| 1. |
- Nagatake, Takahiro, et al.
(author)
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The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques
- 2018
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In: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 142:2, s. 470-482.e12
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Journal article (peer-reviewed)abstract
- Background: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated. Objective: We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE. Methods: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-alpha shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment. Results: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40. Conclusion: 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.
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| 2. |
- Amaral, A. F. S., et al.
(author)
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Changes in IgE sensitization and total IgE levels over 20 years of follow-up
- 2016
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 137:6, s. 1788-1795e9
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Journal article (peer-reviewed)abstract
- Background Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. Objective We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. Methods Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. Results Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. Conclusion Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years. © 2015 The Authors. Published by Elsevier, Inc. on behalf ofthe American Academy of Allergy, Asthma&Immunology. This is an open access article under the CC BY license.
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| 3. |
- Badi, Yusef Eamon, et al.
(author)
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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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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 149:1, s. 89-101
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Journal article (peer-reviewed)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. |
- Berthold, Malin, et al.
(author)
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Association of Sensitization to Specific Pet Allergen Components with Asthma Symptoms in School Children
- 2015
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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 135:2, s. AB22-AB22
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Journal article (other academic/artistic)abstract
- Animal sensitization is a known determinant of asthma in children. The objective was to study the association of asthma with sensitization to pet allergen components in schoolchildren. Methods: A random sample of 696 children (11-12 y) from a Swedish population-based cohort was analyzed for sensitization (≥0.1 kUA/L) to cat, dog and horse dander extracts using ImmunoCAP. Sensitized children were further analyzed for IgE antibodies to animal allergen components using ImmunoCAP ISAC112. An expanded ISAAC questionnaire was completed by the parents. Results: Of 259 animal-sensitized children (37%) the majority (75%) were sensitized to more than one species. Among the 11 % (n=77) with current asthma 69 % were sensitized to at least one animal extract, as compared to one third of children without current asthma (p<0.001). Current asthma and asthma symptoms upon contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. Already at moderate levels of IgE antibodies to Fel d 4 (1-15 ISU), at which level most children were sensitized also to Fel d 1, the prevalence of asthma symptoms upon contact with cats was significantly increased. Dog-sensitized children were commonly sensitized to several dog components, and the greatest risk for asthma was seen in children co-sensitized to Can f 5 and Can f 1/f 2. Conclusions: Among Northern Swedish schoolchildren furry animals were the main perennial sensitizers. Asthma symptoms were associated with sensitizations to multiple components within an animal species. In particular, cat Fel d 4 sensitization was strongly related to asthma symptoms.
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| 5. |
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| 6. |
- Bianchi, Matteo, et al.
(author)
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Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent
- 2011
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 127:5, s. 1243-1252 e.7
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Journal article (peer-reviewed)abstract
- BACKGROUND: Aspergillus spp infection is a potentially lethal disease in patients with neutropenia or impaired neutrophil function. We showed previously that Aspergillus hyphae, too large for neutrophil phagocytosis, are inhibited by reactive oxygen species-dependent neutrophil extracellular trap (NET) formation. This process is defective in chronic granulomatous disease (CGD) because of impaired phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function.OBJECTIVE: To determine the antifungal agent and mechanism responsible for reconstitution of Aspergillus growth inhibition within NETs after complementation of NADPH oxidase function by gene therapy (GT) for CGD.METHODS: Antifungal activity of free and NET-released calprotectin was assessed by incubation of Aspergillus nidulans with purified calprotectin, induced NETs from human controls, and CGD neutrophils after GT in the presence or absence of Zn(2+) or alpha-S100A9 antibody, and with induced NETs from wild-type or S100A9(-/-) mouse neutrophils.RESULTS: We identified the host Zn(2+) chelator calprotectin as a neutrophil-associated antifungal agent expressed within NETs, reversibly preventing A nidulans growth at low concentrations, and leading to irreversible fungal starvation at higher concentrations. Specific antibody-blocking and Zn(2+) addition abolished calprotectin-mediated inhibition of A nidulans proliferation in vitro. The role of calprotectin in anti-Aspergillus defense was confirmed in calprotectin knockout mice.CONCLUSION: Reconstituted NET formation by GT for human CGD was associated with rapid cure of pre-existing therapy-refractory invasive pulmonary aspergillosis in vivo, underlining the role of functional NADPH oxidase in NET formation and calprotectin release for antifungal activity. These results demonstrate the critical role of calprotectin in human innate immune defense against Aspergillus infection.
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| 7. |
- Bousquet, Jean, et al.
(author)
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Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018) : Change management in allergic rhinitis and asthma multimorbidity using mobile technology
- 2019
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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:3, s. 864-879
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Journal article (peer-reviewed)abstract
- Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.
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| 8. |
- Brandsma, Joost, et al.
(author)
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Stratification of asthma by lipidomic profiling of induced sputum supernatant
- 2023
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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 152:1, s. 117-125
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Journal article (peer-reviewed)abstract
- Background: Asthma is a chronic respiratory disease with significant heterogeneity in its clinical presentation and pathobiology. There is need for improved understanding of respiratory lipid metabolism in asthma patients and its relation to observable clinical features.Objective: We performed a comprehensive, prospective, cross-sectional analysis of the lipid composition of induced sputum supernatant obtained from asthma patients with a range of disease severities, as well as from healthy controls.Methods: Induced sputum supernatant was collected from 211 adults with asthma and 41 healthy individuals enrolled onto the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study. Sputum lipidomes were characterized by semiquantitative shotgun mass spectrometry and clustered using topologic data analysis to identify lipid phenotypes.Results: Shotgun lipidomics of induced sputum supernatant revealed a spectrum of 9 molecular phenotypes, highlighting not just significant differences between the sputum lipidomes of asthma patients and healthy controls, but also within the asthma patient population. Matching clinical, pathobiologic, proteomic, and transcriptomic data helped inform the underlying disease processes. Sputum lipid phenotypes with higher levels of nonendogenous, cell-derived lipids were associated with significantly worse asthma severity, worse lung function, and elevated granulocyte counts.Conclusion: We propose a novel mechanism of increased lipid loading in the epithelial lining fluid of asthma patients resulting from the secretion of extracellular vesicles by granulocytic inflammatory cells, which could reduce the ability of pulmonary surfactant to lower surface tension in asthmatic small airways, as well as compromise its role as an immune regulator.
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| 9. |
- Brinkman, Paul, et al.
(author)
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Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma
- 2019
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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:5, s. 1811-1820.e7
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Journal article (peer-reviewed)abstract
- Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes.Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to withinpatient clinical and inflammatory changes.Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability.Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNosedriven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045).Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.
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