A significant increase in expression of FOXP3 and IL-17 genes in patients with allergic rhinitis underwent accelerated rush immunotherapy

Document Type: Original Article

Authors

1 Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Allergic rhinitis (AR) is a common hypersensitivity disease worldwide. Immunotherapy has been performed as the best treatment for years. This study aimed to study the gene expression pattern of immune system cells following an accelerated rush immunotherapy protocol (ARIT) in patients with AR.
Materials and Methods: Fifteen patients with AR (15–55 years old) resident in Mashhad, Iran, with positive prick test to regional aeroallergens (weed mix, grass mix, tree mix, and Salsola) enrolled in this study. All patients were treated for three months with 3-day ARIT protocol between July 2015 and August 2016. Clinical symptoms and quality of life were recorded by two questioners. The expression levels of FOXP3, TGF-β, IL-10, IL-17, IL-4, and IFN-γ genes in patient’s peripheral blood mononuclear cells were evaluated by SYBR Green real-time RT-PCR technique.
Results: The severity of disease and quality of life showed significant improvement following ARIT (P-value<0.05). Gene expression of IFN-γ and IL-10 was increased whereas TGF-β and IL-4 down-regulated, following ARIT, but these changes were not significant. However, gene expression of FOXP3 and IL-17 was significantly increased after intervention when compared with the baseline (P-value< 0.002).
Conclusion: Significant up-regulation of FOXP3 and IL-17 genes, additionally, a significant improvement in the clinical signs following ARIT might be related to increases in HLA-DR- and FOXP3+ Treg population at the initiation phase of ARIT. Employing the flow cytometry technique to study the phenotype of these cells is suggested for future studies.

Keywords

Main Subjects


1. Kakli HA, Riley TD. Allergic rhinitis. Prim Care 2016;43:465-475.
2. Varshney J, Varshney H. Allergic rhinitis: an overview. Indian J Otolaryngol Head Neck Surg 2015;67:143-149.
3. Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet 2012;378:2112-2122.
4. Min Y-G. The pathophysiology, diagnosis and treatment of allergic rhinitis. Allergy Asthma Immunol Res 2010;2:65-76.
5. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens W, Togias A, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008. Allergy 2008;63:8-160.
6. Lee S-M, Gao B, Dahl M, Calhoun K, Fang D. Decreased FoxP3 gene expression in the nasal secretions from patients with allergic rhinitis. Otolaryngol Head Neck Surg 2009;140:197-201.
7. Bayrak Degirmenci P, Aksun S, Altin Z, Bilgir F, Arslan I, Colak H, et al. Allergic Rhinitis and Its Relationship with IL-10, IL-17, TGF-β, IFN-γ, IL 22, and IL-35. Dis Markers 2018;2018:1-6.
8. Baumann R, Rabaszowski M, Stenin I, Tilgner L, Scheckenbach K, Wiltfang J, et al. Comparison of the nasal release of IL-4, IL-10, IL-17, CCL13/MCP-4, and CCL26/eotaxin-3 in allergic rhinitis during season and after allergen challenge. Am J Rhinol Allergy 2013;27:266-272.
9. Boghdadi G, Marei A, Ali A, Lotfy G, Abdulfattah M, Sorour S. Immunological markers in allergic rhinitis patients treated with date palm immunotherapy. Inflammation Res 2012;61:719-724.
10.    Maggi E, Vultaggio A, Matucci A. T-cell responses during allergen-specific immunotherapy. Curr Opin Allergy Clin Immunol 2012;12:1-6.
11.    Micheal S, Minhas K, Ishaque M, Ahmed F, Ahmed A. IL4 gene polymorphisms and their association with atopic asthma and allergic rhinitis in Pakistani patients. J Investig Allergol Clin Immunol 2013;23:107-111.
12.    Wei W, Liu Y, Wang Y, Zhao Y, He J, Li X, et al. Induction of CD4+ CD25+ Foxp3+ IL-10+ T cells in HDM-allergic asthmatic children with or without SIT. Int Arch Allergy Immunol 2010;153:19-26.
13.    Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, et al. IL-17–producing human peripheral regulatory T cells retain suppressive function. Blood 2009;113:4240-4249.
14.    Afzali B, Mitchell PJ, Edozie FC, Povoleri GA, Dowson SE, Demandt L, et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL‐17 in a STAT3‐dependent manner. Eur J Immunol 2013;43:2043-2054.
15.    Mohr A, Malhotra R, Mayer G, Gorochov G, Miyara M. Human FOXP 3+ T regulatory cell heterogeneity. Clin Transl Immunology 2018;7:1-11.
16.    Llosa NJ, Geis AL, Orberg ET, Housseau F. Interleukin-17 and type 17 helper T cells in cancer management and research. Immunotargets Ther 2014;3:39-54.
17.    Nieminen K, Valovirta E, Savolainen J. Clinical outcome and IL‐17, IL‐23, IL‐27 and FOXP3 expression in peripheral blood mononuclear cells of pollen‐allergic children during sublingual immunotherapy. Pediatr Allergy Immunol 2010;21:e174-e184.
18.    Liu Z, Yelverton R, Kraft B, Tanner S, Olsen N, Aune T. Highly conserved gene expression profiles in humans with allergic rhinitis altered by immunotherapy. Clin Exp Allergy 2005;35:1581-1590.
19.    Ring J, Gutermuth J. 100 years of hyposensitization. history of allergen‐specific immunotherapy (ASIT). Allergy 2011;66:713-724.
20.    Calabria CW. Accelerated immunotherapy schedules. Curr Allergy Asthma Rep 2013;13:389-398.
21.    Davis LS, Bhutani S, Barnett SR, Khan DA. Early gene expression changes with rush immunotherapy. Clin Mol Allergy 2011;9:12-22.
22.    Lachanas VA, Tsea M, Tsiouvaka S, Hajiioannou JK, Skoulakis CE, Bizakis JG. The sino-nasal outcome test (SNOT)-22: validation for Greek patients. Eur Arch Otorhinolaryngol 2014;271:2723-2728.
23.    Van Oene C, Van Reij E, Sprangers M, Fokkens W. Quality‐assessment of disease‐specific quality of life questionnaires for rhinitis and rhinosinusitis. a systematic review. Allergy 2007;62:1359-1371.
24.    Giulietti A, Overbergh L, Valckx D, Decallonne B, Bouillon R, Mathieu C. An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. Methods 2001;25:386-401.
25.    Zheng R, Wu X, Huang X, Chen Y, Yang Q, Li Y, et al. Gene expression pattern of Treg and TCR Vγ subfamily T cells before and after specific immunotherapy in allergic rhinitis. J Transl Med 2014;12:24-31.
26.    Xu G, Mou Z, Jiang H, Cheng L, Shi J, Xu R, et al. A possible role of CD4+ CD25+ T cells as well as transcription factor Foxp3 in the dysregulation of allergic rhinitis. Laryngoscope 2007;117:876-880.
27.    Urra J, Carrasco P, Feo-Brito F, De La Roca F, Guerra F, Cabrera C. Immunotherapy reduces CD40L expression and modifies cytokine production in the CD4 cells of pollen allergy patients. J Investig Allergol Clin Immunol 2014;24:98-105.
28.    Han D, Wang C, Lou W, Gu Y, Wang Y, Zhang L. Allergen-specific IL-10-secreting type IT regulatory cells, but not CD4+ CD25+ Foxp3+ T cells, are decreased in peripheral blood of patients with persistent allergic rhinitis. Clin Immunol 2010;136:292-301.
29.    Sabat R, Grütz G, Warszawska K, Kirsch S, Witte E, Wolk K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev 2010;21:331-344.
30.    Lou W, Wang C, Wang Y, Han D, Zhang L. Responses of CD4+ CD25+ Foxp3+ and IL‐10‐secreting type IT regulatory cells to cluster‐specific immunotherapy for allergic rhinitis in children. Pediatr Allergy Immunol  2012;23:141-150.
31.    Savolainen J, Laaksonen K, Rantio‐Lehtimäki A, Terho E. Increased expression of allergen‐induced in vitro interleukin‐10 and interleukin‐18 mRNA in peripheral blood mononuclear cells of allergic rhinitis patients after specific immunotherapy. Clin Exp Allergy 2004;34:413-419.
32.    Ahmadiafshar A, Taymourzadeh B, Shaikhi A, Mazloomzadeh S, Torabi Z. Evaluation of IL10, TGF-B and Specific IgE and IgG Levels during Sublingual Rye Grass Immunotherapy. J Aller Ther 2013;4:132.
33.    Hoseini R, Jabbari F, Rezaee A, Rafatpanah H, Yousefzadeh H, Ariaee N, et al. House dust mite sublingual-swallow immunotherapy in perennial rhinitis: a double-blind, placebo-controlled Iranian study. J Biol Regul Homeost Agents 2018;32:83-88.
34.    Krishna M, Huissoon A. Clinical immunology review series: an approach to desensitization. Clin Exp Immunol 2011;163:131-146.
35.    Pawankar R, Hayashi M, Yamanishi S, Igarashi T. The paradigm of cytokine networks in allergic airway inflammation. Curr Opin Allergy Clin Immunol 2015;15:41-48.
36.    Li CW, Lu HG, Chen DH, Lin ZB, Wang DY, Li TY. In vivo and in vitro studies of Th17 response to specific immunotherapy in house dust mite-induced allergic rhinitis patients. PLoS One 2014;9:e91950.
37.    Li H, Xu E, He M. Cytokine responses to specific immunotherapy in house dust mite-induced allergic rhinitis patients. Inflammation 2015;38:2216-2223.
38.    Jin W, Dong C. IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect 2013;2:e60.
39.    Ciprandi G, Fenoglio D, Di Gioacchino M, Ferrera A, Ferrera F, Sormani M, et al. Sublingual immunotherapy provides an early increase of interferon-gamma production. Biol Regul Homeost Agents 2008;22:169-173.