Rev. Bras. Reumatol. vol.57 número5

w w w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Review

article

Intestinal

parasites

infection:

protective

effect

in

rheumatoid

arthritis?

夽

Sandra

Maximiano

de

Oliveira

,

Ana

Paula

Monteiro

Gomides

,

Lícia

Maria

Henrique

da

Mota

,

Caliandra

Maria

Bezerra

Luna

Lima

,

Francisco

Airton

Castro

Rocha

a_{HospitalUniversitáriodeBrasília(HUB),Brasília,DF,Brazil}

b_{UniversidadedeBrasília(UnB),FaculdadedeMedicina,Brasília,DF,Brazil}

c_{UniversidadedeBrasília(UnB),ProgramadePós-Graduac¸ão,FaculdadedeMedicina,Brasília,DF,Brazil}

d_{UniversidadeFederaldaParaíba(UFPB),JoãoPessoa,PB,Brazil}

e_{UniversidadeFederaldaParaíba(UFPB),ProgramadePós-Graduac¸ãoInterdisciplinaremModelosdeDecisãoeSaúde,JoãoPessoa,PB,}

Brazil

f_{UniversidadeFederaldoCeará,FaculdadedeMedicina,Fortaleza,CE,Brazil}

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Articlehistory:

Received16September2015 Accepted3April2016 Availableonline22July2016

Keywords:

Rheumatoidarthritis Helminthinfections Immunomodulation

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b

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Rheumatoid arthritis(RA)isasystemicautoimmuneinflammatorydisease,witha pro-gressivecourse,characterizedbychronicsynovitisthatmayevolvewithdeformitiesand functionaldisability,andwhoseearlytreatmentminimizesjointdamage.Its etiopathogen-esisisnotfullyelucidatedbutcomprisesimmunologicresponsesmediatedbyThelpercells (Th1).AnapparentminorseverityofRAinpatientsfromregionswithlowerincomecouldbe associatedwithahigherprevalenceofgutparasites,especiallyhelminths.Strictly,ashiftin theimmuneresponsetowardthepredominanceofThelpercells(Th2),duetothechronic exposuretohelminths,couldmodulatenegativelytheinflammationinRApatients, result-inginlowerseverity/jointinjury.Theinteractionbetweentheimmunologicalresponsesof parasitichelminthsinrheumatoidarthritispatientsisthepurposeofthispaper.

©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Parasitoses

intestinais:

efeito

protetor

na

artrite

reumatoide?

Palavras-chave: Artritereumatoide Parasitosesintestinais Imunomodulac¸ão

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e

s

u

m

o

Aartritereumatoide(AR)éumadoenc¸ainflamatóriaautoimune,sistêmica,decurso pro-gressivo, caracterizadaporexuberantesinovitecrônica,quepodegerar deformidadese incapacidadefuncional,cujotratamentoprecoceminimizaodanoàsjuntas.Sua etiopato-geniaaindanãoestácompletamenteelucidada,mascompreenderespostasimunológicas comaparticipac¸ãodecélulasTauxiliares(Th1).UmaaparentemenorgravidadedaAR

夽

StudyconductedattheRheumatologyDepartment,HospitalUniversitáriodeBrasília(HUB),Brasília,DF,Brazil. ∗ _{Correspondingauthor.}

E-mail:sandramaximianoo@gmail.com(S.M.Oliveira).

http://dx.doi.org/10.1016/j.rbre.2016.06.004

empacientesderegiõescommenorrendapoderiaestarassociadaamaiorprevalência deparasitosesintestinais,especialmenteashelmintíases.Arigor,umdesvionaresposta imuneparaopredomíniodecélulasTauxiliares(Th2),decorrentedaexposic¸ãocrônicaa helmintos,modularianegativamenteainflamac¸ãoemdoentescomAR,elevariaamenor gravidadeedanoarticular.Arevisãodeaspectosdainfluênciadarepostaimunológicanas parasitosesintestinais,especialmenteashelmintíases,empacientescomartrite reuma-toideéoobjetivodessetrabalho.

©2016ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Rheumatoidarthritis(RA)isachronic,progressive,systemic inflammatoryautoimmunediseasecharacterizedbya sym-metricalinvolvementofthesynovialmembraneofperipheral joints with joint damage and destruction.1 _{Its prevalence}

is estimated at 0.2–1% of the population,2 _{predominantly}

inwomenand withits highestincidenceinthe agegroup of30–50years.1 _{RAisa multifactorial diseaseofunknown}

etiology, for which genetic (HLA-DR1 and HLA-DR4) and environmental(exposuretoinfections andsmoking,among others)factorscontributeforthelossoftoleranceandorgan damage.3_{Ifnottreatedproperly,thediseasecanleadto}

func-tionallimitations,withirreversibledeformitiesandareduced lifeexpectancy.1_{TheimpactofRAissignificantforboththe}

patient(morbidityandmortalityanddecreasedqualityoflife) andsociety(functionalimpairmentwithdecreased productiv-ityandlowercapacitytoparticipateinthelabormarket).2

Intestinalparasitesinfectionsincludeinfectionscausedby protozoaand helminthswithhighmorbidityand mortality. Theirprevalenceisestimatedat30%ofthepopulationofthe Americas.4,5

Despitethemorbidityand,lesscommonly,mortalitythat may be associated withparasitic infections, specifically in thecaseofhelminths,subclinicalinfestationsoccur,which denouncesanadaptationofthehosttotheparasite,with con-tainmentofdamageandconsequentsurvivalofbothsides. Thishost/parasiteadaptationisrelatedtocomponentsofthe innate immune response and,in the case of the adaptive immuneresponse,tothe predominanceofaTh2response, with increased release of the so-called anti-inflammatory cytokines,suchasinterleukins(IL)4,10and13.5

In the literature, there are reports of lower prevalence and/orseverityofRAinpopulationsofsub-SaharanAfrica; inourmidst,astudyconductedinNatal/RN,whileaddressing patientswithsystemiclupuserythematosus,founda simi-larlevelofseverityinlupuspatients versuspopulationsof areasofgreatereconomicpower.6_{Morerecently,inastudy}

on children with juvenile idiopathic arthritis cared for at atertiary center inthe stateofCeará,their authors found that about two-thirds of patients could achieve remission using methotrexateand/or leflunomide, despitethe preva-lenceofthepolyarticularsubtype,whichwouldhaveaworse prognosis.7 _{Thedelaysinestablishingthe diagnosisand in}

offeringanearlytreatment,aswellasthelowfamily educa-tion/incomefoundinourpopulation,arefactorsconsideredas capabletoaggravatetheprognosisinautoimmunediseases.It

iscurious,therefore,thatthelong-termprogressionofthese patients isatleastequivalent, ifnot lesssevere, than that observedinpopulationswithbettersocioeconomicindicators. Thisgoodresponseinpotentiallymoreseverepatients,when comparedtocaseseriesfromrichcountriesoftheNorthern hemisphere,opensthepossibilitythatenvironmentalfactors maybeactingintheclinicalcourseofautoimmunediseases. The aimofthis study is toelucidate the potential pro-tectiveeffectthattheconcomitantinfectionwithintestinal parasites,especiallyhelminths,couldprovidetopatientswith RA.IntheperiodfromMaytoJuly2015,aliteraturereview was carried out through Pubmed (1970–2015) and Scopus databases (EnglishandPortugueseidioms), withthe useof the followingkeywords: ‘rheumatoid arthritis,’‘helminths,’ ‘immunopathogeny’and‘hygienehypothesis’.

Immunopathogenesis

of

rheumatoid

arthritis

Thesynoviumorsynovialmembraneisconsideredasthat tis-suewheretheinflammatoryprocessbeginsandperpetuates inRA,withtheoccurrenceofapredominantlymononuclear inflammatory infiltrate, synovial hyperplasia and vascular proliferation associated with the production of proinflam-matory cytokines. This hyperplastic synovium constitutes the synovialpannusthat, throughtheinvasionofthe sub-chondralboneandunderlyingcartilageandalsooftendons andligaments,leadstojointdestruction.3,8_Thebasic

mech-anism proposed is the loss of immunological tolerance to self-antigensinageneticallysusceptibleindividual,triggering synovitis.3_{Inrelationtomechanismsoftheinnateimmune}

response, neutrophils, macrophages, mast cells and natu-ral killer cells participateinthis inflammatoryresponsein the synovium.3_{Macrophagesparticipatebothintheroleof}

antigen-presentingcells,aseffectorcells,throughtherelease oftheso-calledpro-inflammatorycytokines(e.g.tumor necro-sisfactor(TNF)-␣andIL-1␤,IL-6,IL-12,IL-15,IL-18andIL-23), reactiveoxygen species,andproductionofprostanoids and extracellularmatrixmetalloproteinases.3 _{Itisassumedthat}

TNF-␣playsacentralroleinthepathogenesisofRA, promot-ingthereleaseofotherinflammatorymediators(i.e.,cytokines withautocrineandparacrineaction)andthattheactivation oflymphocytesandmacrophagescontributetoexacerbatethe synovitis,besidespromotingadirectactivationofosteoclasts, whichinduceboneresorption.3

Thedifferentiationofmonocytesintoosteoclastsisindirectly promotedbyTNFthroughtheactivationofthereceptor acti-vator ofnuclear factor kappa-B ligand(RANKL),a member ofthesuperfamily ofTNF.9 _{ThisactionofTNFturnsout to}

implicate this factor in the inflammatory bone resorption incasesofRA,sincethe resultofRANKLactivation stimu-latesthedifferentiationandactivationofosteoclasts,besides inhibitingtheapoptosis ofthesecells.10 _{Furthermore,IL-17}

productionbyTh17 lymphocytes, present in high levels in thesynoviaofpatientswithRA,regulatestheexpressionof RANKL,contributingtoosteoclastogenesisandprogressionof jointdamage.9 _{AlthoughthefrequencyofregulatoryTcells}

CD4+_andCD25+_{,responsibleforinhibitingtheproliferation}

andproductionofcytokinesbyeffectorTcells,isincreased in the synovial fluid ofRA patients, it is unclear whether these cells are activated in this environment, taking into accountthatthereisalossofself-tolerancetoself-antigens, whichcontributestothepersistenceofthejointinflammatory process.9_{Moreover,Tcellapoptosisisinhibited,probablydue}

tothehighlevelofanti-apoptoticcytokinessuchasIL-2,IL-4, andIL-15,presentearlierinRA.9

Thereisalsoacontributionofhumoralimmuneresponse inRA,throughthedifferentiationandproliferationofBcells that produce cytokines and can function as class II anti-gen presenting cells, contributing to the perpetuation of synovitis.9 _{The presence of autoantibodies against the Fc}

portionofIgGmolecules,suchastherheumatoidfactor,which illustrates the humoral component in RA, is detectable in 70–80%of patients, but such moleculescan also be found inhealthy individuals and inpatients withother systemic diseases.9_{Antibodiesagainstthecitrullinationofarginineto}

citrullineasaresultofdeamination(anti-cycliccitrullinated peptides)maybepresentinupto70%ofpatients,andthese moleculesappearearlyinpatientswithRA.9_{Theexactroleof}

theseautoantibodiesinthepathogenesisofRAhasstillnot beenclearedup,butitisknownthatseropositivepatientsin hightiterstotheseantigenstendtoexhibitamoreaggressive disease,withgreaterjointdamageandboneerosion,aswell aswithextra-articularmanifestations.3,5

Immunopathogenesis

of

intestinal

parasites

infection

Parasites such as helminths may modulate the immune response,inducingananti-inflammatory environmentthat favors their survival within the host, that is, these para-sitessuppressproinflammatoryimmuneresponsesinorder tomaintaintheirlifecycle.3,11_{Intestinalparasiticinfections}

are chronic phenomena, and re-infestation is often seen; and suchorganisms, inaddition tothe inhibitorychanges thattheycauseininnateand adaptiveimmuneresponses, alsohavemechanismstoescapethehostimmuneresponse by reducing their immunogenicity.5 _{In general, helminths}

survivewithinthehostandcausepersistentinfections, appar-entlybecauseofadecreaseintheinnateimmuneresponse againsttheparasites.5,12 _{Thecombinedactionofmastcells}

andeosinophilscontributestothecontainmentofintestinal parasites.5 _{Suchparasitesareresistanttophagocytosisand}

tocytocidalmechanismsofmacrophagesandneutrophils.5

Moreover,somehelminthsmayalsoactivatethealternative pathwayofthecomplementsystemandareresistanttothe lysismediatedbyproteinspertainingtothatsystem.5

Inhelminthinfections,theparasitesinducethe produc-tionofIL-10andofTh2cytokines(IL-4,IL-5,IL-9,andIL-13), modifying the stimulation of macrophages to an alterna-tiveactivatedphenotype,whichfavorstheanti-inflammatory response of Th2 cells and the eosinophilic response.3,12

HelminthsalsoinhibitIFN-␣,IL-1␤andIL-17,suppressingthe inflammatoryimmuneresponseofTh1andTh17cells.3,12,13

The helminths secrete excretory-secretory products, such as ES-62, which are glycosylated and act by inducingTh2 cytokines and the expansion ofregulatoryT cells.13

More-over,theamountofregulatoryTcells(CD4+_CD25+ _FOXP3+₎

that produce IL-10 and TGF-␤ increases after infection by helminths,3,11_{thuscontributingtothepermanenceofthe}

par-asiteinsidethehost.

Thehomeostasisgeneratedbytheseimmuneresponses preventsanoverreactionagainstparasites,athingwhichalso wouldimpairthehost,ensuringthesurvivalofhelminths.11,13

Protective

effect

of

helminth

infections

in

rheumatoid

arthritis

In 1970, Greenwood noted that individuals living in Nige-rian villages, despite the high incidence of positive cases for rheumatoid factor, had rheumatic disease of a benign course, witha good prognosisand no radiologicalsigns of severity.14 _{Giventhe highprevalenceofparasitic infectious}

diseases inthatpopulation, itwas suggestedthat thehost responsetomultipleparasiteswouldsomehowinterferein thecourseofautoimmunediseases.14_{Thedelayinthe}

estab-lishment ofdiagnosis, the difficulties ofaccess tomedical expertise, the low compliance to treatment and failure or delay in the prescription of disease-modifying drugs neg-atively impact the prevalenceand severityof autoimmune diseases.15_{Thus,patientsfromdevelopingcountriesshould}

presentmoresignificantmorbidityandmortality.15_However,

RAislesscommonincertainareasoftropicalcountries,where a highincidenceofinfectious diseases,especiallyparasitic ones,isobserved.16_{InnortheasternBrazil,lesssevere}

autoim-mune rheumatic disease was also observed, partly due to possiblyendemicparasitic infestations.17 _{In1989, Strachan}

proposed his“hygienehypothesis”theory:the reductionof exposuretocommonpathogens,suchashelminths,increased theprevalenceofallergicandautoimmunediseasesinareas wheresanitaryconditionsimproved.3,6,12,13,18–21

Intestinal parasites are suppressors of proinflammatory immune response, so these organisms can live in equilib-riumwiththehostimmunesystem.3,12_{Thus,inadditionto}

causing disease,theyalso actaspotentmodulators ofthe immunesystem.3_{Theparasitesrelatedtoprotectiveeffectsof}

theaggressivenessofthediseaseinpatientswithRA,already described inthe literature,are Schistosoma mansoni, Schisto-somajaponicum,Ascarissuum,Heligmosomoidespolygyrusbakeri andHymenolepsisdiminuta.3,12,20,21_{Suchpathogensinhibitthe}

byS. japonicum can modifythe function of dendritic cells, macrophages,NKcellsandBcells,leadingtoanexpansion ofTh2cellsandofregulatoryTcellsresponsiblefor maintain-ingself-tolerance.11,18_{TheinfectionofmicewithSchistosoma}

japonicumpriortotheinductionofarthritisbycollagen (inter-valof2weeks)significantlyattenuatedtheclinicalsignsof arthritis,withdecreasesinsynovialhyperplasia,infiltrationof synovialmononuclearcells,angiogenesisininflamedsynovia, osteoclastactivation,andjointdestruction.11_Alower

produc-tionofIFN-␥andanincreaseinIL-4andIL-10wereobserved, togetherwithdecreases inproinflammatory cytokine

(TNF-␣,IL-1␤,IL-6andIL-17,IFN-␥,RANKL)levels;thesefindings suggestapredominanceofTh2responseandareductionof Th1response.11,18 _{Thischangeintheimmunologicalprofile}

explainsthelower aggressivenessand eventheabsence of jointdiseaseinthestudiedmodels.11,18_{However,theinfection}

ofmicewithSchistosomajaponicumafterthecollagen-induced arthritis could not reverse the immune response already installed,northesubsequentjointdamage.11

StudiesusingAscarissuumextract(anon-pathogenic prod-ucttohumans)administeredbothorallyandparenterallyin amurinemodelofarthritisinducedbyzymosanand colla-gendemonstratedanti-inflammatoryeffectsoftheextract,in ordertoreducehyperalgesiaandthedamagetothearticular cartilage.15,17_{Themechanismassociatedwiththeresponseto}

thishelminthextractwasadiminishedreleaseof inflamma-torymediators–nitricoxide,IL-10,andIL-1␤–tothemice’s joints.17_{TherewasnochangeinTNF-␣levels.}17

Inanindividualwithanautoimmunerheumaticdisease suchasRA,thehelminthinfectionhasthepotentialto allevi-atethesymptomsandimprovetheprogressivecourseofthe disease,thankstotheinductionofanimmuneresponseby Th2cells,antagonistictotheresponsebyTh1cellspresent in autoimmune disease.6,19 _{In addition to inhibiting Th1}

cytokines, the induction ofregulatory cytokines (IL-10and TGF-␤), theproductionofregulatoryTcells FOXP3 andthe activity of alternatively activated macrophages also would influenceinthe protective effectofhelminth infections in patientswithRA.20

Given the hypothesis that individuals infected with helminthswouldbelesssusceptibletoother inflammatory diseases,theparasiticinfectioncouldinfluencethetreatment ofdiseasesmediatedbyTh1cells.20

Thehelminthinfections and the products derivedfrom helminths(such as ES-62)are valuable toolstothe under-standingoftheimmuneresponsescausedbytheseparasites, possiblyhelpinginidentifying newclinicallyrelevant ther-apeutictargets.13_{Immunomodulatoryproducts–purifiedor}

synthesized–obtainedfrom helminthsmustbestudied,in ordertobeusedclinically.15,19_{Thechallengeistoidentifyand}

characterizespecificantigensofagivenhelminththat tar-gettheprotectiveresponse,andalsoantigens/moleculesthat wouldserveasindicatorsinthedevelopmentofnew biophar-maceuticalagentsfortreatinganumberofdiseases,among themRA.20

Conclusion

RA is a debilitating and painful systemic illness, whose immunopathogenesisinvolvesinnateandadaptiveimmune

mechanisms,especiallywithTh1cellactivityandreleaseof inflammatorycytokines,forexample,TNF-␣.Anearly treat-mentcanmodifytheaggressiveanddisablingcourseofthis disease.Today,wecanrelyoneffectivebiologicaltherapies forthetreatmentofRA,targetedtoblockingspecific inflam-matory cytokines. Itis assumedthat the generation ofan immunologically balanced environment, as a result of the infectionbyhelminths,couldreducetheseverityofa concur-rentautoimmunerheumaticdisease.Abetterunderstanding ofthemodulationpathwaysoftheanti-inflammatoryaction providedbytheinfectionwithhelminths,orbytheir secre-toryproducts,mayleadtonewtherapeuticstrategies(capable ofinhibitingmorebroadlytheinflammatorycytokines)and amplifythetherapeuticarsenalcurrentlyavailableforRA.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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