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Asthma is a heterogeneous disease consisting of several inflammatory phenotypes of which neutrophilic asthma is associated with poorer responses to classic therapies, namely (inhaled) corticosteroids. The development of targeted therapies requires the identification of biomarkers to distinguish these phenotypes. Currently, we lack validated biomarkers for non-eosinophilic asthma. The aim of this study is to examine serum calprotectin (SC) in asthmatics and its potential as biomarker for neutrophilic asthma. Hundred-seventeen severe asthmatics were referred for sputum induction and data were obtained from their medical records. To evaluate the association between SC and asthma phenotypes, patients were divided into subgroups based on sputum cell count (3% eosinophils and 61% neutrophils). Additionally, SC levels of asthmatics were compared with these of patients with chronic obstructive pulmonary disease, non-cystic fibrosis bronchiectasis and healthy controls. Asthmatics (n = 45) had significantly higher levels of SC than healthy controls. No significant differences were found between the different asthma phenotypes and in comparison with COPD patients. SC was significantly higher in asthmatics with a lower FEV1/FVC ratio (<70) and non-significantly elevated SC levels were seen in asthmatics with frequent exacerbations (>2 in the last year). In conclusion, there was no difference in SC levels between the different inflammatory subtypes in asthmatics. Nevertheless, severe asthmatics seemed to have higher SC levels suggesting that SC may be a marker of disease severity rather than a marker for specific inflammatory subtypes in asthmatics. Further research in larger cohorts is necessary to validate SC as biomarker in severe asthmatics. [ABSTRACT FROM AUTHOR]

Background Programmed cell death-1 (PD-1) is a negative regulator of T-cell responses. Expression of PD-1 and its ligands PD-L1 and PD-L2 in chronic rhinosinusitis with nasal polyps (CRSwNP) is poorly studied. Methods Expression of PD-1, PD-L1, PD-L2, TGF-β, IL-5, and IL-10 mRNA was measured by real-time quantitative PCR on tissue homogenates of patients with CRSwNP ( n = 21) and healthy controls ( n = 21) and on primary epithelial cells. Disease severity was scored using the Lund-Mackay scores of maxillofacial computed tomography (CT) scans. Expression of PD-1 and PD-L1/L2 was evaluated at the cellular and tissue levels ( n = 6) by flow cytometry and immunohistochemistry. Results Programmed cell death-1 mRNA expression was increased in tissue homogenates from patients with CRSwNP compared with controls, irrespective of the atopy status. Importantly, expression of PD-1 correlated with the total CT scan scores ( r = 0.5, P = 0.02). Additionally, a significant association was found between PD-1 mRNA and expression of IL-5 mRNA in control nasal tissue ( r = 0.95, P < 0.0001) and in CRSwNP ( r = 0.63, P = 0.002). PD-1 was expressed on different subsets of T cells and CD11b− dendritic cells. Both PD-1 and its ligands were expressed on primary epithelial cells from control nasal tissue and nasal polyp tissue. Conclusions Higher PD-1 expression was found in CRSwNP than in nasal tissue from controls. This was associated with disease severity and tissue IL-5 expression but unrelated to the patients' atopy status. [ABSTRACT FROM AUTHOR]

Background: Asthma is a chronic inflammatory disorder of the airways driven by I cell activation. Th2 cells and their cytokines are thought to play a role in the pathophysiology of allergic as well as non-allergic asthma. Methods: Airway cells were obtained by sputum induction from 15 healthy and 39 asthmatic individuals and the airway I cell cytokine profiles (interleukin (IL)-4, IL-5, IL-13, IL-10 and interferon (IFN)-γ) at the mRNA level were studied by real time RT-PCR. Results: Asthma patients had increased expression of IL-5 (p=0.001) and IL-13 (p=0.03) mRNA in sputum compared with non-asthmatic controls. IL-4 mRNA and IFN-γ mRNA were detectable in the sputum of 44% and 21% of patients, respectively, but not in controls. Sputum IL-10 mRNA levels did not differ significantly between patients and controls. Sputum mRNA expression levels of IL-4, IL-5, and IL-13 were significantly correlated with the percentage of easinophils and were higher in subjects with allergic asthma than in those with non-allergic asthma (p = 0.03, p = 0.02 and p = 0.0002, respectively); they did not differ between mild asthmatic subjects and those with moderate to severe asthma. In contrast, IFN-γ mRNA expression was higher in non-allergic than in allergic patients (p=0.04) and higher in patients with moderate to severe asthma than in those with mild asthma (p<0.01). Sputum IL-5 mRNA levels (but not the other cytokine mRNA levels) were also correlated with exhaled nitric oxide (eNO) and with bronchial hyperreactivity expressed as the histamine concentration resulting in a 20% decrease in forced expiratory volume in 1 second. Conclusion: Real time RT-PCR analysis of mRNA in induced sputum confirms a predominance of Th2 cytokines in bath allergic and non-allergic asthma. IL-5 levels reflect eosinophil infiltration as well as eNO levels and hyperreactivity, and levels of the Th1 cytokine IFN-γ indicate asthma severity. The technique is a promising tool for use in further studies of asthma severity and disease activity. [ABSTRACT FROM AUTHOR]

4-1BB ligand (4-1BBL) expressed on antigen-presenting cells interacts with 4-1BB on activated T cells (especially CD8+ cells) and co-stimulates the latter to secrete cytokines and to proliferate. The role of 4-1BB−4-1BBL interaction was studied here in a model of colitis based on naive CD4+ T cell transfer to SCID mice, a disease model in which CD8 cells do not take part. We found that CD4+ T cells from 4-1BB-deficient mice, after transfer in SCID mice, proliferated more rapidly compared to wild-type CD4+ T cells. Mice reconstituted with naive CD4+ T cells from 4-1BB-deficient mice developed colitis, however, with a mixed Th1/Th2 response, in contrast to the Th1-type response in mice reconstituted with wild-type naive CD4+ T cells. Importantly, this altered cytokine response did not temper colitis severity. Although it has been reported previously that 4-1BB co-stimulation may contribute to regulatory T cell functioning, we found that CD4+CD25+ regulatory T cells from 4-1BB-deficient mice were perfectly able to prevent naive CD4+ T cell-induced colitis. In conclusion, our data provide evidence that 4-1BB−4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function. [ABSTRACT FROM AUTHOR]

Abstract Background T helper 17 (Th17) cells can recruit neutrophils to inflammatory sites through production of IL-17, which induces chemokine release. IL-23 is an important inducer of IL-17 and IL-22 production. Our aim was to study the role of Th17 cells in cystic fibrosis (CF) lung disease by measuring IL-17 protein and mRNA levels and IL-22 and IL-23 mRNA in sputum of clinically stable CF patients and by comparing these levels with healthy controls. Methods Sputum induction was performed in adult CF patients outside of an exacerbation and healthy control subjects. IL-17A protein levels were measured in supernatants with cytometric bead array (CBA) and RNA was isolated and quantitative RT-PCR was performed for IL-17A, IL-22 and IL-23. Results We found significantly higher levels of IL-17A protein and mRNA levels (both: p < 0.0001) and IL-23 mRNA levels (p < 0.0001) in the sputum of CF group as compared to controls. We found very low levels of IL-22 mRNA in the CF group. The levels of IL-17 and IL-23 mRNA were higher in patients chronically infected with Pseudomonas aeruginosa (P. aeruginosa) as compared to those who were not chronically infected with P. aeruginosa. The presence of Staphylococcus aureus (S. aureus) on sputum did not affect the IL-17 or IL-23 levels. There was no correlation between IL-17 or IL-23 levels and FEV1 nor sputum neutrophilia. Conclusion The elevated levels of IL-17 and IL-23 might indicate that Th17 cells are implicated in the persistent neutrophil infiltration in CF lung disease and chronic infection with P. aeruginosa.

Abstract Background The role of Th2 cells (producing interleukin (IL-)4, IL-5 and IL-13) in allergic asthma is well-defined. A distinct proinflammatory T cell lineage has recently been identified, called Th17 cells, producing IL-17A, a cytokine that induces CXCL8 (IL-8) and recruits neutrophils. Neutrophilic infiltration in the airways is prominent in severe asthma exacerbations and may contribute to airway gland hypersecretion, bronchial hyper-reactivity and airway wall remodelling in asthma. Aim to study the production of IL-17 in asthmatic airways at the mRNA level, and to correlate this with IL-8 mRNA, neutrophilic inflammation and asthma severity. Methods We obtained airway cells by sputum induction from healthy individuals (n = 15) and from asthmatic patients (n = 39). Neutrophils were counted on cytospins and IL-17A and IL-8 mRNA expression was quantified by real-time RT-PCR (n = 11 controls and 33 asthmatics). Results Sputum IL-17A and IL-8 mRNA levels are significantly elevated in asthma patients compared to healthy controls. IL-17 mRNA levels are significantly correlated with CD3γ mRNA levels in asthmatic patients and mRNA levels of IL-17A and IL-8 correlated with each other and with sputum neutrophil counts. High sputum IL-8 and IL-17A mRNA levels were also found in moderate-to-severe (persistent) asthmatics on inhaled steroid treatment. Conclusion The data suggest that Th17 cell infiltration in asthmatic airways links T cell activity with neutrophilic inflammation in asthma.

Background: Intense physical exercise in athletes increases the risk to develop exercise-induced bronchocontriction (EIB). We aimed to study EIB prevalence and explore methods for effective EIB screening., Methods: Three hundred twenty-seven adolescent athletes (12-18 years) performing at least 12 h of sports a week were included. The evaluation consisted of spirometry, eucapnic voluntary hyperpnoea test (EVH) to evaluate for EIB, FeNO, skin prick testing, blood sampling (serum markers of epithelial damage and mast cell activation), and questionnaires (AQUA © , ACT, ACQ, and exposure and symptom-related questions)., Results: Of all athletes, 22% tested positive for EIB (n = 72), 14% reported a previous asthma diagnosis and 40% were atopic. Eighty percent of EIB + athletes did not use any inhalation therapy. EIB + athletes were significantly younger, had decreased FEV 1 /FVC (%), and increased post-EVH-reversibility (%) post-salbutamol compared with EIB - athletes. Furthermore, EIB was significantly associated with previous asthma diagnosis and atopy. The best predictors for a positive EVH test were AQUA © score ≥ 6 (sensitivity of 78%, p = .0171) and wheezing during exercise (specificity of 82%, p = .0002). FeNO negatively and significantly correlated with maximal fall in FEV 1 post-EVH test in atopic athletes (r = -.2735, p = .0056). Maximal fall in FEV 1 was also associated with prior PM 10 exposure (p = .036). Serum markers of epithelial damage were significantly associated with training type, training intensity, EIB severity, and prior air pollution exposure., Conclusion: Our findings support the effectiveness of a systematic respiratory screening approach, including baseline questionnaires, lung function tests, and FeNO measurement, to improve EIB detection in adolescent athletes in whom respiratory response to EVH testing is associated with prior exposure to air pollution., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis (CRS) is a highly prevalent airway disease worldwide. Whereas eosinophilic CRS with nasal polyps (eCRSwNP) represents its most severe phenotype, pathogenic mechanisms remain poorly understood despite a wide spectrum of in vitro and in vivo experimental models. A mouse model of experimental ovalbumin (OVA)-induced airway allergy with coadministration of Staphylococcus aureus enterotoxin B (SEB) has been widely used to study eosinophilic eCRSwNP. This study revisits the features of this model and its suitability for studying eCRS., Methodology: We implemented the most used eCRSwNP mouse model based on OVA+SEB intranasal challenges. Readouts including inflammatory features by (immuno)histology of the sinonasal epithelium (NP formation, eosinophils, epithelial and basement membrane thickness, fibrosis, goblet cells, Charcot-Leyden crystals (CLC)-like, tight junctions) and IgE production by enzyme-linked immunosorbent assay (ELISA), were compared to features of the corresponding human disease., Results: The OVA+SEB model induced eosinophilic inflammation of upper and lower airways, with epithelial and basement membrane thickening, goblet cell hyperplasia and subepithelial fibrosis in the sinuses, along increased IgE production. Except local IgE in nasal lavage (NL), which was only increased in OVA+SEB group, all other features did not differ between OVA and OVA+SEB groups. Macro- or microscopic NP were not detected., Conclusions: With the notable exception of local IgE production, the addition of SEB did not induce additional inflammatory or structural change in the sinuses from mice exposed to and challenged with OVA. This model might represent a model for severe upper airway allergy rather than a specific model of human eCRSwNP.