The type I interferon system in the etiopathogenesis of auto(2)

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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

ThetypeIinterferoninautoimmunediseases

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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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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

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