The type I interferon system in the etiopathogenesis of auto(4)

230L.Rönnblom

processthateventuallyleadstoseveraldifferentauto-immunediseases.

InducersoftypeIIFNproductioninautoimmunediseases

Normally,typeIIFNsynthesisistriggeredbyviruses,andtheproductionistightlyregulatedandlimitedintime.Animportant ndingwasthereforetheobserva-tionthatserafromSLEpatients’IChavethecapacityspeci callytoactivatepDCs(45,46).FurtherstudiesrevealedthatsuchinterferogenicICscontainnucleicacidsandareinternalizedviatheFcgRIIaexpressedonpDCs(47),reachtheendosome,andstimulatetherelevantTLRwithsubsequentactivationoftranscrip-tionfactorsandIFN-aproduction(48).Thismecha-nismforinductionoftypeIIFNproductionhasbeendemonstratedinvitroforbothDNA-andRNA-containingICs.Thenucleicacid-containingautoanti-gensintheinterferogenicICscanbegeneratedfromapoptoticornecroticcells(49),whichisrelevantgiventheincreasedapoptosisandreducedclearanceofapo-ptoticcellsinSLE(50,51).Recentstudieshaveshown.

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thatneutrophilsundergoingso-calledNETosisalsolno havethecapacitytoprovideinterferogenicautoantigensesu(52,53),demonstratingthatseveralpathwayscanleadl anotopDCactivationinSLE.Thecomplementcompo-srenentC1qhasthecapacitytodecreasetheIFN-ap rproductionbyinterferogenicICs(54,55),andthisFoeffectmayatleastpartiallyexplaintheincreasedinci-denceofSLEinC1q-de cientindividuals(56).

ICscontainingbothDNAandRNAhavethecapac-itytoactivatepDCs,butRNA-containingICs(RNA-IC)thattriggerTLR7seemtobeespeciallypotentasIFN-ainducers(57,58).AmongtheseareICsgeneratedbyautoantibodiesagainstsnRNPorSSAincombinationwiththeappropriateautoantigen.ThereisinSLEpatientsacorrelationbetweenserumIFN-aactivityandpresenceofautoantibodiestoRNA-bindingproteins(59).Sincesomeoftheseauto-antibodiesappearseveralyearsbeforetheappearanceofclinicallyovertSLEdisease(60)andshowcross-reactivitywithviralepitopes(61),theinitialtriggerfortheproductionofantibodieswithIFN-a-inducingcapacitycouldwellbeaviralinfection.ThisscenariowouldconnectviralinfectionswiththegenerationofinterferogenicICs,whichpartlycouldexplainthelong-soughtconnectionbetweeninfectiousdiseasesandautoimmunity.

ItisimportanttonoticethatICswiththecapacitytotriggerpDCtoIFN-aproductioncanbegeneratedbyautoantibodiesfrompatientswithalldiseasesdisplayinganinterferonsignature(43,44,62).So,althoughitremainstobeshownwhetherinterferogenicICsinfactareresponsible

fortheon-goingtypeIIFNproductioninthesediseasesinvivo,ourdatasuggestthatthismaywellbethecase.

TheregulationoftypeIIFNresponseinautoimmunity

AnobviousquestioniswhythetypeIIFNsystemisnotdown-regulatedinpatientswithautoimmunedisease,becausebothtypeIIFNproductionandautoantibodyformationregularlyoccurduringinfec-tions.Animportant ndingwastheobservationthatpDCsareregulatedbyotherimmunecellsandthatnaturalkiller(NK)cellsenhancetheIFN-aresponsebypDCstimulatedwithRNA-IC(63).Incontrast,monocyteshaveastronginhibitoryeffectontheNKcells,whichismediatedviaprostaglandinE2,TNF-a,orreactiveoxygenspecies.Interestingly,thisinhibi-toryfunctionbymonocytesisdiminishedinSLEpatients(63),whichmaycontributetothecontinuousactivationofthetypeIIFNsystem.Recently,wehaveshownthatNKcellsenhancethepDCresponsetoRNA-ICviaMIP-1bandLFA-1,andthatthepDC-NKcross-talkinSLEispromotedbyIL-12andIL-18(64).MuchlessisknownabouttheroleoftheadaptiveimmunesystemonthepDCfunction,butthisisanimportantareaforfurtherstudies.However,itisclearthatifweunderstoodtheregu-lationofthetypeIIFNsystem,wecoulddevelopmorepowerfultherapeuticstrategies.

GenevariantsinthetypeIIFNsystemandriskforautoimmunity

Amongthemanyidenti edriskgenesforSLE,alargenumberareconnectedtopathwaysthatareinvolvedintheIFN-aproductionorsensitivity(Figure1).ThetranscriptionfactorIRF5,whichisconstitutivelyexpressedinpDC(65),wasthe rstidenti edgenedirectlyinvolvedinIFN-ageneactivationthatwasassociatedtoincreasedriskforSLE(66).SubsequentstudieshaveshownthatpolymorphismsinIRF5areimportantforthesusceptibilitytoseveralotherauto-immunediseases,includingrheumatoidarthritis(67)andpSS(68).Recently,theallelevariantswiththehighestprobabilityofbeingcausalinSLEwereiden-ti edandshowntoaffecttheIRF5expression,whichisincreasedinPBMCfromSLEpatients(69).WehaveshownthatalternativesplicingofIRF5issignif-icantlyup-regulatedinPBMCfromSLEpatientsandthatariskhaplotypeisassociatedwiththeenhancedIRF5transcriptandproteinexpression(70).AnIRF5riskhaplotypeisassociatedtoahighserumIFN-aactivityinpatientsandespeciallyinthosewithautoantibodiestoRNA-bindingproteins

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