The type I interferon system in the etiopathogenesis of auto(6)

232L.Rönnblom

ordouble-strandedDNA(71),linkingSLEgeneticsusceptibilitytothepresenceofinterferogenicICs.Recently,wefoundthatalsoagenevariantofIKBKE(IKK-e),whichisacentralsignal-transducingmole-culeforthecytosolicRNA/DNAsensorsandTLR4,isassociatedwithSLE(72).

AmonggeneproductsinvolvedintheresponsetoIFN-a,theSTAT4thatinteractswiththecytoplasmicpartoftheIFNAR(73)isstronglyassociatedtoSLE(74).InSLEpatientsthereisanassociationbetweenSTAT4genotypeandamoreseverephenotype,whichincludesnephritisandpresenceofanti-dsDNAauto-antibodies(75,76).PolymorphismsintheJanuskinaseTYK2,whichbindstoIFNARandisrequiredforsignalingthroughthisreceptor,arealsoassociatedtoSLE(66,77).ThesedataprovidefurtherevidenceforalinkbetweentheIFN-aresponseandthediseaseprocessinSLE.AdditionalsusceptibilitygenesforSLEcanbeinvolvedintheactivationofthetypeIIFNsystembyothermechanisms,forinstanceviagenerationofautoantigensthatcontainnucleicacidorincreasedproductionofautoantibodiescausingtheformationofincreasedlevelsofinterferogenicICs(78)..

y

lno eTheconnectionbetweenthetypeIIFNsystemsul anddiseasemanifestation

anosreSeveralobservationssuggestthatIFN-amayplayp ranimportantroleinsomeoftheclinicalmanifestationsFoinSLEpatients.ThereisanassociationbetweenincreasedserumlevelsofIFN-aandfever,skinrash,andleukopenia(29),whichperhapsisnotsurprisingconsideringthatthesesymptomsarecommonlyseenduringviralinfections.TheIFN-regulatedchemokinesareconnectedtoorgandamage,whichindirectlysup-portsarolefortypeIIFNindiseaseoutcome(79).Amongthemorespeci cSLEmanifestations,anearlystudyobservedthatpatientswithlupuspsychosishavedetectablelevelsofIFN-ainthecerebrospinal uid(CSF)(80),whichisintriguinggiventheobservedneuropsychiatricadverseeffectsduringIFN-atreat-ment(81).Recently,autoantibodieswiththeabilitytoformverypotentinterferogenicICstogetherwithRNA-containingautoantigensweredemonstratedintheCSFofSLEpatientswithneuropsychiatricmani-festations(82).TheseICsalsoinducedotherchemo-kinesandpro-in ammatorycytokinesofpossiblerelevancefortheCNSmanifestationsfrequentlyseeninSLE,whichindicatesthattheinterferogenicICsmaybedirectlyinvolvedinCNSlupus.

ResultsfromanexperimentalmodelsuggestthatIFN-acandrivethenephritisandend-organdamageinSLE(83),andithasbeenshownthatpDCsaccu-mulateinactivehumanSLEnephritis(42).MajororganinvolvementinSLEpatients,suchasnephritis,

isalsoconnectedtoamorepronouncedIFN-asig-nature(23),andIFN-a-regulatedgenesareover-expressedintheglomerulifromSLEnephritis(84).TheroleofIFN-aintheprematureatherosclerosistypicallyseeninSLEpatientsisunclear,butthetypeIIFNsystemmaycontributetotheatheroscleroticprocessbyseveralmechanisms(85).Forinstance,IFN-amayimpairendothelialcelldifferentiation(86)andaffectplateletfunction(87),butalsopromotefoamcellformation(88).Furthermore,pDCsarepresentinatheroscleroticplaquesfromcarotidlesionswheretheycanact,viatheIFN-aproduced,asin am-matoryampli ersanddestabilizetheplaque(89).ThereisalsoapossibilitythatgeneswithinthetypeIIFNsignalingpathwaycanbeusedasmarkersfororganinvolvementandseverity.Thus,thereisanassociationbetweenSTAT4genotypeandriskforamoreseverediseasephenotypethatincludesnephri-tis(75,76)andstroke(90).Thelatterobservationisinteresting,becausetheassociationbetweenaSTAT4riskvariantandstrokewasofthesamemagnitudeastheassociationbetweenstrokeandhypertension,indicatingthatautoimmuneprocessesmaybeveryimportantformanydiseasemanifestationsinSLE,eventhosethattraditionallyarenotregardedasauto-immune.Furthermore,acombinationofriskalleleswithinthetypeIIFNsignalingpathwaydramaticallyincreasestheriskforSLE(76),whichillustrateshowgeneticmappinginthefutureperhapscouldaidinthepredictionofriskfordisease.

TheroleofthetypeIIFNsysteminthedevelopmentofautoimmunity

Themany ndingsconcerningthetypeIIFNsysteminSLEpatientshavebeenputtogetherintoanetiopathogenicmodelofSLE,whichalsoincludesotherobservationsinthisdisease(Figure2).Thismodelwas rstdescribedbyusin1999(45)andhassubsequentlybeenupdated(39,91).ItisenvisionedthataninitialinfectionbyavirusinducestypeIIFNproductionandreleaseofcellularmaterialfromdyingcells.TheextracellularautoantigensfromapoptoticandnecroticcellsaswellasNETsfromgranulocytesthentriggerBcellstoautoantibodyproductionagainstRNAandDNA-bindingproteinsinindivi-dualspronetoautoimmunereactions.ICswillbeformed,whichactasendogenoustypeIIFNinducersthatcauseaprolongedstimulationoftypeIIFNproductionbypDC.Theexcessivereleaseofendog-enousDNA/RNAincombinationwithimpairedclearanceofapoptoticcellmaterialwillfacilitatethegenerationofinterferogenicIC.Severaldrugsandenvironmentalfactorscancontributetothegenera-tionofautoantigensthatcanformmoreICs.Thetype

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