The type I interferon system in the etiopathogenesis of auto(7)

ThetypeIinterferoninautoimmunediseases

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Figure2.TheroleofthetypeIinterferonsystemintheetiopathogenesisofsystemicautoimmunediseases.AviralinfectioninducesIFN-aproductioninpDCandthereleaseofautoantigensfromdyingcells.TheproducedIFN-aactivatesboththeinnateandadaptiveimmunesystemasdescribedinthetext.Inindividualswithageneticset-upthatcausesastrongIFN-aproductionand/oramarkedIFN-aresponse,toleranceisbroken,andantibodiesagainstnucleicacid-containingautoantigensareproduced.TheseantibodiestogetherwiththeautoantigensforminterferogenicICsthatstimulatethepDCtoIFN-asynthesisandtheBcellstoincreasedautoantibodyproduction,whichcausesaviciouscirclewithacontinuousIFN-aproductionandanon-goingautoimmunereaction.NKcellspromotetheIFN-aproductionandactivatedmonocytesdown-regulatetheNKcells,butthislatterfunctionseemstobede cientinlupus.Figuremodi edfrom(101).(DC=dendriticcell;IC=immunecomplex;IFN=interferon;Mo=monocyte;NK=naturalkiller;pDC=plasmacytoiddendriticcell;TCR=Tcellreceptor).

IIFNproducedactivatesBcelldifferentiation,Igswitch,andgenerationofantibody-producingplasmacellsaswellaslong-livedmemorycells.EstrogenswillfurtheraidintheactivationofautoreactiveBcells.IFN-awillcauseincreasedexposureofautoantigenssuchasRo52andprimeforenhancedIFN-apro-ductionbypDC.Asaconsequence,conventionalDCsandmacrophagesup-regulatetheirexpressionofco-stimulatorymoleculesandbecomemoreeffec-tiveintheirantigenpresentation.Inaddition,typeIIFNsprolongthesurvivalofactivatedTandBlym-phocytesandsuppressregulatoryTcells.TakentogetherachronicactivationofthetypeIIFNsystemwilloccuranddriveanautoimmuneprocessleading

tochronicin ammationandtissuedamageinaviciouscirclemanner.

IFN-aasatherapeutictarget

ThedevelopmentoftherapiesaimingtoinhibittypeIIFNproductioninautoimmunediseaseshasbeenstimulatedbytheobservationthattypeIIFNARknock-outmurinelupusmodelshaveareduceddis-easeactivity(92,93).Resultsfromthe rstphaseIclinicaltrialusingasingleinjectionofanti-IFN-amonoclonalantibodiesinSLEpatientswererecentlyreported(94,95).Theanti-IFN-atreatmentcausedadose-dependentinhibitionoftypeIIFNinducible

234L.Rönnblom

genesinbothperipheralbloodandskinbiopsies,aswellasareductioninclinicaldiseaseactivity.Inaddition,GM-CSF,TNF-a,IL-10,andIL-1binduciblegenesignatures,aswellasBAFFmRNAexpression,wereneutralizedinsomepatients(96),demonstratingthecloseinteractionbetweenthetypeIIFNsystemandotherpro-in ammatorypathways.Theobservationthatasingleinjectionofananti-IFN-aantibodycouldgiveasustainedneutralizationoftheIFNsignatureisofparticularinterestandsupportstheviewthattheon-goingproductionofIFN-ainSLEisatleastpartlyaresultofaself-perpetuatingviciouscircle(97).Sofar,noincreaseinseriousviralinfectionshasbeenreportedamonganti-IFN-a-treatedpatients,whichcouldbeduetothefactthat,besidesIFN-a,severalothertypeIIFNsexistwithstrongantiviralactivity(98).WhethertheselattertypeIIFNsaresuf cientlypotenttoprotectanti-IFN-a-treatedSLEpatientsfromseriouscomplica-tionsduringforinstancea upandemicremainstobeestablished,andthiscanonlybeaddressedinlargerclinicaltrials.OtherpossibletherapeutictargetsexistwithinthetypeIIFNsystem,suchasthetypeI.

y

IFNreceptor,theBDCA-2antigenonpDC(38,99),lno oroligodeoxyribonucleotideoroligoribonucleotideesuTLRantagonists(100).Noneoftheseagentshavel anobeentestedsofarinhumanSLEpatients.srep rFoConclusion

ThetypeIIFNsystemisactivatedinpatientswithseveralsystemicautoimmunediseases,whichseemstobeofmajorimportanceinthediseaseprocess.ThegeneticandimmunologicalbackgroundtotheincreasedproductionofIFN-aistosomeextentclari ed,butseveralquestionsstillremaintobeanswered.Amongthesearethemechanismsthatleadtodifferentdiseasephenotypes,despiteasimilarIFNsignature,andtheoptimalwaytodown-regulatethetypeIIFNsystem.Despitethis,anumberofstudiesthattargettheincreasedIFN-alevelsinseveralautoimmunediseasesareinanearlyclinicalphase.Acknowledgements

IthankProfessorGunnarV.Almforcriticalreadingofthemanuscript.ThisworkwassupportedbytheSwedishResearchCouncil,theSwedishRheumatismAssociation,Söderbergsfoundation,theKingGustafV80thBirthdayFoundation,andCOMBINE.Declarationofinterest:Theauthorreportsnocon ictsofinterest.Theauthoraloneisresponsibleforthecontentandwritingofthepaper.

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