| 1. |
- Östling, Jörgen, et al.
(författare)
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IL-17-high asthma with features of a psoriasis immunophenotype
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 144:5, s. 1198-1213
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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.
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| 2. |
- Abdel-Aziz, Mahmoud I., et al.
(författare)
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A multi-omics approach to delineate sputum microbiome-associated asthma inflammatory phenotypes
- 2022
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 59:1
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Tidskriftsartikel (refereegranskat)abstract
- A multi-omics approach revealed the underlying biological pathways in the microbiome-driven severe asthma phenotypes. This may help to elucidate new leads for treatment development, particularly for the therapeutically challenging neutrophilic asthma.
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| 3. |
- Badi, Yusef Eamon, et al.
(författare)
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Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 149:1, s. 89-101
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Tidskriftsartikel (refereegranskat)abstract
- Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma.Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P <.05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P <.05) and particularly in neutrophilic and mixed granulocytic sputum (P <.05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways.Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
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| 4. |
- Burg, Dominic, et al.
(författare)
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Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome
- 2018
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 17:6, s. 2072-2091
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Tidskriftsartikel (refereegranskat)abstract
- Analysis of induced sputum supematant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMSE applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in >= 40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in >= 3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accuracy and consistency of measurement of sputum proteins and analyze the distribution of sputum proteins in the healthy population. The analysis showed that quantitation of proteins by HDMSE is influenced by several factors, with some proteins being measured in all participants' samples and with low measurement variance between samples from the same patient. The measurement of some proteins is highly variable between repeat analyses, susceptible to sample processing effects, or difficult to accurately quantify by mass spectrometry. Other proteins show high interindividual variance. We also highlight that the sputum proteome of healthy individuals is related to sputum neutrophil levels, but not gender or allergic sensitization. We illustrate the importance of design and interpretation of disease biomarker studies considering such protein population and technical measurement variance.
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| 5. |
- Emma, Rosalia, et al.
(författare)
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Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort
- 2018
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF(2 alpha) and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF(2 alpha); IS-transcriptomics; BB-transcriptomics; BBrtranscriptomics). Urinary 8-iso-PGF(2 alpha) was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF(2 alpha) was increased in SAs/ex, median (IQR) = 31.7 (24.5 +/- 44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6 +/- 36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4 +/- 47.7), vs. ESA, median (IQR) = 29.4 (22.3 +/- 40.5), and NSA, median (IQR) = 26.5 (19.6 +/- 16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF(2 alpha) in the smokers/ex-smokers group.
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| 6. |
- Hou, Ruihua, et al.
(författare)
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The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts
- 2023
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Ingår i: Brain, behavior, and immunity. - : Academic Press. - 0889-1591 .- 1090-2139. ; 111, s. 249-258
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Tidskriftsartikel (refereegranskat)abstract
- Background: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project. Methods: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate. Results: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05). Conclusions: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition.
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| 7. |
- Kolmert, Johan, et al.
(författare)
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Urinary Leukotriene E-4 and Prostaglandin D-2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation A Clinical Observational Study
- 2021
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - NEW YORK, USA : AMER THORACIC SOC. - 1073-449X .- 1535-4970. ; 203:1, s. 37-53
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE(2) pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE(2) metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD(2) metabolite 2,3-dinor-11 beta-PGF(2 alpha). High concentrations of LTE4 and PGD(2) metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOARED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.
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| 8. |
- Kuo, Chih-Hsi Scott, et al.
(författare)
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A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED
- 2017
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 194:4, s. 443-455
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes.METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement.RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity.CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity.
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| 9. |
- Kuo, Chih-Hsi S., et al.
(författare)
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Contribution of airway eosinophils in airway wall remodeling in asthma : Role of MMP-10 and MET
- 2019
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 74:6, s. 1102-1112
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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.
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| 10. |
- Perotin-Collard, Jeanne-Marie, et al.
(författare)
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Subtypes of eosinophilic asthma with discrete gene pathway phenotypes
- 2019
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Ingår i: European Respiratory Journal. - : European Respiratory Society Journals. - 0903-1936 .- 1399-3003. ; 54
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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.
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