The type I interferon system in the etiopathogenesis of auto

UpsalaJournalofMedicalSciences.2011;116:227–237

REVIEWARTICLE

ThetypeIinterferonsystemintheetiopathogenesisofautoimmunediseases

LARSRÖNNBLOM

DepartmentofMedicalSciences,SectionofRheumatology,UppsalaUniversity,Uppsala,Sweden

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Winner of the Wyeth Prize for Clinical Research in Rheumatology, 2009 for his pioneering research on interferon and its importance for the understand-ing of Systemic Lupus Erythematosus. In 2011, he was awarded the Thure’us prize from the Royal Society of Science for his outstanding research concerning the etiology of autoimmune diseases.

Lars Rönnblom

Abstract

ManypatientswithsystemicautoimmunediseaseshavesignsofacontinuousproductionoftypeIinterferon(IFN)anddisplayanincreasedexpressionofIFN-a-regulatedgenes.Thereasonfortheon-goingIFN-asynthesisinthesepatientsseemstobeanactivationofplasmacytoiddendriticcells(pDCs)byimmunecomplexes(ICs),consistingofautoantibodiesincombinationwithDNAorRNA-containingautoantigens.SuchinterferogenicICsareinternalizedviatheFcgRIIaexpressedonpDCs,reachtheendosome,andstimulateToll-likereceptor(TLR)-7or-9,whichsubsequentlyleadstoIFN-agenetranscription.VariantsofgenesinvolvedinboththeIFN-asynthesisandresponsehavebeenlinkedtoanincreasedrisktodevelopsystemiclupuserythematosus(SLE)andotherautoimmunediseases.AmongtheseautoimmunityriskgenesareIFNregulatoryfactor5(IRF5),whichisinvolvedinTLRsignaling,andthesignaltransducerandactivatoroftranscription4(STAT4)thatinteractswiththetypeIIFNreceptor.SeveralothergenevariantsintheIFNsignalingpathwayalsoconferanincreasedrisktodevelopanautoimmunedisease.TheobservationsthatIFN-atherapycaninduceautoimmunityandthatmanyautoimmuneconditionshaveanon-goingtypeIIFNproductionsuggestthatthetypeIIFNsystemhasapivotalroleintheetiopathogenesisofthesediseases.PossiblemechanismsbehindthedysregulatedtypeIFNsysteminautoimmunediseasesandhowtheIFN-aproducedcancontributetothedevelopmentofanautoimmuneprocesswillbereviewed.

Keywords:Autoimmune,immunecomplex,interferon,plasmacytoiddendriticcell,systemiclupus

erythematosus

Correspondence:ProfessorLarsRönnblomMDPhD,DepartmentofMedicalSciences,UppsalaUniversity,SE-75185Uppsala,Sweden.Fax:+4618500952.E-mail:Lars.Ronnblom@medsci.uu.se

(Received14September2011;accepted14September2011)

ISSN0300-9734print/ISSN2000-1967onlineÓ2011InformaHealthcareDOI:10.3109/03009734.2011.624649

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,andnormallyalmo …… 此处隐藏：6088字，全部文档内容请下载后查看。喜欢就下载吧 ……