Background The pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether this improvement is the result of better mechanical properties of the airways or decreased systemic and bronchial inflammation remains unclear. Methods A longitudinal study in obese patients with asthma (bariatric surgery and asthma group (BS+A), n=27) and obese control (bariatric surgery without asthma group (BS−A), n=39) subjects undergoing bariatric surgery, and obese patients with asthma without intervention (no bariatric surgery and asthma group (NBS+A), n=12). Lung function, asthma control, cellular infiltrates in bronchial biopsies and circulating markers of systemic inflammation were measured during follow up at 3, 6 and 12 months. Results Bariatric surgery resulted in a profound weight loss at 12 months. In the BS+A group as well as the BS−A group FEV₁, functional residual capacity, total lung capacity improved, whereas FEV₁/FVC only improved in the BS−A group. In addition, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire, inhaled corticosteroid use and PD₂₀ improved in BS+A, whereas in the NBS+A group only ACQ improved. Small airway function R₅–R₂₀ improved in both surgery groups, however the change in the BS+A group was greater, resulting in a comparable R₅–R₂₀ between BS+A and BS−A at 12-month follow-up. Besides improvement of systemic inflammation (high sensitivity C-reactive protein, adiponectin and leptin) after BS, only a decrease in mast cell numbers was detectable in the BS+A group. Conclusions Bariatric surgery improved small airway function, decreased systemic inflammation and number of mast cells in the airways. These effects could explain the improvement of asthma control, quality of life and lung function. Therefore bariatric surgery, in addition to all other positive effects, also improves asthma in subjects with morbid obesity. Trial registration number 3204.

Inflammasome activation and caspase-1–dependent (CASP1-dependent) processing and secretion of IL-1β and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1β promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence, and protection against allergic asthma, which is a hallmark of H. pylori–infected mice and humans. Here, we show that inflammasome activation in DCs requires the cytoplasmic sensor NLRP3 as well as induction of TLR2 signaling by H. pylori. Screening of an H. pylori transposon mutant library revealed that pro–IL-1β expression is induced by LPS from H. pylori, while the urease B subunit (UreB) is required for NLRP3 inflammasome licensing. UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. ureB-deficient H. pylori mutants were defective for CASP1 activation in murine bone marrow–derived DCs, splenic DCs, and human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants failed to induce IL-1β and IL-18 secretion and to promote Treg responses. Unlike WT H. pylori, ureB mutants were incapable of conferring protection against allergen-induced asthma in murine models. Together, these results indicate that the TLR2/NLRP3/CASP1/IL-18 axis is critical to H. pylori–specific immune regulation.

Aims Limited data exist on the risk of developing cardiac sarcoidosis (CS) and/or adverse events in sarcoidosis patients. Using LV global longitudinal strain (GLS), an emerging sensitive parameter of LV function, we evaluated the prevalence of subclinical cardiac dysfunction in sarcoidosis and investigated whether LVGLS predicts adverse outcomes in this population. Methods and results A total of 130 patients with proven sarcoidosis undergoing echocardiography at our referral centre were identified. Following exclusion of those with evidence of CS (n = 14) or other pre-existing structural heart disease (n = 16), 100 patients (55 ± 13 years, 48% male, 90% pulmonary involvement) and 100 age- and gender-matched controls were included. LVGLS was measured by speckle-tracking analysis. The primary endpoint was a composite of all-cause mortality, heart failure hospitalization, device implantation, new arrhythmias, or future development of CS on advanced cardiac imaging modalities. LVGLS was significantly impaired in sarcoidosis patients compared with controls (–17.3 ± 2.5 vs. –20.0 ± 1.6%, P < 0.001). Overall, 27 patients (27%) reached the endpoint during a median follow-up of 35 months. On Cox proportional hazards model analysis, abnormal 24-h Holter, larger LV end-diastolic diameters, and more impaired LVGLS were significantly associated with the endpoint; however, only LVGLS remained independently associated on multivariate analysis [hazard ratio (HR) 1.4, 95% confidence interval (CI) 1.1–1.7, P = 0.006]. Patients with LVGLS less than –17.3% were significantly more likely to be free of the primary endpoint (log-rank P = 0.01). Conclusion LVGLS is impaired in sarcoidosis patients, suggesting subclinical cardiac dysfunction despite the absence of conventional evidence of cardiac disease, and is independently associated with occurrence of cardiac events and/or development of CS.

Significance: Allergic asthma represents an increasingly common public health problem. Here, we provide preclinical evidence for the efficacy of active tolerization using Helicobacter pylori components as a viable strategy for asthma prevention. We use a mouse model of allergic asthma to show that regular treatment with H. pylori extract effectively alleviates all hallmarks of the disease. Successful treatment depends on the regulatory cytokine IL-10 and on basic leucine zipper ATF-like 3 (BATF3)-dependent dendritic cell lineages. H. pylori extracts lacking the γ-glutamyl-transpeptidase GGT or the vacuolating cytotoxin VacA fail to protect against asthma; conversely, both factors can be administered in purified form to achieve protection. In conclusion, the immunomodulatory properties of the common infectious agent H. pylori can be exploited for therapeutic purposes in an allergy model.

Human studies demonstrated that allergen-specific immunotherapy (IT) represents an effective treatment for allergic diseases. IT involves repeated administration of the sensitizing allergen, indicating a crucial contribution of T cells to its medicinal benefit. However, the underlying mechanisms of IT, especially in a chronic disease, are far from being definitive. In the current study, we sought to elucidate the suppressive mechanisms of IT in a mouse model of chronic allergic asthma. OVA-sensitized mice were challenged with OVA or PBS for 4 wk. After development of chronic airway inflammation, mice received OVA-specific IT or placebo alternately to airway challenge for 3 wk. To analyze the T cell–mediated mechanisms underlying IT in vivo, we elaborated the role of T-bet–expressing Th1 cells, T cell–derived IL-10, and Ag-specific thymic as well as peripherally induced Foxp3⁺ regulatory T (Treg) cells. IT ameliorated airway hyperresponsiveness and airway inflammation in a chronic asthma model. Of note, IT even resulted in a regression of structural changes in the airways following chronic inhaled allergen exposure. Concomitantly, IT induced Th1 cells, Foxp3⁺, and IL-10–producing Treg cells. Detailed analyses revealed that thymic Treg cells crucially contribute to the effectiveness of IT by promoting IL-10 production in Foxp3-negative T cells. Together with the peripherally induced Ag-specific Foxp3⁺ Treg cells, thymic Foxp3⁺ Treg cells orchestrate the curative mechanisms of IT. Taken together, we demonstrate that IT is effective in a chronic allergic disease and dependent on IL-10 and thymic as well as peripherally induced Ag-specific Treg cells.

Mesenchymal stromal cells (MSCs) are investigated for their potential to reduce inflammation and to repair damaged tissue. Inflammation and tissue damage are hallmarks of chronic obstructive pulmonary disease (COPD) and MSC infusion is a promising new treatment for COPD. Inflammatory mediators attract MSCs to sites of inflammation and affect their immune-modulatory properties, but little is known about their effect on regenerative properties of MSCs. This study investigates the effect of the pro-inflammatory cytokines TNF-α and IL-1β on the regenerative potential of MSCs, using an in vitro wound healing model of airway epithelial cells. Standardized circular wounds were created by scraping cultures of the airway epithelial cell line NCI-H292 and primary bronchial epithelial cells cultured at the air-liquid interface (ALI-PBEC), and subsequently incubated with MSC conditioned medium (MSC-CM) that was generated in presence or absence of TNF-α/IL-1β. Remaining wound size was measured up to 72 h. Phosphorylation of ERK1/2 by MSC-CM was assessed using Western blot. Inhibitors for EGFR and c-Met signaling were used to investigate the contribution of these receptors to wound closure and to ERK1/2 phosphorylation. Transactivation of EGFR by MSC-CM was investigated using a TACE inhibitor, and RT-PCR was used to quantify mRNA expression of several growth factors in MSCs and NCI-H292. Stimulation of MSCs with the pro-inflammatory cytokines TNF-α and IL-1β increased the mRNA expression of various growth factors by MCSs and enhanced the regenerative potential of MSCs in an in vitro model of airway epithelial injury using NCI-H292 airway epithelial cells. Conditioned medium from cytokine stimulated MSCs induced ERK1/2 phosphorylation in NCI-H292, predominantly via EGFR; it induced ADAM-mediated transactivation of EGFR, and it induced airway epithelial expression of several EGFR ligands. The contribution of activation of c-Met via HGF to increased repair could not be confirmed by inhibitor experiments. Our data imply that at sites of tissue damage, when inflammatory mediators are present, for example in lungs of COPD patients, MSCs become more potent inducers of repair, in addition to their well-known immune-modulatory properties.