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Serum IL-17 levels in patients with allergic rhinitis

2008; Elsevier BV; Volume: 122; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2008.06.005

1097-6825

Giorgio Ciprandi, Daniela Fenoglio, Mara De Amici, Silvana Quaglini, Simone Negrini, Gilberto Filaci,

Dermatology and Skin Diseases

To the Editor: Allergic rhinitis (AR) is characterized by an inflammatory reaction sustained by TH2 polarization. This TH bias is evidenced by the PBMCs of patients with AR, which display a predominant IL-4 production by TH2 cells compared with IFN-γ expression by TH1 cells. This functional dichotomy between TH1 and TH2 has been more recently modified by the discovery of another T-lymphocyte subset, namely TH17 cells. In particular, the discovery of TH17 cells has been fundamental to our understanding of how TH1 cells can actually mediate inflammatory events by producing IFN-γ.1Schmidt-Weber C.B. Akdis M. Akdis C.A. Th17 cells in the big picture of immunology.J Allergy Clin Immunol. 2007; 120: 247-254Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar TH17 cells are characterized by the production of various cytokines, including IL-17, IL-6, TNF-α, and IL-22. IL-17 is involved in tissue pathology in autoimmune models, and anti-IL-17 reduced joint inflammation and bone erosion in an experimental arthritis model.1Schmidt-Weber C.B. Akdis M. Akdis C.A. Th17 cells in the big picture of immunology.J Allergy Clin Immunol. 2007; 120: 247-254Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar Furthermore, anti-IL-17 reduced neutrophil infiltration in an experimental murine asthma model2Hellings P.W. Kasran A. Liu Z. Vandekerckhove P. Wuyts A. Overbergh L. et al.IL-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma.Am J Respir Cell Mol Biol. 2003; 28: 42-50Crossref PubMed Scopus (355) Google Scholar and increased eosinophil infiltration, whereas IL-17 induced recruitment and was identified as a survival factor for airway macrophages.3Sergejeva S. Ivanov S. Lotvall J. Linden A. IL-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation.Am J Respir Cell Mol Biol. 2005; 33: 248-253Crossref PubMed Scopus (143) Google Scholar These facts seem to suggest a regulatory role for IL-17.4Schnyder-Candrian S. Togbe D. Couillin I. Mercier I. Brombacher F. Quesniaux V. et al.IL-17 is a negative regulator of established allergic asthma.J Exp Med. 2006; 203: 2715-2725Crossref PubMed Scopus (490) Google Scholar However, the role of TH17 cells in allergic inflammation is still obscure. Experimental studies seem to suggest that TH17 cells might be involved in the process of neutrophil infiltration that occurs during the acute phase of the allergic reaction.1Schmidt-Weber C.B. Akdis M. Akdis C.A. Th17 cells in the big picture of immunology.J Allergy Clin Immunol. 2007; 120: 247-254Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar One study exploring the role of IL-17 in patients with allergic or viral rhinitis showed increased concentrations of IL-17 in nasal secretions only in the latter group.5Klemens C. Rasp G. Jund F. Hilgert E. Devens C. Pfrognen F. et al.Mediators and cytokines in allergic and viral-triggered rhinitis.Allergy Asthma Proc. 2007; 28: 434-441Crossref PubMed Scopus (39) Google Scholar The assessment of a cytokine at the serum level would certainly simplify clinical evaluation. Previous studies have shown that IL-17 serum levels are increased in several disorders: acute hepatic injury,6Yasumi Y. Takikawa Y. Endo R. Suzuki K. Interleukin-17 as a new marker of severity of acute hepatic injury.Hepatol Res. 2007; 37: 248-254Crossref PubMed Scopus (74) Google Scholar rheumatoid arthritis,7Hussein M.R. Fathi N.A. El-Din A.M. Hassan H.I. Abdullah F. Al-Hakeem et al.Alteration of the CD4(+), CD8 (+) T cell subsets, interleukins-1beta, IL-10, IL-17, tumor necrosis factor-alpha and soluble intercellular adhesion molecule-1 in rheumatoid arthritis and osteoarthritis: preliminary observations.Pathol Oncol Res. 2008; (Apr 8 [epub ahead of print])Google Scholar and McArdle disease.8Lucia A. Smith L. Naidoo M. Gonzalez-Freire M. Perez M. Rubio J.C. et al.McArdle disease: another systemic low-inflammation disorder?.Neurosci Lett. 2008; 431: 106-111Crossref PubMed Scopus (10) Google Scholar However, a very recent study failed to demonstrate increased IL-17 serum levels in allergic asthmatic subjects.9Lei Z. Liu G. Huang O. Ly M. Zu R. Zhang G.M. et al.SCF and IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic asthma.Allergy. 2008; 63: 327-332Crossref PubMed Scopus (91) Google Scholar Therefore the aim of the present study was to evaluate whether there is an increase in IL-17 serum levels in patients with AR. The study included 19 birch-monosensitized patients (11 male and 8 female patients; mean age, 42.1 years) with a history of moderate-to-severe persistent AR and 8 healthy control subjects (4 male and 4 female subjects; mean age, 46.3 years). All subjects were healthy (except for AR) without any active disorder, including rhinosinusitis, and asthma was excluded in all patients with rhinitis. Skin prick tests, blood sampling for assessment of peripheral eosinophil counts and serum IgE and IL-17 levels, and allergen-specific conjunctival challenges were performed in all patients. The study was conducted during the winter, outside the pollen season, when all patients were symptom free. The study was approved by the local ethics committee and performed with the written informed consent of all participants. AR was diagnosed according to validated criteria.10Bousquet J. Khaltaev N. Cruz A.A. Denburg J. Fokkens W.J. Togias A. et al.Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 Update (in collaboration with the World Health Organization, GA2LEN and AllerGen).Allergy. 2008; 63: 8-160Crossref PubMed Scopus (3752) Google Scholar Skin prick tests were performed according to the guidelines of the European Academy of Allergy and Clinical Immunology.11Dreborg S. Backman A. Basomba A. Skin tests used in type I allergy testing. Position paper.Allergy. 1989; 44: 1-59Google Scholar Total and specific IgE levels were measured by using the Fluorenzyme immunoassay (calibrator range, 2-5000 and 0-100 kU/L, respectively; Phadia, Uppsala, Sweden), allergen-specific conjunctival challenges were performed according to validated criteria,5Klemens C. Rasp G. Jund F. Hilgert E. Devens C. Pfrognen F. et al.Mediators and cytokines in allergic and viral-triggered rhinitis.Allergy Asthma Proc. 2007; 28: 434-441Crossref PubMed Scopus (39) Google Scholar and the allergen threshold dose was determined for each patient. The test was performed after blood drawing. The human IL-17 immunoassay (Quantikine IL-17 Immunoassay; R&D Systems, Inc, Milan, Italy) measures IL-17A and uses the quantitative sandwich enzyme immunoassay technique. It was performed according to the manufacturer's instructions, and results were expressed as picograms per milliliter. The range of IL-17 detectable in the ELISA was 0.28 to 5.47 pg/mL in healthy subjects and 1.81 to 141.29 pg/mL in allergic subjects. Descriptive statistics were first performed, and quantitative parameters were reported as the median and number of subjects (allergic and healthy) with detectable serum IL-17 (including values <15 pg/mL). The nonparametric Wilcoxon test and Pearson test were used to compare samples and to study correlation, respectively. The package S-Plus (MathSoft Corp, Needham, Mass) was used for all analyses. Allergic patients exclusively sensitized to birch alone presented significantly higher median levels of IL-17 (median, 25.63 pg/mL; minimum, 1.81 pg/mL; maximum, 141.29 pg/mL) compared with healthy control subjects (median, 1.33 pg/mL; minimum, 0.28 pg/mL; maximum, 5.47 pg/mL; P = .018; see Fig E1 in this article's Online Repository at www.jacionline.org). Moreover, IL-17 was evidenced in a higher percentage of allergic patients than in healthy individuals (7/19 vs 1/8): therefore 7 allergic patients and 1 healthy subject were defined as IL-17+. The subanalysis between IL-17–producing (IL-17+) and non–IL-17–nonproducing (IL-17−) allergic patients showed that IL-17+ patients had significantly higher serum total IgE levels (IL-17+ patients: median, 402 kU/L; minimum, 350 kU/L; maximum, 722 kU/L; IL-17− patients: median, 134 kU/L; minimum, 10 kU/L; maximum, 280 kU/L; P = .0001), specific IgE levels to birch (IL-17+ patients: median, 84.3 kU/L; minimum, 71.3 kU/L; maximum, 101 kU/L; IL-17− patients: median, 16.75 kU/L; minimum, 4.13 kU/L; maximum, 65 kU/L; P = .0004), lower allergen threshold dose (IL-17+ patients: median, 25 biologic unit [BU]; minimum, 12.5 BU; maximum, 25 BU; IL-17− patients: median, 50 BU; minimum, 50 BU; maximum, 100 BU; P = .0002), and a trend toward higher eosinophil counts (IL-17+ patients: median, 5.2/mm3; minimum, 4.1/mm3; maximum, 8/mm3; IL-17− patients: median, 3.95/mm3; minimum, 0.2/mm3; maximum, 7.7/mm3; P = .07; see Fig E2 in this article's Online Repository at www.jacionline.org). No significant correlation was found between IL-17+ patients and specific IgE levels, eosinophil counts, and allergen threshold doses. A negative correlation trend, even if not statistically significant (r = −0.7, P = .06), was found between IL-17+ patients and total IgE levels. These data show that the patients with the most severe birch allergy, evaluated during a period without exposure to the causal pollen, have measurable serum IL-17 levels. However, the present study is in conflict with previous studies,5Klemens C. Rasp G. Jund F. Hilgert E. Devens C. Pfrognen F. et al.Mediators and cytokines in allergic and viral-triggered rhinitis.Allergy Asthma Proc. 2007; 28: 434-441Crossref PubMed Scopus (39) Google Scholar, 9Lei Z. Liu G. Huang O. Ly M. Zu R. Zhang G.M. et al.SCF and IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic asthma.Allergy. 2008; 63: 327-332Crossref PubMed Scopus (91) Google Scholar likely because the patient populations were different, as was the period of observation. Klemens et al5Klemens C. Rasp G. Jund F. Hilgert E. Devens C. Pfrognen F. et al.Mediators and cytokines in allergic and viral-triggered rhinitis.Allergy Asthma Proc. 2007; 28: 434-441Crossref PubMed Scopus (39) Google Scholar showed that only patients with viral rhinitis had increased IL-17 levels in nasal secretions. These contradicting results might be justified by both the different site of evaluation and patient characteristics. Lei et al9Lei Z. Liu G. Huang O. Ly M. Zu R. Zhang G.M. et al.SCF and IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic asthma.Allergy. 2008; 63: 327-332Crossref PubMed Scopus (91) Google Scholar reported that IL-17 serum levels in asthmatic patients are similar to those in healthy control subjects, and in this study the contrasting results might be explained by the different clinical characteristics of the patients, mainly concerning the type of sensitization. Moreover, neither study considered the atopic status of patients, such as IgE level, eosinophil count, and allergy degree assessed by means of allergen challenge. Therefore the careful assessment of patients could allow us to detect IL-17 producers. Indeed, the present study evaluated a very select group of patients who were monosensitized to birch. Birch allergy in Ligurian patients has been characterized by a relevantly increased prevalence and severity of symptoms.12Troise C. Voltolini S. Delbono G. Negrini A.C. Allergy to pollens from Betulaceae and Corylaceae in a Mediterranean area (Genoa, Italy)—a ten-year retrospective study.J Invest Allergol Clin Immunol. 1992; 2: 313-317PubMed Google Scholar Of interest, patients with the highest degree of birch allergy were IL-17 producers. This finding is particularly relevant considering that the period of observation was outside the pollen season. This phenomenon is not a complete surprise, however, because it might be dependent on a chronic allergic reaction to birch in hypersensitized patients. In this scenario TH17 cells are implicated in chronic events of allergic reaction that endure over time.13Romagnani S. Regulation of the T cell response.Clin Exp Allergy. 2006; 36: 1357-1366Crossref PubMed Scopus (315) Google Scholar In fact, independent of allergen exposure, IgE production is typically continuous and persistent. Thus IL-17 measurement might define severe immune response, such as that seen in IL-17+ allergic patients, confirming a previous study that proposed high IL-17 serum levels as a new marker of severity of acute hepatic injury.6Yasumi Y. Takikawa Y. Endo R. Suzuki K. Interleukin-17 as a new marker of severity of acute hepatic injury.Hepatol Res. 2007; 37: 248-254Crossref PubMed Scopus (74) Google Scholar On the other hand, this study has some limitations. First, we evaluated a limited number of patients (it is very difficult to enroll monosensitized patients). Second, patients were evaluated only outside the pollen season because all were successively treated with specific immunotherapy. Therefore further studies are required to confirm these preliminary data, mainly concerning the evaluation of patients during the pollen season. In conclusion, this study provides the first evidence that serum IL-17 levels might be increased in patients monosensitized to birch with the most severe AR. Thus increased IL-17 serum levels can be considered a marker of severe allergy. We thank Cristina Torre (Clinica Pediatrica, Fondazione IRCCS Policlinico S. Matteo) for outstanding technical support and Vania Giunta (Dipartimento di Informatica e Sistemistica, Università di Pavia) for data analysis.