ArticleContents AutoimmuneDiseaseCommonMechanismsdoi1010029780470015902a0020193 ENCYCLOPEDIAOFLIFESCIENCES2007JohnWileySonsLtdwwwelsnet dizygotictwins50Howeverifautoimmunediseaseisduetoen ID: 936989
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AutoimmuneDisease:DeLisaFairweather,JohnsHopkinsUniversity,BloombergSchoolofPublicHealth,Baltimore,Maryland,USATheimmunesystemprovidesprotectionagainstinfectiousorganismsandrepairstissuedamageinducedbyinfectionsorphysicaldamage.Autoimmunediseaseoccurswhentheimmuneresponseinflictsdamagetotissuesinthebody.Theimmunesystemspecicallyrecognizesandeliminatesforeignagentstherebyprotectingthehostagainstinfec-tion.Duringmaturationoftheimmunesystem,immune ArticleContents AutoimmuneDiseaseCommonMechanismsdoi:10.1002/9780470015902.a0020193 ENCYCLOPEDIAOFLIFESCIENCES2007,JohnWiley&Sons,Ltd.www.els.net dizygotictwins50%.However,ifautoimmunediseaseisduetoenvironmentalfactors,theconcordancerateshouldbesimilarinmonozygoticanddizygotictwins.Compar-isonoftheoccurrenceofautoimmunediseasesingenet-icallyidentical,monozygotictwinsfoundaconcordancerateintherangeof10 50%indierentstudiesand2 40%fordizygotictwins.Thelowdiseaseconcordanceinmono-zygotictwins(50%)indicatesthatenvironmentalagentsareimportantinthedevelopmentofautoimmunediseases.Thus,heredityaccountsforonlyaboutone-thirdoftheriskofdevelopinganautoimmunedisease,whilenonin-herited,environmentalfactorsaccountfortheremaining70%risk(Figure1Externalenvironmentalfactorssuchashormones,diet,drugs,toxinsand/orinfectionsareimportantindeterminingwhetheranindividualwilldevelopautoimmunedisease.Environmentalagentsareabletoamplifyautoimmunityingeneticallysusceptibleindividualsandtobreaktoleranceingeneticallyresistantindividuals,therebyincreasingtheriskofdevelopingautoimmunedisease(Figure2SeealsoAutoimmuneDiseaseMostautoimmunediseasesaremoreprevalentinwomenthanmen.Conservativeestimatesindicatethatnearly80%ofindividualswithautoimmunediseasesarewomen.Exceptionsincludediabetesmellitus,ankylosingspondy-litisandinammatoryheartdisease,whichoccurmorefrequentlyinmen.Hormonesareobtainedfromexternalsourceslikediet(i.e.soy),drugs(i.e.birthcontrolpills)orskinproductsinadditiontoproductionofsteroidsbythebody.Sexhormones(naturalandsynthetic)directlyinteractwithcellsoftheimmunesystemviareceptorsonthesurfaceorinsideimmunecells.Steroidhormones,includingoestrogensandandrogens,areknowntoinu-enceantibodyproductionandimmunecellproliferation.Thus,hormonescanamplifyorinhibittheimmuneresponse.Womenproduceelevatedantibodyresponsescomparedtomen,whilemenoftendevelopmoresevereinammation.Mostofourund
erstandingofsexdier-encesandtheimmuneresponseisderivedfromstudiesconductedinanimalmodels.Manyanimalmodelsshowasex-biasinprevalenceandseverityofdiseasethatissimilartohumanautoimmunediseases.UnderstandinghowsexhormonesregulatetheimmuneresponseisanareaofavidAnynumberofenvironmentalagentspresentinourdiet,suchaschemicalfoodadditivesorpesticides,couldinter-ferewithregulationoftheimmuneresponsecontributingtothedevelopmentofautoimmunediseaseingeneticallysusceptibleindividuals.Onedietarycomponentthathasbeenshowntoincreaseautoimmunediseaseisiodine.TheincreasedprevalenceofautoimmunethyroiddiseaseinUnitedStatesandWesternEuropeanpopulationshasbeenassociatedwithincreaseduseofiodizedsalt.Iodinebindstothethyroidhormoneprecursor,thyroglobulin,makingitatargetfortheimmunesystemresultinginincreasedautoantibodiesagainstthyroglobulinandrecruitmentofinammationtothethyroidgland.Coeliacdiseaseresultingfromgluten-sensitivityalsohasthehallmarksofanautoimmunedisease.Geneticallysusceptibleindividualsdevelophypersensitivitytowheatglutenandsimilarproteinsofbarley,ryeandoatsresultingininammationoftheintestineandautoantibodiesagainsttheenzymetransglutaminaseaswellascalreticulinandactin.Althoughconsiderableprogresshasbeenmade Environment+1) Increaseautoimmunity2) Decreaseregulation ofAutoimmunedisease Figure2Alterationsinmechanismsthatregulateinflammation,whetherduetogenesand/orenvironment,contributetotheprogressionfromautoimmunitytoautoimmunedisease.Autoimmuneresponsesareusuallygeneratedintheprocessofmountinganimmuneresponsetoforeignantigens,butautoimmunediseaseresultsonlyifautoimmunitypersistsandispoorlyregulated. 30%Environment70%Autoimmunedisease + Figure1Thedevelopmentofautoimmunediseasedependsonacombinationofgeneticandenvironmentalfactorslikehormones,diet,toxins,drugsandinfections.Geneticpredispositionaccountsforonlyaboutone-thirdoftheriskofdevelopinganautoimmunedisease,whilenoninheritedenvironmentalfactorsaccountfortheremaining70%risk. AutoimmuneDisease:Mechanisms regardingthemolecularbasisofcoeliacdisease,manyquestionsremainregardingitsstatusasanautoimmunedisease.Animportantquestioniswhetherotherautoim-munedisorderscanbeinitiatedbyimmuneresponsestoforeign,yetunidentied,antigens.Toxins/drugsForquitesometime,toxinslikeheavymetalsordrugsintendedfortherapyhavebeenassociatedwithdiseasesyndromesresemblingautoimmunedisease
s.Forexample,drugslikeprocainamideandhydralazinecaninduceauto-antibodiesandlupus-likedisordersinpatients.Penicil-laminehasbeenassociatedwithmyastheniagravisand-methyldopaisknowntocauseaformofhaemolyticanaemia.However,inallcasesofdrug-inducedautoim-munediseasesdescribedthusfar,thediseasedisappearswhenthedrugisremoved.Variousheavymetals,suchasmercury,silverorgold,caninduceanautoantibodyresponsetocellnuclearantigensinsusceptiblestrainsofmice.Byyetunknownmechanisms,mercurialcompoundshavebeenshowntoexacerbateauto-immunediseaseinexperimentalanimalmodels.Recently,administrationofmercuricchloridetosusceptiblestrainsofmicewasfoundtoincreaseautoantibodiesandcell-mediatedautoimmunityinacollagen-inducedmodelofarthritis.Thesendingssuggestthatenvironmentalfactorslikethemicrobialcomponentofadjuvantinthecollagen-inducedmodelandmercuryexposurecanactsynergisticallytopromoteautoimmunedisease.InfectionsBacterialandviralinfectionsweresomeoftherstagentsassociatedwithautoimmunediseasesmorethanacenturyago.However,mostoftheclinicalevidencelinkingauto-immunediseaseswithprecedinginfectionsisonlycircum-stantial.Forexample,diabeteshasbeenassociatedwithcoxsackievirusandcytomegalovirusinfections,multiplesclerosiswithEpstein Barrvirusandmeaslesvirusinfec-tions,rheumatoidarthritiswithmycobacteriaandEpstein Barrinfectionsandmyocarditiswithcoxsackievirusandcytomegalovirusinfections,tonameafew.Sinceinfectionsgenerallyoccurwellbeforetheonsetofsignsandsymp-tomsofautoimmunedisease,linkingaspeciccausativeagenttoaparticularautoimmunediseaseisdicult.Themostdirectevidencethatinfectiousagentscaninduceautoimmunediseaseisthedevelopmentofdiseaseinexper-imentalanimalsfollowinginoculationwithself-antigensincombinationwithadjuvantcontaininguninfectiousmicrobialantigens.Thefactthatmultiple,diversetypesofmicroorganismsareassociatedwithasingleautoimmunediseasesuggeststhatinfectiousagentsinduceautoimmunediseasethroughcommonmechanisms.Severalmechanismshavebeenproposedforhowinfec-tionscanleadtoautoimmunediseaseincludingdirectviraldamage,releaseofcrypticself-peptides,antigenicspread,molecularmimicry,bystanderactivationandtheadjuvanteect.Molecularmimicryistheconceptthatantigensofthemicroorganismcloselyresembleself-antigensandsowhenaninfectionoccursautoimmunityisalsoinduced.Bystanderactivationmayoccurwhentheimmuneresponseisnonspecicallystimulated
bytheinfectionresultinginactivationofautoimmunityingeneticallysusceptibleindividuals.Theadjuvanteectdescribesthespecicactivationoftheinnateimmuneresponsebymicro-bialantigensasoccurs,forexample,duringadministrationofadjuvantsinvaccines.Anumberofautoimmunediseasescanbeinducedexperimentallybyadministeringself-antigenwithadjuvant,suchasrheumatoidarthritiswithcollagen,multiplesclerosiswithmyelinbasicproteinandmyocarditiswithcardiacmyosin.Animalmodelsofautoimmunedisease,whetherinducedwithadjuvantsorchemicals,spontaneousasinthenonobesediabetic(NOD)mouseorbiobreeding(BB)ratmodelsofdiabetesorgenet-icallyengineeredmodels,providevaluableinformationonthemechanismsleadingtodiseaseandtheecacyofther-apeuticstrategiesdesignedtocombatautoimmunedisease.Seealso:AutoimmuneDisease:AnimalModelsAutoimmuneDiseaseAcommonfeatureofallautoimmunediseasesisthepresenceofautoantibodiesandinammation,includingmononuclearphagocytes,autoreactiveTlymphocytesandplasmacells(autoantibodyproducingBcells).Autoimmunediseasescanbeclassiedasorgan-specicornonorgan-specicdependingonwhethertheautoimmuneresponseisdirectedagainstaparticulartissuelikethethyroidinHashimotosthyroiditis,oragainstwidespreadantigenssuchascellnuclearantigensinlupus.Seealso:Auto-immuneDisease;AutoimmuneDisease:AnimalModels;AutoimmuneDisease:DiagnosisAntibody-mediateddamageAntibodiesorimmunoglobulinsareafamilyofglycopro-teinspresentintheserumandtissueuidsofallmammals.AntibodiescanbecarriedonthesurfaceofBcells,actingasreceptors,orfreeinthebloodorlymph.Specicbindingofantigens(selforforeign)causesBcellstoproducelargeamountsofantigen-specicantibody.Theseantibodiesprovidecriticalprotectionagainstinfectiousmicroor-ganismsimmediatelyfollowinginfectionandarethekeyprotectiveimmuneresponseinducedbyvaccination.Similarly,self-reactiveorautoantibodiesareimportantinclearingcellulardebrisinducedbyinammationorphys-icaldamagetothebody.Acommonfeatureofallautoimmunediseasesisthepresenceofautoantibodies,whichareanimportantfactorinthediagnosisorclassicationoftheautoimmune AutoimmuneDisease:Mechanisms immuneresponse,impactingtheprogressiontoautoim-munedisease.Infectiousmicroorganismshavelongbeenconsideredimportantaetiologicagentsinthedevelopmentofautoimmunedisease.Althoughtheirroleinpatientshasbeendiculttosubstantiate,animalmodelshavedemon-stratedthatsomeautoimmunediseasescanb
einducedbyinfectiousagentssuchasinammatoryheartdiseasefol-lowingcoxsackievirusinfection.Thatmanydiversemicro-organismshavebeenassociatedwithasingleautoimmunedisease(e.g.viral,bacterialandparasiticinfectionsassoci-atedwithinammatoryheartdisease)andonetypeofmicroorganismassociatedwithmanydierentautoimmunediseases(e.g.coxsackievirusinfectionassociatedwithdiabetes,thyroiditisandinammationintheheart)furtherindicatesthatinfectionsmayinduceautoimmunediseasebycommonpathogenicmechanisms.Thatis,theinamma-toryresponsetoinfectionismoreimportantthanthepar-ticularinfectiousagentintriggeringautoimmunedisease.InnateimmunityActivationoftheinnateimmunesystemisessentialforthedevelopmentofaprotectiveadaptiveimmuneresponseagainstinfectionandforthedevelopmentofautoimmunedisease.Innateimmunecellsproduceresponsestopartic-ularclassesofpathogensviapatternrecognitionreceptors(PRR),suchasToll-likereceptors(TLR).Interactionofpathogen-associatedmolecularpatterns(PAMP)onmicroorganismswithPRRonantigen-presentingcells(APC)likemacrophagesanddendriticcellsresultsintheupregulationofsurfacemoleculesessentialforantigenpresentationandtheproductionofproinammatorycytokines.Microbialcomponentsofadjuvants,likelipo-polysaccharide(LPS)orthemycobacteriaincompleteFreundsadjuvant,activatetheinnateimmuneresponsewhenadministeredwithself-antigensresultinginautoim-munediseaseinanimalmodelssuchascollagen-inducedarthritisorcardiacmyosin-inducedmyocarditis.Inocula-tionofadjuvantswithoutself-antigendoesnotusuallyresultinthedevelopmentofautoimmunedisease.Micro-organismsnotonlystimulatetheimmuneresponsebystimulatingPRRlikeTLR2andTLR4,butalsoprovideself-antigenstotheimmunesystembydamagingtissues,bothofwhicharenecessaryforthedevelopmentofauto-immunediseaseinanimalmodels.Recentstudiesinanimalmodelshavedemonstratedthatstimulatingtheinnateimmuneresponseiscriticalforthelaterdevelopmentofautoimmunedisease.Thus,exposuretoenvironmentalagentsthatalterorinuencetheinnateimmuneresponsemayincreasetheriskofdevelopinganautoimmunediseaseingeneticallysusceptibleindividuals.ProinflammatorycytokinesAnotherpathogenicmechanismcommontoautoimmunediseasesistheincreasedproductionofthecytokinesTNFandIL-1.Theseproinammatorycytokinesareproducedduringtheinnateandadaptiveimmuneresponseandactinalong-rangeendocrinemanner,aectingimmunecellsfarremovedfromthesiteofinfectionori
noculation.IfTNForIL-1levelsareincreasedbyinoculationofmicewiththeadjuvantLPS(whichstimulatesTNFandIL-1tion)orwitheithercytokine,autoimmunediseasecanbeincreasedingeneticallysusceptiblestrainsofmiceortolerancebrokeningeneticallyresistantstrains.Thisindicatesthatgeneticresistancetodevelopingautoim-munediseasecanbeovercomebyenvironmentalfactorslikeinfectionsoradjuvantsthatincreaseproinammatorycytokines.Someepidemiologicalevidenceforthisexistsinstudiesofindividualsfromregionsoftheworldwheretheincidenceofautoimmunediseaseislow(i.e.theEquator)movingtoregionswhereautoimmunediseasesaremorecommon(i.e.theNorthernhemisphere)whogoontodevelopautoimmunedisease.Sinceonlytheenvironmentchangedandnotthegeneticbackgroundoftheindividual,environmentappearstoexertadominantinuenceonwhetheranindividualwilldevelopanautoimmunediseaseFigures1).Furthermore,autoimmunediseasecanbepreventedinhumansoranimalmodelsifTNForIL-1levelsarereducedusingneutralizingmonoclonalantibod-ies.RecentclinicaltherapiesblockingTNFhaveproducedremarkableeectsinreducingtheseverityofautoimmunediseaseslikerheumatoidarthritis,inammatoryboweldisease,ankylosingspondylitis,psoriasisandmultiplesclerosis.Experiencehasshown,however,thatitisdiculttoturnoanongoingautoimmuneresponseandinter-ventionduringtheearlieststagesofantigenrecognitionislikelytobenecessaryforsuccessfultreatmentorpreven-tionofdisease.Seealso:AutoimmuneDiseases:GeneTherapy;AutoimmuneDisease:TreatmentRegulatingtheimmuneresponseTheinductionofanimmuneresponsemustbefollowedbydownregulationoftheresponsetomaintainhomeostasisoftheimmunesystemandtopreventorreducetissuedamage.Likewise,inammationassociatedwithautoim-munediseasecanbereducedorpossiblyevenpreventedifproinammatoryresponsesareappropriatelydownreg-ulated.Multipleinhibitorypathwayskeeptheimmuneres-ponseincheckincludingtheinhibitoryreceptorsCTLA-4andTim-3,anti-inammatorycytokineslikeIL-10andandspecializedcellslikeregulatoryTcells.Recently,ithasbeendemonstratedthatsignalsleadingtobothactivationandregulationoftheimmuneresponseareinitiatedduringinnateimmunity.Inadjuvant-inducedanimalmodelsofautoimmunedisease,depletionofreg-ulatoryTcellsincreasesinammationwhileadministeringthesecellscanreduceorevenpreventdisease.Thus,thebalancebetweeneectorTcellsandregulatoryTcellsmaydeterminewhetherautoimmunediseasedevelopsor AutoimmuneDisease:Mechan