The type I interferon system in the etiopathogenesis of auto(3)

IRF9complextranslocatestothenucleus,bindstoIFN-stimulatedresponseelements(ISRE),andacti-vatesthetranscriptionofhundredsofISGs(20).TheexactfunctionofthemajorityoftheISGproductsisfarfromclear.However,someofthemechanismsconferringanantiviralstatehavebeenthoroughlyinvestigated,showingthattypeIIFNinterfereswithseveraldifferentstepsinviralreplication.ThetypeIIFNinducesandactivatesenzymes,suchasmyxovirusresistanceMxA,2’5’-oligoadenylatesyn-thetase,andproteinkinase(PKR16),whichcaninhibitviraltranscriptionandtranslationandpromotedegradationofviralRNA(21).

TypeIIFNalsoaffectsmanykeyfunctionsintheinnateandacquiredimmunityasbrie ydescribedabove.SeveralofthesetypeIIFNeffectspromotetheactivationofimmunecellsandenhanceanimmuneresponse.Inaddition,IFN-acaninduceincreasedexpressionofautoantigens,suchasRo52(22,23),andpromotethereleaseofautoantigensbyinductionofapoptosis(24),whichincombinationwithanactiva-tionoftheimmunesystemcanpromotethedevel-opmentofanautoimmunereaction,iftheIFN.

y

productionisnotproperlycontrolled.lno esul SLEandotherautoimmunerheumaticanodiseases

srep rComparedtorheumatoidarthritis,SLEisarelativelyForaredisease,withanincidenceofaround5casesper100,000personsamongNorthernEuropeans(25).Thereisaclearfemalepreponderance(femaletomaleratiois9:1),andmostpatientsdevelopthediseasebetweentheagesof15and50years.SLEisregardedastheprototypeautoimmunedisease,andthereasonisthatalargenumberofdifferentautoanti-bodiesareproducedinthesepatientsandthatmost,ifnotall,cellsintheimmunesystemseemtobeinvolvedinthediseaseprocess(26).AprominentfeatureinSLEisanimmuneresponsetonucleicacidandassociatedproteins,whichresultsinautoantibodyproduction,immunecomplex(IC)formation,andorganin ammation.Beforemoderntreatmentwasintroduced,majororganinvolvementand/orinfec-tionswerethemostimportantcausesofdeath.Today,cardiovasculardiseasesduringlatestageofSLEareoneofthemostchallengingproblems.Forinstance,inourSLEcohortatotalof10%ofthepatientsareaffectedbystrokeatamedianageof55years.

IncreasedserumlevelsofIFNweredescribedinSLEpatientsmorethan30yearsagoandinitiallysuggestedtobeIFN-g(27)butwerelatercharac-terizedasIFN-a(28).FurtherstudiesshowedthatserumIFN-alevelscorrelatedtodiseaseactivity

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andtosignsofimmuneactivation,butalsotoseveralclinicaldiseasemanifestations(29).Earlyon,increasedlevelsofIFN-a-inducedproteins,suchas2’-5’oligoadenylatesynthetase(30)andMxA(31),couldalsobedemonstratedinthemajor-ityofSLEpatients,con rmingthatbioactivetypeIIFNisproducedinthesepatients.Whengenome-widegeneexpressionpro lingbecameavailable,severalresearchgroupsobservedthatamajorityofSLEpatientsdisplayanincreasedexpressionoftypeIIFN-regulatedgenes(anIFNsignature),whichisconnectedtoamoresevereclinicalpic-turewithnephritisorhematologicalmanifestations(22,23,32,33).PediatricSLEpatients,whousuallyhaveamoreseverediseasecomparedtoadultSLEpatients,almostinvariablydisplayanIFNsignatureatearlydiseasestages(22),whichsuggeststhatactivationofthetypeIIFNsystemmaybeespeciallyimportantintheinitiationofthediseaseprocess.Studiesofotherrheumaticconditionshavedem-onstratedthatseveraldiseasesshowanIFNsigna-tureinbothperipheralbloodmononuclearcells(PBMC)andtissuesfromaffectedorgans.PatientswithprimarySjögren’ssyndromehaveanIFNsig-natureinspecimensfromsalivaryglandsbutalsoinPBMC(34,35).Similarly,thissignaturecanbefoundinaffectedtissuesandPBMCfrompatientswithmyositis,systemicsclerosis(SSc),andasub-groupofpatientswithRA(36).Alltheseobserva-tionssuggestacentralandgeneralroleofthetypeIIFNsysteminthedevelopmentofautoimmunerheumaticdiseases.BecausepDCsarethekeyplayersintheproductionofIFN-a,itseemslogicaltoclarifytheirroleinallthesediseases.

Theplasmacytoiddendriticcellautoimmunediseases

InourearlystudieswenoticedthatthefrequencyofcirculatingpDCsismarkedlyreducedinSLEpatients(37,38).However,functionalstudiesofSLEpDCrevealedthatremainingsinglecellsuponstimulationhaveanormalIFN-a-producingcapacity.SeveralstudiessuggestthatthereasonforthedecreasednumberofcirculatingpDCsseemstobeamigrationofthesecellstotissues,becauseanincreasednumberofpDCscanbedetectedinskin(39,40),lymphnodes(41),andrenaltissue(42)fromSLEpatients.ThesepDCsareactivatedinvivoandsynthesizeIFN-a,whichindicatesthatthesecellsinfactareresponsibleforthecontinuousIFN-aproductionseeninSLEpatients.WecouldalsodemonstrateIFN-a-contain-ingcellsinsalivaryglandbiopsiesfrompatientswithpSS(43)andmyositis(44).Consequently,aber-rantpDCactivationmaybeanimportantstepinthe

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