IL23IL17 immunity as a hallmark of Crohns disease.docx
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IL23IL17 immunity as a hallmark of Crohns disease.docx
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IL23IL17immunityasahallmarkofCrohnsdisease
IL-23/IL-17immunityasahallmarkofCrohn'sdisease
VeeraHöltt
MD1,
PaulaKlemettiMD,PhD1,3,*,
TainaSipponenMD2,
MiaWesterholm-OrmioMD,PhD3,
GuillermoKociubinskiPhD1,
HarriSaloPhD1,
LauraR
s
nen1,
Kaija-LeenaKolhoMD,PhD3,
MarttiF
rkkil
MD,PhD2,
ErkkiSavilahtiMD,PhD3,
OutiVaaralaMD,PhD1
Articlefirstpublishedonline:
29MAY2008
DOI:
10.1002/ibd.20475
Copyright©2008Crohn's&ColitisFoundationofAmerica,Inc.
Issue
InflammatoryBowelDiseases
Volume14,Issue9,pages1175–1184,September2008
AdditionalInformation(ShowAll)
HowtoCiteAuthorInformationPublicationHistoryFundingInformation
HowtoCite
Höltt
V.,Klemetti,P.,Sipponen,T.,Westerholm-Ormio,M.,Kociubinski,G.,Salo,H.,R
s
nen,L.,Kolho,K.-L.,F
rkkil
M.,Savilahti,E.andVaarala,O.(2008),IL-23/IL-17immunityasahallmarkofCrohn'sdisease.InflammatoryBowelDiseases,14:
1175–1184.doi:
10.1002/ibd.20475
AuthorInformation
1
LaboratoryforImmunobiology,DepartmentofViralDiseasesandImmunology,NationalPublicHealthInstitute,Helsinki,Finland
2
DepartmentofMedicine,DivisionofGastroenterology,HelsinkiUniversityHospital,Helsinki,Finland
3
HospitalforChildrenandAdolescents,UniversityofHelsinki,Helsinki,Finland
Email:
PaulaKlemettiMD,PhD(paula.klemetti@ktl.fi)
*Correspondence:
PaulaKlemettiMD,PhD,LaboratoryforImmunobiology,DepartmentofViralDiseasesandImmunology,NationalPublicHealthInstitute,Mannerheimintie166,FIN-00300Helsinki,Finland
PublicationHistory
Issuepublishedonline:
5AUG2008
Articlefirstpublishedonline:
29MAY2008
ManuscriptReceived:
5MAR2008
ManuscriptAccepted:
5MAR2008
Fundedby
AcademyofFinland
SigridJuseliusFoundation
FinnishCulturalFoundation
FoundationforPediatricResearch
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Keywords:
IL-17;
Th17cell;
IL-23;
Crohn'sdisease;
inflammatoryboweldisease;
Foxp3;
immunohistochemistry
Abstract
Topofpage
Abstract
PATIENTSANDMETHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
Background:
WestudiedthebalancebetweenilealT-effectorcellsversusT-regulatorycellsinactiveandinactiveCrohn'sdisease(CD).
Methods:
WecomparedeffectorandregulatoryT-cell-relatedmarkerssuchasinterleukin(IL)–17,interferon(IFN)-
IL-4,andFoxp3transforminggrowthfactor(TGF)–βCTLA-4andmarkersforinnateimmuneactivationsuchasIL-6,IL-10,IL-18,IL-23,tumornecrosisfactor(TNF)–
andIL-12p70,studiedwithimmunohistochemistryandRT-PCRinilealbiopsiesfrompatientswithactiveorinactiveCDandfromcontrolsubjects.IL-17infecalsampleswasdetectedbyELISA.TheeffectofIL-17onIL-8andTNF-
mRNAexpressioninepithelialcelllineCaco-2wasstudied.
Results:
ThenumbersofIL-4-,IL-17-,andIL-23(p19)-positivecellsinthelaminapropriawerehigherinpatientswithCD,bothactiveandinactive,thaninthecontrols.mRNAexpressionofIL-17A,IL-6,andFoxp3wasincreasedinthebiopsiesbothfrompatientswithactivediseaseandthoseinremission,whereasmRNAexpressionofIL-23wasincreasedonlyinactivedisease.FecalIL-17concentrationwasincreasedinpatientswithactivedisease.IL-17enhancedtheIL-8andTNF-
responseoftheepithelialcelllinetolipopolysaccharide(LPS)invitro.
Conclusions:
OurfindingssuggestthatactivationoftheIL-23/IL-17axisisfundamentallyconnectedtotheetiologyofCDandmayrepresentthebasisfortherelapsingnatureofthediseasebyincreasingthesensitivityofepitheliumtomicrobialLPS.
(InflammBowelDis2008)
Crohn'sdisease(CD)isachronicrelapsinginflammatoryboweldiseasethatwasoriginallydefinedasadiseaseoftheileumcharacterizedbygranuloma-likeimmunepathology.TheimmunologicalpathogenesisofCDisstillpoorlyunderstood.ThemucosallesionsinthecolonhavebeensuggestedtobearesultofaTh1-mediatedimmuneresponsetriggeredbytheintestinalbacteria,buttheevidenceforthisisnotconclusive.Somereportsindicateincreasedinterferon(IFN)–
activationinintestinalsamples,thatis,colonbiopsies,frompatientswithCD.1,2TheroleoftheinnateimmunesysteminthedevelopmentofCDhasbeensuggestedtobeofimportance;supportingthisisthattreatmentofCDwithatumornecrosisfactor(TNF)–
-blockingdrughasbeensuccessful.Also,thefindingoftheNOD2geneticpolymorphismidentifyingtheCARD15alleleasariskfactorforCDsupportstheviewthatanabnormalinnateimmuneresponsecontributestothedevelopmentofdisease.3Furthermore,recentstudieshaveindicatedthattheinterleukin(IL)–23receptor(IL-23R)genepolymorphismisassociatedwithCD.4IL-23isacytokinesecretedbycellsoftheinnateimmunesystem,anditsupportsthefunctionofIL-17-secretingTcells.IL-17-producingTh17cellshavebeenconnectedtothedevelopmentofautoimmunediseasessuchasmultiplesclerosisandrheumatoidarthritis.5IL-17-positivecellshavebeenalsoreportedincolonicbiopsiesfrompatientswithCD,6buttheirroleinthepathogenesisofortheirrelationtoTh1effectorcellsorregulatoryTcellshasnotyetbeenstudiedfurtherinhumans.Accordingtothecurrentliterature,T-effectorcellsaredividedinto3groups:
IFN-
-secretingTh1-typecells,IL-4-secretingTh2-typecells,andIL-17-secretingTh17cells.ThedevelopmentofIL-17effectorTcellsistriggeredbytransforminggrowthfactor(TGF)–βandIL-6,andthiscytokineenvironmenthasbeenreportedtoinhibitregulatoryTcells,CD4+CD25highTcells,whichcontrolinflammation.7TherecentfindingofTh17cells,someofwhichproducedbothIL-17andIFN-
inthegutsofpatientswithCD,makesthispicturemorecomplicated.8
TounderstandthecytokineandT-cellnetworkinCD,westudiedthebalancebetweenT-effectorcells,IFN-
-,IL-4-,andIL-17-expressingcells,versusTregulatorycells,Foxp3-,CD25-,andCTLA-4-expressingcells,inilealbiopsysamplesfrompatientswithactiveCDandfrompatientsinremission.WedemonstrateherethatinfiltrationofIL-17-,IL-23-,andIL-4-expressingcellsinthelaminapropriaoftheileumisseeninpatientswithCD,boththosewithactivediseaseandthoseinremission,whereasup-regulationoftheIL-23transcriptwasonlyseeninactiveCD.AlsoIL-17levelsinfeceswereincreasedinpatientswithactivediseasebutnotinthosewithinactiveCD,suggestingthathighproductionofIL-17isassociatedwithmucosaltissuedamage.IL-17enhancedtheinflammatoryresponseoftheepithelialcelllinetolipopolysaccharide(LPS)invitro.AlthoughthenumberofilealFoxp3-expressingcellswasnotincreasedintheCD,up-regulationofFoxp3mRNAwasseeninbothactiveandinactivedisease.OurfindingssuggestthatactivationoftheIL-23/IL-17axisisfundamentallyconnectedtotheetiologyofCDandmayrepresentthebasisfortherelapsingnatureofthediseasebyincreasingthesensitivityofepitheliumtomicrobialLPS.
PATIENTSANDMETHODS
Topofpage
Abstract
PATIENTSANDMETHODS
RESULTS
DISCUSSION
Acknowledgements
REFERENCES
Subjects
IntheHelsinkiUniversityCentralHospital,ClinicofGastroenterology,24adultpatientswithilealorileocolicCDreferredtoileocolonoscopywererecruitedbetweenJanuary2005andOctober2006(Table1).TheCDdiagnosiswasbasedontheclinical,endoscopic,radiological,andhistologicalfindingsandwasclassifiedaccordingtotheViennaclassification.9TheCDdiagnosisof4patientswasbasedontheircurrentendoscopicandhistologicalfindings.Exclusioncriteriaforthestudywerepregnancy,historyofanextensivebowelresection(ileosigmoideostomy,ileorectostomy),ostomy,long-termuseofNSAIDs,orsymptomsrelatedmainlytoperianalfistulizingdisease.Aroundthetimeofendoscopy(±14days),patientsfilledintheirdiariesfortheCrohn'sdiseaseactivityindex(CDAI),10providedasinglestoolsample,andgaveaheparinizedbloodsample.Stoolsampleswerestoredat−40°Cuntilanalysis.Fourexperiencedgastroenterologistsperformedtheendoscopiesandgradedthefindingsaccordingtothecurrentstandardofevaluationforendoscopicactivity,theCrohn'sdiseaseindexofseverity(CDEIS).11Inthisstudy,criteriaforanactivediseasewerebasedonendoscopicsignsofactiveulcerativeinflammationintheileum,andcriteriaforremissionwerebasedonendoscopicallyuninflamedileum.Diseasewaseitherilealorileocolicinbothpatientgroups.Routinehistologyshowedactiveinflammationinilealsamplesofallpatientsinactivegroup.Inremissiongroupnoactiveinflammationwasseeninbiopsiesfrom10patients,whereasmildinflammatoryactivitywasseenin3patientswithmacroscopicallynormal-appearingmucosa.Thecontrolgroupconsistedof14patientswhowerereferredtoileocolonoscopyforthefollowingindications:
changeinbowelhabitsin3patients,diverticulardiseasein2patients,colorectalcancerfollow-upin2patients,historyofpolypsin1patient,historyofadenomain2patients,rectalbleedingin2patients,exclusionofCDin1patientwithahistoryofperianalabscessesandin1patientwithabdominalpain.Allcontrolsubjectsshowednormalfindingsinroutinehistologicalanalysisofilealbiopsies.Fecalsampleswereavailablefrom9patientswithactivediseaseandfrom11patientswithin
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