The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations

Rhinovirus infections are the major cause of asthma exacerbations. We hypothesised that IL-15, a cytokine implicated in innate and acquired antiviral immunity, may be deficient in asthma and important in the pathogenesis of asthma exacerbations. We investigated regulation of IL-15 induction by rhinovirus in human macrophages in vitro, IL-15 levels in bronchoalveolar lavage (BAL) fluid and IL-15 induction by rhinovirus in BAL macrophages from asthmatic and control subjects, and related these to outcomes of infection in vivo. Rhinovirus induced IL-15 in macrophages was replication-, NF-κB- and α/β interferon-dependent. BAL macrophage IL-15 induction by rhinovirus was impaired in asthmatics and inversely related to lower respiratory symptom severity during experimental rhinovirus infection. IL-15 levels in BAL fluid were also decreased in asthmatics and inversely related with airway hyperresponsiveness and with virus load during in vivo rhinovirus infection. Deficient IL-15 production in asthma may be important in the pathogenesis of asthma exacerbations

Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD4+ and CD8+ T cells in atopic asthma

Increased Th2 cytokine production in asthma is widely accepted, but excess production by asthmatic human airway CD4+ T cells has not been demonstrated, nor has a relationship with disease severity. The importance of airway CD8+ T cell type 1 and type 2 cytokine production in asthma is unknown. We investigated frequencies of IFN-{gamma}, interleukin (IL)-4 and IL-5 producing CD4+ and CD8+ blood and sputum T cells from normal subjects and subjects with asthma and compared between cell subsets, subject groups, and body compartments with and without in vitro stimulation and investigated relationships between cytokine production and asthma severity. Production of IL-4, IL-5, and IFN-{gamma} by unstimulated sputum CD4+ and CD8+ T cells was increased in subjects with asthma and related to disease severity, more for CD8+ than for CD4+ T cells. Frequencies of sputum CD8+ T cells producing type 1 and type 2 cytokines were similar to those of CD4+ T cells. In vitro stimulation polarized peripheral blood cytokine production toward IFN-{gamma} production, significantly more in subjects with asthma than in normal subjects. These data demonstrate increased type 1 and 2 cytokine production in CD4+ and CD8+ T cells in sputum and relate production to disease severity. Findings in blood did not reflect those in airways

Vitamin D modulation of innate immune responses to respiratory viral infections.

International audienceVitamin D, in addition to its classical functions in bone homeostasis, has a modulatory and regulatory role in multiple processes, including host defense, inflammation, immunity, and epithelial repair. Patients with respiratory disease are frequently deficient in vitamin D, implying that supplementation might provide significant benefit to these patients. Respiratory viral infections are common and are the main trigger of acute exacerbations and hospitalization in children and adults with asthma and other airways diseases. Respiratory monocytes/macrophages and epithelial cells constitutively express the vitamin D receptor. Vitamin D, acting through this receptor, may be important in protection against respiratory infections. Whether the in vitro findings can be translated into a substantial in vivo benefit still remains uncertain. Here we review the in vitro data on the role of vitamin D in antiviral innate immunity, the data concerning the deficient levels of vitamin D in lung diseases, and the in vivo role of supplementation as protection against respiratory viral infections in healthy individuals and in patients with chronic respiratory diseases. Finally, we suggest ways of improving the effectiveness of vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections

Effect of desloratadine and loratadine on rhinovirus-induced intercellular adhesion molecule 1 upregulation and promoter activation in respiratory epithelial cells

Background: Rhinoviruses have been recently associated with the majority of asthma exacerbations for which current therapy is inadequate. Intercellular adhesion molecule 1 (ICAM-1) has a central role in airway inflammation in asthma, and it is the receptor for 90% of rhinoviruses. Rhinovirus infection of airway epithelium induces ICAM-1. Desloratadine and loratadine are compounds belonging to the new class of H1-receptor blockers. Anti-inflammatory properties of antihistamines have been recently documented, although the underlying molecular mechanisms are not completely defined. Objective: We have investigated the effects of desloratadine and loratadine on rhinovirus-induced ICAM-1 expression, mRNA upregulation, and promoter activation.Methods: Cultured primary bronchial or transformed (A549) respiratory epithelial cells were pretreated with desloratadine and loratadine for 16 hours and infected with rhinovirus type 16 for 8 hours. ICAM-1 surface expression was evaluated with flow cytometry, and ICAM-1 mRNA was evaluated with specific RT-PCR. In A549 cells promoter activation was evaluated with a chloramphenicol acetyltransferase assay, and binding activity of nuclear factor ?B in nuclear extracts was evaluated with an electrophoretic mobility shift assay.Results: Desloratadine and loratadine (0.1-10 ?mol/L) inhibited rhinovirus-induced ICAM-1 upregulation in both primary bronchial or transformed (A549) respiratory epithelial cells. In A549 cells the 2 compounds showed a dose-dependent inhibition with similar efficacy (inhibitory concentration of 50%, 1 ?mol/L). Desloratadine and loratadine also inhibited ICAM-1 mRNA induction caused by rhinovirus infection in a dose-dependent manner, and they completely inhibited rhinovirus-induced ICAM-1 promoter activation. Desloratadine also inhibited rhinovirus-induced nuclear factor ?B activation. Desloratadine and loratadine had no direct effect on rhinovirus infectivity and replication in cultured epithelial cells.Conclusion: These effects are unlikely to be mediated by H1-receptor antagonism and suggest a novel mechanism of action that may be important for the therapeutic control of virus-induced asthma exacerbations

Bronchial mucosal IFN-α/β and pattern recognition receptor expression in patients with experimental rhinovirus-induced asthma exacerbations

Background: The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. Objectives: We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. Methods: Immunohistochemistry was used to detect expression of IFN-α, IFN-β, and the PRRs: Toll-like receptor 3, melanoma differentiation–associated gene 5, and retinoic acid–inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. Results: We observed IFN-α/β deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/β expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection–increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. Conclusions: Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β–expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity