I型干扰素的生物学概况

IntroductionTypeIinterferonscomprisealargegroupofstructurallysimilarcytokinesthatincludes13subtypesofIFNαanduniqueIFNβ,IFNε,IFNκandIFNωinhumans,whichexertsimilarbutnotidenticaleffectsduetotheirdifferentbindingaffinitiestoacommoncognatereceptor[1,2].GenescodingforthetypeIinterferonsareclusteredonhumanchromosome9p22andapparentlyoriginatedfromaduplicationofasinglegene[3].Boththenumberofgenesandtheirintronlessstructurepointtothevitalroleofinterferonsinhostdefenceagainstviruses.Duringaviralinfection,typeIinterferonsactivateinnateimmuneresponsesandexertanti-proliferativeandcytotoxiceffectsoncells.TypeIinterferonsalsoinducesurvival,maturationandactivationofdifferentsubsetsofdendriticcells,therebyenhancingtheirantigen-presentingabilities.Activateddendriticcellsupregulateexpressionofhumanleucocyteantigenandotherco-stimulatorymolecules,suchasCD40,CD80,CD83andCD86[4-6],andinitiatetheproductionofcytokinessuchasTNFα,IL-6,IL-10,IL-12,IL-15,IL-18,IL-23[7-10],B-cellactivatingfactor[11,12],andthechemokinesCCL3,CCL4,CCL5,andCXCL10[13-17],whichinturnexertco-stimulatoryeffectsonallotherimmunecells.TypeIinterferonslinktogetherbothinnateandadap-tiveimmunesystems.TheireffectsinadaptiveimmunityaremediatedthroughactivateddendriticcellsandalsobydirectbindingtointerferonreceptorsonBcells,T cells,neutrophilsandnaturalkiller(NK)cells.TheypromoteimmunoglobulinclassswitchingandantibodyproductioninBcells,promoteT-celleffectoractivityandpromotesynthesisofIFNγbyTcellsandNKcells,andtheyprotectbothBcellsandTcellsfromapoptosis[18-32].TypeIinterferonscanalsopromotepathologicauto-immunity;IFNαisabletobreakself-tolerancebyactivatingantigen-presentingcellsafteruptakeofselfmaterial[33].ThefirstgeneticlinkbetweentypeIinterferonsandautoimmunediseaseswasprovidedbytheobservationofanelevatedIFNαlevelintheseraofpatientswithsystemiclupuserythematosus(SLE),andthefamilialaggregationofthistraitinhealthyrelatives[34-37].ThisobservationsuggestedthatthealterationoftheinterferonpathwayisaprimaryeventinSLEpatho-genesis,ratherthanaconsequenceofthediseasepheno-type.ThelevelsofIFNαactivityinpatientswithSLEarepositivelycorrelatedwithbothclinicalandserologicalAbstractTypeIinterferonsplayanoutstandingroleininnateandadaptiveimmunitybyenhancingfunctionsofdendriticcells,inducingdifferentiationofmonocytes,promotingimmunoglobulinclassswitchinginBcellsandstimulatingeffectorfunctionsofTcells.TheincreasedproductionofIFNα/βbyplasmacytoiddendriticcellscouldberesponsiblefornotonlyefficientantiviraldefence,butitalsomaybeapathologicalfactorinthedevelopmentofvariousautoimmunedisorders.ThefirstevidenceofageneticlinkbetweentypeIinterferonsandautoimmunediseaseswastheobservationthatelevatedIFNαactivityisfrequentlydetectedintheseraofpatientswithsystemiclupuserythematosus,andthatthistraitshowshighheritabilityandfamilialaggregationintheirfirst-degreehealthyrelatives.Todate,anumberofgenesinvolvedininterferonsignallinghavebeenassociatedwithvariousautoimmunediseases.Patientswithsystemiclupuserythematosus,Sjögren’ssyndrome,dermatomyositis,psoriasis,andafractionofpatientswithrheumatoidarthritisdisplayaspecificexpressionpatternofinterferon-dependentgenesintheirleukocytes,termedtheinterferonsignature.Here,inanattempttounderstandtheroleoftypeIinterferonsinthepathogenesisofautoimmunity,wereviewtherecentadvancesinthegeneticsofautoimmunediseasesfocusingontheassociationofgenesinvolvedintypeIinterferonpathways.©2010BioMedCentralLtdGeneticassociationsintypeIinterferonrelatedpathwayswithautoimmunityAngélicaMDelgado-Vega1,MartaEAlarcón-Riquelme1,2,3andSergeyVKozyrev*1REVIEW*Correspondence:[e-mail]1DepartmentofGeneticsandPathology,RudbeckLaboratory,UppsalaUniversity,DagHammarskjöldsväg20,75185Uppsala,SwedenFulllistofauthorinformationisavailableattheendofthearticleDelgado-Vegaetal.ArthritisResearch&Therapy2010,12(Suppl1):S2©2010BioMedCentralLtdmarkersofdiseaseactivity[34,35,37,38].IncreasedlevelsofIFNαwerealsoobservedinpatientswithrheumatoidarthritis(RA),sclerodermaandprimarySjögren’ssyndrome(pSS)[34].Moreover,about20%ofpatientswithlong-termtreatmentofhaematologicalmalignanciesandviralhepatitisinfectionswithrecombinantIFNαdeveloplupusorotherautoimmunediseases,suchastype1diabetes,psoriasis,inflammatoryarthritisandpSS,orshowsymptomsresemblingautoimmunediseases[39,40].TheseresultstogetherfurthersubstantiatetheinvolvementofIFNαinthedevelopmentofvariousautoimmunedisorders.SLEpatientsdisplayanotherimportantfeatureofanactiveinterferon-mediatedsignalling:anoverexpressionofgenesregulatedbytypeIinterferon,termedtheinterferonsignature,whichismoreprominentinpatientswithseveredisease[41].Inagreementwiththeideaofasharedgeneticbasisofautoimmunediseases[42],theinterferonsignaturehasalsobeendemonstratedforpSS,dermatomyositis,psoriasisandsomeRApatients[43].InthepresentreviewwewillgiveabriefoverviewofthetypeIinterferonsignalling,withthemainfocusonthegeneticlinkagebetweentypeIinterferon-mediatedpathwaysandautoimmunediseases.Truefunctionalvariantsforthemajorityofassociatedge