• John W Steinke, Lixia Liu, Phillip Huyett, Julie Negri, Spencer C Payne, and Larry Borish.
• Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, Va; Carter Immunology Center, University of Virginia Health System, Charlottesville, Va. Electronic address: js3ch@virginia.edu.
• J. Allergy Clin. Immunol. 2013 Oct 1; 132 (4): 856-65.e1-3.

BackgroundAspirin-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).ObjectiveWe defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of IFN-γ in the differentiation of eosinophils.MethodsQuantitative real-time PCR was performed for TH1 and TH2 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.ResultsGene expression analysis revealed that tissue from both aspirin-tolerant subjects and patients with AERD display a TH2 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.ConclusionsHigh IFN-γ levels distinguish AERD from aspirin-tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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