Raised interferon-ß, type 3 interferon and interferon-stimulated genes - evidence of innate immune activation in neutrophilic asthma.

BACKGROUND: Interferons play an important role in innate immunity. Previous studies report deficiency in virus induction of interferon (IFN)-α, IFN-ß and IFN-λ 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 this study was to investigate whether 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-ß, IFN-λ1 (IL-29), IFN-λ2/3 (IL-28A/B) and the interferon-stimulated genes (ISGs) such as 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-ß, IFN-λ1/IL-29, OAS and viperin in asthmatics compared with 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 observed according to clinical asthma severity. CONCLUSION AND CLINICAL RELEVANCE: Neutrophilic, but not eosinophilic, asthmatics display overexpression of IFN-ß, IFN-λ1/IL-29 and ISGs in their sputum cells that may reflect ongoing innate immune activation.

The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease­a systematic review.

BACKGROUND: Despite the increasing knowledge on the role of viruses in exacerbations of COPD (AECOPD), it is less clear which viruses are involved and to what extent they contribute to exacerbations. This review aims to systematically combine and evaluate the available literature of the prevalence of respiratory viruses in patients with AECOPD, detected by PCR. METHODS: An electronic search strategy was performed on PubMed and Embase and reference lists were screened for eligible studies. Cross-sectional, prospective studies and case-control studies were included. The primary outcome measure was the prevalence of respiratory viruses (adenovirus, bocavirus, coronavirus, EBV, hMPV, influenza, parainfluenza, rhino-/enterovirus, RSV) in respiratory secretions of patients during an AECOPD. Secondary outcomes were the odds of the presence of the viruses in different respiratory secretions and the odds of the presence of viruses in upper and lower respiratory tract (URT/LRT) samples. RESULTS: Nineteen studies with 1728 patients were included. Rhino-/enteroviruses (16.39%), RSV (9.90%) and influenza (7.83%) were the most prevalent viruses detected with lower detection rates of coronaviruses (4.08%) and parainfluenza (3.35%). Adenovirus (2.07%), hMPV (2.78%) and bocaviruses (0.56%) appear to be rare causative agents of AECOPD. Definitive conclusions regarding the role of EBV cannot be made. Seven of the eight analyzed viruses had a higher prevalence in LRT samples. Coronaviruses were detected more frequently in the URT. CONCLUSIONS: Respiratory viruses are frequently detected in both URT and LRT samples in AECOPD with rhino-/enteroviruses, RSV and influenza viruses the most prevalent viruses. Detection rates vary between the two sites for different viruses.

CXC chemokines and antimicrobial peptides in rhinovirus-induced experimental asthma exacerbations.

RATIONALE: Rhinoviruses (RVs) are the major triggers of asthma exacerbations. We have shown previously that lower respiratory tract symptoms, airflow obstruction, and neutrophilic airway inflammation were increased in experimental RV-induced asthma exacerbations. OBJECTIVES: We hypothesized that neutrophil-related CXC chemokines and antimicrobial peptides are increased and related to clinical, virologic, and pathologic outcomes in RV-induced exacerbations of asthma. METHODS: Protein levels of antimicrobial peptides (SLPI, HNP 1-3, elafin, and LL-37) and neutrophil chemokines (CXCL1/GRO-α, CXCL2/GRO-ß, CXCL5/ENA-78, CXCL6/GCP-2, CXCL7/NAP-2, and CXCL8/IL-8) were determined in bronchoalveolar lavage (BAL) fluid of 10 asthmatics and 15 normal controls taken before, at day four during and 6 weeks post-experimental infection. RESULTS: BAL HNP 1-3 and Elafin were higher, CXCL7/NAP-2 was lower in asthmatics compared with controls at day 4 (P = 0.035, P = 0.048, and P = 0.025, respectively). BAL HNP 1-3 and CXCL8/IL-8 were increased during infection (P = 0.003 and P = 0.011, respectively). There was a trend to increased BAL neutrophils at day 4 compared with baseline (P = 0.076). BAL HNP 1-3 was positively correlated with BAL neutrophil numbers at day 4. There were no correlations between clinical parameters and HNP1-3 or IL-8 levels. CONCLUSIONS: We propose that RV infection in asthma leads to increased release of CXCL8/IL-8, attracting neutrophils into the airways where they release HNP 1-3, which further enhances airway neutrophilia. Strategies to inhibit CXCL8/IL-8 may be useful in treatment of virus-induced asthma exacerbations.

IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection.

Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

γδT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations.

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.

RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells.

The cytokine interleukin (IL)-15, major histocompatibility complex (MHC) class I molecules and MHC class I chain-related proteins (MIC) A and B are involved in cellular immune responses to virus infections but their role in respiratory syncytial virus (RSV) infection has not been studied. We aimed to determine how RSV infection modulates IL-15 production, MHC class I and MICA expression in respiratory epithelial cells, the molecular pathways implicated in virus-induced IL-15 production and how interferon (IFN)-γ alters RSV-induced IL-15 production and MHC class I and MICA expression. We infected respiratory epithelial cell lines (A549 and BEAS-2B cells) and primary bronchial epithelial cells with RSV and measured production of IL-15, expression of MHC I and MICA and the role of the transcription factor nuclear factor (NF)-κB. We report here that RSV increases IL-15 in respiratory epithelial cells via virus replication and NF-κB-dependent mechanisms. Furthermore, RSV infection of epithelial cells upregulated cell surface expression of MICA and levels of soluble MICA. IFN-γ upregulated RSV induction of soluble IL-15 but inhibited induction of MICA. Upregulation of IL-15, MHC I and MICA are likely to be important mechanisms in activating immune responses to RSV by epithelial cells.

Mechanisms of virus-induced asthma exacerbations: state-of-the-art. A GA2LEN and InterAirways document.

Viral infections of the respiratory tract are the most common precipitants of acute asthma exacerbations. Exacerbations are only poorly responsive to current asthma therapies and new approaches to therapy are needed. Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium, generate local and systemic immune responses, as well as neural responses, inducing inflammation and airway hyperresponsiveness. Using in vitro and in vivo experimental models the role of various proinflammatory or anti-inflammatory mediators, antiviral responses and molecular pathways that lead from infection to symptoms has been partly unravelled. In particular, mechanisms of susceptibility to viral infection have been identified and the bronchial epithelium appeared to be a key player. Nevertheless, additional understanding of the integration between the diverse elements of the antiviral response, especially in the context of allergic airway inflammation, as well as the interactions between viral infections and other stimuli that affect airway inflammation and responsiveness may lead to novel strategies in treating and/or preventing asthma exacerbations. This review presents the current knowledge and highlights areas in need of further research.

Exacerbations of asthma and chronic obstructive pulmonary disease (COPD): focus on virus induced exacerbations.

Asthma and chronic obstructive pulmonary disease (COPD) are the 2 most prevalent chronic airway diseases. Much of the morbidity, mortality and health care costs of the diseases are associated with acute exacerbations, which are episodes of increased symptoms and airflow obstruction. Over the last decade evidence has emerged implicating virus respiratory tract infections as a major cause of exacerbations of both asthma and COPD. Current therapies are not very effective in the prevention or treatment of virus-induced exacerbations and exacerbations are therefore a major unmet medical need. The development of new and novel treatments requires a better understanding of the molecular and cellular mechanisms linking virus infection with exacerbations of asthma and COPD. This article provides an overview of current knowledge regarding the mechanisms of virus-induced exacerbations in both asthma and COPD. It will also review existing treatments and future treatments that are in advanced stages of development.

Cystic fibrosis presenting in adults.

Cystic fibrosis is a common genetic disease occurring in children. Milder forms of cystic fibrosis are increasingly being recognized as presenting in adults as well. This article describes the various ways in which cystic fibrosis can present in adult patients.