Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

• Published in: Journal of allergy and clinical immunology 2017-06, Vol.139 (6), p.1819-1829.e11
• Main Authors: Andersson, Cecilia K., PhD, Adams, Alexandra, MBBS, Nagakumar, Prasad, MBBS, Bossley, Cara, MDRes, Gupta, Atul, MDRes, De Vries, Daphne, BSc, Adnan, Afiqah, BSc, Bush, Andrew, MD, Saglani, Sejal, MD, Lloyd, Clare M., PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Age; Allergies; Allergy and Immunology; Alveoli; Asthma; Asthma - immunology; Asthma - pathology; Asthma - physiopathology; Asthma and Lower Airway Disease; Biopsy; Bronchoalveolar Lavage Fluid - immunology; Bronchoscopy; Bronchus; Budesonide; Child; Child, Preschool; Children; Cytokines; Epithelial cells; Epithelium; Female; Gene expression; Humans; IL-17A; IL-17A receptor; Infant; Inflammation; Interleukin 22; Interleukin 8; Interleukin-17 - immunology; Interleukins - immunology; Leukocytes (neutrophilic); Lung - immunology; Lung - pathology; Lungs; Male; Neutrophilia; Neutrophils; Neutrophils - immunology; Pediatric asthma; Pediatrics; Receptors, Interleukin-17 - immunology; Respiratory function; Respiratory Mucosa - cytology; Respiratory Mucosa - immunology; Respiratory tract; severe therapy-resistant asthma; Smooth muscle; Steroid hormones; Steroids; Stimulation; Studies
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.09.022

Background Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown. Objectives We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA). Methods Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA–expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide. Results Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted ( r  = 0.43; P  = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A–positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA–positive cells in the submucosa and epithelium in children with STRA compared with controls ( P  = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide. Conclusions A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.