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Immunological Effects of Silica and Asbestos

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Immunological Effects of Silica and Asbestosof,and

    Immunological Effects of Silica and

    Asbestos

    Cellular&MolecularImmunology

    lqeview

    26l

    ImmunologicalEffectsofSilicaandAsbestos

    TakemiOtsuki,MegumiMaeda,ShukoMurakami,HiroakiHayashi,YoshieMiura,

    MasayasuKusaka3

    ,

    TakashiNakano4,

    KazuyaFukuoka4

    ,

    TakumiKishimoto,FuminoriHyodoh,

    AyakoUekiandYasumitsuNishimura

    Silicosispatients(SILs)andpatientswhohavebeenexposedtoasbestosdevelopnotonlyrespiratorydiseasesbut

    alsocertainimmunolo~icaldisorders.Inparticular,SILsometimescomplicatesautoimmunediseasessuchas

    systemicscleroderma,rheumatoidarthritis(knownasCaplansyndrome),andsystemiclupuserythematoses.In

    addition.malignantcomplicationssuchaslungcancerandmalignantmesotheliomaoftenoccurrinpatients

    exposedtoasbestos.andmaybeinvolvedinthereductionoftumorimmunity.Althoughsilica.induceddisordersof

    autoimmunityhavebeenexplainedasaajuvant-typeeffectsofsilica,morepreciseanalysesareneededandshould

    reflecttherecentprogressinimmunomolecularfindings.Abriefsummaryofourinvestigatio

nsrelatedtothe

    immunologicaleffectsofsilica/asbestosispresented.Recentadvancesinimmunomolecularstudiesledtodetailed

    analysesoftheimmunologicaleffectsofasbestosandsilica.Bothaffectimmuno.competentcellsandtheseeffects

    maybeassociatedwiththepathOphysiOlOgicaldevelopmentofcomplicationsinsilicosisandasbestos.exposed

    patientssuchastheoccurrenceofautoimmunedisordersandmalignanttumors,respectively.Inaddition,

    immunologicalanalysesmayleadtothedevelopmentofnewclinicaltoolsforthemodificationofthe

    pathophysiologicalaspectsofdiseasessuchastheregulationofautoimmunityortumorimmunityusingcel1.

    mediatedtherapies,variouscytokines,andmolecule-targetingtherapies.Inparticular,astheincidenceofasbestos.

    relatedmalignanciesisincreasingandsuchmalignancieshavebeenamedicalandsocialproblemsincethesummer

    of2OO5inJapan.effortsshouldbefocusedondevelopingacureforthesediseasestoeliminatenationwideanxiety.

    Ce//ular&MolecularImmunology.20O7:4(4):261.268.

    KeyWords:silica,asbestos,immunology,Fas,regulatoryTcell,apoptosis Introduction

    Silicosispatients(SILs)developrespiratoryfibrosisand

    impairedtheirpulmonaryfunction.Inaddition.silicais

    knownasoneofthestrongestenvironmentalsubstances

    causingautoimmunitydysfunctionf1.3).SILsoftendevelop

    immunologicalcomplicationssuchasrheumaticarthritis

    (knownasCaplansyndrome(4.6)),systemicsclerosis(SSc).

    andsystemiclupuserythematoses(SLE).Theeffectsofsilica

    DepartmentofHygiene,KawasakiMedicalSchool,Matsushima577,

Kurashiki7010192,Japan;

    EppleyInstituteforCancerResearch,UniversityofNebraskaMedical Center,Omaha,Nebraska68198,USA;

    DepartmentofInternalMedicine,KusakaHospital,1122Nishikatagami, Bizen7050021,Japan;

    DepartmentofRespiratoryMedicine,HyogoMedicalCollegeofMedicine, 1-1Mukogawacho,Nishinomiya,Hyogo6638131,

    Japan;

    ReceivedJun2,2007.AcceptedJul19,2007

    Copyright@2007byTheChineseSocietyofImmunology

    onautoimmunityhavealsobeenassumedaspatientswho

    haveundergoneplasticsurgerywithimplantscontaining silicone([Si02O一】n)showfrequentcomplicationsof

    autoimmunedisordersf7-9).Theseaccumulatedfindings clearlyindicatethatcrystallinesilicacausesdysregulation and/ordisturbanceofthehumanimmunesystem,particularly autoimmunity.

    Regardingasbestos,whichiscategorizedasasilicate

    (mineralogicalcomplexescontainingmetals,suchasironand magnesium)includingchrysotile,crocidolite,andamosite, patientsexposedtoasbestosalsodeveloppulmonaryfibrosis OkayamaRosaiHospital,1-10.25Chikkou.midori.machi.Okayama 7028055,Japan;

    DepartmentofRehabilitation,FacultyofHealthSciencesandTechnology, KawasakiUniversityofMedicalWelfare,288Matsushima,Kurashiki 7010193,Japan;

    DepartmentofNursing,KawasakiCollegeofAlliedHealthProfessions, 316Matsushima,Kurashiki7010194,Japan;

    Correspondingto:Dr.TakemiOtsuki,DepartmentofHygiene,Kawasaki MedicalSchool,577Matsushima,Kurashiki7010192,Japan.Tel:+81.86.

462-1111,Fax:+81-86_464-1125,E-mail:takemi@reed.kawasakim.

    ac|ip

    Volume4Number4August2007

    262ImmunologicalEffectsofSilicaandAsbestos Apoptosis?Resistancetoasbestos-inducedapoptosis _Long-termsurvival

    ?ActivationofmultipleTCR-v13repertoires resembledsuperantigenexposure

    

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    Figure1.Experimentalfindingsofimmunologicaleffec~ofchrysotile,aformofasbestos,ind

    ucedbyshort-termandhigh-dose

    exposure(1eftpane1)orlong-termandlow-doseexposureusingMT-2,anHTLV-1immortali

    zedhumanpolyclonalTcellline?

    knownasasbestosis,mesothelialplaque,andmalignant diseasessuchaslungcancerandmesothelioma(10-13). Someofthesemalignanciesmaybeconsideredaresultofa declineintumorimmunityowingtoexposureofimmuno-

competentcellstoasbestos.

    Silicaandsilicatesmaydisturbimmunefunctionssuchas autoimmunityandtumorimmunity.Inisarticle,abrief

    summaryofourinvestigationsrelatedtotheimmunological effectsofsilica/asbestosispresented.DetailsofeachSUbject canbefoundinthereferencescited.

    Immunologicaleffectsofchrysotileandasbestos TheInternationalAgencyforResearchonCancer(IARC) categorizesbothasbestosandcrystallinesilicaasgroupI carcinogens,becauseitiswellknownthatasbestos(e.g., chrysotile,crocidolite,andamosite)causesmalignantlung cancerormesothelioma(10-13).AccordingtotheIARC classification,asbestosaffectsalveolarepithelialand mesothelialcells.Therehavebeenmanystudiesof asbestos.inducedapoptosisofthesecellsfl4.22).In comparisonwithmostOthersolidtumors,mutationofthe P53geneisrare.Insteadofthealterationofp53,lossof pl6texpressionhasbeendetectedinmostmesotheliomas andcelllines.Inaddition,pl,ap53regulator,is simultaneouslydeleted(23.25).Underexperimental conditions,thesecellsundergoapoptosisuponhigh.1evel, short-termexposuretoasbestosasaresultoftheproduction ofreactiveoxygenspecies(ROS)andreactiveniwogen species(RNS1viaactivationofthemitochondrialapoptotic pathway.Furthermore,severalnon.smal1.celllungcancer celllinesconstitutivelycontaintheactivesignaltransducer andactivatoroftranscription3(STAT3)(26,27).Moreover, inhibitionoftumor.derivedinterleukinfIL).10andIL.10 receptorfIL.IOR)interactionbyanautocrine/paracrine1oop resultsinadecreaseintheexpressionlevelofconstitutively

    activeSTAT3andthesubsequentinhibitionofBc1.2 Volume4Number4August2007

264ImmunologicalEffectsofSilicaandAsbestos

    Figure2.Schematicpresentationoftheactivationmechanismsofautoimmunityfoundinsilic

    osispatientsfocusingonthealterations

    ofFasandFas.relatedmolecules.andattenuatedfunctionoftheCD4+CD25Tcellfraction.

    involvingtheactivationofCAD/CPAN,DFF40byremoving itsinhibitor,ICAD/DFF45.DNAfragmentation.andfinally apoptosis(4145).

    Themosttypicalalternativelysplicedvariantofthe wild.typefasgenetranscriptissolublefas.Asthisvariant transcriptlacks63bpofthetransmembranedomain.its product(solubleFas)issecretedfromcellstosuppress membraneFas.mediatedapoptosisbyblockingthebinding betweenmembraneFasandtheFasligandinthe

    extracellularregionf46.47).IfthereiSahighlevelofsoluble Fasintheextracellularregion,lymphocytesintheseregions mayavoidapoptosisandsurvivelonger.Indeed.therehave beenseveralstudiesshowingelevatedlevelsofserum

    solubleFasinpatientswithautoimmunediseases(48.51): therefore,wecomparedcellularandmolecularchangesinthe levelsofFasandFas.relatedmoleculesbetweenSILsand healthydonors(HDs1:

    Thelevelofset'tim.solubleFaswashigherinSILsthan HDs(521.Thelevelofserum.solubleFasliganddidnot dierbetweenSILsandHDs(531.AlthoughtheFasligandiS usuallylocalizedinthemembraneofnaturalkiller(NK)cells, activatedTcells,andcytotoxicTcellsitiSsometimes

    cleavedbymatrix..metalloproteinase..1ikeenzymesand secretedintoextracellularspaces(54,55).Althoughthe percentageofFas.positivelymphocytes(membraneFas expression)didnotdifferbetweenSILsandHDs,themean fluorescenceintensity(MFI)ofmembraneFaswaslowerin SILsthaninHDs.Inaddition.weakermembraneFas

    expressersamonglymphocyteswereidentifiedtobeweaker fasmessageexpressers(52,56).Therelativegeneexpression ratioofwild-typeandsolublefasandvariOUSgenesrelatedto Fas.mediatedapoptosis,suchasdecoyreceptor3(dcr3),the apoptosis.acceleratinggenescaspase8,3,and.9andcpan

    (caab.andtheintracellularapoptosis.inhibitorygenesiaP Volume4Number4August2007

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Cellular&MolecularImmunology

    Figure3.Summaryofimmunologicaleffectsofsilica/asbestos. survivin,dff45(icad),toso,i:flice,andsentrin,inperipheral bloodmononuclearcells(PBMCs1wasanalyzed(57.60). DcR3wasinitiallydiscoveredasaproteinsecretedfromlung andcoloncancercellsthatpreventstheFas1igandfrom targetingthem.andiSalsoexpressedoncytotoxicTcellsand naturalkillercells(61,62).Thus,DcR3functionssimilarly tosolubleFas,namely.itinhibitsmembraneFas.mediated apoptosis.Thefindingswereasfollows,(i,soluble/as mRNAiSpredominantlyexpressedinPBMCsfromSILs.but

    notfromHDs(57,(iithedcr3geneexpressionlevelis higherinPBMCsfromSILsthanfromHDsf59)andthese Dysregulatedautoimmuni~

    Variousautoantibodies

    Complicatedautoimmune

    diseases

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    mayinducetheinhibitionofFasandFasligandbinding similartothecaseswithahigherlevelofsolubleFas moleculesandfiii)thegeneexpressionlevelsofintracellular inhibitorsofFas.mediatedapoptosissuchasi:flice.sentrin. survivin,andicadwerelowerinSILsthaninHDs(59.60). Alternativelysplicedvariantsoffasandmutationalscreening for/asand/asZandgeneswerethendetected(63). Althoughsignificantmutationsin/asand/asfandcoding sequenceswerenotdetected,manyalternativelyspliced variantswerefoundandanalysisofamino.acidtranslation fromdetectedvariantsshowedthatalloftheseaswellasthe Volume4Number4August2007

266

    typicalsolublefas,possessthebindingsiteoftheFasligand, butlackthetransmembranedomainanddeathdomain.These findingsindicatethatallthesevariantsmayinhibitthe bindingbetweenmembraneFasandtheFasligand,similarto solubleFasandDcR3molecules(63).

    /nvitroexposureofTcellsderivedfromHDtosilica causesslowbutpreciseactivationofthesecells,asindicated bytheexpressionofCD69.atypicalearlymarkerofTcell activation(64).

ThepercentageoftheperipheralbloodCD4CD25

    fraction.whichincludesCD4CD25FoxP3regulatoryT cells(Treg)suppressingexcessautoreaction,inthescarce self-recognizingTcellfractioninperipheralblood.was slightlylowerinSILsasdeterminedintermsof

    agepredictedvaluescalculatedfromtheanalysisofHD.In addition.thefunctionofthisfractioninSILswasless significantthaninHDs,asdeterminedbyalloreactivemixed lymphocytereaction(MLR1analysisf651.

    Fromthesefindings,ahypothesisforactivated autoimmunityinSILshasbeenproposed.asshowninFigure 2andpreliminarilyreportedpreviously(56,66).Thefindings ofthelevelsoffactorsinextracellularspaces.suchassoluble Fas,DcR3,andproductsfromvariOUSalternativelyspliced fasvariants,indicatethatapoptosismediatedbymembrane FasseemstointerferewiththesemoleculesandFasmediated

    apoptosisisreduced.However,sincetherewasareduced expressionofintracellularmoleculesforantiFasmediated

    apoptosissuchasi-flice,sentrin,andsurvivingeneproducts inSILscomparedwiththoseinHDs.itseemedlikelvthat Fasmediatedapoptosisisenhancedinlymphocytesderived fromSILs.Inaddition.theantiFasautoantibodyfoundin

    serumfromSILsmaycontributetotheenhancedapoptosisof lymphocytes,becauseoftheFasstimulatingfunctionofthis

    antibody.AscomparedwithHDs,inwhichtheapoptosisof lymphocytesisassumedtobeneitherenhancednorreduced, itseemsthatthetwofractionsoflymphocyteswould respectivelyshowenhancedandreducedFasmediated

    apoptosisinSILs.

    Thus,therearetwopopulationsofCD4lymphocytes,

    thestrongerexpresserofmembraneFasandtheweaker expresserofFas.inSILs.Weakerexpressersmayhave developedowingtoexcessivetranscriptionofthe alternativelysplicedfasgeneandothervariantmessages; therefore,thesecellsmayberesistanttothefunctional antiFasautoantibody,becausemembraneFasisrelatively scarce.Consequently.itisspeculatedthatthereisaparticular fractionofCD4TlymphocytesinSILsthatexpressesweak levelsofmembraneFas,secreteshigherlevelsofsolubleFas. DcR3,andsplicedvariants,andisresistanttoantiFas

    autoantibodyinducedapoptosis,asshowninFigure2and previousreports(56,66).AspatientswithaweakerMFIof membraneFashaveahighertiterofantinuclearantigens

    (ANA),asreportedpreviously(56),self-recognizingclones inSILsmaybeincludedinthisfraction.becausetheseclones maysurvivelongerandshowresistancetoapoptosis. ItispossiblethatFasmediatedapoptosisoccurstoa

    certaindegreeinlymphocytesofSILs,becauseofthe observeddecreaseinthelevelsofintracellularinhibitorsof ImmunologicalEffectsofSilicaandAsbestos

    Fasmediatedapoptosis.Thismaybeexplainedbythe presenceofadiffe:rentfractionoflymphocytesinSILs, whicharestronglypositiveformembraneFas,sensitiveto theantiFasautoantibody,andundergoapoptosls;however, thisfractionmayberecruitedfrombonemarrowafter reachingthefinalstageofcelldeath.Thisrecruitedfraction wouldnothaveencounteredsilicaandwouldbesensitiveto silica/silicateinducedapoptosis.Asaresult.cellsinthis fractionwouldbecontinuouslyundergoingrenewaland apoptosis(56,66).

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