Allergy and risk of hematologic malignancies: Associations and mechanisms

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Leukemia

Research

j o u r n al ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / l e u k r e s

Invited

review

Allergy

and

risk

of

hematologic

malignancies:

Associations

and

mechanisms

C.

Musolino

a,1

,

A.

Allegra

a,∗,1

,

P.L.

Minciullo

b

,

S.

Gangemi

b,c,1 aDivisionofHematology,DepartmentofGeneralSurgeryandOncology,UniversityofMessina,Messina,Italy

bSchoolandDivisionofAllergyandClinicalImmunology,DepartmentofClinicalandExperimentalMedicine,UniversityHospital“G.Martino”,Messina,

Italy

cInstituteofClinicalPhysiology,IFCCNR,MessinaUnit,Messina,Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received5May2014

Receivedinrevisedform2August2014 Accepted4August2014

Availableonline12August2014 Keywords: Immunesystem Allergicdysregulation Hematologicmalignancies Tcelltolerance

a

b

s

t

r

a

c

t

Increasingevidenceindicatesthatadysregulatedimmunesystem,astheonefoundinallergic disor-ders,canaffectsurvivaloftumorcells.Apossibleassociationbetweenallergiesandriskofhematologic malignancieshasbeenexaminedinseveralepidemiologicalstudies;however,resultswerenotalways consistent.

Theaimofthisreviewistoreportthepreclinicalandclinicaldata,whichsupportacorrelationbetween allergyandhematologicneoplasms.

Immunesystemmodulationcouldrepresentapowerfultoolinthepreventionandtreatmentof hema-tologicmalignancies.

©2014TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/3.0/).

Contents

1. Introduction... 1137

2. Allergyandhematologicmalignancies... 1138

3. Allergyasriskfactor:possiblemechanisms ... 1139

4. Allergyasprotectivefactor:possiblemechanisms ... 1140

5. Allergy,sexandsolidneoplasticdiseases... 1141

6. Conclusionsandfutureperspectives... 1141

Conflictofintereststatement... 1142

Acknowledgments... 1142

References... 1142

1. Introduction

Allergicdiseasesrequiresensitizationofapredisposed individ-ualtoaspecificantigen.Exposureofasusceptibleindividualtoan allergenresultsinitsprocessingbyantigenpresentingcells(APC), includingmacrophagesanddendriticcells(DC)locatedthroughout thebodysurfacesincontacttheoutsideenvironment,suchasnose, lungs,eyes,skin,and intestine.TheseAPCsprocesstheallergen proteinandpresenttheepitopebearingpeptidesviatheirMHCto particularTcellsubsets.Tcellresponsesdependonbothcognate

∗ Correspondingauthor.Tel.:+390902212364;fax:+390902213397. E-mailaddress:aallegra@unime.it(A.Allegra).

1 Theseauthorshaveequallycontributedtothework

recognitionthroughvariousligand/receptor interactionsand on thecytokine micro-environment,withIL-4 directinga T helper (Th)2responseandinterferon(IFN)␥aTh1profile.

PeripheralTcelltolerancetoenvironmentalantigensiscrucial forahealthyimmuneresponseandnoallergy.Thebalancebetween Th2cellsandTregulatory(Treg)cellshasacriticalroleinthe gen-erationofimmuneresponsestoenvironmentalantigens.Allergic individuals displayanaberrantactivationand expansionofTh2 cells.ItappearsthataberrantactivationofTh2cellsinallergyis secondarytoimpairedmechanismsofperipheralTcelltolerance thatisnormallymediatedbyantigen-specificTcellanergy,Treg cells,andsuppressivecytokines,IL-10andTGF-␤[1].

However,increasingevidenceindicatesthatdysregulationof theimmunesystem,astheonefoundinallergicdysregulation,can affectsurvivaloftumorcells.[2].

http://dx.doi.org/10.1016/j.leukres.2014.08.004

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Theaimofthisreviewistoreportthepreclinicalandclinical data,whichsupportacorrelationbetweenallergyandhematologic neoplasms.

2. Allergyandhematologicmalignancies

Themajorityofstudiesreportedinliteraturehaveexploredthe relationshipbetweenallergyandlymphomaoracute lymphoblas-ticleukemia.Infact,itisonlyforthesediseasesthatthestrongest correlationswiththeallergicstatehavebeendetected,whileforthe otherhematologicaldiseasesreportsaresporadicandsometimes anecdotal.

Apossibleassociationbetweenallergiesandriskofhematologic malignancies(HM)hasbeenexaminedinseveralepidemiological studies;however,resultswerenotalwaysconsistent[3].

Incontrast,inverseassociationswerereportedmainlyin case-control design studies. There have been several investigations regardingdefinitionandmeasurement ofallergiesand the sub-typesofHMassessed,however,aninverseassociationwithhistory ofallergieshasbeenreportedforHMasagroup[4],lymphoma overall[5,6],Hodgkin’slymphoma(HL),NonHodgkinlymphoma (NHL)[7–10], Acute Lymphoblastic Leukemia (ALL) [11,12], and multiplemyeloma(MM)[13](Table1).

Shadmanetal.usedtheVitaminsandLifestyle(VITAL)cohort toexaminetheassociationbetweenallergiesandriskof hemato-logicmalignancies.From2000to2002,66,212participants,aged 50–76,completedabaselinequestionnaireoncancerriskfactors, medicalconditions,allergies,andasthma.Through2009,incident HMs(n5681)wereidentifiedvialinkagetotheSurveillance, Epi-demiology,andEndResultsCancerRegistry.

After adjustment for factors possibly associated with HMs, a history of airborne allergy was associated with increased risk of HMs (hazard ratio [HR]=1.19 [95% confidence interval: 1.01–1.41],P=0.039) in Cox proportional hazards models.This associationwaslimitedtoallergiestoplants/grass/trees(HR=1.26 [1.05–1.50], P=0.011) and was strongest for some mature B-celllymphomas(HR=1.50[1.14–2.00],P=0.005).Gender-stratified analysesrevealed thatthe associations betweenairborne aller-gies overall and those to plants, grass, and trees were only seen in women (HR=1.47 [1.14–1.91], P=0.004; and HR=1.73 [1.32–2.25],P<0.001)butnotmen(HR=1.03[0.82–1.29],P=0.782; and HR=0.99 [0.77–1.27], P=0.960)[14].The studyindicates a moderatelyincreasedriskofHMsinwomenbutnotinmenwitha historyofallergiestoairborneallergens,especiallytoplants,grass, ortrees.However,thisassociationwasnotuniformacrossallthe subtypesofHM,ratheritwasprimarilyfoundinsomematureB-cell neoplasms.

Severalotherstudieshaveattemptedtoascertaintheriskof acute and chronic lymphoid malignancies in patients suffering fromallergicdiseases.InaUSveteransstudy,ahistoryof“total allergicconditions” as documentedin thehospital recordswas associatedwithadiagnosisofNHL(riskratio[RR]=1.4[1.3–1.5]). Significantassociationswerealsoobservedwithspecificallergic conditionssuchas alveolitis,dermatitis, anderythema, but not asthma[15].

Other studies indicate a positive association, especially for HodgkinLymphoma(HL)[16,17]ornoeffect[18].

Moreover,inapopulation-basedstudyfromtheSwedish can-cerregistries,anincreasedriskoflymphoplasmacyticlymphoma wasreportedinpatientswhohadahistoryof“anytypeofallergy orchronicinflammatoryconditions” basedonprevioushospital dischargeinformation(RR=1.2[1.0–1.4])[19].

Differentworkshaveshownacorrelationbetweenspecific aller-gicdiseasesandhematologicalmalignancies.InaSwedishcohortof morethan16,000twins,theriskofleukemiawashigherinpatients withself-reportedhistory of hives(RR=2.1 [1.0–4.5]) whileno

associationwasfoundbetweendifferentsubtypesofallergiesand incidenceofleukemia,CLL,NHLorMM[20]

However,whenevaluatingriskofacutechildhoodleukemiain allergicpatients,Changetal.[21]utilizedapopulation-based case-controldesignusingmedicalclaimsdatafromtheNationalHealth InsuranceResearchDatabaseofTaiwan.Eighthundredforty-six childhoodALLpatientswhowerenewlydiagnosedduring2000to 2008andwereolderthan1butlessthan10yearsofagewere indi-viduallymatchedwith3374controlsbasedonsex,age,andtime atdiagnosis(referencedateforthecontrols).Conditionallogistic regressionwasperformedtoassesstheassociationbetween child-hoodALLandallergies.AnincreasedriskofALLwasobservedin thosewithallergylessthan1yearbeforeALLdiagnosis(oddsratio (OR)=1.7,95%CI:1.5,2.0),morethan1yearallergybeforeALL diag-nosis(OR=1.3,95%CI:1.1,1.5),andbefore1yearofage(OR=1.4, 95%CI:1.1,1.7).

Inthisstudy,childhoodALLwaspositivelyassociatedwith sub-jecthavingallergiesbefore1yearofagelessthan1yearbefore diagnosis,andmorethan1yearbeforediagnosis.

AssociationbetweenchildhoodALLandallergiesiscontraryto theresultsofmostpreviousstudies.Theinconsistencycanpartly beexplainedbythesourcesofexposuredata(medicalrecordsvs. parentalreport),participationrate,andexposurelatency.

Moreover,Nunez-Enriquezetal.conductedamultiinstitutional population-basedcase-controlstudyonchildrenwithDown syn-dromeandfoundthatasthmawasariskfactorfordevelopment ofacuteleukemia(OR=4.18and95%CI:1.47–11.87)while,other allergieshadnoeffectorwereprotective[22].

Theintrinsicimmunedysregulationthatwaswelldescribedin childrenwithDownsyndrome,likelyhadasignificantroleinthe associationbetweenallergicphenomenaandALL[23].

However,Downsyndromemightbeaconfounderintherelation betweenasthmaandacuteleukemia.Altogether,Downsyndrome maybeconsideredasthecauseforbothasthmaandacuteleukemia thusdrawingacausativelinkbetweenasthmaandacuteleukemia inthissettingcouldbearawconclusion[24].

Nonetheless,similarresultswerealsoreportedbyotherauthors. Infact,severalpaperssuggestthatasthmaisariskfactorforAL inchildrenwithDS,whereasskinallergiesseemedtoprotectthe populationfromAL.ChildrenwithDSaremorevulnerabletothe effectsofenvironmentalfactorsthathavebeenassociatedwiththe developmentofAL[25,26].

Finally,childrenborntomotherswithallergiesaremorelikely tohaveimpairmentofTregscells[27]andadecreasedabilityto respondtomicrobialchallenges [28].Similarly,highermaternal serumimmunoglobulinE,anindicatorofmaternalallergystatus, wasassociatedwithahigherriskofchildhoodALL[29].

However, while prospective cohort studies suggested an increasedriskofHM,case-controlstudiesfailedtoconfirmthese findings,rathertheyhaveshownaninverserelationship[30].

Infact,ithasbeenproposedthatallergiesinfluencethe develop-mentofchildhoodleukemia.Differentstudieshavebeenconducted inthisfield;however,theirresultsarenotconclusive,asseveral workshaveconcludedthatallergiesareriskfactorsorprotective factors[31–34].

Moreover,beyondthis inverseassociationofallergic history withchildhoodALL,asimilarassociationishighlightedwhen sero-logicmarkersofallergicpredispositionareusedasanalternative measureofallergy.

Inastudyconductedon252casesofchildhood(0–14years) ALL,newlydiagnosed allergen-specificIgEs,asmarkersof aller-gic predisposition,against 24 ofthemost prevalentrespiratory andfoodallergens,weredetermined,usinganenzyme immunoas-sayprocedurefor199childrenwithALLand113controls.Cases werecomparedwithcontrolsthroughfrequencydistributionsand unconditionalmultiplelogisticregressionmodelstoestimateORs

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Table1

Summaryofstudiesonallergyandriskofhematologicneoplasms.

Firstauthor/year Referencenumber Typeofallergy TypeofHM Statistics

ShadmanM/2013 [14] Airbornallergy(plants/grass/trees) HMmatureB-celllymphomas HR=1.19[95%CI:1.01–1.41],P=0.039

HR=1.50[1.14–2.00],P=0.005 KoshiolJ/2011 [15] Totalallergicconditions NHL [RR]=1.4[1.3–1.5]

KristinssonSY/2010 [19] Anyallergyorchronicinflammatory conditions

Lymphoplasmacyticlymphoma RR=1.2[1.0–1.4] SoderbergKC/2004 [20] Hives Leukemia RR=2.1[1.0–4.5]

ChangJS/2011 [21] Notspecified ALL OR=1.7,95%CI:1.5,2.0,lessthan1 yearbeforethecase’sALLdiagnosis OR=1.3,95%CI:1.1,1.5,morethan1 yearbeforethecase’sdiagnosis OR=1.4,95%CI:1.1,1.7,beforetheage of1year

Nunez-EnriquezJC/2013 [22] Asthma Acuteleukemia OR=4.18and95%CI:1.47–11.87 LariouMS2013 [35] Self-reported-allergichistory

SerumspecificIgE FoodIgE

ALL OR=0.49,95%CI:0.34-0.72 OR=0.43,95%CI:0.22-0.84) OR=0.39,95%CI:0.18-0.83 DikaliotiSK/2012 [36] Notspecifiedasthma NHL OR=0.50,95%CI:0.27–0.92 OR=0.43,95%CI:0.21–0.88 LandgrenO/2006 [38] Notspecified MM OR=0.4;95%CI:0.3–0.7

HM:hematologicalmalignances;NHL:nonHodgkinlymphoma;ALL:acutelymphoblasticleukemia;MM:multiplemyeloma;HR:hazardratio;CI:confidenceinterval;RR: riskratio;OR:oddsratio.

and 95% (CIs) regarding associations of allergy with childhood ALL.

Self-reported-allergichistory(OR=0.49,95%CI:0.34–0.72)and practicallyeveryoneofitsmaincomponents(respiratory,food,any otherclinicalallergy)werestronglyandinverselyassociatedwith ALL.Likewise,theserumIgEinverseassociationwasofthesame magnitude(OR=0.43,95%CI:0.22–0.84)mainlyduetofoodIgE (OR=0.39,95%CI:0.18–0.83)[35].

Thereisasimilardiscrepancybetweenworksreportedin litera-tureonlymphoma.Furthermore,thepapersappeartohighlightthe directcorrelationbetweenallergyandchronic lymphoprolifera-tivedysregulationswhileotherpapersseemtolighttheprotective effect.

Between1996and2008,277children(aged0–14years)with HL(N=111)orNHL(N=166)wereenrolledinNationwideRegistry forChildhoodHematologicalMalignancies(NARECHEM),froma Greekhospital-basedregistryofchildhoodhematological malig-nancies.Hospitalcontrolswereindividuallymatchedtocaseson ageandsex.Multivariateconditionallogisticregressionwasused toestimateORswith95%CIsforassociationsofallergicdiseasesand othercovariateswithchildhoodHLorNHLrisk.Subsequently,the authorscombinedtheirresultswiththoseofaFrenchcase-control studyinameta-analysiscountingatotalof330NHLcases/1478 controls and 239 HL cases/959 controls.After investigating on sociodemographic,perinatalandenvironmentalfactors,childhood NHLwaslessprevalentamong children withallergyassociated symptoms(OR=0.50, 95%CI:0.27–0.92)ora history ofasthma (OR=0.43,95%CI:0.21–0.88).Bycontrast,allergydidnotseemtobe associatedwithchildhoodHLrisk,althoughstatisticalpowerwas limited.However,fewerseasideholidaysandhigherbirthweight werealsoassociatedwithincreasedchildhoodNHLrisk.The com-binedORofthetwo studiesfortheassociationofasthma with NHLriskwas:0.52,95%CI:0.32–0.84,whereasforHL:0.86,95% CI:0.51–1.45.Thus,allergyseemedtobestronglyandinversely associatedwithchildhoodNHL[36].

ApowerfulpooledanalysisofadulthoodNHLalsoshowedan apparentprotectiveeffectofasthma,hayfeverandallergyagainst B-cellNHL[37].

Finally,areducedMMriskwasfoundamongwomenwhohada medicalhistoryofallergy(OR=0.4;95%CI:0.3–0.7).However,this studyshows conflictingresultsbecausecertainconditions(such asallergy,bronchitis,psoriasis,andeczema)wereassociatedwith reducedriskofMM,whereasothers(suchasasthmaandhayfever) werenotassociatedwithmultiplemyelomarisk[38].

3. Allergyasriskfactor:possiblemechanisms

Variousexplanationshavebeenproposedtoaccountfor the observedincreasedincidenceofHMinpatientswithimmune dys-regulation.Relevantfactorscouldbegeneticandenvironmental riskfactors,chronicactivationandreplicationoflymphocytesand thesubsequentincreasedchanceofmutations,andfinally epige-neticchanges,forexample,viaeffectsonantigenrecognitionbyT cells[39].

Effects of thetreatments used bypatients withallergies on thecancerrisk donotseemtoexplaintheassociation,as asso-ciationsbetweenusesofantihistamines,leukotrieneagonists,or othercommontherapeuticagentsforallergieswithHMhavenot beenreported.

TheassociationbetweenallergyandchildhoodALLsuggeststhat thetwodiseasesmayhaveacommonbiologicmechanism.

Two paradigms, “missing immune deviation” and “reduced immunesuppression,”havebeenproposedtoexplainthebiologic basis of thishypothesis [40]. Moreover,inorder toexplain the roleofallergiesasariskfactorforcancer,itisworthconsidering theantigenicstimulationhypothesiswhichproposesthatchronic stimulationoftheimmunesystemwillprovokerandomly occur-ringpro-oncogenicmutationsinactivelydividingcells[20].

For instance,chroniclymphocytic leukemia(CLL)is a tumor ofcirculatingBcells,variablystimulatedandanergizedfollowing exposuretoantigeninlymphoidtissues[41].

ThehyperreactivityoftheB-cellreceptor(BCR)tounknown antigenligationplaysa pivotalrole inCLLcellsurvival. Several authors aimed to investigate the BCRsignaling pathway using proteomicstoidentifynovelproteinswhichmayhaveclinical rel-evanceinthisdisease[42].

Almost30%ofCLLpatientsshareBCRswithrestricted, quasi-identical “stereotyped” immunoglobulin (IG) sequences with highly homologous IG variable heavy-chain complementarity-determiningregion3(VHCDR3),thekeydeterminantofantigen specificity.Thisfinding,alongwithotherstructurallyunique fea-turesofCLLBCRs,stronglysuggestthatantigens,superantigensor bothmayplayanactiveroleinthedisease[43].Thelatterstrongly supportsaroleforpersistentantigenstimulationintheclonal evo-lutionofCLL[44].

Adifferentlymphoprolipherativediseasewiththesame patho-genesiscouldbetheLargeGranularLymphocyte(LGL)leukemia. LGL leukemia represents a rare chronic lymphoproliferative dysregulation of CTLs, a malignancy that involves lymphocyte

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infiltrationofmultipleorgans,includingtheBM,liver,andspleen. Phenotypically,LGLleukemiacanarisefromeitherCD3+CTLsor

CD3− NK cells. The World Health Organization (WHO) classifi-cation includesT-cell LGL leukemiain the subgroupof mature peripheralT-cellneoplasmsanddistinguishesitfromaggressive NK-cellleukemia[45].

LGLleukemiaisthoughttoarisefromchronicantigenic stim-ulation, withthelong-term survival of LGLbeing promotedby constitutiveactivationofmultiplesurvivalsignalingpathways[46]. DuringinfectionexposureorAgstimulation,LGLsundergo vig-orousproliferationbyapproximately50,000-folduponprimingby targetcells,andatalatertimeafterAgclearance,areselectively eliminatedbyaprocesscalledactivationinducedcelldeath(AICD). However,inLGLleukemiapatients,theAICDprocessis dysfunc-tionalandactivatedCTLcellsdonotundergoapoptosisefficiently, leadingtoanelevatednumberofLGLsintheperipheralblood. Mul-tiplecellsurvival pathways, includingJAK2/STAT3,sphingolipid signaling,RAS/MEK/ERK,andSFK/PI3K/Akt,havebeenfoundtobe constitutivelyactivatedinLGLleukemiapatients.Asystembiology approachidentifiedIL-15andPDGFasmastersurvivalsignaling switchesthatmayhaveadeepeffectonallknownderegulations inT-LGLleukemia[47–55].

Aninterestingdatumcouldbethatthetreatmentofleukemic LGLisbasedonimmunosuppressivetherapy,primarilyusinglow dosesofmethotrexateorcyclophosphamide.

Associationsbetweenmultiple myelomaand past history of disorders characterizedby chronic immune dysfunction and/or antigenstimulationhavealsobeensuggestedinepidemiological studies;however,thereareinconsistenciesintheliteratureonthis topic[56–59].

Antigenictargetsofmonoclonalgammopathyofundetermined significance (MGUS) and multiple myeloma (MM) paraproteins havebeensuggestedtoplayanimportantrole asgrowth stim-ulatorsinthepathogenesisoftheseneoplasms.Toidentifysuch targets,Preussetal.screenedcDNAlibrariesfromhumantestis, lung and breast cancer, bovine and porcine muscle and wheat germ for reactivity with paraproteins in the sera from 115 patientswithMGUSandMM.Of>6×10(8)paraprotein–antigen interactionsscreened,anIgAparaprotein fromafemalepatient boundtosperm-specificcylicin-2,and3IgGparaproteinsbound to tripeptidyl-peptidase-II (TPP-2), insulin-like growth-factor binding-protein-2(IGFBP-2)andporcinekinesin.Specificitywas confirmedbyreverseWesternblotsusingrecombinantantigens. Thebroadspectrumofauto-,allo-andheteroantigensastargetsof humanparaproteinsinpatientswithoutsignsofchronicantigenic stimulationrendersacausalroleoftheantigenicstimulusinthe pathogenesisofMGUSandMMasunlikely[60].

Theimportanceofclinicalorsubclinicalimmunedysregulation indevelopmentofHMincasesoccurringinthegeneralpopulation, whocomprisethemajorityofcases,isunclear.However,inallergic individuals,antigenicstimulationsubjectstheimmunesystemto achronicallyhyperreactivestate,leadingtoaninflammatory cas-cadeofcellularandcytokinereactionsthattaxthehostimmune response,provoketissueinjury,andeventuallyresultinlymphoid neoplasia[61].

Thus,aB-cellstimulatoryhostenvironmentincreasestherisk ofB-cellNHLamongimmuno-competentpersons,andamodified patternofcytokinesproductioncouldberelevantintheonsetof HM.

IL-12isimportantfornormalimmunedevelopmentthatshifts theimmuneprofilefromT-helper2dominantamongnewbornsto T-helper1dominantwithincreasingage[62].Theabsenceofthis shiftandthepresenceofaT-helper2-dominantimmuneprofileare associatedwithanincreasedriskofallergy,butIL-12alsoappears importantfor childhood ALL.Infact, a previousstudyreported thatthevariantGalleleofthesinglenucleotidepolymorphism

rs583911oftheinterleukin12Agene,whichcodes forapartof IL-12cytokine,isassociatedwithanincreasedriskofchildhood ALL[63].

Moreover,althoughIL-10canbeproducedbymanycelltypes,it isproducedbyatypeofT-regulatorycellknownasT-regulatory1 atparticularlyhighlevelstosuppressoveractiveimmunereaction

[64],andarecentstudyshowedthatchildrenwithALLhadlower IL-10levelatbirththandidhealthychildren[65],whilecordblood samplesofchildrenwithallergyhaveexhibitedalowerimmune responseof theTregulatory1-relatedcytokineIL-10compared withhealthychildren[66,67].

Finally,increasedserum/plasmalevelsofmoleculesinvolvedin B-cellactivation,includingsolublesCD23,sCD27,sCD30,sCD44, andCXCL13,havebeenassociatedwithsubsequentdevelopmentof AIDS-relatedNHL.B-cellactivationischaracterizedbylymphocyte proliferation,classswitchrecombination,andsomatic hypermuta-tion,allofwhicharepronetoresultanterrorsinDNAthatmaylead tolymphomagenesis[68–71].

Adifferenthypothesis couldexplainthecorrelationbetween allergyandHM.

Althoughthe definite causesof childhood leukemiaare still largelyunknown,itisbelievedthatalackof“priming”byinfections duringearlychildhoodmaycauseadysregulatedimmuneresponse toinfections later in childhood, leading tothe developmentof childhood leukemia, particularly acute lymphoblastic leukemia (ALL)(Greaves’“delayedinfection”hypothesis)[72].Moreoverthe underlyingbiologicmechanisminthedelayedinfectionhypothesis isalsoapplicabletothehygienehypothesisproposedbyStrachanto explaintherisingprevalenceofallergyintheWesternpopulation

[73].

Giventhesimilaritiesbetweenthedelayedinfectionhypothesis ofchildhoodleukemiaandthehygienehypothesisofallergy,itis counterintuitivethatinthemajorityofstudies,aninverse associ-ationbetweenallergyandchildhoodleukemia(mostlychildhood ALL)[12,31,33,34,74–78]wasobservedwithonlyoneexception

[32].

Anoveractiveanddysregulatedimmunereactioninresponseto pathogensmayleadtotheexpansionofapreleukemicclone, result-ingintheoccurrenceofadditionalmutationsandthedevelopment ofchildhoodleukemia[72].

4. Allergyasprotectivefactor:possiblemechanisms

Incomparison,allergiesasprotectivefactorscanbeexplainedin termsoftheimmune-surveillancehypothesis,whichsuggestthat allergicdiseasesenhancetheimmunesystem’sabilitytodetectand eliminateneoplasticcells.

Theimmunesystemhastheabilitytorecognizeandeliminate nascenttransformedcellsinthebody,thuspreventingamajority ofpotentialcancersfromdeveloping.Thepresenceofanallergic conditioncouldbeasurrogatemarkerofincreasedvigilanceofthe immunesysteminscrutinizing,identifying,anddestroyingcancer cells[11].

In allergicsubjects,there is bonemarrow involvement with reprogrammingof bonemarrowstemcells, regardedas‘reflex” natureofallergic disease.Allergicphenotypein anatopic child mayleadtoepigeneticreprogrammingthatinturnaffectsimmune surveillance by increasing antigen-presenting cell activity [79]. Hence,itseemsthatincreasedsurveillancebyhyperactiveimmune systemofallergicpatientsisareality.

Anotheristheadrenalhypothesis,whichproposesthat infec-tionsproducechangesinthehypothalamus-pituitary-adrenalaxis andsubsequentlyanelevationinplasmaticcortisol,provokingthe eliminationof leukemicand preleukemiccells. Thismechanism ispossibleunderallergicconditionsbecausethedrugscommonly

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usedtotreatallergiesincludecorticosteroids,whichcouldprovide thesameprotectiveeffectagainstthedevelopmentofALthatearly infectionsprovide[80].

Alessplausibleexplanationcouldpointtotheantitumoractivity ofhistamine[81],achemicalmediatorofallergicreactionsthat pro-tectsnaturalkillercellsandTcellsagainstoxygenradical-induced damageanddeathbysuppressingoxygenradicalformation,and alsooptimizeslymphocyteactivationby cytokines[82].Clinical trialsinmalignanciessuchasmetastaticmalignantmelanomaand acutemyeloidleukemiahavedemonstratedthathistamine dihy-drochlorideincombinationwithimmunotherapyhasthepotential toimprovetreatmentoutcome,furthersupportingtheposssible antitumoreffectofhistamine[83,84].

Ontheotherside,ithasalreadybeendemonstratedthat his-tamine may play a role in mycosis fungoides, particularly in advancedstagesofthedisease.Histamines,butalsoother medi-atorsreleasedbymastcells,arenotonlyassociatedwithpruritus, butmayhavetumorgrowthpromotionandimmune-regulating properties[85,86].

Theantihistaminesclemastineanddesloratadinecanpossess immune suppressive or regulatory properties including inhibi-tionofantigen-specificaswellasmitogen-inducedlymphocytes proliferation.These propertieswereindependenton histamine-1-receptor expression, but dependent on extracellular signal regulated kinase (ERK)-dependent proinflammatory cytokines suchasTNF-aandIL-6[87,88].

Döbbelingetal.evaluatedtheeffectofclinicallyapproved anti-histaminesonthegrowthofCTCLcelllines.CTCLcelllinesaswell asbloodlymphocytesfrompatientswithSézarysyndromewere culturedwithantihistamines,andthecellswereanalyzedfor prolif-eration,apoptosis,andexpressionofprogrammeddeathmolecules andtranscriptionfactors.Thetwoantihistaminesclemastineand desloratadine, inducedpotent reduction of theactivities ofthe constitutivelyactivetranscription factorsc-Myc, STAT3,STAT5a andSTAT5binmycosisfungoidesandSézarysyndromecelllines. Thisinhibition wasfollowed byapoptosisand celldeath, espe-cially in theSézarysyndrome-derived celllineHut78 thatalso showedincreasedexpressionoftheprogrammeddeath-1(PD-1) afterclemastinetreatment.InlymphocytesisolatedfromSézary syndromepatients,theCD4-positivefractionunderwentapoptosis afterclemastinetreatment,whileCD4-negativelymphocyteswere hardlyaffected[89].

Therearemorethingsinheavenandhearth...

5. Allergy,sexandsolidneoplasticdiseases

Recentstudieshavedemonstratedthatserumeosinophilcount isinverselyassociatedwithcolorectalcancerdevelopment,anda historyofallergydecreasestheriskofpancreaticcancer[90,91], whileatopicexposuresmaybeprotectiveagainstchildhood rhab-domyosarcoma(RMS).Ina case-controlstudyof322childhood RMS casesand 322pair-matched controlsLupo et al. assessed thefollowingatopicconditionswereassessed:allergies,asthma, eczema,andhives.Asthetwomostcommonhistologictypesof RMSareembryonal(n=215)andalveolar(n=66),theyevaluated effectheterogeneityoftheseexposures.Allergies(OR=0.60,95%CI: 0.41–0.87),andhives(OR=0.61,95%CI:0.38–0.97)wereinversely associatedwithchildhoodRMS.Theseexposuresdidnotdisplay significanteffectheterogeneitybetweenhistologictypes.Thisis thefirststudyindicatingthatatopicexposuresmaybeprotective againstchildhoodRMS,suggestingadditionalstudiesareneeded toevaluatetheimmunesystem’sroleinthedevelopmentofthis tumor[92]

Thus,therelationshipbetweenallergyandsolidneoplastic dis-easesalsoappearstobeanimportantfieldofinvestigation.

However,adifferentandinterestingfieldofresearchisthe dif-ferentinfluenceofsexontheriskofHMinallergicpatients.Infact, genderdifferencesarereportedintheassociationbetweenhistory ofallergiesandcancer.Itistemptingtospeculatethatthe addi-tionaleffectofallergymayreachstatisticalsignificanceinwomen becauseoftheirlowerbaselineriskforthedevelopmentof HM compared tomen.However,hormonaleffects onthe (dysregu-lated)immunesystemandinteractionswithcarcinogenesismay offeranalternativebiologicalexplanationthatwillrequiredfurther mechanisticstudies.

6. Conclusionsandfutureperspectives

Inthefuture,manyotherfactorsshouldbestudiedtoinvestigate therelationshipbetweenallergiesandcancer,suchasthe influ-enceoftumorsonthepossiblemanifestationofallergysymptoms. Wehavetoconsiderthatindividualswithpre-clinicalNHL expe-rienceimmunesuppressionthatleadstothereductionofallergic symptoms[8].

However,afterwe havereviewed themostrecentliterature ontherelationshipbetweenallergyandcancer, wemusttryto justifythediscrepanciesthatexistandthedifferentconclusions reachedbyvariousauthors.Itisprobablethatdifferent immuno-logicalalterationsthataccompanydifferentallergies,mayaffect tumorsusceptibilityinacompletelydifferentway.

Inbothallergyandcancerbiology,forexample,antibodiesmay bebeneficialordetrimental,dependingontheirepitopespecificity

[93,94].In allergy, specificimmunotherapy (SIT)with allergens aimstoinduceantibodieswhichblock,but donot enhancethe allergicreaction.Similarly,inimmunologicaltargetingofantigens overexpressedbymalignantcells,growth-inhibitoryantibodiesare preferred,whereasgrowth-stimulatingspecificitiesshouldbe pre-vented.Therefore,inbothcasesitisimportanttodirectimmune responsestoinhibitoryantibodyepitopesoftheallergen/antigen

[95].

Theimportanceofantibodiesinactivatingimmuneresponses againsttumorsisnowbetterappreciatedwiththeemergenceof checkpointblockadeantibodiesandwithengineeredantibodyFc domainsfeaturingenhancedcapacitytofocuspotenteffectorcells againstcancercells.AntibodiesdesignedwithFcregionsoftheIgE classcanconfernatural,potent,long-livedimmunesurveillancein tissuesthroughtenaciousengagementofhigh-affinitycognateFc receptorsondistinct,oftentumor-residentimmuneeffectorcells, andthroughability toactivatethesecells undertumor-induced Th2-biasedconditions.IgEisanovelanti-cancermodality,and sev-eralIgE-basedactiveandpassiveimmunotherapeuticapproaches havebeentried indifferentinvitroand invivomodelsystems, collectively suggestingthepotential ofIgEimmunotherapies in oncology[96].

The assumption on an inverse association between allergy andIgElevelsandcancerderivesfromepidemiologicaldata[97]. IgEantibodiesdirectedagainstatumor-associatedantigencould specificallytriggeranimmediatelocaleffectorcellresponseagainst thetumorcells[98]

Engineered anti-tumor IgE antibodieshave a high cytotoxic capacity duetointeraction withpotent effectorcells. However, naturalIgEhasalsobeendescribed insquamouscellcarcinoma oftheheadandneck[99]andinpancreaticcancerwhereits cyto-toxicpotentialwasalsodemonstrated[100].Themechanismsof anti-tumorIgEshavealreadybeenstudiedindetailinseveral pre-viousexperiments,among themADCCand antibody-dependent cell-mediated phagocytosis (ADCP) seem tobe mostimportant

[101–103].

However,althoughseveralstudiessuggestanincreasedriskof HMinpatientswithreportedhistoryofallergies,thisassociation

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wasnotuniformacrossallthesubtypesofHMandithasbedenied inseveralworks.

Inthisregarditshouldberememberedthateventhoughwe havelistedseveralstudiesontheassociationbetweenallergies andhematologicalmalignancies,avastmajorityofthesestudies areepidemiologicalstudies.Althoughthecontributionof epidemi-ologic methods in elucidating thedeterminants and etiological factorsinhumandiseasehasalonghistory,somepractical limi-tationsofepidemiologicmethodshavetobehighlighted.

Therearetwomainlimitationstoepidemiologicalstudies:the firstisstatisticalandgivesrisetorandomerrors;theother con-cernsdemographyandgivesrisetosystematicerrors.Groupsofat leastseveralthousandpeoplewouldneedtobefollowed through-outtheirlivesinordertoidentifyastatisticallysignificantexcess ofcancerbetweentwopopulations.Thesecondlimitationresults fromtheneedtomatchthestudyandcontrolgroupsforany con-foundingfactorsthatmayinfluencetheincidenceofcancer.Unless thestudyandcontrolgroupsaredrawnfromasinglehomogeneous population,itisrarelypossibletomatchthegroups,ortomake allowancesforthedifferences,withsufficientaccuracytodetect, withconfidence,asmallincreaseincancermortality.Any inade-quacyinthematchingmaygiverisetoabiasthatcannotbereduced merelybyexpandingthesizeofthegroups[104].

Despite these limitations, epidemiologic studies have been remarkablyproductiveinelucidatingetiologicalfactors.

Inconclusion,severalstudiesprovideempiricalevidencethat allergicdisordersare associatedwitha directorinverserisk of developinghematologicmalignancies.

Infact,adysregulationoftheimmunesystemmighthaveboth positiveandnegativeinfluenceontheoccurrenceofcancer.The presenceofanallergicconditioncouldbeasurrogatemarkerof increasedvigilanceoftheimmunesysteminscanningfor, iden-tifyinganddestroyingcancercells.Ontheotherhand,inallergic individuals,antigenicstimulationsubjectstheimmunesystemto achronicallyhyperreactivestate,leadingtoaninflammatory cas-cadeofcellularandcytokinereactionsthatprovoketissueinjury andeventuallyresultinneoplasia.

Itisthereforecertainthatthereisaclearspecificitybetween alterationof theimmune systemandthe onsetof hematologic malignancies.Thecelltypeconcerned,myeloidorlymphoid,age, sex,andcomorbiditiesseemabletochangethetypeofinfluence exertedbytheimmunesystem.Therefore,generalizationsabout theinfluenceoftheimmunesystemonhematologicmalignancies appearunnecessaryandmisleading.

Furtherstudiesshouldassesstherealimpactofallergiesonany specifichematologicaldisease.

Epidemiologicalstudiesthatincludetheevaluationofdifferent immunologicaleffectorswillbeneededforaconfirmationofthis associationandtoexplaintheintimatemechanismsthat under-lietheincreasedsusceptibilityortheprotectiveeffectexertedby allergyonneoplasticdiseases.

Conflictofintereststatement

Theauthorsdeclarenoconflictofinterest.

Acknowledgments

WewouldliketothankMs.AntoninaDonatofortheeditingof thetext.

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