| 1. |
- Östling, Jörgen, et al.
(författare)
-
IL-17-high asthma with features of a psoriasis immunophenotype
- 2019
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 144:5, s. 1198-1213
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required.Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity.Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes.Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin.Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
|
|
| 2. |
- Roth-Walter, Franziska, et al.
(författare)
-
Comparing biologicals and small molecule drug therapies for chronic respiratory diseases : An EAACI Taskforce on Immunopharmacology position paper
- 2019
-
Ingår i: Allergy: European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538. ; 74:3, s. 432-448
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals’ therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases.
|
|
| 3. |
- Kuo, Chih-Hsi S., et al.
(författare)
-
Contribution of airway eosinophils in airway wall remodeling in asthma : Role of MMP-10 and MET
- 2019
-
Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 74:6, s. 1102-1112
-
Tidskriftsartikel (refereegranskat)abstract
- Background Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. Methods We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. Results Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. Conclusion Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
|
|
| 4. |
- Perotin-Collard, Jeanne-Marie, et al.
(författare)
-
Subtypes of eosinophilic asthma with discrete gene pathway phenotypes
- 2019
-
Ingår i: European Respiratory Journal. - : European Respiratory Society Journals. - 0903-1936 .- 1399-3003. ; 54
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Blood eosinophil counts ≥0.3x109/L are used to define Type-2, eosinophilic asthma. However, differential responses to T2 biologics of patients with eosinophilic asthma suggests that this may be a heterogeneous phenotype with subsets driven by different molecular mechanisms.Methods: Blood transcriptomic data, acquired from 99 severe asthmatics from the U-BIOPRED study (62% female, mean age 54 yr, 41% on oral steroids), were clustered by topological data analysis and cluster boundaries defined by the MORSE method. Gene pathway signatures were identified by Ingenuity Pathway Analysis.Results: Analysis revealed 3 clusters with different modulated gene pathways, i.e. molecular phenotypes. Subtype 1 had high IFN-γ, low IL5, low IL13 and low IL17 gene expression, with reduced glucocorticoid-induced gene expression. Subtype 2 had low IFNγ, high IL5, high IL13 and low IL17 gene expression. Subtype 3 had low IFNγ, high IL5, high IL13 and high IL17 gene expression. Pathway analysis suggested a strong steroid response in Subtypes 2 and 3. Clinically, the three clusters were not different in respect of age, gender, prevalence of atopy, blood or sputum eosinophil counts. Subtype 3 was characterized by high neutrophil counts in blood and bronchial epithelium, frequent sinus disease and asthma exacerbations, OCS treatment, low allergic sensitisation and low exhaled NO. Subtype 1 was characterized by high exhaled NO and more frequent IgE therapy.Conclusion: This study suggests that eosinophilic severe asthma (≥0.3x109/L) can be stratified further into 3 subtypes with distinct gene expression profiles that could be developed as molecular diagnostic biomarkers to guide treatment and thereby improve patient outcomes.
|
|
| 5. |
- Ravanetti, Lara, et al.
(författare)
-
IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity
- 2019
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 143:4, s. 16-1370
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive. Objective: We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33–dependent mechanisms that underlie severe asthma exacerbations. Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both. Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-β expression and prevent the TH1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response. Conclusion: Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations.
|
|
| 6. |
- Schleich, Florence, et al.
(författare)
-
Research highlights from the 2018 European Respiratory Society International Congress : airway disease
- 2019
-
Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 5:1
-
Forskningsöversikt (refereegranskat)abstract
- The annual European Respiratory Society (ERS) International Congress (held in Paris in 2018) was once again a platform for discussion of the highest-quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses only some of the high-quality research studies presented at this year's Congress, with a particular focus on airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and cough, as presented through Assembly 5 of the ERS (Airway Diseases: Asthma and COPD). The authors establish the key take-home messages of these studies, compare their findings and place them in the context of current understanding.
|
|
