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
a,∗,
Ana
Paula
Monteiro
Gomides
b,
Lícia
Maria
Henrique
da
Mota
b,c,
Caliandra
Maria
Bezerra
Luna
Lima
d,e,
Francisco
Airton
Castro
Rocha
faHospitalUniversitáriodeBrasília(HUB),Brasília,DF,Brazil
bUniversidadedeBrasília(UnB),FaculdadedeMedicina,Brasília,DF,Brazil
cUniversidadedeBrasília(UnB),ProgramadePós-Graduac¸ão,FaculdadedeMedicina,Brasília,DF,Brazil dUniversidadeFederaldaParaíba(UFPB),JoãoPessoa,PB,Brazil
eUniversidadeFederaldaParaíba(UFPB),ProgramadePós-Graduac¸ãoInterdisciplinaremModelosdeDecisãoeSaúde,JoãoPessoa,PB,
Brazil
fUniversidadeFederaldoCeará,FaculdadedeMedicina,Fortaleza,CE,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:Received16September2015 Accepted3April2016 Availableonline22July2016
Keywords:
Rheumatoidarthritis Helminthinfections Immunomodulation
a
b
s
t
r
a
c
t
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
r
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:[email protected](S.M.Oliveira).
http://dx.doi.org/10.1016/j.rbre.2016.06.004
2255-5021/©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
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.3Ifnottreatedproperly,thediseasecanleadto
func-tionallimitations,withirreversibledeformitiesandareduced lifeexpectancy.1TheimpactofRAissignificantforboththe
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.6Morerecently,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.3,8Thebasicmech-anism proposed is the loss of immunological tolerance to self-antigensinageneticallysusceptibleindividual,triggering synovitis.3Inrelationtomechanismsoftheinnateimmune
response, neutrophils, macrophages, mast cells and natu-ral killer cells participateinthis inflammatoryresponsein the synovium.3Macrophagesparticipatebothintheroleof
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
Classically, RA is described as an autoimmune disease mediatedbyTcells,especiallyeffectorTh1andTh17cells.5,8
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.9Moreover,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.9Antibodiesagainstthecitrullinationofarginineto
citrullineasaresultofdeamination(anti-cycliccitrullinated peptides)maybepresentinupto70%ofpatients,andthese moleculesappearearlyinpatientswithRA.9Theexactroleof
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.3,11Intestinalparasiticinfections
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-1andIL-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,3,11thuscontributingtothepermanenceofthe
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.14Thedelayinthe
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.15Thus,patientsfromdevelopingcountriesshould presentmoresignificantmorbidityandmortality.15However,
RAislesscommonincertainareasoftropicalcountries,where a highincidenceofinfectious diseases,especiallyparasitic ones,isobserved.16InnortheasternBrazil,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.3,12Thus,inadditionto
causing disease,theyalso actaspotentmodulators ofthe immunesystem.3Theparasitesrelatedtoprotectiveeffectsof
theaggressivenessofthediseaseinpatientswithRA,already described inthe literature,are Schistosoma mansoni, Schisto-somajaponicum,Ascarissuum,Heligmosomoidespolygyrusbakeri andHymenolepsisdiminuta.3,12,20,21Suchpathogensinhibitthe
secretion ofTh1/Th17 cytokines, inducethe appearanceof tolerantdendriticcellsandpromotetheproliferationof reg-ulatory T cells.21 The infection by Schistosoma mansoni or
byS. japonicum can modifythe function of dendritic cells, macrophages,NKcellsandBcells,leadingtoanexpansion ofTh2cellsandofregulatoryTcellsresponsiblefor maintain-ingself-tolerance.11,18TheinfectionofmicewithSchistosoma
japonicumpriortotheinductionofarthritisbycollagen (inter-valof2weeks)significantlyattenuatedtheclinicalsignsof arthritis,withdecreasesinsynovialhyperplasia,infiltrationof synovialmononuclearcells,angiogenesisininflamedsynovia, osteoclastactivation,andjointdestruction.11Alower
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.11,18However,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.15,17Themechanismassociatedwiththeresponseto
thishelminthextractwasadiminishedreleaseof inflamma-torymediators–nitricoxide,IL-10,andIL-1–tothemice’s joints.17TherewasnochangeinTNF-␣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.13Immunomodulatoryproducts–purifiedor
synthesized–obtainedfrom helminthsmustbestudied,in ordertobeusedclinically.15,19Thechallengeistoidentifyand
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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