Serum and Tear Leptin Levels in Patients with Allergic Conjunctivitis

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1 ORİJİNAL ARAŞTIRMA Serum and Tear Leptin Levels in Patients with Allergic Conjunctivitis Burak TURGUT, MD, a Jülide KURT, MD, a Nevin İLHAN, MD, b Süleyman Serdar KOCA, MD, c Tamer DEMİR, MD, a Ülkü ÇELİKER, MD a Department of a Ophthalmology, b Biochemistry, c Rheumatology, Fırat University Faculty of Medicine, Elazığ Ge liş Ta ri hi/re ce i ved: Ka bul Ta ri hi/ac cep ted: Ya zış ma Ad re si/cor res pon den ce: Burak TURGUT, MD Fırat University Faculty of Medicine, Department of Ophthalmology, Elazığ, TÜRKİYE/TURKEY drburakturgut@yahoo.com ABS TRACT Ob jec ti ve: The pro duc ti on of lep tin that acts as a pro-inf lam ma tory me di a tor is in cre - a sed in pa ti ents with va ri o us inf lam ma tory and al ler gic di se a ses. Our aim was to in ves ti ga te the se - rum and te ar lep tin le vels in pa ti ents with pe ren ni al al ler gic con junc ti vi tis and to com pa re them with he althy con trols. Ma te ri al and Met hods: Fif te en pa ti ents with pe ren ni al al ler gic con junc ti vi - tis (8 fe ma les and 7 ma les, me an age: 22 ye ars, me an body mass in dex: ± 5.64 (±SD) kg/m 2 ) we - re inc lu ded in the study. Gen der, body mass in dex and age-matc hed 15 he althy sub jects (8 fe ma les, 7 ma les, me an age: 25, me an BMI: ± 3.56 kg/m 2 ) we re se lec ted as the con trol gro up. Se rum and te ar lep tin le vels we re me a su red with enz yme-lin ked im mu no sor bent as say (ELI SA) met hod. Re sults: Se rum lep tin le vels sho wed no sig ni fi cant dif fe ren ce bet we en the pa ti ents and con trols (9.79 ± 7.73 n g/ml vs ± 7.26 n g/ml, p> 0.05). Te ar lep tin le vels sho wed no sig ni fi cant dif fe - ren ce bet we en the pa ti ents and con trols (8.90 ± 1.81 pg/ml vs ± 1.70 pg/ml, p> 0.05). Conc lu - si on: Our da ta sug gest that se rum and te ar lep tin le vels do not chan ge in pa ti ents with pe ren ni al al ler gic con junc ti vi tis. Furt her stu di es are ne e ded to in ves ti ga te the le vels of fre e and bo und lep tin and to de ter mi ne lep tin s ro le in the pat ho ge ne sis of pe ren ni al al ler gic con junc ti vi tis. Key Words: Lep tin; con junc ti vi tis, al ler gic; inf lam ma ti on ÖZET Amaç: Lep tin, bir di zi al ler jik ve enf la ma tu ar has ta lık ta ar tış gös te ren pro-enf la ma tu ar bir si to kin dir. Biz, bu ça lış ma da pe ren ni al al ler jik kon jonk ti vit li has ta lar da se rum ve göz ya şı lep tin dü - zey le ri ni araş tır ma yı ve sağ lık lı bi rey ler de ki dü zey le riy le kar şı laş tır ma yı amaç la dık. Ge reç ve Yön - tem ler: Pe ren ni al al ler jik kon jonk ti vit li 15 has ta (8 ka dın ve 7 er kek) ile 15 sağ lık lı bi rey (8 ka dın ve 7 er kek) ça lış ma kap sa mı na alın dı. Or ta la ma yaş has ta gru bun da ± 6.3 yaş, kon trol gru bun - da 24.8 ± 7.9 yaş idi. Vü cut kit le en dek si has ta gru bun da ± 5.64 kg/m 2, kon trol gru bun da ise ± 3.56 kg/m 2 idi. Se rum ve göz ya şı lep tin dü zey le ri enz yme-lin ked im mu no sor bent as say (ELI SA) yön te miy le öl çül dü. Bul gu lar: Se rum lep tin dü zey le ri has ta (9.79 ± 7.73 ng/ml) ve kon trol (10.49 ± 7.26 ng/ml) grup la rı ara sın da is ta tis tik sel an lam lı bir fark gös ter me di (p> 0.05). Göz ya şı lep tin dü zey le rin de de has ta (8.90 ± 1.81 pg/ml) ve kon trol (8.68 ± 1.70 pg/ml) grup la rı ara sın da an lam lı fark lı lık sap tan ma dı (p> 0.05). So nuç: Pe ren ni al al ler jik kon jonk ti vit li has ta lar da se rum ve göz ya şı lep tin dü zey le rin de fark lı lık ol ma dı ğı gö rül dü. Ser best ve bağ lı lep tin se vi ye le ri nin araş tı - rıl dı ğı ça lış ma lar la al ler jik göz has ta lık la rın da lep ti nin ro lü an la şı la bi le ce ği ka na a tin de yiz. Anah tar Ke li me ler: Lep tin; al ler jik kon jonk ti vit; inf la mas yon Turkiye Klinikleri J Med Sci 2010;30(1):233-8 Cop yright 2010 by Tür ki ye Kli nik le ri e ren ni al al ler gic con junc ti vi tis (PAC) usually begins in se cond de ca - de of li fe, and it is one of the most com mon di se a ses of yo ung adults. Most of pa ti ents ha ve per so nal or fa mily his tory of ot her al ler gic condi ti ons such as al ler gic rhi ni tis, ato pic der ma ti tis and ast hma. 1,2 Pe ren ni al aller gic con junc ti vi tis is an inf lam ma tory ocu lar di se a se that af fects the Turkiye Klinikleri J Med Sci 2010;30(1) 233

2 Turgut ve ark. qu a lity of li fe of the pa ti ents for a long pe ri od of ti - me. Ho we ver it ra rely ca u ses vi si on loss. Pe ren ni - al al ler gic con junc ti vi tis is usu ally diagnosed cli ni cally. The signs and symptoms inc lu de itc hing, te a ring, con junc ti val ede ma, hype re mi a, wa tery disc har ge, bur ning, pho top ho bi a and lid ede ma. The ma in tar get tis su e is con junc ti va. In pe ren ni al al ler gic con junc ti vi tis, the al ler gen di rectly co mes in con tact with the con junc ti va and in du ces type I hyper sen si ti vity re ac ti on. 3 It in te racts with the IgE bin ding tis su e mast cells and le ads to re le a se of che - mi cal me di a tors. 4,5 Cyto logy of te ars and con junc - ti val scra pings de mons tra ted in cre a sed ne ut rop hils and eo si nop hils. The definitive di ag no sis of pe ren - ni al al ler gic con junc ti vi tis is dif fi cult and requires la bo ra tory tests which do not al ways ref lect the cli - ni cal di ag no sis. 6 Ho we ver, in da ily prac ti ce, di se a - se can be ea sily di ag no sed by the his tory of al ler gic di se a se, itchy symptoms and pa pil la for ma ti on of con junc ti va wit ho ut the ne ed to me a su re the se - rum IgE. 7 Lep tin, a ple i ot ro pic pro te in sec re ted by the adi po se tis su e, plays an im por tant ro le in the re gu - la ti on and mo du la ti on of body we ight and, in me ta bo lism, he ma to po e sis, an gi o ge ne sis and immu nity. 8 Body mass in dex (BMI) has be en re por ted to be one of the im por tant as so ci a ted fac tors, and a po si ti ve as so ci a ti on bet we en BMI and se rum leptin has be en shown. Furt her mo re, lep tin has structu ral si mi la ri ti es with so me cyto ki nes, inc lu ding IL (In ter le u kin)-6, IL-11, IL-12, and IL-15, as well as with gra nu locy te co lony-sti mu la ting fac tor. 9,10 Leptin pro duc ti on is in cre a sed in pa ti ents with ato pic ast hma and ot her inf lam ma tory and al ler gic di se a - ses. 11,12 So me evi den ce de mons tra ted that lep tin acts as a pro-inf lam ma tory me di a tor. Pre vi o us stu - di es in di ca ted that se rum lep tin con cen tra ti on increases in al ler gic re ac ti ons of the res pi ra tory tract, as well as IgE-as so ci a ted ato pic der ma ti tis, and it may play a ro le in the pat ho ge ne sis of al ler gic inf - lam ma ti on. 13,14 In our study, we as ses sed the se rum and te ar lep tin le vels in pa ti ents with al ler gic con junc ti vi tis and he althy con trols. The aim of this study was to eva lu a te a pos sib le re la ti on bet we en lep tin le vel and pe ren ni al al ler gic con junc ti vi tis. Göz Hastalıkları MA TE RI AL AND MET HODS Fif te en ca ses with comp la ints of ocu lar al lergy and 15 he althy con trols with si mi lar age, sex and BMI we re en rol led in the study. Di ag no sis of pe ren ni al al ler gic con junc ti vi tis was ba sed on his tory and cli ni cal exa - mi na ti on. Inc lu si on cri te ri a for the pa ti ents we re diag no sis of al ler gic con junc ti vi tis, sympto ma tic pe ri od and patients that did not receive and me di ca ti on for at le ast previous thre e months. Exc lu si on cri te ri a we - re preg nancy or the pos si bi lity of preg nancy, acu te syste mic and lo cal inf lam ma ti on/in fec ti on, and syste - mic di se a ses such as hyper ten si on, mac ro-al bu mi nu - ri a, dep res si on, he art di se a se, re nal fa i lu re, di a be tes mel li tus, and mor bid obe sity. Pa ti ents who we re on syste mic or to pi cal an ti his ta mi nics, or an ti al ler gic or an ti-inf lam ma tory agents in the previous thre e months we re al so exc lu ded from the study. Con trol sub jects we re se lec ted among pa ti ents with no al lergy or atopy his tory, acu te in fec ti on or inf lam ma ti on, syste mic di se a se, and obe sity. Sub jects in both gro ups dec la red that the ir we ight had be en stab le for at le ast three months pre ce ding their entry to the study. The BMI (de fi ned as we ight in ki log rams di vi ded by the squ a re of the he ight in me ters) was cal cu la ted for all of the sub jects. The pro to col for the study was ap pro - ved by the Ins ti tu ti o nal Re vi ew Bo ard of Fi rat Univer sity, Tur key. Samp le col lec ti on and bi oc he mi cal pro ce du res we re per for med fol lo wing the te nets of the Dec la ra ti on of Hel sin ki and in for med con sent was ob ta i ned from all sub jects. SE RUM LEP TIN ANALY SIS The de sign of the study ru les out any in ter fe ren ce by the di ur nal va ri a ti on in lep tin le vels, be ca u se all samp les we re col lec ted at ho urs af ter over - night fas ting in all sub jects. Se rum was se pa ra ted (1500g. 10 min) and fro zen at -80 C un til the ti me of the as say. Se rum lep tin le vels we re me a su red with a so lid-pha se sand wich enz yme-lin ked im mu - no sor bent as say (ELIS A) using a hu man lep tin kit (Bi o so ur ce, Bi o so ur ce Eu ro pe S.A. Bel gi um). The as say used mo noc lo nal an ti bo di es (M Abs) di rec ted aga inst dis tinct epi to pes of hu man lep tin. The intra as say co ef fi ci ents of va ri a ti on for the lep tin ELI - SA we re 3.4%, and the mi ni mum de tec tab le li mit of the as say was 0.1 ng/ml. 234 Turkiye Klinikleri J Med Sci 2010;30(1)

3 Ophthalmology TE AR LEP TIN ANALY SIS Te ar samp les (vo lu me 5-10 μl) we re col lec ted from the con junc ti val sac with What mann 3 MM fil ter pa per discs (6 mm in di a me ter) or with glass ca pil - la ri es from the pa ti ents with PAC and with nor mal Schir mer I test wit ho ut app lying an ir ri tant from he althy pe op le. Te ar samp les we re im me di a tely fro zen and sto red at 70 C un til analy zed. Lep tin was me a su red in te ar samp les using Hu man Lep tin ELI SA kit (Ray Bi o tech, Inc. Nor cross, GA, USA) ac cor ding to the ma nu fac tu rer s pro to col. The mi - ni mum de tec tab le do se of Lep tin was typi cally less than 6 pg/ml. The in tra- and in te ras say co ef fi ci ents of va ri a ti on for lep tin we re < 10% and < 12%. STA TIS TI CAL ANALY SIS Sta tis ti cal analy sis was per for med using the Sta tis - ti cal Pac ka ge for the So ci al Sci en ces ver si on 11.0 (SPSS, Chi ca go, IL, USA). Nu me ric va ri ab les we re com pa red by using the Mann-Whit ney U test, ca t- e go ri cal va ri ab les we re com pa red by Chi-squ a re test. Cor re la ti ons we re as ses sed using the Pe ar son pro duct mo ment test. Re sults we re gi ven as me ans ± stan dard de vi a ti ons. Lep tin le vels of the gro ups we re al so analy zed af ter ad jus ting for the BMI using analy sis of co va ri an ce (AN CO VA). P va lu e less than 0.05 was con si de red sig ni fi cant. RE SULTS De mog rap hic fe a tu res and se rum and te ar lep tin le - vels in pe ren ni al al ler gic con junc ti vi tis and controls are gi ven in Tab le 1. Both the pa ti ent and con trol gro ups inc lu ded 7 ma les and 8 fe ma les. Me - an BMI was ± 3.56 in the con trol gro up, and ± 5.64 in the pa ti ent gro up. The two gro ups we re matc hed in terms of age and BMI, and the re was no sig ni fi cant dif fe ren ce bet we en the gro ups (p= and p= 0.336, res pec ti vely). The me an age was 25 ye ars (ran ge: 16-28) in the con trols and 22 ye ars (ran ge: 14-25) in the study gro up, res pec ti - vely. The dif fe ren ce bet we en the gro ups was not sta tis ti cally sig ni fi cant (p= 0.281). Se rum lep tin le vels we re ± 7.26 ng/ml in the con trol gro up and 9.79 ± 7.73 ng/ml in the study gro up (Tab le 1). The dif fe ren ce bet we en the gro ups was no sta tis ti cally sig ni fi cant (p= 0.833). Turgut et al TABLE 1: Demographic features, serum and tear leptin levels in perennial allergic conjunctivitis and controls groups. Control (mean ± S.D.) Patient (mean ± S.D.) p Age(year) ± ± 6.30 p= BMI (kg/m 2 ) ± ± 5.64 p= Serum Leptin (ng/ml) ± ± 7.73 p= Tears Leptin (pg/ml) 8.90 ± ± 1.70 p= BMI; body mass index. P values were determined by Mann-Whitney U test. Te ar lep tin le vels we re 8.90 ± 1.81 pg/ml in the con trol gro up and 8.68 ± 1.70 pg/ml in the study gro up (Tab le 1). The dif fe ren ce bet we en the gro - ups was not sta tis ti cally sig ni fi cant (p= 0.805). Te ar and se rum lep tin le vels po si ti vely cor re - la ted in the study gro up (r= 0.552, p= 0.041, Fi gu - re 1). Ho we ver this cor re la ti on was not ob ser ved in the he althy con trol sub jects (r= 0.032, p= 0.934). FIGURE 1: Tear and serum leptin levels were positively correlated in the study group with perennial allergic conjunctivitis but this correlation was not seen in the healthy control subjects. Turkiye Klinikleri J Med Sci 2010;30(1) 235

4 Turgut ve ark. In sig ni fi cant dif fe ren ces for age and BMI at the ti me of ad mis si on we re ob ser ved bet we en gro - ups, and the re fo re AN CO VA was per for med to ma - ke cor rec ti on the se rum and te ars lep tin le vels for the age and BMI. Se rum and te ar lep tin le vels we - re still fo und to be in sig ni fi cantly dif fe rent bet we - en the pa ti ent and con trol gro up af ter ad jus ting (p= and p= 0.791, res pec ti vely). DIS CUS SI ON Cyto ki nes ha ve be en shown to play im por tant pat - ho ge ne tic ro les in al ler gic inf lam ma ti on. 15,16 Lep tin plays an im por tant ro le in inf lam ma ti on as it ac ti - va tes mo nocy te/mac rop ha ges and po ten ti a tes produc ti on of the pro inf lam ma tory cyto ki nes, tu mor nec ro sis fac tor-α, IL-6, IL-9, IL-12, and di rects T cell dif fe ren ti a ti on to Th1 phe noty pe it ex pres ses the ad he si on mo le cu les on en dot he li al cells, IL-2 and in ter fe ron-γ as a strong pro-inf lam ma tory cyto ki ne and it has al so be en re por ted to mo du la te T- hel per cell ac ti vity in the cel lu lar im mu ne res pon - se The ele va ti on of se rum lep tin le vels that ta - kes pla ce du ring in fec ti on and inf lam ma ti on strongly sug gests that lep tin is a part of the cyto ki - ne net work that ma na ges the inf lam ma tory-im - mu ne res pon se. 10,15,19 Ad di ti o nally, lep tin has be en shown to be an eo si nop hil sur vi val fac tor and to me di a te pro li fe ra ti ve and an ti a pop to tic ac ti vi ti es in dif fe rent cell types inc lu ding T cells and eo si nop - hils. 19 The pro-inf lam ma tory me di a tors re le a sed by mast cells inc lu de his ta mi ne, le u kot ri e ne 4, pros - tag lan din D2, trypta se, chyma se, car boxy pep ti da se A, cat hep sin G, pla te let ac ti va ting fac tor, and ot her eo si nop hil and ne ut rop hil che mo at trac tants. 20 In ex pe ri men tal stu di es, it has be en de ter mi - ned that lep tin le vel acu tely in cre a ses by inf lam - ma tory sti mu li li ke en do to xins, and by the ad mi nis tra ti on of pro-inf lam ma tory cyto ki nes li ke as men ti o ned abo ve. 21,22 Ho we ver, da ta re por ted from hu man stu di es do not al ways ag re e with re sults ob ta i ned from ani mals. Re sults from stu di es con duc ted in pa ti ents with sep sis de mons tra ted eit her the ele va ti on of lep tin le vel or no al te ra ti on. 23,24 Göz Hastalıkları Ho we ver, no cor re la ti on bet we en lep tin le vels and di se a se ac ti vity and no in cre a se in se rum lep tin le vels ha ve be en re por ted in pa ti ents with rhe u ma to id art hri tis or inf lam ma tory bo wel di se a - se. 25,26 In chro nic obs truc ti ve pul mo nary di se a se, cir cu la ting lep tin le vels ha ve be en re por ted to be eit her physi o lo gi cally re gu la ted or re la ted to the inf lam ma tory sta tus. 27,28 Gu ler et al in ves ti ga ted the se rum lep tin le vels in ast hma tic chil dren and he althy con trols, and fo - und sig ni fi cantly hig her le vels in chil dren with ato pic ast hma. 10 Ma i et al in ves ti ga ted the se rum lep tin and IFN-γ in ast hma tic chil dren, and they did not find a sta tis ti cally sig ni fi cant dif fe ren ce bet we en the non over we ight ast hma tic chil dren and he althy con trols. 29 Unal et al. in ves ti ga ted the se rum lep tin le vels in al ler gic rhi ni tis and he althy con trols, and they re por ted that the se rum lep tin le vels we re sig ni fi - cantly hig her in pa ti ents with al ler gic rhi ni tis. 30 To the best of our know led ge, this is the first re port in ves ti ga ting the relation of se rum and te ar lep tin le vel in PAC. In this study, we hypothetized that the le vels of lep tin in se rum and te ar were increased in pa ti - ents with PAC. Ho we ver, se rum and te ar lep tin con cen tra ti ons we re not fo und to be sig ni fi cantly dif fe rent in pa ti ents and con trols. The se re sults suggest that se rum and te ar lep tin le vels do not change in pa ti ents with PAC. Alt ho ugh our re sults do not con firm any sig ni fi cant al te ra ti on in se rum and te - ar lep tin con cen tra ti ons in pa ti ents with PAC, it is pos sib le that lep tin may play a ro le in the pat hoph ysi o logy of PAC as it is pro-inf lam ma tory and eo si nop hil sur vi val fac tor. The in sig ni fi cant re sults con cer ning with the le vels of se rum lep tin in our study may be du e to lo cal inf lam ma ti on. Ho we ver, in this con di ti on, an ele va ted lep tin le vels is ex pec - ted in the te ar. The le vel of te ar lep tin might not always ref lect the cli ni cal di ag no sis as the eo si nop hil co unt does in te ar. It sho uld be no ted that the stu di es re por ted only syste mic cir cu la ting lep tin le - vels. So, as with ot her re gu la tors of the inf lam ma Turkiye Klinikleri J Med Sci 2010;30(1)

5 Ophthalmology tory res pon se, lep tin func ti on may be mo du la ted by the ra ti o bet we en fre e and bo und lep tin, by the ex pres si on of dif fe rent forms of the re cep tors, the ra ti o bet we en sig na ling and non-sig na ling re cep - tors, and the pre sen ce of spe ci fic in hi bi tors. The se fac tors ha ve to be ta ken in to ac co unt to eva lu a te the pos sib le ro le of lep tin in ocu lar al ler gic di se a - se. Furt her stu di es are ne e ded to have more information mo le cu lar re gu la ti on and ef fects of leptin, and to in ves ti ga te the le vels of fre e and bo und lep tin and to de ter mi ne lep tin s ro le in the pat ho - ge ne sis of al ler gic con junc ti vi tis. Turgut et al LIMITATIONS OF STUDY The re are so me li mi ta ti ons in this study. The re we - re only 30 (15 pa ti ent and 15 con trols) sub jects who par ti ci pa ted in the comp le te study. Our hos pi tal is an uni ver sity hos pi tal and a tertiary he alth ins ti tu - ti on in our co untry. Thus, the ad mis si ons to our out-pa ti ent cli nic of the pa ti ents with pe ren ni al aller gic con junc ti vi tis are li mi ted. Ad di ti o nally, beca u se only the pa ti ents which are sympto ma tic and wit ho ut me di ca ti ons en rol led in to this study, the num ber of the par ti pi ci ants is li mi ted. Com pe ting in te rests: The aut hors dec la re that they ha ve no com pe ting in te rests. 1. To maç N. [Al ler gic con junc ti vi tis]. Tur ki ye Kli - nik le ri J Med Sci 2004;24(4): Gro ne berg DA, Bi e lory L, Fisc her A, Bo ni ni S, Wahn U. Ani mal mo dels of al ler gic and inf - lam ma tory con junc ti vi tis. Al lergy 2003;58(11): Fri ed la en der MH, Swe et J. Con junc ti val pro - vo ca ti on tests and na tu rally oc cur ring al ler gic con junc ti vi tis in cli ni cal tri als. Int Oph thal mol Clin 1988;28(4): Fu jis hi ma H, Sa i to I, Ta ke uc hi T, Shi no za ki N, Tsu bo ta K. Me a su re ment of in ter le u kin-4 and his ta mi ne in su per fi ci al cells of con junc ti va in pa ti ents with al ler gic con junc ti vi tis. Curr Eye Res 1996;15(2): Fu jis hi ma H, Sa has hi N, Shi ma za ki J, Tsu bo - ta K. Al ler gic con junc ti vi tis ca u sed by su gi (Crypto me ri a ja po ni ca D. Don) pol len out of se a son. Asi an Pac J Al lergy Im mu nol 1995;13 (2): Fri ed la en der MH. Con junc ti vi tis of al ler gic origin: cli ni cal pre sen ta ti on and dif fe ren ti al di ag - no sis. Surv Oph thal mol 1993;(38 Suppl): Fu jis hi ma H, Oka mo to Y, Sa i to I, Tsu bo ta K. Res pi ra tory syncyti al vi rus and al ler gic conjunc ti vi tis. J Al lergy Clin Im mu nol 1995;95(3): Ote ro M, La go R, La go F, Ca sa nu e va FF, Di - e gu ez C, Gómez-Re i no JJ, et al. Lep tin, from fat to inf lam ma ti on: old qu es ti ons and new insights. FEBS Lett 2005;579(2): Co nus S, Bru no A, Si mon HU. Lep tin is an eo - si nop hil sur vi val fac tor. 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