医学类英文论文

Genes,autoimmunityandpathogenesisofrheumaticheartdiseaseLGuilherme1,KFKöhler1,EPostol1,JKalil21HeartInstitute(InCor),SchoolofMedicine,UniversityofSãoPaulo,SãoPaulo;InstituteforImmunologyInvestigation,NationalInstituteforScienceandTechnology,UniversityofSãoPaulo,SãoPaulo,Brazil2HeartInstitute(InCor),SchoolofMedicine,UniversityofSãoPaulo,SãoPaulo;InstituteforImmunologyInvestigation,NationalInstituteforScienceandTechnology,UniversityofSãoPaulo,SãoPaulo;ClinicalImmunologyandAllergyDivision,SchoolofMedicine,UniversityofSãoPaulo,SãoPaulo,BrazilClickhereforcorrespondenceaddressandemailAbstractPathogenesisofrheumaticheartdisease(RHD)remainsincompletelyunderstood.SeveralgenesassociatedwithRHDhavebeendescribed;mostoftheseareinvolvedwithimmuneresponses.SinglenucleotidepolymorphismsinanumberofgenesaffectpatientswithRHDcomparedtocontrols.Molecularmimicrybetweenstreptococcalantigensandhumanproteins,includingcardiacmyosinepitopes,vimentinandotherintracellularproteinsiscentraltothepathogenesisofRHD.AutoreactiveTcellsmigratefromtheperipheralbloodtotheheartandproliferateinthevalvesinresponsetostimulationwithspecificcytokines.Thetypesofcellsinvolvedintheinflammationaswellasdifferentcytokineprofilesinthesepatientsarebeinginvestigated.HighTNFalpha,interferongamma,andlowIL4arefoundintherheumaticvalvesuggestinganimbalancebetweenTh1andTh2cytokinesandprobablycontributingtotheprogressiveandpermanentvalvedamage.AnimalmodelofARFintheLewisratmayfurthercontributetowardsunderstandingtheARF.Keywords:Autoimmunity,rheumaticHeartdisease,susceptibilitygenesHowtocitethisURL:GuilhermeL,KöhlerKF,PostolE,KalilJ.Genes,autoimmunityandpathogenesisofrheumaticheartdisease.AnnPediatrCard[serialonline]2011[cited2012Nov2];4:13-21.Availablefrom:(RHD)isstillamajorhealthprobleminseveralcountriesduetotheheartlesionsthatfollowarheumaticfever(RF)episodein30-45%ofpatients.TheincidenceofacuteRF(ARF)insomedevelopingcountriesexceeds50per100,000children.TheworldwideprevalenceofRHDisatleast15.6millioncases,andthisdiseaseisresponsibleforaround233,000deaths/year.[1]RHDresultsfromautoimmunereactionstriggeredbyanuntreatedS.pyogenesthroatinfectionleadingtoseverevalvulardamageingeneticallysusceptibleindividuals.RecurrencesofARFplayanimportantroleintheworseningofvalvularlesionss.[2],[3]Inthepresentreview,wefocusongeneticsusceptibilityfactors,theirroleinthedevelopmentofRFandRHD,andthemechanismsthatleadtoautoimmunereactionsandpermanentvalvulardamage.Animalmodelsofthediseasewillalsobediscussed,aswillprospectivevaccinesforthepreventionofRFandRHD.InnateandAdaptiveImmuneResponses:ABriefReviewProtectionagainstpathogensinthehumansreliesoncomplexinteractionsbetweeninnateandadaptiveimmunity.Mostofthepathogensthatenterthebodyarerecognizedinitiallybytheinnateimmunesystem.[4]Thisdefensemechanismisnotantigen-specificandisinsteadfocusedontherecognitionofalimitednumberofspecificpatternsthataresharedbygroupsofpathogens(pathogen-associatedmolecularpatterns-PAMPs)bypatternrecognitionreceptors(PRRs)inthehost.ThesePRRscanbesolubleinhumanserumorcell-associated.[5],[6]ThemoleculesthatinitiatethecomplementcascadeareexamplesofsolublePRRs.Thecomplementsystemispartoftheinnateimmunesystemandconsistsofmanyproteinsinvolvedinacascadeofproteolysisandproteincomplexassemblythatculminatesintheeliminationofinvadingpathogens.[6]SeveralcomponentsofthebacterialcellsurfacecombinewithPRRssuchasFicolinfamilyofproteins,orMannanbindinglectins(MBL).Thesecomplexes,inturncombinewithserineproteasesandleadtocomplementactivationvialectinpathwayresultinginopsonophagocytosisoftheinvadingpathogen,apoptosis,ormodulationofinflammation.[7],[8],[9],[10]Toll-likereceptors(TLRs)arepivotalcell-associatedPRRsintheinnateimmunesystem.Thesereceptorsarecapableofrecognizingawidespectrumoforganisms,includingviruses,bacteriaandotherparasites,andareclassifiedintodifferentgroupsbasedontheirlocalization(cellsurfaceorintracellular)andthetypeofPAMPstheyrecognize.TLRactivationleadstotheproductionofproinflammatorycytokinesthatenablemacrophagesanddendriticcells(DC)toeliminateinvadingpathogens.DCscanstimulateTcellexpansionanddifferentiation,initiatinganadaptiveimmuneresponse.[4]Themoleculesproducedduringtheinnateimmuneresponseactassignalstoactivateadaptiveimmuneresponses.Antigenpresentingcells(APCs),suchasDCs,areactivatedandexpresscostimulatory(CD80andCD86)andMHCmoleculesontheircellsurfacethatenablethesecellstopresentprocessedantigenstoTcellsthroughtheTcellreceptor(TCR).ClassIMHCmolecules,suchasHLA-A,-Band-C,presentpeptidesderivedfromintracellularpathogenstoCD8+Tcells,whileclassIIMHCmolecules,suchasHLA-DR,-DQand-DP,presentpeptidesderivedfromextracellularpathogenstoCD4+Tcells,whichsecreteawiderangeofcytokinesandhavebotheffectorandregulatoryroles.CytokinessuchasTNF-aandIFN-gactatthesiteofinfectionandcanaffectpathogensurvivalandcontroltheimmuneresponse.ActivationofCD4+TcellsnotonlyleadstotheexpansionofCD4+effectorcells,butalsocanpromotetheexpansionanddifferentiationofantigen-specif