Atopic Dermatitis Epidemiology and Pathogenesis Update(3)

TheseadvancesinunderstandingADpathogenesisoc-curredfollowingtheidenti cationofasetofmutationsintheskinthatareassociatedwithbarrierdefects,speci cally,mu-tationsinthe laggringene(FLG).Interestingly,asearlyas1985,Sybertandcolleagues5hadproposedthat laggrinab-normalitieswerethecauseofichthyosisvulgaris,whichisaconditionthatwasknowntobepresentinasubsetofpatientswithAD.However,thesigni canceofthisworkwasnotappreciateduntiltherevolutioningeneticsoccurredwithinthepastdecade,withthemappingofthehumangenomeandtheidenti cationoftheFLG.WhentheworkofSybert’sgroupandotherswasrevisited,6,7itbecameclearthatFLGmutationswere,infact,thecauseofichthyosisvulgaris.(Foracomprehensivecommentaryonthisbreakthrough,Segre’sarticle,“Epidermaldifferentiationcomplexyieldsasecret:Mutationsinthecorni cationprotein laggrinunderlieich-thyosisvulgaris,”isrecommended.8)

Toreviewbrie y,thestratumcorneumlayer,alsoreferredtoastheepidermalskinbarrier,hasseveralmajorfunctions,includingthepreventionofinvasionofthebodybyenviron-mentalpathogensandthecontrolofwaterlossacrosstheepidermis(ie,transepidermalwaterloss[TEWL]).Thestra-tumcorneumconsistsofbetween10and30layers(depend-ingonanatomicsite)ofkeratinocytesthathavedifferentiatedtobecomeanucleatedcorneocytes;inthesecells,theplasmamembraneisreplacedbyalayeroflargeproteinmolecules—thecorni edenvelope.Filaggrin,anessentialstructuralpro-teininthecorni edenvelope,isexpressed rstaspro lag-grin,whichplaysanimportantrolein“packing”thekeratinocytesintothestratumcorneum.

Inadditiontoitscontributiontocreatingamortarlike,impermeablestructure, laggrinisalsobrokendown,throughproteolysis,intohumectants—hygroscopicaminoacidsreferredtoasnaturalmoisturizingfactor.Filaggrinde- ciencycanadverselyaffectthesefunctions,impairingstra-tumcorneumadhesion,enhancingTEWL,andcausingdys-

L.F.Eichen eldetal

regulationoftheskinpHresultinginincreasedskinpermeability.9

Loss-of-functionmutationsintheFLGarequitecommon:10%ofindividualsofEuropeanancestrycarrysuchmuta-tions,whichareassociatedwithareductionofabout50%in laggrinproteinproduction.7Clinically,loss-of-functionmutationshavebeenassociatedwiththedevelopmentofAD.7,10Inaddition,patientswhohaveADandtheFLGmu-tationalsohaveagreatertendencythandothosewithoutthemutationtohavemoresevereorpersistentAD,11anin-creasedriskforacquiringherpesvirusinfection(eczemaher-peticum),12andanincreasedriskforearlysensitizationandmultipleallergies(includingpeanutallergy)andasthma.10,13

Itisnowrecognizedthatavarietyofcytokinesmaymedi-atein ammationinatopicskin.AcuteADmaybeassociatedwithT-helpertype2(TH2)cytokines,includinginterleukin(IL)-4andIL-13,whichin uenceimmunoglobulinEsynthe-sisandadhesionmoleculeexpression.Inaddition,IL-31hasbeenidenti edasauniqueTH2cytokinethatisassociatedwiththedevelopmentofdermatitisandpruritusinexperi-mentalanimals.

Further,recentstudieshavedemonstratedthatthymicstromallymphopoietin(TSLP)maybeexpressedinkeratin-ocytes,affectedbyskinbarrierdefects.TSLPmaymediatein ammationoftheskinandotherorgans,includingthebronchialtree.14

MicrobesinAD:RecentFindings

ColonizationwithStaphylococcusaureusisverycommoninAD,andpatientswithADareatincreasedriskforimpetig-inizedlesions,pustules,and,occasionally,moresigni cantskinorsystemicinfections.

Withtheemergenceofcommunityepidemicsofmethicil-lin-resistantS.aureus(MRSA),concernwasraisedthatpa-tientswithADmightbeparticularlysusceptibletosuchin-fections.However,severalstudieshavefoundthattheactualratesofMRSAinfectionsinpatientswithADarenotespe-ciallyhigh;infact,comparedtoclinicalinfectionsseeninnonatopiccommunitymembers,patientswithADmorecommonlyhavemethicillin-sensitivestaphylococcalinfec-tionsthanMRSA.15,16

Ithasalsobeenshownthatthecutaneousimmunedefenseisin uencedbyinnatedefenseproteinsintheskinandthatarelativede ciencyofantimicrobialpeptidescanbeseenintheskinofpatientswithADcomparedtopatientswithotherin ammatoryskindiseases.Thisde ciencymaybeassoci-atedwithstaphylococcalcolonization.17

Interestingly,recentstudieshaveshownthatthereisaninteractionbetweenresidentcommensalmicrobesontheskinandantimicrobialpeptides.Infact,thereappearstobeadegreeofmicrobialsymbiosiswiththeinnateimmunesys-tem.Forexample,Staphylococcusepidermidisinnormalskincauseskeratinocytestoproduceantimicrobialpeptides,andthesesuppresscytokinereleaseafterminorepidermalinjury.Thus,S.epidermidiscontributesasabarrieragainstcoloniza-

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