rev bras hematol hemoter. 2015;37(6):361–363
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Scientific
Comment
Haptoglobin:
an
emerging
candidate
for
phenotypic
modulation
of
sickle
cell
anemia?
夽
Magnun
Nueldo
Nunes
dos
Santos
UniversidadeEstadualdeCampinas(UNICAMP),Campinas,SP,Brazil
Sicklecellanemia(SCA)ischaracterizedbyasingle homozy-gousmutation(A→T)inthesixthcodonofthe-globingene that results in hemoglobin S (Hb S), in which a glutamic acid residue is substituted by valine in the sixth position ofthe -globin chain(HBB; glu(E)6val(A);GAG-GTG; rs334).1 Thischangeleadstoawidevarietyofsymptoms,including chronicintravascular hemolysis,increasedcell-freeplasma hemoglobin(Hb)andhemelevelsandvascularalterations.2 SCAhasbeencharacterizedasachronicinflammatorystate withabnormalendothelialactivation asaresultofvarious associated factors. The mechanisms that induce the pro-ductionofinflammatorymediatorsandthe effectsofthese moleculesontheinflammatoryresponsearelittleunderstood inthisdisease.3
Sickledredbloodcellsarestiffandthereforehavea predis-positiontohemolysis;onethirdofthecellsaredestroyedin theintravascularspaceleadingtoincreasedcell-freeplasma Hbandhemelevels.4 Thepathophysiologicaleffects associ-atedwithfreeHb/hemeare acutehemodynamicinstability andacuteorchronicvascularinjury.5Thetoxicityand inflam-matorynatureoffreeHbarearesultofthegreaternitricoxide consumptionitpromotesandtheconsequentaccumulation ofhydroxylradicalsandreactiveoxygenspeciesintheblood vessels.Theorganism’sfirstdefensemechanismagainstthe harmfuleffectsoffreeHbinvolveshaptoglobin(Hp),whose primaryfunctionistobindtofreeHbintheplasma,thereby preventingtheexcretionofironbythekidneysand protec-tingbloodvesselsfromitsoxidativeeffects.6,7Inadditionto beinganantioxidant,Hpisapositiveacute-phase glycopro-teinpresentinplasmawithimmunomodulatoryproperties.6,7
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2015.07.006.
夽
SeepaperbyPierrot-Galloetal.inRevBrasHematolHemoter.2015;37(5):329–35.
Correspondingauthorat:DepartmentofClinicalPathology,SchoolofMedicalSciences,UniversidadeEstadualdeCampinas(UNICAMP), 13083-970Campinas,SP,Brazil.
E-mailaddresses:magnun@fcm.unicamp.br,magnun.nunes@gmail.com
It is mainly synthesized in hepatocytes whose production is induced by the secretion ofinterleukin (IL)-6, IL-1 and tumornecrosisfactor-alpha(TNF-␣).8 Hphasastrong affin-ityforHb,formingahighlystablecomplexbybindingtoHb dimers(Figure1).ThisHb–HpcomplexbindstoCD163 recep-torsexpressedonthesurfaceofmacrophagesinthespleen, liver,bonemarrowandkidneys,andisremovedfromtheblood vessels.9However,whenthissystemforeliminatingfreeHb isoverloadedbecauseofintravascularhemolysis,asinSCA, freeHb/hemetriggeradverse clinicaleffects, suchasnitric oxidedepletion,oxidativestress,endothelialdysfunctionand exposureofthekidneystotheironinHb/heme.4
In humans, the HP gene, on the long arm of
chromo-some 16 (16q22), is polymorphic. There are two principal codominant alleles (HP1 and HP2) resulting in three main genotypes/phenotypes(Hp1-1,Hp2-1andHp2-2),whichhave distinctbiochemicalandbiophysicalpropertiesandhavebeen correlated tosusceptibilitytoandclinicalevolutionof vari-ousdiseases.6,7,10TheHP2alleleisapartiallyduplicatedgene derivedfromarareunequalcrossoverbetweentheHP1alleles. Becauseofitslargesize,theHp2-2proteinhasbeenshownto belessefficientatclearingHbfromtheplasmathantheHp1-1 protein.Thus,subjectswithHp2-2aremorepronetooxidative stress.6,11,12
Recently,severalstudieshaveinvestigatedthepossibility ofthetherapeuticuseofHpinhemolyticanemias.4,5,13Itwas demonstratedinguineapigsthatHpisefficientatpreventing arterialhypertensionandkidneydamageinducedbyplasma freeHb.4Morerecently,Chintagarietal.,inaninvitrostudy and inmicewithsicklecell disease(SCD), showedthatHp
http://dx.doi.org/10.1016/j.bjhh.2015.08.009
362
revbrashematolhemoter.2015;37(6):361–363RBC hemolysis
Hemoglobin
Hb dimers
Free heme
Hp1-1:Hb: Small molecule
Hp2-1:Hb: Intermediate molecule
Hp2-1:Hb: complex (example)
Hp2-2:Hb: complex (example)
Hp2-2:Hb: Large molecule
Hp-Hb
CD163 receptor
Recycling
Lysosome
Degradation
Heme
Nucleous
Macrophage
HaptoglobinFigure1–TheHp–HbcomplexisclearedbytheCD163receptorsexpressedonthesurfaceofmacrophagesanddigestedin lysosomestoreleaseheme.TheHp2-2proteinremovesironfromcirculationmoreslowlybecauseitisalargermolecule. Consequently,inindividualswiththisphenotype,freeHbremainsinthecirculationlongerandcausesgreateroxidative stress.Ontheotherhand,theHp1-1phenotypemaybeadvantageousbecausetheHp1-1:Hbcomplexisremovedtothe extravascularspacemorerapidlythantheotherHpcomplexes.
attenuatesthe expressionofheme oxygenase-1 (HO-1), an importantantioxidant and anti-inflammatoryprotein that, stimulatedbyplasmafreeHb, mediatesthe degradationof hemetobiliverdin,iron,andcarbonmonoxide.14Theseresults suggest that treatment withHp can reducethe toxicity of freeHbafterhemolysis.9Preclinicalstudiesarebeingcarried outwithaviewtoevaluatehowHpcouldbeusedasa spe-cificmodulatorinSCDandinvestigatepossibleadverseeffects ofitsuse. Abetterunderstandingofthismechanismcould providemoreknowledgetoexploitthetherapeuticpotential ofHptoneutralizefreeHb/hemeinhemolyticanemias.4,5
In this volume of the Revista Brasileira de Hematologia e Hemoterapia,Pierrot-Galloetal.15analyzethepossible influ-enceofHpgenotypesonthesecretionofIL-6andIL-8in60 patientswithstableSCA(aged15–50years old,53%males; recruitedintheHereditaryAnemiaOutpatientClinicofthe HematologyandBlood TransfusionUnit,Universidade Fed-eraldeSãoPaulo–UNIFESP,Brazil).Agroupof74apparently healthyindividuals (aged 17–60years old,53%males;from thesameBrazilianregion)wasusedasacontrol.Inthestudy, SCApatientswerefoundtohavesignificantlyhigherlevels ofIL-6 and IL-8 than controls, corroborating other studies. However,noassociationsbetween Hpgenotypesand these cytokines were identified. Furthermore,an investigation of
theprevalenceofHpgenotypesdidnotrevealanysignificant differences.
revbrashematolhemoter.2015;37(6):361–363
363
leadingtoamultiplicityofeffectsthatquiteoftenmakesit virtuallyimpossibletoanalyzeeachfactorinisolation.
TheresultsreportedbyPierrot-Galloetal.15 donot sup-portaconclusionthat theHpgenotypescan modulatethe inflammatoryresponseinthepatientstheystudied. Neverthe-less,thepossibilitythatHppolymorphismsmaycontributeto theclinicaldiversityobservedinthiscondition,in combina-tionwithothergeneticandenvironmentalfactors,shouldnot beexcluded.Studiesoftheinflammatorycomponentsusing morerepresentativesamplesizestogetherwith experimen-talanalysescouldhelptoelucidateimportantaspectsofthe clinicalbehaviorandsurvivalofSCApatients.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
Acknowledgments
The author would like to thank Prof. Maria de Fátima
Sonati for sharing her knowledge of haptoglobin over the years; and to Fundac¸ão de Amparo à Pesquisa do Estado deSãoPaulo-FAPESP(grantnumber2014/00984-3),Conselho NacionaldeDesenvolvimentoCientíficoeTecnológico-CNPq, and Coordenac¸ão de Aperfeic¸oamento de Pessoal de Nível Superior-CAPESforthefinancialsupporttoourlaboratory.
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