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