Prominent role of IFN-γ in patients with aspirin-exacerbated respiratory disease

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 4; pp. 856 - 865.e3
• Main Authors: Steinke, John W., PhD, Liu, Lixia, MD, Huyett, Phillip, MD, Negri, Julie, BS, MBA, Payne, Spencer C., MD, Borish, Larry, MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-10-2013; Elsevier
• Subjects: Allergy and Immunology; Aspirin - adverse effects; Aspirin-exacerbated respiratory disease; aspirin-tolerant asthma; Asthma - drug therapy; Asthma, Aspirin-Induced - immunology; Asthma, Aspirin-Induced - physiopathology; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; chronic sinusitis; Cysteine - metabolism; cytokines; Cytokines - metabolism; eosinophils; Eosinophils - cytology; Eosinophils - immunology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; IFN-γ; Immunopathology; Interferon-gamma - metabolism; Leukotrienes - metabolism; Male; Medical sciences; nasal polyps; Nasal Polyps - immunology; Nasal Polyps - physiopathology; Pneumology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sinusitis - immunology; Sinusitis - physiopathology; NP; Nasal polyp; Cysteinyl leukotriene; Aspirin-exacerbated respiratory disease; AERD; eosinophils; Flt3L; LTC 4S; CHES; CysLT; EDN; Sialic acid–binding immunoglobulin-like lectin 8; IFN-γ; Chronic hyperplastic eosinophilic sinusitis; nasal polyps; Allophycocyanin; cytokines; qPCR; chronic sinusitis; EF1α; Quantitative real-time PCR; Fms-like tyrosine kinase 3 ligand; Hematoxylin and eosin; Eosinophil-derived neurotoxin; H&E; Elongation factor 1α; Siglec-8; ECP; Leukotriene C 4 synthase; APC; PE; Phycoerythrin; aspirin-tolerant asthma; Eosinophil cationic protein; LTC4S; Prostaglandin-endoperoxide synthase; Nose disease; Upper respiratory tract; Granulocyte; Acetylsalicylic acid; Sinusitis; Immunology; ENT disease; Bronchus disease; Obstructive pulmonary disease; Salicylates; Human; Lung disease; Immunopathology; Enzyme; Respiratory disease; Cytokine; Enzyme inhibitor; Eosinophil; Antiplatelet agent; Asthma; Chronic; Paranasal sinus disease; Oxidoreductases; Gamma interferon; LTCS; Leukotriene C synthase
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.05.008

Background Aspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin-tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their overexpression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs). Objective We defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of IFN-γ in the differentiation of eosinophils. Methods Quantitative real-time PCR was performed for TH 1 and TH 2 signature cytokines on tissue from control subjects, patients with chronic hyperplastic eosinophilic sinusitis, and patients with AERD, and their cellular source was determined. The influence of IFN-γ on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined. Results Gene expression analysis revealed that tissue from both aspirin-tolerant subjects and patients with AERD display a TH 2 cytokine signature; however, AERD was distinguished from chronic hyperplastic eosinophilic sinusitis by the prominent expression of IFN-γ. Intracellular and immunohistochemical cytokine staining revealed that the major sources of these cytokines were the eosinophils themselves. IFN-γ promoted the maturation of eosinophil progenitors, as measured by increased mRNA and surface expression of CCR3 and sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8). Additionally, IFN-γ increased the expression of genes involved in leukotriene synthesis that led to increased secretion of CysLTs. IFN-γ–matured eosinophil progenitors were also primed, as demonstrated by their enhanced degranulation. Conclusions High IFN-γ levels distinguish AERD from aspirin-tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.