The type I interferon system in the etiopathogenesis of auto(2)

228L.Rönnblom

Introduction

ThetypeIinterferons(IFNs)areafamilyofrelatedproteins,whichwereoriginallyde nedbytheircapac-itytointerferewithviralreplicationincellcultures(1).Thisviralinterferencewasthereasonthatthename‘interferon’wascoined.TypeIIFNisrapidlypro-ducedduringviralinvasionand,viainhibitionofviralreplication,constitutesourmajordefensesystemagainstviralinfections.TypeIIFNalsohaveimmu-nomodulatoryfunctionswhichcanbestbedescribedasageneralactivationofimmunecells.Forinstance,typeIIFNinducesdendriticcell(DC)maturationandactivation,withincreasedexpressionofMHCclassIandIImolecules,chemokinesandchemokinerecep-tors,aswellasco-stimulatorymolecules(2).ThedevelopmentofhelperTcellsalongtheTh1pathwayispromoted,andcytotoxicTcellsarestimulatedbytypeIIFNs(3,4).ItcanalsocauseBcellactivation,differentiation,antibodyproduction,andIgisotypeclassswitching(5,6).Thus,typeIIFNisapotentimmuneadjuvant,andthisobservationhasledtomanyclinicaltrialswheretypeIIFNisadministeredto.

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patientswithbothinfectiousandmalignantdiseases.lno InUppsala,ProfessorGunnarV.AlmattheBiomed-esuicalCentresetupaproductionoftypeIIFNforl anoclinicalusealreadyin1980.BuffycoatsfrombloodsrecentersinSwedenwereused,andwhitebloodcellsp rwereinfectedwithSendaivirusfortheinductionofFoIFNproduction.Puri edIFNwasusedmainlyforpatientswithmalignanciesattheUniversityHospitalinUppsala,andbene cialeffectswerereportedinseveraldiseases(7–10).However,earlyonseveralcolleaguesinUppsalanotedanincreasedoccurrenceofautoantibodiesandautoimmunediseaseduringtypeIIFNtreatment(11–13).Thesereportswerethe rstindicationsofacausativeroleoftypeIIFNinhumanautoimmunediseases.Wenotedinacohortofpatientswithmalignantcarcinoidtumorsthatasmanyas19%ofpatientsreceivinglong-termtreatmentwithIFN-aeventuallymanifestedanautoimmunedisease(14),includingsystemiclupuserythematosus(SLE).Pre-existingautoantibodieswerenotnecessaryfordevelopmentofautoimmunity,althoughpresenceofautoantibodiesbeforeIFN-atherapyconsiderablyincreasedtheriskforautoim-munedisease.Theconclusionsfromtheseobserva-tionsarethattypeIIFNcanbothbreaktoleranceandpromoteanon-goingautoimmunereactioninman.TheIFN-induceddiseasesalsoraisedthequestionofthepossibleroleoftypeIIFNinspontaneouslyoccurringautoimmunediseases.Thisquestionhasbeenintensivelystudiedbyseveralresearchgroupsduringthelastdecade.Inthisreview,theroleoftypeIIFNintheetiopathogenesisofautoimmune

diseaseswillbediscussedwiththefocusonimportantdiscoveriesbyourresearchgroup.Thepotentialappli-cationinclinicalpracticeofourpresentknowledgeofthetypeIIFNsystemwillalsobrie ybementioned.ThetypeIIFNsystem

Thereare3differenttypesofIFNs(I–III),andamongthemthetypeIIFNsarethelargestfamilythatcanbedividedinto5classes(IFN-a,-b,-w,-e,and-k),ofwhichIFN-acanbefurtherdividedinto12subtypesencodedby13highlyhomologousgenesclusteredonchromosome9.ThetypeIIFNsystemisde nedasthetypeIIFNsthemselvesandallinducers,cells,andmoleculesinvolvedinthepathwaysleadingtotheproductionandeffectsoftypeIIFN.ThetypeIIFNproteinsbindtothesameheterodimerictypeIIFNreceptor(IFNAR)consistingoftwomembrane-spanningpolypeptidechains,IFNAR1andIFNAR2(15).MosttypesofcellscanproducesmallamountsoftypeIIFN,buttheprincipaltypeIIFNproduceristheplasmacytoiddendriticcell(pDC),originallydesig-natedthenaturalIFN-producingcellanddescribedin1982–1983(16–18).Plasmacytoiddendriticcellsareinfrequentbutproduceupto109IFN-amoleculespercellwithin24huponactivation.ThetypeIIFNgenesarestrictlyregulated,andnormallyalmostnoconstitutiveIFN-aproductioncanbedetectedinhealthyindividuals.Typically,thetypeIIFNproduc-tionisinducedbyviruses,bacteria,ormicrobialnucleicacidswhensensedbythepatternrecognitionreceptors(PRRs),suchasToll-likereceptors(TLRs),retinoicacidinduciblegene1(RIG-I)-likereceptors(RLRs),andnucleotideoligomerizationdomain(NOD)-likereceptors(NLRs)(reviewedin(19)).PlasmacytoiddendriticcellsexpressTLR7andTLR9intheirendosomalmembranesandcanthereforebecomeactivatedbypathogensthatinvadepDCthroughreceptor-mediatedendocytosis.The rststepintheactivationchaininvolvesmyeloiddifferentiationfactor88(MyD88)thatassociateswithacomplexconsistingoftumornecrosisfactorreceptor-associatedfactor6(TRAF6)andinterleukinreceptorassociatedkinase(IRAK)1and4.TheseeventsleadtophosphorylationofIFNregulatoryfactor(IRF)-3,5,and7,translocationtothenucleus,and nallytranscriptionofthetypeIIFNgenes.

LigationoftheIFNARbytypeIIFNsinitiatesseveralsignaltransductionpathwaysleadingtoexpressionofIFN-stimulatedgenes(ISGs).Theclas-sicalIFNARsignalingpathwayistheJak-StatpathwayinvolvingJanusfamilykinases,tyrosinekinase(Tyk)2andJak1.Theactivatedkinasesrecruitandphos-phorylatethetranscriptionfactorsStat1andStat2,which nallyassociatewithIRF9.TheStat1/Stat2/

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