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Benha Journal Of Applied Sciences, Vol.(5) Issue(3) Part (1) (2020(
Study of Serum Interleukin-17 Level in PatientsiwithiAllergiciRhinitis andiNasaliPolyposis
M.A.Ismael 1, K.M.Kassem1, A.M. El Abd2, M.H.Fikry1
1 Professor of OtorhinolaryngologyDept., Faculty of Medicine, Benha Univ., Benha, Egypt
2Professor of MedicaliBiochemistry andiMoleculariBiology Dept., Faculty of Medicine, Benha Univ., Benha, Egypt E-Mail: [email protected]
Abstract
Rhinitis is aiheterogeneous disordericharacterized by one or more of the following nasalisymptoms: isneezing, iitching, irhinorrhea, and/or nasal congestion. iRhinitis frequently is accompanied byisymptoms involving the eyes, iears, andithroat, including postnasalidrainage. To evaluateithe expressioniof interleukin-17iin patients presentingiwithiallergic rhinitisiand nasalipolyposis. This Aicase-control study was conductedion total of 60 subjects at BenhaiUniversity and BenhaiTeaching Hospitals. They wereidivided into two equaligroups; the casesigroup which included 15 allergicirhinitis case, and 15 nasalipolyposis cases, and theicontrol group whichiincluded 30 healthyisubjects. All cases were subjected toicomplete historyitaking and thorough rhinologicaliexamination. In addition, iserum and tissueiIl-17 were measures for all cases, whereas only theiserum level was measured inicontrols. Expression ofiIL-17 was significantly upregulated iniNP patients and was more severe iniatopic patients. In addition, there wereisignificantly positive correlationsibetweeniIL-17 and clinical and histological features. Our study suggests an important role for IL-17iiniNP. Overall, we hopeithat present study would enable us to obtain a deeper insight into the pathogenesisiofiNP and provide a potential target for the treatment of NP. Based on our study results, increasediIL-17 serumilevels might be considered a marker ofiallergy severity iniallergic rhinitisiand nasalipolyposis patients.
This implies that IL-17 mayibe one of theietiologies in the pathogenesis of bothiAR andiNP. Based on these results, we propose that IL-17icontribute to the developmentiof NP and have an impact on clinical severity.
1. Introduction
Theremaremmanyidifferenticausesiofirhinitisiin childreniandiadults. iApproximately 50% of allicases ofirhinitis areicaused byiallergy. In theicaseiofirhinitisicausedibyiallergens, symptomsiarise as airesult ofiinflammation induced by
aigammaiglobuliniEi (IgE)-
mediatediimmuneiresponseitoispecificiallergens such asipollens, imolds, ianimalidander, and dustimites. The
immuneiresponse involvesithe
releaseiofiinflammatoryimediatorsiand theiactivation andirecruitment oficellsito theinasalimucosa [1].
Sinonasalmpolyposis (SNP) or chronic rhinosinusitis with
nasalmpolyps is a chronic
inflammatorympathologymofmthemnasalmandmparanasal cavities [2], whichi affectsii fromi1% toi 4%i ofi ithe
ipopulationi andi hasi ai cleari
associationiwithiasthma,aspirinmsensitivity andicysticifibrosis [3].
Patientsi withmSNP typically present withi nasalmobstruction, rhinorrhea, mhyposmia and reducedmquality of life [4]. Althoughmpolyps seemi toi bei
ammanifestation of thei chronici
inflammationiofinasali/paranasalisinusimucosa in bothiallergicmand noni-allergici subjectsi, the pathogenesismof nasalmpolyposis remains unknown,butiitiisiprobablyiamultifactoriali
diseaseiwithiseveralidifferentietiologicalifactorsi[5].
Upon exposure to an allergen – atopic individual respond bymproducing allergen specific IgE, whichmbind tomIgE receptor on the mast cell of themrespiratory mucosa. On re-exposure to the same allergen IgE bridged on the cell surface by allergen resulting in activation of mastmcell and release granules
associatedmchemical mediators, which cause the symptoms of (AR) [6].
Forimoremthanitwoidecadesi,immunologistsihaveibeen musingithe Th1/Th2i paradigmi to explainmmost of the phenomenai relatediito adaptivemimmunity. Thei Thi17i icells, wasi recentlymdescribed as a distinctilineageithati doesi notmshare developmentalipathwaysiwith eitheri Th1i ori Th2icellsi. mShen etiali. suggestedi thati themimbalance
of Treg/Th17i
mayiplayianiimportantiroleiinitheidevelopment ofmSNP andithat atopyimay aggravatemSNP [7] . Shenietiali.,onianotheristudy,suggestedman
importantipartiof iIL-17Ai inmSNP, andi
demonstratedmthat expressioniofmIL-
17Amwasmsignificantly upregulatediiniSNP patientsiand wasimore severeiin atopiciSNP [8].
Aim of the Work
Theiaim of thisistudy was toievaluate the expressioniofiinterleukin-17 in patients presenting withiallergic rhinitis andinasal polyposis.
2. Subjects and methods
This A case-controlistudy was conducted on 30 patients sufferigmfrom allergic rhinitis and nasalmpolyposis (Group A) and 30 apparently healthy individuals of matched age and sex as a controligroup (Group B).Patients wereirecruited from the outpatienticliniciiof Otorhinolaryngologyi iDepartment, iBenha Universityi Hospitali andi Benhai Teaching Hospitali.
Theistudy was approved by theilocal ethic committeeiof Benha Faculty of Medicine. An
Benha Journal Of Applied Sciences, Vol.(5) Issue(3) Part (2) (2020(
Informediconsent was obtained from each individualibefore sample collection.
The study included patients having sneezing, irhinorrhea, inasaliobstruction, irritabilityiandifatigue, attack accompanied by itchingiof the nose, eyesiandicough, attacks relieved spontaneously or with antihistaminic therapy.
While patientsiwith ages more than 40 years or less than 15 years, any patient use systemicicorticosteroid for a longiperiod in order not to affectiinterleukin 17 serum level, patientsisuffering fromirhinitis due to other cause thaniallergy and patientsisuffering from any systemicidisorder asihypertension and diabetesimellitusiwereiexcludedifromithei studyi.
Methods
Alliipatientsi werei subjecteditoithe followings Fullihistoryitaking: Personal historyi: Name, iage, isex, occupation, residence, specialihabits ofimedical importance, maritalistatus. Present history: Onset,
icourse, iduration of nasalisymptoms as
nasaliobstruction, inasalidischarge andisneezing. Family history of allergic rhinitis. Past history ofimedications (type, dose and duration), ioperations and general diseases. Clinical examination: Full general examination to exclude other inflammatory and systemic diseases.
Detailedirhinological examination; inspection, ipalpation, anteriorirhinoscopy, posterior rhinoscopy andinasal endoscopy. Laboratory investigations: All studied subjects were tested for: Serumiand tissue level of Interleukini17.
Assay principle
The kitiwas provided by aimicrotiter plateiwhich has beenipre-coated with an antibody specific to targetiantigen. Then standards and serumisamples were added to appropriateimicrotiter plate wells with aibiotin- conjugated antibodyipreparation specific to targetiantigen and then avidiniconjugated to HorseiRadish Peroxidasei (HRPi) is addedi to eachi microplateiwell and incubatedi. Theni a TMBi (3, 3’, 5, 5’-Tetramethylbenzidine) substratei solutionii wasi addedi toi eachi welli. Onlyi thosei wellsi thati containi targetiantigen,biotin-conjugatediantibody and enzymei -
conjugatedi avidiniexhibit change in color. The reaction was terminated by addingisulphuric acid (H2SO4) isolution andi theicolorichangeiwasimeasuredispectro- photometrically atia wavei lengthi 450 nm ± 2nmi according toi the manufacturer’s protocol.
The concentration ofiIL17 was directly proportional to the coloriintensity of the tested sample.
The concentration ofiIL 17 in thei samplesi wasi theni determinedi by comparingi thei opticaliidensity (O.D.) of theisamples to the plotted standardiicurvei.
Statistical analysis
Thei clinicali datai werei recordedi oni a reporti formi. Thesei datai werei tabulatedi andi analyzedi usingi thei computeri programi SPSSi (Statisticali packagei fori sociali sciencei) versioni 20 toi obtaini: Descriptivei datai: Descriptivei statisticsi werei calculatedi fori thei datai ini thei formi ofi: Meani andi standardi deviationi
SD
fori quantitativei datai. Frequencyi andi distributioni fori qualitativei datai. Analyticali statisticsi:Ini thei statisticali comparisoni betweeni thei differenti groupsi, thei significancei ofi differencei wasi testedi usingi onei ofi thei followingi testsi:- Student'sit- test andiMann-Whitney test:- Usedii toi comparei meani ofi twoi groupsi ofiquantitative datai ofiparametric andiinon-parametriciirespectivelyi. 2- ANOVAitest (F valuei) iandikruskali-wallisitest:-Usedi toi comparei meani ofi morei thani twoi groupsi ofi quantitativei datai ofi parametrici andi non-parametrici respectivelyi. 3- Interi-groupi comparisoni ofi categoricali datai wasi performedi by usingichi squareitest (X2i-value) iand fisheriexact testi (FET). ProbabilityiP valuei < 0.05 was considered significant.
3. Results Age
In this study there wasino significantidifference (P.0.054 asimeasured byiT test) iniage between caseiand controligroups the average age of the patientsi20.2 years andiranged from 15ito 40 years. The averageiage of controligroup was 22.08iyears and ranged from 15ito 40iyears.
Table (1) Age distribution.
Casesi groupi (n= 30)
Controli groupi (n= 30)
Statisticali test pi value
Age Mean ±SD 20.2±4.44 22.08±4.12 t= 1.96 0.054
Gender
Our study underwent oni12 femalesi (40%) andi18 malesi (60%) included asicases group.
11ifemalesi(36.6%) and 19 malesi (63.3%)iincluded as controligroup.
Benha Journal Of Applied Sciences, Vol.(5) Issue(3) Part (2) (2020(
Fig (1) Gender distribution Clinical Data of the studied patients
Clinical assessment of studied patients revealed that;21 (70%) patients had gradual onset, 27 (90%) patients had progressive course of AR and NP. Mean disease duration was 3.14years. Regarding history of
previous treatment;30(100%) patients had previous treatment for AR and NP. 15(50%) patients were giving positive family history of AR and NP as shown in table
Table (2) Clinical Data of the studied patients.
Variable n=30 %
Onset Sudden 9 30
Gradual 21 70
Course Progressive 27 90
Stationary 3 10
Duration (years) Mean±SD 3.14±3.66
History of previous treatment Positive 30 100
Negative 0 0
Family history Positive 15 50
Negative 15 50
Laboratory investigations
On comparisoniof IL17ilevelibetween patientsiincludingiAR andiNP andicontroligroups, there was a statistically significant increase iniIL17 leveliin ARiand NPipatients thanicontrols as shown in table.
Table (3) Mean ± SD & p values of serum & Tissue of IL-17 in nasal polyposis group and allergic rhinitis group compared with control group.
Biochemical parameters
Control Cases
IL-17 level NP AR
Serum Serum Tissue Serum Tissue
2.6599 ± 1.1027 3.363 ± 0.8249 P:<0.05
2.584 ± 1.0618 2.9085 ± 1.030 P<0.05 P1 <0.05
2.093 ± 1.0361 P1<0.05
4. Discussion
Theremare severali studiesi ini thei literaturei describingi themrelationship betweeni ARi andi
cytokinesi. Iti isi knowni thatmAR is a Th2- dominantii diseasemand therei arei manyi studiesi exhibitingi thei
0 5 10 15 20 25 30
Cases Group
Control Group 12
11 18
19
Number of cases
Genderi
Female Male
Benha Journal Of Applied Sciences, Vol.(5) Issue(3) Part (2) (2020(
relationshipi ofi cytokinesi withmAR suchi asimTh2- basedii IL-4i andi IL-13i [9].
Polyposismis an endi disorderi ofi mucosai thati stemsi fromi variousi inflammationsi ini thei nasali
cavityi, suchi asmnasal allergyi,
chronicisinusitisiiandmaspirin-exacerbatedi respiratoryi diseasei. Thei pathogenesisi isinot yetifullyiunderstood.
iPublishedidataiiindicate thatmAR isi involvedi ini thei pathogenesisi ofmnasal polyposis [10].
Howeveri, noti alli patientsi withmAR have polyposisi, or vice versa. Recenti studies indicatei that there is a sub population ofmT cellsi in peripherali bloodi and lymphoidi tissuei that expressesimIL-17i [11].
Our datai arei in linei withi thesei pioneeri studies by
providingi evidencemthat a
subsetiiofiiTicellsiiiniitheiinasaliimucosam expressesi IL-17. Whetheri thismT cell subseti plays a role ini the pathogenesisi of nasalmpolyposis needsi furtheri investigationi. However, we foundi thati IL-17+ T icellsi had a closei relationi withi the specifici pathogenici conditioni of bothmAR andmNP, but noti in patientsiwithmAR alonei. This impliesi thatmIL-17+ T cellsi mayi be onei of the etiologiesi in the pathogenesisi of bothmAR and NPi. Previousmstudies also indicatei that IL-17i playsi a criticali rolei in nasalmpolyposis [12].
Datai formIL-17 mediatedi allergicirhinitis in humansiiareiquite limitedi comparedi to murinei experimentalmmodels. Moreover, recenti studiesi have been demonstratedi that cytokinemsettingiiinducingi Thi17 differentiationi in humansi and micei is differenti [13].
Wang and Liu statedmthe rolei ofi ILi-17 producingi cellsi inmallergic reactionsi asi “largelyi uncleari”. In 2010 fori thei firsti timeiIL-17 havei been foundi to playi a causativei rolei in airwayi remodelingi in asthmatici mouseimodei. iBut the ideai on participationi ofmILi-17 in upperi airwayi tissueiiremodelingiiis notmclear and is stillmcontroversial [14].
ILi-17 isi anii importanti effectori ofimTh17 cellsi with a strongi pro-inflammatoryi rolei in rheumatoidi arthritisi. Increasedmexpression of IL-17 has beenmobserved in multiplei sclerosisi, asthmai, systemicmlupus erythematosusi and transplanti rejectioni.15 IL- 17 mayi play a pathogenici rolemin an established ARi mouseimodel [15,16].
Expressionmof IL-17iis significantlyi higheri in themperipheral bloodi of ARi patientsi than in themcontrol groupi [17]. Studiesiin recenti yearsmhave shown that γδT-cellsi are an importanti sourcei ofi IL- 17mproductioni[18].
Th17 cells aremnewly emergingiiTh cell subsetsi that linkmthe immunei responsei to tissuei inflammationi. IL- 17Ai and IL-22i are the predominanti prototypei cytokinesi [19]. Although thei main functionmof Th17 cells is supposedi to be inductioni ofmprotection againstmpotentiallyiharmfuliifungiiandm extracellulari bacteriai, a large batterymof experimentswithiIL-17 neutralizingmantibodies [20], as well as relativelymhigh levelsi of IL-17iA, showed the potentialmrole of Th17 cellsi inmthe pathogenesisi of nasali diseases [21].
Foriexample, mWang etial. showedi IL-17 antagonismmsignificantly attenuatedi Th2 responsesi andminfiltration of neutrophili and eosinophili in ARi mouseimodel [16]. Quani etial. alsomreported that IL- 17A–deficienti miceishowed amsignificant decrease inmallergic symptomsi, serumi IgE levelsi, and eosinophiliiinfiltrationi; decreased histaminei andicysteinylileukotrieneirelease; iand significantlymloweredidegranulationiandmsecretion of TNFi- in marrowi-derivedmmast cellsm [15].
Thesemfindings togetheri showed thempotential rolei of anti-Th17i cellsi in the managementi of allergici rhinitisi.
A recentmstudy on IgE productioni in humani Bmcells foundi thati IL-17i could inducei Bicellsmswitching to IgE which impliesiTh17 involvementmin the atopici phenomenoni [14].
Theirolemof IL-17 producingi cellsmas thei subjecti of researchi in the fieldi of allergici sensitizationi ismessential noti only fori increasingi our understandingi of themAR mechanismi [22].
This study was conducted at Benha University and Benha Teaching Hospitals aiming toi evaluatei thei expressioni of interleukin-17 in patientsi presenting with allergici rhinitisi and nasali polyposisi.
We included a total ofi60 subjectsiwho were divided into twoiequal groups; the cases groupiwhich included 15iallergicirhinitisicase, and 15 nasalipolyposis cases, and theicontrol group whichiincluded 30 healthyisubjects. The meaniage oficases andicontrols wasi20.2 and 22.08 yearsirespectively. No statisticallyi significanti differencei was detectedi between thei twoi groupsi (pi > 0.05).
Another study handling thei same perspective also included 96 subjects who were divided into two groups;
the cases group which included 65 allergic rhinitis patients, and the control group which included 31 healthy subjects. Likei ouri studyi, noi significanti differencei wasi detectedi betweenithe two groupsi regarding patienti age [9].
Ini theicurrent study, theicases group included 18imalesi (60%) and 12ifemales (40%),iwhereas the controligroup included 19 malesi (63.3%) and 11 femalesi (36.6%). Noi significanti differencei wasi foundi betweeni the twoi groupsi regardingigender.
In anotheristudy, authorsiincludedi14 malesiand 8 femalesiin theicontrol group, while the casesigroup included 26 malesiand 10ifemales. Like our studyiresults, noi significanti differencei wasidetected betweeni thei twoi groupsiregardingigender (pi> 0.05i) [23].
In this study, the meaniduration of the disease in theicase group wasi3.14 years (SD 3.66).
Another studyireported that the mean durationiof the disease wasi6.78 years in the casesigroup [9].
In our study, iserum IL-17ilevels were significantlyihigher inpatientsiserum compared toicontrols (p < 0.05). In allergicirhinitis cases, the meanivalue of serum IL-17iwasi2.908, while it wasi3.36 for the nasalipolyposis group. However, tissueilevels of thatibiomarker were lower than the serumilevels in the
Benha Journal Of Applied Sciences, Vol.(5) Issue(3) Part (2) (2020(
included controls. Moreover, tissue IL-17iwas significantlyihigher in theipolyposis cases when compared to allergicirhinitisigroup (p = 0.03).
Thesei resultsi suggesti thati Th17i celli mayi bei involvei in ARi pathogenesisi andi thati T-cellsi may havei an immunomodulatoryi functioni on Th17i cellsi ini thei peripherali bloodi of ARi patientsi.
Ouri datai demonstratedi increasedi expressioni ofi IL-17i ini ARi andi NPi patientsi thani controli groupi andi therei was increasei in leveli of IL-17i ini NPi than ARi patientsi, suggestingi thati IL-17i mayi playi an importanti rolei in thei developmenti of NPi.
Another study reported that serumi levelsi of IL-17i weremsignificantly higheri in the allergici rhinitisi casesi comparedi to controlsi (0.68 vs. 0.45 – p = 0.038) [9]
This agrees with ouri studyi results.
Ini manyi studiesi of literaturei, serumi IL-17i and IL-22i levelsi ofmAR patientsi are higheri than ithosei of controli groupsi which is similari to ouri studyi [18,22,23,24].
Ini the studyi of Ciprandi and colleaguesi, serumi ILi-17 levelsi of ARi patientsi were detectedi higheri than thosei of controlsi and also, a positivei correlationi wasi indicatedi betweeni serumi IL-i17 leveli and symptomi severity [25].
Ini anotheri studyi, it wasi showni that serumi ILi- 17 leveli in iAR patientsi was higheri while iTGF-β ilevel was ilower ithan thati iin icontrols [26].
iAnother istudy ireported ithat iserum iIL-17 ilevels iin the iAR and icontrol igroups iwere (668.55 ± 45.15 pg/ml) iand (573.53 ± 17.42 pg/ml), irespectively. iThe IL-17 ilevel iin the iAR igroup iwas isignificantly ihigher than ithat iin ithe icontrol igroup (ip < 0.0001) [18].
Tang and his associates also stated that d ILi-22 iand iIL-17A iTh icells, ias iwell as iserum ilevels iof IL- i22 and iIL-17A, iwere isignificantly iincreased iin iAR ipatients. Moreoveri, they iprovided ithe ifirst ievidence thati IL-i22 iTh icells, iin iaddition to iIL-17A Th icells, iwere iassociated withi the iclinical severityi of ARi patientsi [23].
iAnother istudy ireported ithat iaverage percentagesi ofi IL-17i iproducing iT icells determinedi iwith iflow icytometer iwere betweeni 0.57 ito 1.84% iin ihealthy isubjects andi 1.34i to 6.84% iin thei patientsi.
iThe meani valuesi of iIL-17 iwere isignificantly higheri iin ipatients (5.10 ± 4.40) pg/ml ias comparedi to iasymptomatic isubjects (3.46 ±1.28) pg/mli, (p = 0.04) [22].
Regarding the localmexpression of IL-17, Ba eti al.
ishowed ithat ithe inumber iof iIL-17 icells iin itissues iof iAR ipatients iwas ihigher thani thati of icontrols (p <
0.05). Theymalso showedi thati thei eosinophilici celli counti correlatedi withi thei numberi ofi IL-i17 icells (pi
< 0.05) [26].
Interestinglyi, in amdifferent reporti, the samei authorsi idescribed ithat thei expressioni ofi ILi-17 wasi onlyi apparenti ini thei inasal mucosai of ipatients iwith iAR [27].
Liui etiial. ireported thati therei werei no isignificant idifferences ibetween iAR and nonallergici rhinitisi patientsi
ini thei proteini expressioni ofi ILi-17 iin iinferior iturbinate tissuesi [28].
iLocal IL-17 iexpression in themsinonasal mucosai is iknown to ihave iethnic and/or regionali differencesi (29). Anothermstudy by Katoto-michelakis et al. strengthensi the importancei of studiesi in the Asiani populationi becausei therei is a idifference in cytokineiprofile in Europeani populationsi that ichanges overi timei [30].
iA more irecent istudy has idemonstrated thati Antii-IL-17 Absi markedlymreduced the numberi of nasali rubbingi motionsi and sneezesi, decreasedi eosinophili andmneutrophil infiltrationi, ireducedmTh2 and Th17 iresponses, and iincreased the Treg responsei [31].
Iti isi thoughti thatmfuture studiesi to bei conductedi relatingi to thisi subjecti willi formi newi itargets in itreatment.
5. Conclusion
iBased on iour studyi resultsi, increasedi IL-i17 iserum levelsmmight be consideredi a imarker of iallergy iseverity in allergici rhinitisi and nasali polyposisi patientsi.
This impliesmthat IL-17 may ibe ione iof ithe ietiologies in thempathogenesis of iboth ARi and iNP.
Basedi oni thesei resultsi, wempropose that IL-17 contributei to themdevelopment of iNP and havei an impacti on iclinical iseverity.
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