Type III IFN‐λ mRNA expression in sputum of adult and school‐aged asthmatics

Bullens, Dominique; Decraene, Ann; Dilissen, Ellen; Meyts, Isabelle; Boeck, K. De; Dupont, Lieven; Ceuppens, Jan L.

doi:10.1111/j.1365-2222.2008.03045.x

Cited by 57 publications

(44 citation statements)

References 23 publications

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“…Comparison of volunteers with and without asthma experimentally infected with an attenuated HRV showed lower type III IFN-l 1 and type III IFN-l 2 levels in respiratory secretions of patients with asthma (14). Conversely, other studies have shown elevated IFN-l 1 in people with asthma compared with people without asthmas (33,34).…”

Section: Type III Ifn-l 1 As a Determinant Of Disease Severitymentioning

confidence: 86%

A Mechanistic Role for Type III IFN-λ₁ in Asthma Exacerbations Mediated by Human Rhinoviruses

Miller

Hernandez

Wimmenauer

et al. 2012

Am J Respir Crit Care Med

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Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. Objectives: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P ¼ 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-l 1 levels were higher in wheezing children infected with HRV compared with nonwheezing (P , 0.001) and increased with worsening symptoms (P , 0.001). Moreover, after adjusting for IFN-l 1 , children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P ¼ 0.66). Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-l 1 responses mediate exacerbations caused by HRV. Modulation of IFN-l 1 should be studied as a therapeutic target for exacerbations caused by HRV.Keywords: asthma; interferon-l; rhinovirus; children; asthma exacerbation Asthma exacerbations are the main cause of hospitalization in children, and occur in association with respiratory viral infections (1, 2). Human rhinoviruses (HRV) are frequently isolated in the upper airways of children during respiratory infections and during asthma attacks, and have been postulated to trigger these crises (3, 4). However, whether HRV are detected during asthma crises because they are the most frequent cause of upper respiratory infections (URI; which accompany asthma attacks), or because they can specifically elicit asthma exacerbations is unclear. To our knowledge, no pediatric study has compared the viral etiology of URI in patients with asthma with and without wheezing to investigate the specific association between HRV URI and asthma attacks.Several hypotheses have been advanced to explain the mechanisms that trigger asthma crises during respiratory infections (4-7). Focused mainly on HRV-associated episodes, two nonexclusive theories attribute asthma attacks to direct viral injury and immune-mediated exacerbations ...

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Section: Type III Ifn-l 1 As a Determinant Of Disease Severitymentioning

confidence: 86%

A Mechanistic Role for Type III IFN-λ₁ in Asthma Exacerbations Mediated by Human Rhinoviruses

Miller

Hernandez

Wimmenauer

et al. 2012

Am J Respir Crit Care Med

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“…Because epithelial and immune cells both produce and respond to IFN-l (9-11), it is likely to play an important role in the immune/epithelial interface. Aberrant interactions in this location are particularly important in the asthmatic airway (26), a condition in which IFN-l1 may be deficient (24,25). The IFN-l1 that is produced by airway epithelial cells is critical for mounting efficient antiviral responses and, in parallel, moderating Th2 development; therefore, we characterized the regulation of this gene's expression in this context.…”

Section: Discussionmentioning

confidence: 99%

“…Further, IFN-l1 secretion is itself Th2 cytokine responsive (11,12,(21)(22)(23). Recent studies also showed that IFN-l1 expression is reduced in alveolar macrophages and bronchial epithelial cells of rhinovirus-infected asthmatic individuals (24,25). Two key contributing pathologies in asthma are the upregulation of Th2 responses and remodeling of the airway epithelial cells (26).…”

mentioning

confidence: 99%

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

Siegel¹,

Eskdale²,

Gallagher³

2011

The Journal of Immunology

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The type III (λ) IFNs (IFN-λ1, IFN-λ2, and IFN-λ3) and their receptor are the most recently discovered IFN family. They are induced by viruses and mediate antiviral activity, but type III IFNs have an important, specific functional niche at the immune/epithelial interface, as well as in the regulation of Th2 cytokines. Their expression appears diminished in bronchial epithelial cells of rhinovirus-infected asthmatic individuals. We investigated the regulation of IFN-λ1 expression in human airway epithelial cells using reporter genes analysis, chromatin immunoprecipitation, small interfering RNA knockdown, and DNase footprinting. In this article, we define the c-REL/p65 NF-κB heterodimer and IRF-1 as key transcriptional activators and ZEB1, B lymphocyte-induced maturation protein 1, and the p50 NF-κB homodimer as key repressors of the IFN-λ1 gene. We further show that ZEB1 selectively regulates type III IFNs. To our knowledge, this study presents the first characterization of any type III IFN promoter in its native context and conformation in epithelial cells and can now be applied to understanding pathogenic dysregulation of IFN-λ1 in human disease.

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“…However, others have found that control of viral replication and production of IFN may also be defective in airway epithelial cells from patients with other types of inflammatory airway disease, e.g., COPD and cystic fibrosis (65-67). Moreover, even in the case of asthma, not all reports agree on a defect in IFN-dependent control of viral replication ex vivo or in vivo (18,(68)(69)(70)(71)(72). A better understanding of the issue will require a comprehensive analysis of type I, II, and/or III IFN level and/or signaling activity during viral infection in asthma versus normal subjects, but this has been difficult to achieve in part because of the logistical challenge of quantifying IFN and corresponding viral load in vivo.…”

Section: Epithelial Cells and Viral Diseasementioning

confidence: 99%

Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

Holtzman¹

2012

J. Clin. Invest.

146

119

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Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.

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Type III IFN‐λ mRNA expression in sputum of adult and school‐aged asthmatics

Abstract: Our results show that asthmatic subjects have substantial type III IFN-lambda mRNA levels in the airways. Our data furthermore suggest that IL-29 could have an immunoprotective role in the lower airways.

Cited by 57 publications

References 23 publications

A Mechanistic Role for Type III IFN-λ₁ in Asthma Exacerbations Mediated by Human Rhinoviruses

A Mechanistic Role for Type III IFN-λ₁ in Asthma Exacerbations Mediated by Human Rhinoviruses

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

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Type III IFN‐λ mRNA expression in sputum of adult and school‐aged asthmatics

Abstract: Our results show that asthmatic subjects have substantial type III IFN-lambda mRNA levels in the airways. Our data furthermore suggest that IL-29 could have an immunoprotective role in the lower airways.

Cited by 57 publications

References 23 publications

A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses

A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

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A Mechanistic Role for Type III IFN-λ₁ in Asthma Exacerbations Mediated by Human Rhinoviruses

A Mechanistic Role for Type III IFN-λ₁ in Asthma Exacerbations Mediated by Human Rhinoviruses