Uncovering Type 2 inflammatory profiles in severe eosinophilic asthma with nasal polyps: the role of transcript-protein ratios and Staphylococcus aureus enterotoxin B-specific IgE
Main Article Content
Keywords
Asthma, B-cell activating factor, Eosinophil, Factor 13A, Interleukin 5, Nasal polyp, Periostin, Staphylococcus aureus enterotoxin B, Thymus-regulated chemokine
Abstract
Background: Severe eosinophilic asthma with nasal polyps (SEAwNP) is a clinical phenotype characterized by elevated peripheral eosinophil counts and heightened type 2 (T2) inflammation.
Objective: In this study, we aimed to compare the transcript/protein expression ratios of factor XIII-A (F13A), B-cell activating factor (BAFF), interleukin-5 (IL-5), and thymus- and activation-regulated chemokine (TARC), as well as serum Staphylococcus aureus Enterotoxin B-Specific IgE (SEB-IgE) levels, among patients with SEAwNP, SEA without nasal polyps (NP), NP without asthma, and healthy controls groups.
Material and Methods: A total of 73 participants were enrolled and stratified into four groups: SEAwNP (n=20), SEA without NP (n=18), NP without asthma (n=15), and healthy controls (n=20). Peripheral blood samples were analyzed using real-time quantitative PCR and protein levels using ELISA for periostin, F13A, BAFF, IL-5, and TARC. Serum SEB-IgE levels were also assessed.
Results: SEAwNP patients exhibited significantly elevated transcript/protein expression ratios of periostin, F13A, BAFF, and IL-5 compared to SEA without NP (p=0.007, p=0.001, p=0.019, and p=0.017, respectively). Furthermore, periostin, F13A, BAFF, IL-5, and TARC transcript/protein ratios were significantly higher in SEAwNP patients compared to healthy controls (p=0.0001, p=0.001, p=0.003, p=0.014, and p=0.02, respectively). SEB-IgE positivity rates were 45% in SEAwNP, 38% in SEA without NP, 13% in NP without asthma, and 0% in healthy controls.
Conclusion: SEAwNP is associated with elevated transcript/protein expression ratio of key T2 inflammatory mediators and increased SEB-IgE positivity, supporting their potential role in the immunopathogenesis of this phenotype. These findings underscore the importance of biomarker profiling in distinguishing endotypes within the spectrum of eosinophilic airway diseases.
References
1 Buhl R, Humbert M, Bjermer L, Chanez P, Heaney LG, Pavord I, et al., Severe eosinophilic asthma: a roadmap to consensus. Eur. Respir. J. 2017;49(5). 10.1183/13993003.00634-2017
2 Coumou H, Bel EH. Improving the diagnosis of eosinophilic asthma. Expert Rev. Respir. Med. 2016;10(10):1093–103. 10.1080/17476348.2017.1236688
3 de Groot JC, Storm H, Amelink M, de Nijs SB, Eichhorn E, Reitsma BH, et al. Clinical profile of patients with adult-onset eosinophilic asthma. ERJ Open Res. 2016;2(2). 10.1183/23120541.00100-2015
4 Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat. Med. 2013;19(8):977–9. 10.1038/nm.3300
5 Busse WW. Biological treatments for severe asthma: a major advance in asthma care. Allergol. Int. 2019;68(2):158–166. 10.1016/j.alit.2019.01.004
6 Cahill KN, Boyce JA. Aspirin-exacerbated respiratory disease: mediators and mechanisms of a clinical disease. J. Allergy Clin. Immunol. 2017;139(3):764–766. 10.1016/j.jaci.2016.09.025
7 Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 2016;137(5):1449–1456. 10.1016/j.jaci.2015.12.1324
8 van Rijt L, von Richthofen H, van Ree R. Type 2 innate lymphoid cells: at the cross-roads in allergic asthma. Semin. Immunopathol. 2016;38(4): 483–96. 10.1007/s00281-016-0556-2
9 Asano T, Kanemitsu Y, Takemura M, Yokota M, Fukumitsu K, Takeda N et al. Serum periostin as a biomarker for comorbid chronic rhinosinusitis in patients with asthma. Ann. Am. Thorac. Soc. 2017;14(5):667–675. 10.1513/AnnalsATS.201609-720OC
10 Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA, Carter R, et al. Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care. Med. 2013;187(1):49–57. 10.1164/rccm.201207-1292OC
11 Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA, Carter R, et al. Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J. Allergy. Clin. Immunol. 2013;132(3):584–592.e4. 10.1016/j.jaci.2013.02.003
12 Tomasiak-Lozowska MM, Misztal T, Rusak T, Branska-Januszewska J, Bodzenta-Lukaszyk A, Tomasiak M.. Asthma is associated with reduced fibrinolytic activity, abnormal clot architecture, and decreased clot retraction rate. Allergy. 2017;72(2):314-319. 10.1111/all.13054
13 Verbruggen K, Van Cauwenberge P, Bachert C. Anti-IgE for the treatment of allergic rhinitis—and eventually nasal polyps? Int. Arch. Allergy Immunol. 2009;148(2):87–98. 10.1159/000155739
14 Gevaert P, Holtappels G, Johansson SG, Cuvelier C, Cauwenberge P, Bachert C, et al. Organization of secondary lymphoid tissue and local IgE formation to Staphylococcus aureus enterotoxins in nasal polyp tissue. Allergy. 2005;60(1):71–9. 10.1111/j.1398-9995.2004.00621.x
15 Zhang N, Holtappels G, Gevaert P, Patou J, Dhaliwal B, Gould H. Mucosal tissue polyclonal IgE is functional in response to allergen and SEB. Allergy. 2011;66(1):141–8. 10.1111/j.1398-9995.2010.02448.x
16 Tomassen P, Jarvis D, Newson R, Van Ree R, Forsberg B, Howarth P, et al. Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study. Allergy. 2013;68(10):1289–97. 10.1111/all.12230
17 Sintobin I, Siroux V, Holtappels G, Pison C, Nadif R, Bousquet J, et al. Sensitisation to staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort. Eur. Respir. J. 2019;54(3). 10.1183/13993003.00198-2019
18 Kowalski ML, Cieślak M, Pérez-Novo CA, Makowska JS, Bachert C, et al. Clinical and immunological determinants of severe/refractory asthma (SRA): association with Staphylococcal superantigen-specific IgE antibodies. Allergy. 2011;66(1):32–8. 10.1111/j.1398-9995.2010.02379.x
19 Agache I, Strasser DS, Pierlot GM, Farine H, Izuhara K, Akdis CA, et al. Monitoring inflammatory heterogeneity with multiple biomarkers for multidimensional endotyping of asthma. J. Allergy Clin. Immunol. 2018;141(1):442–445. 10.1016/j.jaci.2017.08.027
20 James A, Janson C, Malinovschi A, Holweg C, Alving K, Ono J, et al. Serum periostin relates to type-2 inflammation and lung function in asthma: data from the large population-based cohort Swedish GA(2)LEN. Allergy. 2017;72(11):1753–1760. 10.1111/all.13181
21 Mogensen I, James A, Malinovschi A. Systemic and breath biomarkers for asthma: an update. Curr. Opin. Allergy. Clin. Immunol. 2020;20(1):71–79. 10.1097/ACI.0000000000000599
22 GINA. Global Strategy for Asthma Management and Prevention 2023; Available from: https://ginasthma.org/wp-content/uploads/2023/07/GINA-2023-Full-report-23_07_06-WMS.pdf
23 Esnault S, Kelly EA, Sorkness RL, Evans MD, Busse WW, Jarjour NN, et al. Airway factor XIII associates with type 2 inflammation and airway obstruction in asthmatic patients. J. Allergy Clin. Immunol. 2016;137(3): 767–73. 10.1016/j.jaci.2015.05.053
24 Chaitidis P, O’Donnell V, Kuban RJ, Bermudez-Fajardo A, Ungethuem U, Kühn H, et al. Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and-13. Cytokine. 2005;30(6):366–77. 10.1016/j.cyto.2005.02.004
25 Töröcsik D, Bárdos H, Nagy L, Adány R. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell Mol. Life Sci. 2005;62(18):2132–9. 10.1007/s00018-005-5242-9
26 Smulski CR, Kury P, Seidel LM, Staiger HS, Edinger AK, Willen L. BAFF-and TACI-dependent processing of BAFFR by ADAM proteases regulates the survival of B cells. Cell. Rep. 2017;18(9):2189–2202. 10.1016/j.celrep.2017.02.005
27 Schuepbach-Mallepell S, Das D, Willen L, Vigolo M, Tardivel A, Lebon L, et al. Stoichiometry of heteromeric BAFF and APRIL cytokines dictates their receptor binding and signaling properties. J. Biol. Chem. 2015;290(26):16330–42. 10.1074/jbc.M115.661405
28 Kato A, Peters A, Suh L, Carter R, Harris KE, Chandra R, et al. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 2008;121(6):1385–92. 10.1016/j.jaci.2008.03.002
29 Gevaert P, Nouri-Aria KT, Wu H, Harper CE, Takhar P, Fear DJ, et al. Local receptor revision and class switching to IgE in chronic rhinosinusitis with nasal polyps. Allergy. 2013;68(1):55–63. 10.1111/all.12054
30 Hasegawa T, Uga H, Mori A, Kurata H. Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma. Eur. Cytokine Netw. 2017;28(1):8–18. 10.1684/ecn.2017.0390
31 Oliveria JP, Salter BM, Phan S, Obminski CD, Munoz CE, Smith SG, et al. Asthmatic subjects with allergy have elevated levels of IgE+ B cells in the airways. J. Allergy Clin. Immunol. 2017;140(2):590–593. 10.1016/j.jaci.2016.12.981
32 Alturaiki W. The roles of B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) in allergic asthma. Immunol. Lett. 2020;225:25–30. 10.1016/j.imlet.2020.06.001
33 Kang JS, Yoon YD, Ahn JH, Kim SC, Kim KH, Kim HM, et al. B cell-activating factor is a novel diagnosis parameter for asthma. Int. Arch. Allergy Immunol. 2006;141(2):181–8. 10.1159/000094897
34 Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA, et al. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J. Exp. Med. 1988;167(1):219–24. 10.1084/jem.167.1.219
35 O’Byrne PM, Wood L. Interleukin-5 and allergic inflammation. Clin. Exp. Allergy. 1999;29(5):573–5. 10.1046/j.1365-2222.1999.00556.x
36 Sanderson CJ, Warren DJ, Strath M. Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures. J. Exp. Med. 1985;162(1):60–74. 10.1084/jem.162.1.60
37 Holgate ST. The inflammation-repair cycle in asthma: the pivotal role of the airway epithelium. Clin. Exp. Allergy. 1998;28 (Suppl 5):97–103. 10.1046/j.1365-2222.1998.028s5097.x
38 Kay AB. Asthma and inflammation. J. Allergy. Clin. Immunol. 1991;87(5):893–910. 10.1016/0091-6749(91)90408-G
39 Bachert C, Wagenmann M, Hauser U, Rudack C.. IL-5 synthesis is upregulated in human nasal polyp tissue. J. Allergy Clin. Immunol. 1997;99(6 Pt 1):837–42. 10.1016/S0091-6749(97)80019-X
40 Hamilos DL, Leung DY, Huston DP, Kamil A, Wood R, Hamid Q. GM-CSF, IL-5 and RANTES immunoreactivity and mRNA expression in chronic hyperplastic sinusitis with nasal polyposis (NP). Clin. Exp. Allergy. 1998;28(9):1145–52. 10.1046/j.1365-2222.1998.00380.x
41 Bachert C, Gevaert P, Holtappels G, Cuvelier C, van Cauwenberge P, et al. Nasal polyposis: from cytokines to growth. Am. J. Rhinol. 2000;14(5):279–90. 10.2500/105065800781329573
42 Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J. Allergy Clin. Immunol. 2001;107(4):607–14. 10.1067/mai.2001.112374
43 Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P, Liu S et al. Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J. Allergy Clin. Immunol. 2010;126(5):962–8, 968.e1-6. 10.1016/j.jaci.2010.07.007
44 Alexander AG, Barkans J, Moqbel R, Barnes NC, Kay AB, Corrigan CJ, et al. Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma. Thorax. 1994;49(12):1231–3. 10.1136/thx.49.12.1231
45 Gevaert P, Bachert C, Holtappels G, Novo CP, Van der Heyden J, Fransen L, et al. Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis. Allergy. 2003;58(5):371–9. 10.1034/j.1398-9995.2003.00110.x
46 Fulkerson PC, Rothenberg ME. Targeting eosinophils in allergy, inflammation and beyond. Nat. Rev. Drug Discov. 2013;12(2):117–29. 10.1038/nrd3838
47 Jonstam K, Swanson BN, Mannent LP, Cardell LO, Tian N, Wang Y, et al. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy. 2019;74(4):743–752. 10.1111/all.13685
48 Silkoff PE, Laviolette M, Singh D, FitzGerald JM, Kelsen S, Backer V, et al. Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. J. Allergy Clin. Immunol. 2017;140(3):710–719. 10.1016/j.jaci.2016.11.038
49 Romagnani S. Regulation of the development of type 2 T-helper cells in allergy. Curr. Opin. Immunol. 1994;6(6):838–46. 10.1016/0952-7915(94)90002-7
50 Hamilton JD, Harel S, Swanson BN, Brian W, Chen Z, Rice MS, et al. Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases. Clin. Exp. Allergy. 2021;51(7):915–931. 10.1111/cea.13954
51 Machura E, Rusek-Zychma M, Jachimowicz M, Wrzask M, Mazur B, Kasperska-Zajac A, et al. Serum TARC and CTACK concentrations in children with atopic dermatitis, allergic asthma, and urticaria. Pediatr. Allergy Immunol. 2012;23(3):278–84. 10.1111/j.1399-3038.2011.01225.x
52 Sekiya T, Yamada H, Yamaguchi M, Yamamoto K, Ishii A, Yoshie O, et al. Increased levels of a TH2-type CC chemokine thymus and activation-regulated chemokine (TARC) in serum and induced sputum of asthmatics. Allergy. 2002;57(2):173–7. 10.1034/j.1398-9995.2002.5720256.x
53 Luu Quoc Q, Moon JY, Lee DH, Ban GY, Kim SH, Park HS. Role of thymus and activation-regulated chemokine in allergic asthma. J. Asthma Allergy. 2022;15:157–167. 10.2147/JAA.S351720
54 Yormaz B, Menevse E, Cetin N, Esin Celik Z, Bakir H, Tulek B, et al. Diagnostic value of thymus and activation-regulated chemokine and of periostin in eosinophilic asthma: a prospective study. Allergy Asthma Proc. 2021;42(1):30–39. 10.2500/aap.2021.42.200102
55 Teran LM, Ramirez-Jimenez F, Soid-Raggi G, Velazquez JR. Interleukin 16 and CCL17/thymus and activation-regulated chemokine in patients with aspirin-exacerbated respiratory disease. Ann. Allergy Asthma Immunol. 2017;118(2):191–196. 10.1016/j.anai.2016.11.004
56 Kurokawa M, Kokubu F, Matsukura S, Kawaguchi M, Ieki K, Suzuki S, et al. Effects of corticosteroid on the expression of thymus and activation-regulated chemokine in a murine model of allergic asthma. Int. Arch. Allergy Immunol. 2005;137(1):60–8. 10.1159/000085434
57 Hoshino M, Nakagawa T, Sano Y, Hirai K.. Effect of inhaled corticosteroid on an immunoreactive thymus and activation-regulated chemokine expression in the bronchial biopsies from asthmatics. Allergy. 2005;60(3):317–22. 10.1111/j.1398-9995.2005.00694.x
58 Suh YJ, Yoon SH, Sampson AP, Kim HJ, Kim SH, Nahm DH, et al. Specific immunoglobulin E for staphylococcal enterotoxins in nasal polyps from patients with aspirin-intolerant asthma. Clin. Exp. Allergy. 2004;34(8):1270–5. 10.1111/j.1365-2222.2004.02051.x
59 Song WJ, Chang YS, Lim MK, Yun EH, Kim SH, Kang HR, et al. Staphylococcal enterotoxin sensitization in a community-based population: a potential role in adult-onset asthma. Clin. Exp. Allergy. 2014;44(4):553–62. 10.1111/cea.12239
60 Bachert C, Zhang N, Cavaliere C, Weiping W, Gevaert E, Krysko O. Biologics for chronic rhinosinusitis with nasal polyps. J. Allergy. Clin. Immunol. 2020;145(3):725–739. 10.1016/j.jaci.2020.01.020
61 Humbert M, Bousquet J, Bachert C, Palomares O, Pfister P, Kottakis I, et al. IgE-mediated multimorbidities in allergic asthma and the potential for omalizumab therapy. J. Allergy Clin. Immunol. Pract. 2019;7(5):1418–1429. 10.1016/j.jaip.2019.02.030
62 Bachert C, Humbert M, Hanania NA, Zhang N, Holgate S, Buhl R, et al. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge. Eur. Respir. J. 2020;55(4). 10.1183/13993003.01592-2019
63 Jonstam K, Westman M, Holtappels G, Holweg CTJ, Bachert C, et al. Serum periostin, IgE, and SE-IgE can be used as biomarkers to identify moderate to severe chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 2017;140(6):1705–1708. 10.1016/j.jaci.2017.07.031
2 Coumou H, Bel EH. Improving the diagnosis of eosinophilic asthma. Expert Rev. Respir. Med. 2016;10(10):1093–103. 10.1080/17476348.2017.1236688
3 de Groot JC, Storm H, Amelink M, de Nijs SB, Eichhorn E, Reitsma BH, et al. Clinical profile of patients with adult-onset eosinophilic asthma. ERJ Open Res. 2016;2(2). 10.1183/23120541.00100-2015
4 Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat. Med. 2013;19(8):977–9. 10.1038/nm.3300
5 Busse WW. Biological treatments for severe asthma: a major advance in asthma care. Allergol. Int. 2019;68(2):158–166. 10.1016/j.alit.2019.01.004
6 Cahill KN, Boyce JA. Aspirin-exacerbated respiratory disease: mediators and mechanisms of a clinical disease. J. Allergy Clin. Immunol. 2017;139(3):764–766. 10.1016/j.jaci.2016.09.025
7 Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 2016;137(5):1449–1456. 10.1016/j.jaci.2015.12.1324
8 van Rijt L, von Richthofen H, van Ree R. Type 2 innate lymphoid cells: at the cross-roads in allergic asthma. Semin. Immunopathol. 2016;38(4): 483–96. 10.1007/s00281-016-0556-2
9 Asano T, Kanemitsu Y, Takemura M, Yokota M, Fukumitsu K, Takeda N et al. Serum periostin as a biomarker for comorbid chronic rhinosinusitis in patients with asthma. Ann. Am. Thorac. Soc. 2017;14(5):667–675. 10.1513/AnnalsATS.201609-720OC
10 Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA, Carter R, et al. Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care. Med. 2013;187(1):49–57. 10.1164/rccm.201207-1292OC
11 Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA, Carter R, et al. Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J. Allergy. Clin. Immunol. 2013;132(3):584–592.e4. 10.1016/j.jaci.2013.02.003
12 Tomasiak-Lozowska MM, Misztal T, Rusak T, Branska-Januszewska J, Bodzenta-Lukaszyk A, Tomasiak M.. Asthma is associated with reduced fibrinolytic activity, abnormal clot architecture, and decreased clot retraction rate. Allergy. 2017;72(2):314-319. 10.1111/all.13054
13 Verbruggen K, Van Cauwenberge P, Bachert C. Anti-IgE for the treatment of allergic rhinitis—and eventually nasal polyps? Int. Arch. Allergy Immunol. 2009;148(2):87–98. 10.1159/000155739
14 Gevaert P, Holtappels G, Johansson SG, Cuvelier C, Cauwenberge P, Bachert C, et al. Organization of secondary lymphoid tissue and local IgE formation to Staphylococcus aureus enterotoxins in nasal polyp tissue. Allergy. 2005;60(1):71–9. 10.1111/j.1398-9995.2004.00621.x
15 Zhang N, Holtappels G, Gevaert P, Patou J, Dhaliwal B, Gould H. Mucosal tissue polyclonal IgE is functional in response to allergen and SEB. Allergy. 2011;66(1):141–8. 10.1111/j.1398-9995.2010.02448.x
16 Tomassen P, Jarvis D, Newson R, Van Ree R, Forsberg B, Howarth P, et al. Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study. Allergy. 2013;68(10):1289–97. 10.1111/all.12230
17 Sintobin I, Siroux V, Holtappels G, Pison C, Nadif R, Bousquet J, et al. Sensitisation to staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort. Eur. Respir. J. 2019;54(3). 10.1183/13993003.00198-2019
18 Kowalski ML, Cieślak M, Pérez-Novo CA, Makowska JS, Bachert C, et al. Clinical and immunological determinants of severe/refractory asthma (SRA): association with Staphylococcal superantigen-specific IgE antibodies. Allergy. 2011;66(1):32–8. 10.1111/j.1398-9995.2010.02379.x
19 Agache I, Strasser DS, Pierlot GM, Farine H, Izuhara K, Akdis CA, et al. Monitoring inflammatory heterogeneity with multiple biomarkers for multidimensional endotyping of asthma. J. Allergy Clin. Immunol. 2018;141(1):442–445. 10.1016/j.jaci.2017.08.027
20 James A, Janson C, Malinovschi A, Holweg C, Alving K, Ono J, et al. Serum periostin relates to type-2 inflammation and lung function in asthma: data from the large population-based cohort Swedish GA(2)LEN. Allergy. 2017;72(11):1753–1760. 10.1111/all.13181
21 Mogensen I, James A, Malinovschi A. Systemic and breath biomarkers for asthma: an update. Curr. Opin. Allergy. Clin. Immunol. 2020;20(1):71–79. 10.1097/ACI.0000000000000599
22 GINA. Global Strategy for Asthma Management and Prevention 2023; Available from: https://ginasthma.org/wp-content/uploads/2023/07/GINA-2023-Full-report-23_07_06-WMS.pdf
23 Esnault S, Kelly EA, Sorkness RL, Evans MD, Busse WW, Jarjour NN, et al. Airway factor XIII associates with type 2 inflammation and airway obstruction in asthmatic patients. J. Allergy Clin. Immunol. 2016;137(3): 767–73. 10.1016/j.jaci.2015.05.053
24 Chaitidis P, O’Donnell V, Kuban RJ, Bermudez-Fajardo A, Ungethuem U, Kühn H, et al. Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and-13. Cytokine. 2005;30(6):366–77. 10.1016/j.cyto.2005.02.004
25 Töröcsik D, Bárdos H, Nagy L, Adány R. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell Mol. Life Sci. 2005;62(18):2132–9. 10.1007/s00018-005-5242-9
26 Smulski CR, Kury P, Seidel LM, Staiger HS, Edinger AK, Willen L. BAFF-and TACI-dependent processing of BAFFR by ADAM proteases regulates the survival of B cells. Cell. Rep. 2017;18(9):2189–2202. 10.1016/j.celrep.2017.02.005
27 Schuepbach-Mallepell S, Das D, Willen L, Vigolo M, Tardivel A, Lebon L, et al. Stoichiometry of heteromeric BAFF and APRIL cytokines dictates their receptor binding and signaling properties. J. Biol. Chem. 2015;290(26):16330–42. 10.1074/jbc.M115.661405
28 Kato A, Peters A, Suh L, Carter R, Harris KE, Chandra R, et al. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 2008;121(6):1385–92. 10.1016/j.jaci.2008.03.002
29 Gevaert P, Nouri-Aria KT, Wu H, Harper CE, Takhar P, Fear DJ, et al. Local receptor revision and class switching to IgE in chronic rhinosinusitis with nasal polyps. Allergy. 2013;68(1):55–63. 10.1111/all.12054
30 Hasegawa T, Uga H, Mori A, Kurata H. Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma. Eur. Cytokine Netw. 2017;28(1):8–18. 10.1684/ecn.2017.0390
31 Oliveria JP, Salter BM, Phan S, Obminski CD, Munoz CE, Smith SG, et al. Asthmatic subjects with allergy have elevated levels of IgE+ B cells in the airways. J. Allergy Clin. Immunol. 2017;140(2):590–593. 10.1016/j.jaci.2016.12.981
32 Alturaiki W. The roles of B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) in allergic asthma. Immunol. Lett. 2020;225:25–30. 10.1016/j.imlet.2020.06.001
33 Kang JS, Yoon YD, Ahn JH, Kim SC, Kim KH, Kim HM, et al. B cell-activating factor is a novel diagnosis parameter for asthma. Int. Arch. Allergy Immunol. 2006;141(2):181–8. 10.1159/000094897
34 Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA, et al. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J. Exp. Med. 1988;167(1):219–24. 10.1084/jem.167.1.219
35 O’Byrne PM, Wood L. Interleukin-5 and allergic inflammation. Clin. Exp. Allergy. 1999;29(5):573–5. 10.1046/j.1365-2222.1999.00556.x
36 Sanderson CJ, Warren DJ, Strath M. Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures. J. Exp. Med. 1985;162(1):60–74. 10.1084/jem.162.1.60
37 Holgate ST. The inflammation-repair cycle in asthma: the pivotal role of the airway epithelium. Clin. Exp. Allergy. 1998;28 (Suppl 5):97–103. 10.1046/j.1365-2222.1998.028s5097.x
38 Kay AB. Asthma and inflammation. J. Allergy. Clin. Immunol. 1991;87(5):893–910. 10.1016/0091-6749(91)90408-G
39 Bachert C, Wagenmann M, Hauser U, Rudack C.. IL-5 synthesis is upregulated in human nasal polyp tissue. J. Allergy Clin. Immunol. 1997;99(6 Pt 1):837–42. 10.1016/S0091-6749(97)80019-X
40 Hamilos DL, Leung DY, Huston DP, Kamil A, Wood R, Hamid Q. GM-CSF, IL-5 and RANTES immunoreactivity and mRNA expression in chronic hyperplastic sinusitis with nasal polyposis (NP). Clin. Exp. Allergy. 1998;28(9):1145–52. 10.1046/j.1365-2222.1998.00380.x
41 Bachert C, Gevaert P, Holtappels G, Cuvelier C, van Cauwenberge P, et al. Nasal polyposis: from cytokines to growth. Am. J. Rhinol. 2000;14(5):279–90. 10.2500/105065800781329573
42 Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J. Allergy Clin. Immunol. 2001;107(4):607–14. 10.1067/mai.2001.112374
43 Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P, Liu S et al. Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J. Allergy Clin. Immunol. 2010;126(5):962–8, 968.e1-6. 10.1016/j.jaci.2010.07.007
44 Alexander AG, Barkans J, Moqbel R, Barnes NC, Kay AB, Corrigan CJ, et al. Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma. Thorax. 1994;49(12):1231–3. 10.1136/thx.49.12.1231
45 Gevaert P, Bachert C, Holtappels G, Novo CP, Van der Heyden J, Fransen L, et al. Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis. Allergy. 2003;58(5):371–9. 10.1034/j.1398-9995.2003.00110.x
46 Fulkerson PC, Rothenberg ME. Targeting eosinophils in allergy, inflammation and beyond. Nat. Rev. Drug Discov. 2013;12(2):117–29. 10.1038/nrd3838
47 Jonstam K, Swanson BN, Mannent LP, Cardell LO, Tian N, Wang Y, et al. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy. 2019;74(4):743–752. 10.1111/all.13685
48 Silkoff PE, Laviolette M, Singh D, FitzGerald JM, Kelsen S, Backer V, et al. Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. J. Allergy Clin. Immunol. 2017;140(3):710–719. 10.1016/j.jaci.2016.11.038
49 Romagnani S. Regulation of the development of type 2 T-helper cells in allergy. Curr. Opin. Immunol. 1994;6(6):838–46. 10.1016/0952-7915(94)90002-7
50 Hamilton JD, Harel S, Swanson BN, Brian W, Chen Z, Rice MS, et al. Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases. Clin. Exp. Allergy. 2021;51(7):915–931. 10.1111/cea.13954
51 Machura E, Rusek-Zychma M, Jachimowicz M, Wrzask M, Mazur B, Kasperska-Zajac A, et al. Serum TARC and CTACK concentrations in children with atopic dermatitis, allergic asthma, and urticaria. Pediatr. Allergy Immunol. 2012;23(3):278–84. 10.1111/j.1399-3038.2011.01225.x
52 Sekiya T, Yamada H, Yamaguchi M, Yamamoto K, Ishii A, Yoshie O, et al. Increased levels of a TH2-type CC chemokine thymus and activation-regulated chemokine (TARC) in serum and induced sputum of asthmatics. Allergy. 2002;57(2):173–7. 10.1034/j.1398-9995.2002.5720256.x
53 Luu Quoc Q, Moon JY, Lee DH, Ban GY, Kim SH, Park HS. Role of thymus and activation-regulated chemokine in allergic asthma. J. Asthma Allergy. 2022;15:157–167. 10.2147/JAA.S351720
54 Yormaz B, Menevse E, Cetin N, Esin Celik Z, Bakir H, Tulek B, et al. Diagnostic value of thymus and activation-regulated chemokine and of periostin in eosinophilic asthma: a prospective study. Allergy Asthma Proc. 2021;42(1):30–39. 10.2500/aap.2021.42.200102
55 Teran LM, Ramirez-Jimenez F, Soid-Raggi G, Velazquez JR. Interleukin 16 and CCL17/thymus and activation-regulated chemokine in patients with aspirin-exacerbated respiratory disease. Ann. Allergy Asthma Immunol. 2017;118(2):191–196. 10.1016/j.anai.2016.11.004
56 Kurokawa M, Kokubu F, Matsukura S, Kawaguchi M, Ieki K, Suzuki S, et al. Effects of corticosteroid on the expression of thymus and activation-regulated chemokine in a murine model of allergic asthma. Int. Arch. Allergy Immunol. 2005;137(1):60–8. 10.1159/000085434
57 Hoshino M, Nakagawa T, Sano Y, Hirai K.. Effect of inhaled corticosteroid on an immunoreactive thymus and activation-regulated chemokine expression in the bronchial biopsies from asthmatics. Allergy. 2005;60(3):317–22. 10.1111/j.1398-9995.2005.00694.x
58 Suh YJ, Yoon SH, Sampson AP, Kim HJ, Kim SH, Nahm DH, et al. Specific immunoglobulin E for staphylococcal enterotoxins in nasal polyps from patients with aspirin-intolerant asthma. Clin. Exp. Allergy. 2004;34(8):1270–5. 10.1111/j.1365-2222.2004.02051.x
59 Song WJ, Chang YS, Lim MK, Yun EH, Kim SH, Kang HR, et al. Staphylococcal enterotoxin sensitization in a community-based population: a potential role in adult-onset asthma. Clin. Exp. Allergy. 2014;44(4):553–62. 10.1111/cea.12239
60 Bachert C, Zhang N, Cavaliere C, Weiping W, Gevaert E, Krysko O. Biologics for chronic rhinosinusitis with nasal polyps. J. Allergy. Clin. Immunol. 2020;145(3):725–739. 10.1016/j.jaci.2020.01.020
61 Humbert M, Bousquet J, Bachert C, Palomares O, Pfister P, Kottakis I, et al. IgE-mediated multimorbidities in allergic asthma and the potential for omalizumab therapy. J. Allergy Clin. Immunol. Pract. 2019;7(5):1418–1429. 10.1016/j.jaip.2019.02.030
62 Bachert C, Humbert M, Hanania NA, Zhang N, Holgate S, Buhl R, et al. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge. Eur. Respir. J. 2020;55(4). 10.1183/13993003.01592-2019
63 Jonstam K, Westman M, Holtappels G, Holweg CTJ, Bachert C, et al. Serum periostin, IgE, and SE-IgE can be used as biomarkers to identify moderate to severe chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 2017;140(6):1705–1708. 10.1016/j.jaci.2017.07.031
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Mar 1, 2026
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Yılmaz, İnsu, Taheri, S., Arslan, B., Erdem, Şerife, Eken, A., Paçacı Çetin, G., Türk, M., Yılmaz, Z., Hamurcu, Z., & Tutar , N. (2026). Uncovering Type 2 inflammatory profiles in severe eosinophilic asthma with nasal polyps: the role of transcript-protein ratios and Staphylococcus aureus enterotoxin B-specific IgE. Allergologia Et Immunopathologia, 54(2), 35–44. https://doi.org/10.15586/aei.v54i2.1486
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Yılmaz, İnsu, Taheri, S., Arslan, B., Erdem, Şerife, Eken, A., Paçacı Çetin, G., Türk, M., Yılmaz, Z., Hamurcu, Z., & Tutar , N. (2026). Uncovering Type 2 inflammatory profiles in severe eosinophilic asthma with nasal polyps: the role of transcript-protein ratios and Staphylococcus aureus enterotoxin B-specific IgE. Allergologia Et Immunopathologia, 54(2), 35–44. https://doi.org/10.15586/aei.v54i2.1486