Atopic Phenotype in Children Is Associated with Decreased Virus-Induced Interferon-α Release

Bufe, Albrecht; Gehlhar, Kirsten; Grage-Griebenow, Evelin; Ernst, Martin

doi:10.1159/000048173

Cited by 101 publications

(95 citation statements)

References 28 publications

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“…Several groups of investigators have reported that cultured cells from adults and children with asthma synthesise less type I and type III IFN in response to in vitro infection with live viruses [7][8][9][10]. Our study adds to these earlier studies by highlighting abnormal TLR7 function in asthma, implying that an impaired response to viral ssRNA (the natural ligand for TLR7) may contribute to impaired anti-viral innate immunity in this disease.…”

Section: Discussionsupporting

confidence: 53%

“…When cultured bronchial epithelial cells are infected with RV, cells from asthmatic subjects produce less interferon (IFN)-b and IFN-l relative to healthy donors [7,8]. Alveolar macrophages and circulating leukocytes from asthmatics also appear to have a deficient capacity to synthesise type I and type III IFN [7,9,10], suggesting that the impaired anti-viral response in asthma involves not just structural cells of the lung, but also migratory immune cells and their precursors within the circulation. However, the molecular mechanisms leading to altered anti-viral innate immunity in asthma are not clear.…”

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confidence: 99%

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Toll-like receptor 7 function is reduced in adolescents with asthma

Roponen¹,

Yerkovich²,

Hollams³

et al. 2009

Eur Respir J

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Anti-viral innate immune responses may be impaired in asthma, although the mechanisms are not well understood. Toll-like receptors (TLRs) 7 and 3 are particularly relevant for initiating responses to common respiratory viruses, as they recognise single-stranded viral RNA and double-stranded viral RNA, respectively. The aim of the present study was to investigate TLR7 and TLR3 function in 14-yr-old adolescents with asthma.Blood mononuclear cells obtained from 17 atopic asthmatics, 29 atopic, non-asthmatics and 21 healthy, non-atopic individuals, were stimulated with the TLR7 agonist imiquimod and the TLR3 agonist poly I:C. Expression of anti-viral molecules was measured by real-time PCR. Concentrations of interferon-c-inducible cytokine protein (IP)-10 and interleukin (IL)-6 were measured by ELISA.TLR7-induced myxovirus resistance protein A and 2959 oligoadenylate synthetase mRNA expression and protein levels of IP-10 were significantly lower in asthma subjects compared with healthy subjects (p50.041, p50.003 and p50.001 respectively). There was a significant negative correlation between total serum immunoglobulin E and IP-10 following TLR7 stimulation. However, TLR3-induced responses did not vary with asthma or atopy. IL-10 mRNA and IL-6 protein synthesis were similar in asthmatic and control subjects. In conclusion, TLR7 function is reduced in adolescents with asthma and this may contribute to susceptibility to respiratory viral infections.KEYWORDS: Asthma, innate immunity, Toll-like receptor, virus V iral respiratory infections, especially with rhinovirus (RV), are a major cause of asthma exacerbations in children and adults [1][2][3]. Adults with asthma do not necessarily have more frequent RV infections than healthy individuals, but when RV infections occur they induce more frequent and longer lasting lower respiratory tract symptoms [4].The mechanisms by which viral infections aggravate airway inflammation and hyperresponsiveness in asthma are complex and not fully understood, although defects in anti-viral immune responses are increasingly recognised. Viraemia during acute RV infection is more commonly detected in children with acute asthma exacerbations than in non-asthmatic children with colds [5], suggesting that asthma is associated with a reduced ability to limit systemic spread of virus. Moreover, RV RNA can be detected in respiratory secretions in .40% of asthmatic children several weeks after an acute exacerbation [6], implying a reduced capacity to either clear RV from the respiratory tract, or to prevent new infections during convalescence.Recent studies have provided important insights into anti-viral innate immunity in asthma. When cultured bronchial epithelial cells are infected with RV, cells from asthmatic subjects produce less interferon (IFN)-b and IFN-l relative to healthy donors [7,8]. Alveolar macrophages and circulating leukocytes from asthmatics also appear to have a deficient capacity to synthesise type I and type III IFN [7,9,10], suggesting that the impaired anti-viral re...

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Section: Discussionsupporting

confidence: 53%

mentioning

confidence: 99%

Toll-like receptor 7 function is reduced in adolescents with asthma

Roponen¹,

Yerkovich²,

Hollams³

et al. 2009

Eur Respir J

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“…In support of a common underlying predisposition, low IFN-g responses during early life have been associated with greater risk of early childhood wheeze and allergy (12)(13)(14). Furthermore, impaired innate immune responses have been associated with allergy and asthma (15,16). However, our data regarding the directionality of the observed relationship between allergic sensitization and HRV-wheezing illness demonstrate that the former is significantly more likely to precede the development of the latter.…”

Section: Discussionmentioning

confidence: 51%

Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

Jackson

Evans

Gangnon

et al. 2012

Am J Respir Crit Care Med

310

270

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Rationale: Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. Objective: To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. Methods: A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. Measurements and Main Results: Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1). Conclusions: Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.Keywords: virus; wheezing; allergic sensitization; RSV; human rhinovirus Aeroallergen sensitization and virus-induced wheezing episodes during infancy and early childhood are risk factors for subsequent asthma development, and children with both risk factors in early life are at particularly high risk of having asthma at school age (1, 2). Understanding the sequence of events that lead to sensitization and virus-induced wheezing during early life is important to identifying potential causal relationships in the development of atopic asthma. Early allergic sensitization has consistently been identified as a risk factor for asthma development, and plausible mechanisms by which allergic sensitization leads to greater severity of viral respiratory illnesses have also been proposed (3). If allergic sensitization causes subsequent virus-induced wheezing and asthma inception, then preventing or interrupting the development of allergic sensitization would be a potential strategy for asthma prevention.In contrast to this concept, some animal models of early life infection suggest that virus infection could lead to allergic sensitization (4, 5). In clinical studies, S...

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“…RV-stimulated alveolar macrophages from asthmatics produce less IFN-l than alveolar macrophages from healthy individuals (7). PBMC from asthmatic children and adults secrete less IFN-a following in vitro exposure to viruses (11,12), and this is associated with reduced function of TLR7, the receptor for viral ssRNA (13). Plasmacytoid dendritic cells (pDC) are a potent source of type-I IFN synthesis during virus infections (14), and numerical changes in circulating pDC have been linked both to asthma development in young children (15) and to established asthma in adults (16).…”

mentioning

confidence: 99%

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Pritchard

Carroll

Burel

et al. 2012

The Journal of Immunology

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Human rhinoviruses (RV) cause only minor illness in healthy individuals, but can have deleterious consequences in people with asthma. This study sought to examine normal homeostatic mechanisms regulating adaptive immunity to RV in healthy humans, focusing on effects of IFN-αβ and plasmacytoid dendritic cells (pDC) on Th2 immune responses. PBMC were isolated from 27 healthy individuals and cultured with RV16 for up to 5 d. In some experiments, IFN-αβ was neutralized using a decoy receptor that blocks IFN signaling, whereas specific dendritic cell subsets were depleted from cultures with immune-magnetic beads. RV16 induced robust expression of IFN-α, IFN-β, multiple IFN-stimulated genes, and T cell-polarizing factors within the first 24 h. At 5 d, the production of memory T cell-derived IFN-γ, IL-10, and IL-13, but not IL-17A, was significantly elevated. Neutralizing the effects of type-I IFN with the decoy receptor B18R led to a significant increase in IL-13 synthesis, but had no effect on IFN-γ synthesis. Depletion of pDC from RV-stimulated cultures markedly inhibited IFN-α secretion, and led to a significant increase in expression and production of the Th2 cytokines IL-5 (p = 0.02), IL-9 (p < 0.01), and IL-13 (p < 0.01), but had no effect on IFN-γ synthesis. Depletion of CD1c+ dendritic cells did not alter cytokine synthesis. In healthy humans, pDC and the IFN-αβ they secrete selectively constrain Th2 cytokine synthesis following RV exposure in vitro. This important regulatory mechanism may be lost in asthma; deficient IFN-αβ synthesis and/or pDC dysfunction have the potential to contribute to asthma exacerbations during RV infections.

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Atopic Phenotype in Children Is Associated with Decreased Virus-Induced Interferon-α Release

Cited by 101 publications

References 28 publications

Toll-like receptor 7 function is reduced in adolescents with asthma

Toll-like receptor 7 function is reduced in adolescents with asthma

Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

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