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Background Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. Conclusions Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients. Graphical abstract [ABSTRACT FROM AUTHOR]

Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (F eno ) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had F eno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of F eno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of F eno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics. [ABSTRACT FROM AUTHOR]

Background Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. Objectives We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. Methods Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. Results Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. Conclusion Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways. [ABSTRACT FROM AUTHOR]

Background: Airway inflammation associated with asthma has been reported to be either unaffected or slightly increased by inhaled β-agonist monotherapy, and concerns regarding disease exacerbations with continuous long-acting β-agonist monotherapy have prompted the recommendation of concomitant steroid treatment. Objectives: Using peripheral blood lymphocytes from asthmatic subjects, we aimed to determine (1) whether short- or long-acting β-agonists increase IL-13–producing (IL-13+) or IFN-γ–producing (IFN-γ+) T-cell numbers and (2) the ability of the corticosteroid budesonide to reverse these effects. Methods: Peripheral blood lymphocytes from asthmatic subjects were cultured 6 days ex vivo with IL-2 and various concentrations of albuterol, formoterol, and budesonide. Numbers of IL-13+ and IFN-γ+ T cells were determined by means of flow cytometric analysis. Results: Both albuterol and formoterol increased IL-2–stimulated accumulation of IL-13+ T cells, and this increase was highest at concentrations approximating the dissociation constant of each β-agonist for the β2-adrenergic receptor. Budesonide at greater than 1 nmol/L reversed the augmenting effects of β-agonists on IL-13+ T-cell accumulation, and budesonide at greater than 10 nmol/L inhibited increases in IL-13+ T cells stimulated by IL-2. Budesonide decreased, whereas β-agonist did not affect, numbers of total and IFN-γ+ T cells in IL-2–stimulated cultures. Conclusion: β-Agonists at physiologically and clinically relevant concentrations stimulate increased antigen-independent, cytokine-stimulated accumulation, specifically of type 2 T cells from asthmatic subjects. The corticosteroid budesonide potently reverses this effect. [Copyright &y& Elsevier]

Background: IL4R, the gene encoding the α chain of the IL-4 and IL-13 receptors, has received extensive attention as a candidate gene for asthma risk. However, the results from studies testing for associations of the I50V and Q551R IL4R genetic variants are conflicting. Objective: We sought to determine the average risk of asthma associated with the I50V and Q551R IL4R variants based on the results of case-control studies reported in the literature. Methods: Meta-analyses were performed with data from case-control association studies that met specified inclusion criteria (9 and 8 studies for I50V and Q551R, respectively). Random-effects models were used to calculate combined odds ratios (ORs) and significance of associations. Analyses were performed for asthma in general and for subgroups based on the atopy status of the asthma population. Results: The R551 IL4R variant was significantly associated with increased risk of asthma, most notably atopic asthma (combined OR, 1.6; P = .004). Exclusion of the outlier study reporting an OR of less than 1 greatly increased the significance of association (OR, 1.8; P = 3 × 10−9). I50V variants were not significantly associated with asthma. Conclusions: A meta-analysis of results from case-control studies strongly supports the conclusion that the R551 IL4R variant imparts a modest yet significant risk for atopic asthma. Clinical implications: Knowledge that the R551 IL4R variant is associated with increased asthma risk should provide a basis for understanding the heterogeneity of asthma pathogenesis and for pharmacogenetic approaches to treat individuals carrying this variant. [Copyright &y& Elsevier]

Background: Neurohumoral modulation of immune system function is poorly understood. β-Adrenergic receptor ligands (β-agonists) subserve numerous physiologic processes but also function as pathogenic or therapeutic agents in numerous diseases with inflammatory components. Objectives: We sought to establish the effects of β-agonists and prostaglandin E2 (PGE2) on antigen-dependent and antigen-independent accumulation of IL-13+ (type 2) and IFN-γ+ (type 1) T cells. We also sought to clarify the mechanisms mediating the effects of these G protein–coupled receptor agonists. Methods: Effects of β-agonists or PGE2 on T-cell subtype accumulation were assessed in peripheral blood lymphocytes cultured with αCD3/CD28 or IL-2 by using flow cytometry. The role of cyclic AMP-dependent protein kinase (PKA) in mediating agonist effects was assessed by means of characterization of (1) phosphorylation of an intracellular PKA substrate and (2) T cells from patients with lupus possessing a natural defect in PKA activation. Results: β-Agonists, in contrast to PGE2, increased IL-2–induced accumulation of human type 2 T cells, an effect attributable to differential activation of PKA affecting regulation of cell proliferation and apoptosis. In T cells from patients with lupus exhibiting defective PKA activation, both β-agonists and PGE2 promoted an increase in type 2 T-cell accumulation. Conclusion: Gs-coupled receptors have the capacity to elicit prosurvival signaling in type 2 T cells, which, in most instances, is obscured by concomitant and antimitogenic PKA activation. Clinical implications: β-Agonists and other Gs-coupled receptor agonists have the potential to regulate T-cell development to affect disease pathogenesis or the efficacy of therapies, and variability of effect relates to the ability to stimulate PKA activity. [Copyright &y& Elsevier]

It has been proposed that immune responses to intra- (type 1) and extra-cellular (type 2) pathogens are regulated by two T-cell subsets branching from type 0 cells on T-cell receptor (TCR) engagement and terminally differentiating in distinct cytokine environments. However, analysis at the single-cell level of human T cells and natural killer (NK) cells has revealed that peripheral immature cells of both lineages exist, produce only type 2 cytokines and either proliferate or differentiate to interferon-γ producing cells in distinct cytokine environments, even without TCR engagement. These data support the hypothesis that a modified balance between proliferation and/or survival and differentiation of immature type 2 cytokine-producing cells regulates productive, type 1, immune responses. This new concept provides a simpler and testable framework to understand and manipulate the immune system and immune pathologies. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma," by P. Nair and colleagues in the 2010 issue.

Abstract: We have defined the existence of developmental relationships among human peripheral NK cells with distinct phenotypic and functional characteristics. These findings closely parallel the changes that occur in vivo during NK cell development, and in vitro in experimental culture systems supporting NK cell generation from hematopoietic progenitors. These new insights provide a simplified framework to understand NK cell immunobiology and the cellular bases for their roles in innate immunity, initiation and maintenance of immune responses via regulation of adaptive and accessory cell functions, and immune pathologies. [Copyright &y& Elsevier]