Pulmonary TH2 response in Pseudomonas aeruginosa–infected patients with cystic fibrosis

Hartl, Dominik; Griese, Matthias; Kappler, Matthias; Zissel, Gernot; Reinhardt, D.; Rebhan, Christian; Schendel, Dolores J.; Krauss‐Etschmann, Susanne

doi:10.1016/j.jaci.2005.09.023

Cited by 168 publications

(148 citation statements)

References 41 publications

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“…Consistent with this finding is the normal presentation via the CD1 pathway in blood-derived CF DCs (16). Interestingly, decreased MHCII expression has been seen on CF neutrophils (12), aberrant, Th2-biased cytokine secretion has been reported for CF lymphocytes of patients with pulmonary P. aeruginosa infection (17), and CF monocytes and neutrophils were shown to be abnormally stimulated (7). Bone marrow-derived DCs from CF mice show delayed maturation (11).…”

supporting

confidence: 52%

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Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) leads to chronic inflammation and infection of the respiratory tract. The role of CFTR for cells of the pulmonary immune system is only partly understood. The present study analyzes the phenotype and immune stimulatory capacity of lung dendritic cells (DCs) from CFTR knockout (CF) mice. Total numbers of conventional DCs, plasmacytoid DCs, and CD103-positive DCs were lower in CF mice compared with wild-type (WT) control mice, as was the expression of major histocompatibility complex class II molecules (MHCII), CD40, and CD86. After pulmonary infection with respiratory syncytial virus, DC numbers increased in WT mice but not in CF mice, and the T cellstimulatory capacity of CF DCs was impaired. The culture of CF lung DCs with bronchoalveolar lavage fluid (BALF) from WT mice increased the expression of MHCII, CD40, and CD86. The supplementation of CF BALF with sphingosine-1-phosphate (S1P), a mediator of immune cell migration and activation that is decreased in CF BALF, rescued the reduced expression of MHCII and CD40 in WT lung DCs and human blood DCs. These findings suggest that DCs are impaired in the CF lung, and that altered S1P affects lung DC function. These findings provide a novel link between defective CFTR and pulmonary innate immune dysfunction in CF.

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supporting

confidence: 52%

“…The numbers of both cDCs and pDCs were decreased in CF mice, which may cause a shift in the T-helper cell balance, and could thus be responsible for changes in the type of immune responses to inhaled antigens. Various studies have described a Th2-favoring imbalance in the CF lung (17,33). CD103…”

Section: Discussionmentioning

confidence: 99%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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“…Although TNF-␣ and IFN-␥ induce the expression of HBD-2 and HBD-3, this induction is significantly inhibited by the addition of the Th2 cytokines IL-4 and IL-13. Understanding the mechanism by which IL-4 and IL-13 inhibit HBD expression is important because these cytokines are increased in AD skin and lavage fluid of CF patients (13,26). Additionally, the increased expression of IL-4 and IL-13 in AD skin is thought to increase the propensity of these patients to recurrent bacterial and viral skin infections by reducing AMP expression (5,16,27).…”

Section: Effect Of Socs-1 and Socs-3 Is Regulated By Stat-6mentioning

confidence: 99%

“…Recent studies have shown that HBD-2 and HBD-3 are effective at killing Staphylococcus aureus and Pseudomonas aeruginosa (3,5), two bacteria associated with chronic infection in AD and CF patients, respectively (11,12). Additionally, it has been shown that S. aureus and P. aeruginosa potentiate a Th2 environment (13,14). Previously, we have shown that the Th2 cytokines, IL-4 and IL-13, down-regulate HBD expression in AD keratinocytes (5,10,15).…”

mentioning

confidence: 93%

IL-4 and IL-13 Negatively Regulate TNF-α- and IFN-γ-Induced β-Defensin Expression through STAT-6, Suppressor of Cytokine Signaling (SOCS)-1, and SOCS-3

Albanesi

Fairchild

Madonna

et al. 2007

The Journal of Immunology

181

160

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Human β-defensins (HBDs) are a major class of antimicrobial peptides that play an important role in the innate immune response, however, the induction and regulation of these antimicrobial peptides is not well understood. We demonstrate here that stimulation of keratinocytes with TNF-α/IFN-γ induces HBD-2 and HBD-3 by activating STAT-1 and NF-κB signaling. We further demonstrate that IL-4 and IL-13 activate STAT-6 and induce the suppressors of cytokine signaling (SOCS)-1 and -3. This interferes with STAT-1 and NF-κB signaling, thereby inhibiting TNF-α/IFN-γ-mediated induction of HBD-2 and HBD-3. These data suggest that targeting the STAT-1-signaling pathway or suppressor of cytokine signaling expression enhances β-defensin expression and represents a new therapeutic strategy for reduction of infection in human diseases associated with β-defensin deficiency.

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“…In fact, CF patients were recently characterized to have excessive IL-4 and IL-13 production, which may have a direct influence in the prevalence of allergic asthma in this population. [25][26][27][28] Approximately 5.5% of American children are afflicted with asthma. Although this represents a very high prevalence, asthma is much more common in children with CF, where the rate of bronchial hyper-responsiveness approaches 50%, and up to 10-15% may experience a hyper-IgE asthma variant known as allergic bronchopulmonary aspergillosis (ABPA).…”

Section: Introductionmentioning

confidence: 99%