[en] BACKGROUND: Interferons play an important role in innate immunity. Previous studies report deficiency in virus-induction of interferon (IFN)-alpha, -beta and -lambda in bronchial epithelial and bronchial lavage cells in atopic asthmatics. It is now recognized that asthma is a heterogeneous disease comprising different inflammatory phenotypes, some of which may involve innate immune activation in the absence of overt infection. OBJECTIVE: The aim of the study was investigate if the severity of asthma or a specific cellular sputum pattern may be linked to evidence of innate immune activation. METHODS: Here we investigate the expression of IFN-beta, IFN-lambda1 (IL-29), IFN-lambda2/3 (IL-28A/B) and the interferon-stimulated genes (ISGs) myxovirus resistance 1 (Mx1), oligoadenylate synthetase (OAS) and viperin in unstimulated sputum cells in 57 asthmatics (including 16 mild, 19 moderate and 22 severe asthma patients) and compared them with 19 healthy subjects. RESULTS: We observed increased expression of IFN-beta, IFN-lambda1/IL-29, OAS and viperin in asthmatic compared to healthy subjects while IL-28 was not expressed in any group. The overexpression was restricted to neutrophilic asthmatics (sputum neutrophils >/= 76%) while eosinophilic asthmatics (sputum eosinophils >/= 3%) did not differ from healthy subjects or even showed a lower expression of Mx1. No difference in interferon or ISG expression was seen according to clinical asthma severity. CONCLUSION AND CLINICAL RELEVANCE: Neutrophilic, but not eosinophilic, asthmatics display overexpression of IFN-beta, IFN-lambda1/IL-29 and ISGs in their sputum cells that may reflect ongoing innate immune activation. This article is protected by copyright. All rights reserved.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
da Silva, Jane; Université de Liège
Hilzendeger, Clarissa ; Université de Liège > Département des sciences cliniques > Pneumologie - Allergologie
Moermans, Catherine ; Centre Hospitalier Universitaire de Liège - CHU > Service de pneumologie
SCHLEICH, FLorence ; Centre Hospitalier Universitaire de Liège - CHU > Service de pneumologie - allergologie
HENKET, Monique ; Centre Hospitalier Universitaire de Liège - CHU > Service de pneumologie - allergologie
Kebadze, Tatiana; National Heart and Lung Institute
Mallia, Patrick; National Heart and Lung Institute
Edwards, ichael John; National Heart and Lung Institute
Johnston, Sebastian Lennox; National Heart and Lung Institute
Louis, Renaud ; Université de Liège > Département des sciences cliniques > Pneumologie - Allergologie
Language :
English
Title :
Raised interferon beta, type 3 interferon and interferon stimulated genes - evidence of innate immune activation in neutrophilic asthma.
Publication date :
13 September 2016
Journal title :
Clinical and Experimental Allergy
ISSN :
0954-7894
eISSN :
1365-2222
Publisher :
Blackwell Publishing, Oxford, United Kingdom
Peer reviewed :
Peer reviewed
Commentary :
This article is protected by copyright. All rights reserved.
Hansel TT, Johnston SL, Openshaw PJ. Microbes and mucosal immune responses in asthma. Lancet 2013; 381:861–73.
Contoli M, Message SD, Laza-Stanca V et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med 2006; 12:1023–6.
Wark PA, Johnston SL, Bucchieri F et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med 2005; 201:937–47.
Sykes A, Edwards MR, Macintyre J et al. Rhinovirus 16-induced IFN-alpha and IFN-beta are deficient in bronchoalveolar lavage cells in asthmatic patients. J Allergy Clin Immunol 2012; 129:1506–14.
Edwards MR, Regamey N, Vareille M et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol 2013; 6:797–806.
Sykes A, Macintyre J, Edwards MR et al. Rhinovirus-induced interferon production is not deficient in well controlled asthma. Thorax 2014; 69:240–6.
Bochkov YA, Hanson KM, Keles S, Brockman-Schneider RA, Jarjour NN, Gern JE. Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma. Mucosal Immunol 2010; 3:69–80.
Bakakos P, Schleich F, Alchanatis M, Louis R. Induced sputum in asthma: from bench to bedside. Curr Med Chem 2011; 18:1415–22.
Bettiol J, Sele J, Henket M et al. Cytokine production from sputum cells after allergenic challenge in IgE-mediated asthma. Allergy 2002; 57:1145–50.
Manise M, Schleich F, Gusbin N et al. Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity. Allergy 2010; 65:889–96.
Bullens DM, Decraene A, Dilissen E et al. Type III IFN-lambda mRNA expression in sputum of adult and school-aged asthmatics. Clin Exp Allergy 2008; 38:1459–67.
Schwantes EA, Denlinger LC, Evans MD, Gern JE, Jarjour NN, Mathur SK. Severity of virus-induced asthma symptoms is inversely related to resolution IFN-lambda expression. J Allergy Clin Immunol 2015; 135:1656–9.
Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006; 368:804–13.
Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008; 372:1107–19.
Schleich FN, Chevremont A, Paulus V et al. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J 2014; 44:97–108.
McGrath KW, Icitovic N, Boushey HA et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012; 185:612–9.
Simpson JL, Grissell TV, Douwes J, Scott RJ, Boyle MJ, Gibson PG. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax 2007; 62:211–8.
Staeheli P, Haller O. Interferon-induced human protein with homology to protein Mx of influenza virus-resistant mice. Mol Cell Biol 1985; 5:2150–3.
Hovanessian AG. Interferon-induced and double-stranded RNA-activated enzymes: a specific protein kinase and 2′,5′-oligoadenylate synthetases. J Interferon Res 1991; 11:199–205.
Chin KC, Cresswell P. Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. Proc Natl Acad Sci U S A 2001; 98:15125–30.
Quaedvlieg V, Sele J, Henket M, Louis R. Association between asthma control and bronchial hyperresponsiveness and airways inflammation: a cross-sectional study in daily practice. Clin Exp Allergy 2009; 39:1822–9.
Wenzel SE, Fahy JV, Irvin C et al. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 2000; 162:2341–51.
Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med 2013; 13:11.
Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J 2010; 36:646–54.
Johnston SL, Sanderson G, Pattemore PK et al. Use of polymerase chain reaction for diagnosis of picornavirus infection in subjects with and without respiratory symptoms. J Clin Microbiol 1993; 31:111–7.
Papadopoulos NG, Hunter J, Sanderson G, Meyer J, Johnston SL. Rhinovirus identification by BglI digestion of picornavirus RT-PCR amplicons. J Virol Methods 1999; 80:179–85.
Schwantes EA, Manthei DM, Denlinger LC et al. Interferon gene expression in sputum cells correlates with the Asthma Index Score during virus-induced exacerbations. Clin Exp Allergy 2014; 44:813–21.
Schleich F, Brusselle G, Louis R et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir Med 2014; 108:1723–32.
Simpson JL, Carroll M, Yang IA et al. Reduced antiviral interferon production in poorly controlled asthma is associated with neutrophilic inflammation and high-dose inhaled corticosteroids. Chest 2016; 149:704–13.
Wood LG, Simpson JL, Hansbro PM, Gibson PG. Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia. Free Radic Res 2010; 44:146–54.
Garcha DS, Thurston SJ, Patel AR et al. Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD. Thorax 2012; 67:1075–80.
Hilty M, Burke C, Pedro H et al. Disordered microbial communities in asthmatic airways. PLoS ONE 2010; 5:e8578.
Simpson JL, Daly J, Baines KJ et al. Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma. Eur Respir J 2016; 47:792–800.
Holz O, Richter K, Jorres RA, Speckin P, Mucke M, Magnussen H. Changes in sputum composition between two inductions performed on consecutive days. Thorax 1998; 53:83–6.
Seys SF, Daenen M, Dilissen E et al. Effects of high altitude and cold air exposure on airway inflammation in patients with asthma. Thorax 2013; 68:906–13.
Nightingale JA, Rogers DF, Barnes PJ. Effect of inhaled ozone on exhaled nitric oxide, pulmonary function, and induced sputum in normal and asthmatic subjects. Thorax 1999; 54:1061–9.
Nordenhall C, Pourazar J, Blomberg A, Levin JO, Sandstrom T, Adelroth E. Airway inflammation following exposure to diesel exhaust: a study of time kinetics using induced sputum. Eur Respir J 2000; 15:1046–51.
Wallace J, D'silva L, Brannan J, Hargreave FE, Kanaroglou P, Nair P. Association between proximity to major roads and sputum cell counts. Can Respir J 2011; 18:13–8.
Baines KJ, Simpson JL, Bowden NA, Scott RJ, Gibson PG. Differential gene expression and cytokine production from neutrophils in asthma phenotypes. Eur Respir J 2010; 35:522–31.
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J Allergy Clin Immunol 2011; 127:153–60.
Baines KJ, Simpson JL, Wood LG et al. Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes. J Allergy Clin Immunol 2014; 133:997–1007.
Manise M, Holtappels G, Van CK, Schleich F, Bachert C, Louis R. Sputum IgE and cytokines in asthma: relationship with sputum cellular profile. PLoS ONE 2013; 8:e58388.
Djukanovic R, Harrison T, Johnston SL et al. The effect of inhaled IFN-beta on worsening of asthma symptoms caused by viral infections. A randomized trial. Am J Respir Crit Care Med 2014; 190:145–54.
Gielen V, Sykes A, Zhu J et al. Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons. J Allergy Clin Immunol 2015; 136:177–88.
Contoli M, Ito K, Padovani A et al. Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells. Allergy 2015; 70:910–20.
Bedke N, Sammut D, Green B et al. Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response. PLoS ONE 2012; 7:e44580.
Mathur SK, Fichtinger PS, Kelly JT, Lee WM, Gern JE, Jarjour NN. Interaction between allergy and innate immunity: model for eosinophil regulation of epithelial cell interferon expression. Ann Allergy Asthma Immunol 2013; 111:25–31.
Thomas BJ, Lindsay M, Dagher H et al. Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses. Am J Respir Cell Mol Biol 2009; 41:339–47.