Bellanti, J

Candotti, F

Guarnaccia, S

Kurman, C

La Grutta, S

Nelson, D

Notarangelo, L

Ugazio, A

Archivio istituzionale della ricerca - Università di Palermo

Serum soluble interleukin-2 receptor (IL-2R) inchildren with allersic disordersS Guamaccia, MD; C C Kurman*; L D Notarangelo; SLa Gruttat: F Candotti;A G Ugazio;D L Nelson*: and J A Bellanti. MDtINTRODUCTIONlnflammatory rcsponses play a cen-tlal role in a variety of allergic dis-orders. These inllammatory rc-sponses arc complex and may in-volve seveml immunologicpathways.'* It is now rccognizedthat T-cells may influence a varielyof these pathways. The T-cell-de-dved lymphokine, interleukin-2(IL2), plays a pivotal role in thercgulation of many T-cell mediatedresponses and interacts with a high-aflinity interleukin-2 receptor (IL2R), which is expressed on a varietyol cell types.r 6 Activation oflymphoid cells is associated with se-c.etion of IL2 and with the expres-sion of high affinity IL-2R, whichare composed ofat least lrce chains(a, B, ,r) each interacting with dis-tinct epilopes on the IL-2 molecule.We hav€ prcviously reportedT thaltle activation process is associatedwith the release of one of thesechains, the Tac peptide or solublelL2R (SIL-2R). This soluble formofthe IL-2R is slighdy sma erthanthe cell-membrane-associated formof the same molecule, and is fullycapable ofbinding IL2. Studies iDa number of inflammatory diseasesincluding autoimmunity, AIDS,and allograft reaction llave showntlat levels of soluble Tac protein inserum and other sedetions correlatewith immunologic activation andinflammation orocesses occurrinein vivo.8 In th; present study w;assessed IL-2R levels in the sera ofchildren with allergic disorders.SUBJECT AND METHODSBlood samples were obtained fromIive groups: seven subjects aged l-10 yeals with severe atopic eczema,seven subjects aged 2-10 yeals withmild atopic eczema, seven subjectsaged 5-10 yea6 with severe asthm4seven subjects aged 4-8 years withmild asthma, and seven omal sub-jects aged 1-13 years. Assignmentto mild or severe asthma was basedupon criteria rcported elsewhere."Similarly, the scoring system pro-posed by Sampson and Mccaskll'uwas applied to patients with eczema.Those with a scorc =2+ were clas-sified as aflected with mild eczema,while children with a scorc of 3+/4+ were grouped as affected withsevele eczema.Specific diagDoses werc estab-lished on tle basis of family andpersonal history, physical examina-tion, and clinical follow-up. Noneof the patients had been receivingsleroids or other antiinflammatorydrugs over 2 months before bloodcollection. lnfomed consenl wasobtained from childrcn's parents.Blood CallectionFive milliliters of peripheral bloodwas collected liom each patient andpromptly centrifuged for semm sep-aration. Serum was either immedi-ately processed for biochemicalevaluatiol or stored in small aliquots (0.5 mL) at -70 'C until used.bj a I uat i o n of I I E - m e d iat edhypersensitivityFor each patient, IgE-mediated hy-persensjtjvity was evaluated byprick-test, as well as by total(PRIST) and specific (RAST) ICEserum content, These data werethen comparcd with results ofanaly-sis of soluble IL-2R levels-Assayingfor Soluble Tac ProteinSoluble Tac protein was measuredusing a double epitope "sandwich-enzyme-linked immunoassay," orELISA. This ELISA employs twomonoclonal antibodies binding atdistinct epitopes on the Tac protein.The conversion ofsubstrate to p.od-uct is proportional to the amount ofTac protein present and the assay ismade quantitative by comparison toa standard preparation of solubleTac prolein. The rcsults are ex-pressed as (U/mL). Age-matchednormal control individuals were in-cluded in the study. Linear reges-sion test was used for statisticalanalysis.RESULTSShown in Figure 1 are the results ofIL-2R concentration detecte.d invarious groups of childrcn vrith al-lergic disorders compared with nor-md controls. There wiis considera-ble overlap in the concentations ofsoluble Tac protein between healthychildren, patients with mild asthma,patients with mild eczema, patientswith severe asthma, aDd patientswith severe eczema (Fig 1). A1-though serum Tac peptide concen-trations were slightly el€vated in pa-tients with severe eczema, no signif-icant differences were obse edbetween tlis group and healthy con-trols. Serum Tac concentrationswere not significantly correlatedFrom the Department of Pediarrics, Uni-v*sity of Brescia. ltaly.+lmmunophtsiology Sedion. Mctabo-lism Branch, NCI, Be$esd4 Maryland.t Depanment of Pediatrics. univeuitl' ol* Department of Pediatrics and Microbi-ology a.d the Inlemational Crnter for lnteFdiscillinary Studies of Immulology, George-lown Udve6ily School ofMedicine, wash-ington, DC.Reftived tor pubUcalion D{ember 8,1992.A€epled for publication in revised fomMarch 24, 1993.VOIUME 7I, SEPTEMBIR qA] 259E:cc=.EF_9.?50004000300020001000dete.mined by prick-skin testlng(Table 1).DISCUSSIONElevated serum concentmtions ofsoluble Tac-peptide (ie, of the solu-ble folm of the a-chain of IL2receptor) have been demonstratedin several conditions associated withimmune activation aDd/or dysre-gulation, such as autoimmunity,AIDS, and allogaft rejections andsystemic sclerosis.qlr It has beenpostulated that abnormalities of theimmunoregulatory network mayplay a rcle in the pathogenesis ofallergy.'l'3 lndeed, decreased num-bers of CD3 and CD8 circulating Tlymphoc)-tes, and reduced in vitosuppressor cell activity have beenreponed in patients with aliergic dis-On the basis of these data, wehave analyzed serum concentra-tions ofsoluble IL2R in a cohort of28 a ergic children with atopic-eczema or asthma and seven age-matched healthy contols. SerumconcenfatioDs of soluble lL-2Rwere stgltly elevated in children1206 10 12 14 1.6 1.8 2.O 2.2 -06Normals l\4ild Mild Severe SevereAsihma Eczema Asthma EczemaFigure I . Serun levels of $luble interleukin 2 @eptor in childrea wirh alle€ic djsrdeE andin age-marched controls.with serum IgE concentralons in astlma: r =.379, P=.401; and IgEany ofthe goups under study (Fig in severe asthma: t: .145, P:2) IgE versus mild eczema: r .232, .757). Similarly, serum Tac conce.-P: .617; IgE ve$us severe czema: trations were not significantly cor-t: .121, P = .196,1AE' versus mild rclated wit}l the skin-positivity asz2la'ci: r1.0Mild Eczema0 8 1.0 1.2 1.4 1.6 1.8 2.0 0.6 0.8 1.0 1.2 1.4 16 1.8 2.4 2.2 2.465321.0Serum lgE U/ml (x 103)Figu.e 2. Coftlarion between seron levels of soluble inierleukin-2 receplor and tolal lgE in chiltliet wilh altergic d'sorders- Lintu FSlssionlesi @ agplied in dch group.260 ANNALS OF ALLERGYTable L Corelalion of lL-28 Serum Levels and Skin Test Posilivity exception of patients witl severceczema.REFERENCESl Romagnani S, Del Prete G, MasgiE et al. Role of ir.erleukins in in-duction and re8ulation of humanIgE synthesis. Clin Immunot Im-munopathol 1989;50:3l -523.2. Maggi E, Del Prete GR Pa.ronchlP, et al. Rol€ for T cels, ILz andIL6 in th€ Il-4-d€p€ndenr in vi.rohuman IgE sydhesis. Immunolosy1989;68r300.3. Sampson HA. The role of food al-tersy and m€diator releas€ in atopicdematitis. J Allersy Clin Immunol1988:81r635-45.4. Hsieh KH. Allered interleukin-2productio. andresponsivenessafterhlpos€nsitization to house dust. JAliergy Clin Immunol 1985;76:188-94.5. Farrdr JJ, B€njamin WR, HiuikerML, et al. The biochemistry, bioLogy and role of interleukjn-2 ir theinduction of cltoroxic T c€[ anti-body-foming B cel responses. lm-munot Rev 1982;63:129-66.6. Waldmann TA. The roi€ of themultichain IL2 receptor complexin the contol of normal and malig-nant T-ceI proliferation. EnvironHealrh Pelsp€ct 1987;75:l l-5.7. Rubin LA, Kurman CC, Fritz ME,et al. Soluble interleukin 2 receptorsare released from activated humanlymphoidcells tn vtrro. J Immunol-oey 1985:3172-7.8. Pui CH. S€rum jnterleukin-2 recep-tor: clinical and biological implica-tions. kukemia 1989;31323.9. Guidelines for the diagnosis andmanagem€nt of asthma. J All€rgy_ Clin Immunol l99l:88 n'3, part 2.10. Sampson HA, Mccasl.ill CC. Foodhlpenensitivity and atopic dema-titis: evaluation of 113 patients. JPediat 1985; 107:669-75.tL Kahal€h MB,l,e Roy EC.Interleu-kin-2 in scleroderma: correlation ofserum tevel with extent of skin in-volvement and disease duration.Ann In.er Med 1989;l 10:446-50.12. Chand.a RK, Baker M. Numencaland tunctional deliciency of sup-pressor T c€lls prec€d€s developm€nt of atopic eczema. l-anc€tl983i i i :1393.13. Matsumoto T, Talalashi H, Miik€T. Increase ofT cells b€aring FCER-associated antigen in pati€nts withMitdSkin Skin Skin SkinMitd321445 22aA19822966xt5117761018241299 1654" n : numb€r ol subjects tested.tX: geomeric mean serum lL-2R conceniraliois (U/mL).with severe eczema; however, t]redillerence was not statistrcally sig-nificant as compared with healtlycontrols,lnterestingly, Matsumoto et alhave recendy rcported elevatedsemm levels of soluble IL-2R inchildren with eczema or food ana-phylaxis.5'17 tn both the study ofMatsumoto et al and in the presentstudy, similar assays were employedfor measurement of serum concen-trations of soluble IL-2R. Althoughstatistically significant results wereobtained only in the study of Mat-sumoto et al, in boti studies anoverlap between s€rum concentra-tions ofsoluble Tac protein in chil-dren with eczema nd age-matchedcontrols was clearly observed. As-sessment of serum Tac concentra-tions is therefore of questionableusefulness and significance for mon-itodng alleryic inflammation in thisgroup of patients.Contrcversial results have be€nrcported on serum soluble IL2Rlevels in patients with asthma.Brown et al reported increased lev-els in asthmatic subjects, independ-ent of severity of the disease and ofthe pres€nce of acute symptoms.l3Cor.igan and Kay reported higherserum levels of SIL2R and IFNgamma in adults with acuteasthma.le In contrast, more re-cently, Matsumoto et al have re-ported that serum levels of SIL2Rarc not increased in children withasthma. These apparent discrepan-cies may reflect cellular release ofcltokine during i. vitro clottingprocedure, thus aflecting serum cy-tokine levels. In order to avoid thisproblem, we have imm€diatelyprocessed each blood sample forserum sepamtion.Our rcsults on serum IL-2R levelsin asthmatic childrcn are in keepingwitl lhe obseflations by Matsu-moto et al and support tle notionthat differences in the severity ofalleryic reactions do not appear torcsult in systemic amplification ofthe immunologic adivation, as sug-gested by the lack ofcorrelation ofsoluble IL'2R concentrations in al-lergic children with total IgE RASTor pdck skin test positivity.The rcsults of tie present studyare in agreement witi previous ob-senations demonstrating thatserum IL-2R concentrations arewithin the normal range in childrenwith bronchial asthma and ex-tremely high total IgE levels.s Im-mune activation mechanisms in-votved in IgE synthesis and in theproduclion ofsoluble IL-2R appearto be difTerent. Hawrylko et al haverecer1dy reported inoeased cellu]arpmduction of c)lokines during in-flammatory processes.']o Thus, eval-uation of cltokine production bymononuclear cells might representa b€tter inflammatory index thanserum cltoKne levels.ln conclusion, while it is possiblethat abnormalities of other immu-noregulatory pathways (includingIL-4, gamma-IFN, IgE-binding fac-tor) are associated with allergy'?r "(and their measurement may t]lusbe useful in monitoring oftlese pa-tients), our data suggest tlat evalu-ation of serum soluble IL2R levelsis oflimited value in the assessmentofallergic children, with the possibleVOLUME 7i, SEPTEMBER, I9q] 261t4.15.16.l7.atopic asthma. Ann Allergy 1987;58r261.l-euns DY, Rhodes AR, Geha RSEnumeration of T cell subsets inalopic dermatitis using monoclonalantibodres. JAllergy Clil lmmunol1981;67:450.Hernady Z, G€llis S, Chamb€rc M,€t al. Abnormal tegulation of ln vi,/o IgE synlhesis by T cels obtainedfrom patients with atopic dermati-tis. Clin Immunol Immunopathol1985;35:156.Delespesse G, Demauberge J, Sa.-fati M. Charactedzation of circulating T lymphoc)'le subpopulationsitr alopic eczema. J AIeTCY CLinImmunol 1982;69:135.Matsumoto T, Miik€ T, YamaguchiK, et al. Serum levels of soluble IL2 rcc€ptor, IL4 and lcE-bindingfactors in childhood allersic dis-eases. Clin ErP Immunol l99l;85:288-92.18. Brown PH, Crompton GIa Green-ing AP. Proinnammatory q'tokinesin acute asthma. l,anc€t 1991i338:590-3.19. Codsan CJ, Kay AB. CD4 T-Lynphoc]1€ activation in acute se-vere asthma. Am Rev R€sPn Disr99otl41t9 70-7 7.20. Hawrylko E, Spe(us A, Mele CA,et al. Increased interleukin-2 plo-duction in response to human t)pe1 cola8en stimulation in Pati€ntswilh systemic sclerosis. AnhdtisRheum 1991;34:580-87.21. Claassen JL, Levine AD, BuckleyRH. R€combinaDt human IL4 in-duces IgE and l8G synthesis bY nor-mal and atopic donor mononuclearcells. Simitar dose r€spons€, trmecourse, requirement for T cells, andeff€st of pokeweed mitogen J Im-munol 1990;144:2123.22. Gordon J, Flores-Romo L, CaimsJA, et al. CD23: a mulrifunctionalreceptor/lymphokine? ImmunolToday 1989;10:151.23. Youns M, Geha RS, Maksad KN,et al. Characterization of human Tcel-deriv€d lgE_potentiating factor'Eur J Immunol 1986;16:985.24. Boguniewicz M, Jaffe HS, Izu A, etal. R€combinant gamma-inledbronin treatment ofpatients ith atopicdematitis and elevated IgE levels.Am J Med 1990;88:365-70.Reqrestfor rcprints hould be addresed ta:Depanme\t ofPediatics25123 Brestia262 ANNALS OF ALLERGY

Serum soluble interleukin-2 receptor (IL-2R) in children with allergic disorders

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Serum soluble interleukin-2 receptor (IL-2R) in children with allergic disorders

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