title: Toll-like receptor 9 dependent interferon-α release is impaired in severe asthma but is not associated with exacerbation frequency.
abstract: Patients with asthma and chronic obstructive pulmonary disease (COPD) are susceptible to exacerbations, often caused by microbial pathogens. We hypothesised that intracellular Toll-like receptor (TLR) function in blood mononuclear cells (PBMCs) from these subjects would be impaired and that this impairment is related to exacerbation frequency. PBMCs stimulated with a TLR-9 agonist (but not TLR-3 or 7/8) produced significantly less IFN-α in asthma (26 [3-696]pg/ml) compared to control (943 [164-1651]) and COPD (597 [127-1186]) subjects (p = 0.0019) but this was not related to the number of exacerbations per year in asthma or COPD. In COPD, IFN-α levels were related to KCO (% predicted) in COPD (r = -0.41, p = 0.01). IFN-α was derived from plasmacytoid dendritic cells (pDCs) and their frequency was lower in asthma compared to control subjects (control 0.48% [0.33-0.64] versus asthma 0.29% [0.13-0.34], p = 0.019) whereas pDC function per se was not significantly impaired between groups. The mechanism underlying reduced IFN-α production and the clinical consequences in severe asthma remains to be established.
authors: Institute of Lung Health, Respiratory Biomedical Unit, University Hospitals of Leicester NHS Trust, Leicestershire, UK. Electronic address: Aw287@le.ac.uk.
authors: Adam K A
authors: AK
authors: Wright
authors: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors: Vijay
authors: V
authors: Mistry
authors: Institute of Lung Health, Respiratory Biomedical Unit, University Hospitals of Leicester NHS Trust, Leicestershire, UK.
authors: Matthew
authors: M
authors: Richardson
authors: Institute of Lung Health, Respiratory Biomedical Unit, University Hospitals of Leicester NHS Trust, Leicestershire, UK.
authors: Maria
authors: M
authors: Shelley
authors: Institute of Lung Health, Respiratory Biomedical Unit, University Hospitals of Leicester NHS Trust, Leicestershire, UK.
authors: Tracy
authors: T
authors: Thornton
authors: Institute of Lung Health, Respiratory Biomedical Unit, University Hospitals of Leicester NHS Trust, Leicestershire, UK.
authors: Sarah
authors: S
authors: Terry
authors: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors: Bethan
authors: B
authors: Barker
authors: Department of Respiratory Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, UK.
authors: Mona
authors: M
authors: Bafadhel
authors: Institute of Lung Health, Respiratory Biomedical Unit, University Hospitals of Leicester NHS Trust, Leicestershire, UK; Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors: Chris
authors: C
authors: Brightling
mesh_terms: D000368:Aged; D001249:Asthma / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9
keywords: Asthma; COPD; Emphysema; IFN-α; pDC