptor-interactingprotein1;NLRP3,NACHT,LRR,andPYDdomains-containingprotein3.(SIPL1).OTULINbindstothePNGase/UBAorwithprolongedfevers,jointswelling,diarrhea,UBX-–OTULINinteractionreduceserythematousorpustularrash,painfulskinnodules,OTULIN’scapacitytorestrictLUBAC-[24].LUBAC-deficientpatientsdiagnosedwithchronicatypicalneutrophilichavesusceptibilitytobacterialinfectionsalongwithdermatosiswithlipodystrophyandelevatedepisodesofpathogen-freesystemicinflammationtemperature(CANDLE).Askinlesionbiopsyshowed[25,26].MutantcellsexhibitedimpairedNF-kBevidenceofneutrophilicdermatitisandpanniculitissignalinginfibroblastsandB--1stimulationinmonocytes,whichLUBAC-deficiencies,patientswithotulipeniahaveountsforthefeaturesofimmunodefi---Zhouetal.[27&&],-chainsontargetsubstratesIKK/NEMO,RIPK1,lipeniatodenoteadecreasedexpressionofmutantTNFR1,,,Damgaardetal.[28&&]cellsshowedevidenceforincreasedsignalinginthedescribedthesamePakistanifamilyandnamedcanonicalNF-kBpathwayandoverproductionofthediseaseOTULIN-relatedautoinflammatorysyn-TNF,IL-1b,IL-6,IL-12,IL-17,IL-18,andIFNgindrome(ORAS).Patientspresentedwithneonatal-serumsamplesandinresponsetoLPSstimulationonsetsevereinflammatorydiseasemanifesting().Anti-TNFtherapyisveryeffectivein1040-8711Copyright?2017WoltersKluwerHealth,?2017WoltersKluwerHealth,,CRP,whichhasbeenlinkedtoaspecificmutation,andESR,(),-Otulin-deficientmice(gumby/gumby)areembry-terizedbyrecurrentlong-lastingepisodesoffever,e,anddefectsinneuronaldevelopment[29].sterileskinabscesses,pyodermagangrenosum,Damgaardetal.[28&&]showedthatcell-specificabla-andarthralgia/,,PSTPIP1/-,itisinterestingto14-3-3proteins(,middle).TheelucidationofspeculatethattheDUBscouldbelegitimatethemolecularmechanisminPAANDmakesastrongtherapeutictargetsinthedevelopmentofnovelargumentthattheseverityofinflammationinanti---ASSOCIATEDAUTOINFLAMMATORYDISEASESThepathogenesisoffamilialMediterraneanfeverBEYONDTHEPYRININFLAMMASOME(FMF)hasbeenatopicofgreatinterestsincetheInarecentstudyonthepyrininflammasomeacti-discoveryofcausalgeneMEFV,encodingpyrinvationParketal.[38&&]showedthatpyrininhibitionprotein,almost20yearsago[30].FMFgenerally,correlateswiththeactivityofRhoA/PKN/14-3-3butnotexclusively,af