| 1. |
- Al-Garawi, A., et al.
(författare)
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Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood
- 2011
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 4:6, s. 682-694
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Tidskriftsartikel (refereegranskat)abstract
- The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c(+) CD11b(+) inflammatory dendritic cell and CD8 alpha(+) plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.
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| 2. |
- Andersson, Cecilia, et al.
(författare)
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Alveolar mast cells shift to an FcεRI-expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology.
- 2011
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 66:12, s. 1590-1597
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Tidskriftsartikel (refereegranskat)abstract
- Background: A unique feature of alveolar mast cells is their low high-affinity IgE receptor (FcεRI) expression. Recent discoveries in uncontrolled asthma suggest that the appearance of FcεRI-expressing alveolar mast cells may be a novel disease-specific feature of allergic asthma. This study investigates whether increased FcεRI-expressing alveolar mast cells are present in patients with mild allergic asthma or even in non-asthmatic allergic rhinitis patients (AR) who have developed bronchial hyperactivity (BHR). Methods: Bronchial and alveolar tissues were obtained from healthy controls, AR patients with or without BHR, and AR patients with concurrent asthma. Samples were processed for immunohistochemical identification of MC(T) and MC(TC) and expression of FcεRI and surface-bound IgE. Results: Bronchial mast cell expression of FcεRI was high in all groups. In contrast, in the alveolar tissue, the expression of FcεRI on mast cells was low in healthy controls and in the AR patient groups, whereas a high expression was present in AR patients with concurrent asthma (P = 0.006 compared to controls). The asthmatics had a 29-fold increase in numbers (P = 0.006) and a 19-fold increase in proportion (P = 0.007) of alveolar mast cells that expressed surface-bound IgE. Conclusions: The present data show that alveolar mast cells in patients with mild atopic asthma, but not atopic patients with AR, have turned into a highly FcεRI- and IgE-expressing phenotype. These data support the hypothesis that increased FcεRI expression on alveolar mast cells is a novel disease-specific feature of allergic asthma that is important for understanding asthma phenotypes and designing new therapeutic strategies.
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| 3. |
- Andersson, Cecilia K, et al.
(författare)
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Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis
- 2011
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12:139
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. Methods: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-beta. Results: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-beta. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-beta, correlated negatively with patient lung function. Conclusions: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
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| 4. |
- Andersson, Cecilia K, et al.
(författare)
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Alterations in Lung Mast Cell Populations in Patients with COPD.
- 2010
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 181:3, s. 206-217
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Mast cells have important roles in innate immunity and tissue remodeling but have remained poorly studied in inflammatory airway diseases like COPD. OBJECTIVES: To perform a detailed histological characterization of human lung mast cell popu-lations at different severities of COPD, comparing with smoking and never-smoking controls. METHODS: Mast cells were analyzed in lung tissues from patients with mild to very severe COPD, GOLD IâIV (n = 25, 10 of whom were treated with corticosteroids). Never-smokers and smokers served as controls. The density, morphology and molecular characteristics of mucosal and connective tissue mast cells (MCT and MCTC, respectively) were analyzed in several lung regions. MEASUREMENTS AND MAIN RESULTS: In all compartments of COPD lungs, especially at severe stages, the MCTC population increased in density while the MCT population decreased. The net result was a reduction in total mast cell density. This phenomenon was paralleled by in-creased numbers of luminal mast cells whereas the numbers of TUNEL(+) apoptotic mast cells remained unchanged. In COPD lungs, the MCT and MCTC populations showed alterations in morphology and expression of CD88 (C5a-R), TGF-beta, and renin. Statistically significant cor-relations were found between several COPD-related mast cell alterations and lung function parameters. CONCLUSIONS: As COPD progresses to its severe stages, the mast cell population in the lung undergoes changes in density, distribution, and molecular expression. In COPD lungs, these novel histopathological features were found to be correlated to lung function and they may thus have clinical consequences.
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| 5. |
- Andersson, Cecilia, et al.
(författare)
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Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma
- 2011
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 127:4, s. 123-905
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Tidskriftsartikel (refereegranskat)abstract
- Background: A significant proportion of patients with asthma have persistent symptoms despite treatment with inhaled glucocorticosteroids. Objective: We hypothesized that in these patients, the alveolar parenchyma is subjected to mast cell-associated alterations. Methods: Bronchial and transbronchial biopsies from healthy controls (n = 8), patients with allergic rhinitis (n = 8), and patients with atopic uncontrolled asthma (symptoms despite treatment with inhaled glucocorticosteroids; mean dose, 743 mu g/d; n = 14) were processed for immunohistochemical identification of mast cell subtypes and mast cell expression of Fc epsilon RI and surface-bound IgE. Results: Whereas no difference in density of total bronchial mast cells was observed between patients with asthma and healthy controls, the total alveolar mast cell density was increased in the patients with asthma (P < .01). Division into mast cell subtypes revealed that in bronchi of patients with asthma, tryptase positive mast cells (MCT) numbers decreased compared with controls (P <= .05), whereas tryptase and chymase positive mast cells (MCTC) increased (P <= .05). In the alveolar parenchyma from patients with asthma, an increased density was found for both MCT (P <= .05) and MCTC (P <= .05). The increased alveolar mast cell densities were paralleled by an increased mast cell expression of FceRI (P < .001) compared with the controls. The patients with asthma also had increased numbers (P < .001) and proportions (P < .001) of alveolar mast cells with surface-bound IgE. Similar increases in densities, FceRI expression, and surface-bound IgE were not seen in separate explorations of alveolar mast cells in patients with allergic rhinitis. Conclusion: Our data suggest that patients with atopic uncontrolled asthma have an increased parenchymal infiltration of MCT and MCTC populations with increased expression of FceRI and surface-bound IgE compared with atopic and nonatopic controls. (J Allergy Clin Immunol 2011;127:905-12.)
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| 6. |
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| 7. |
- Chu, Derek K, et al.
(författare)
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Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo.
- 2014
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 211:8, s. 1657-1672
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4(+/+) or il4(-/-) eosinophils. Eosinophils controlled CD103(+) dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.
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| 8. |
- Ekman, Anna-Karin, et al.
(författare)
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Allergen-Induced Accumulation of CD68(-), CD123(+) Dendritic Cells in the Nasal Mucosa
- 2011
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 155:3, s. 234-242
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dendritic cells are antigen-presenting cells central to the immune system. They activate and orchestrate the innate and the adaptive immune systems. This phenotypically diverse group can be further divided into 2 subsets, the CD11c(+) myeloid dendritic cells (mDCs) and the CD123(+) plasmacytoid dendritic cells (pDCs). The aim of the study was to investigate the effect of allergen exposure on dendritic cells in subjects with allergic rhinitis. Methods: Atopic and non-atopic subjects were challenged intranasally with birch or timothy allergen. Nasal biopsies were taken before and 24 h after challenge, and were, after CD68 exclusion, stained for expression of CD11c and CD123 to identify dendritic cell subsets. The effect of allergic mediators on CD68(-), CD123(+) cells was studied with flow cytometry analysis in peripheral blood. Results: The amount of CD68(-), CD123(+) cells increased in the nasal sub-epithelium upon allergen challenge, whereas the number of CD68(-), CD11c(+) cells was unaffected. In vitro study of the effect of inflammatory mediators on pDC phenotype showed an increased activation in response TNF-alpha, IL-4 and CpG. Furthermore, TNF-alpha caused a higher activation among atopic than non-atopic subjects. Conclusions: An increased number of CD68(-), CD123(+) dendritic cells along with the positive pDC response following stimulation with inflammatory mediators suggest that the increased pDCs may be of an activated phenotype. It also suggests that the inflammatory response by pDCs to mediators such as TNF-alpha may be markedly higher in atopic subjects. These data support the notion of pDCs as important participants in allergic rhinitis. Copyright (C) 2011 S. Karger AG, Basel
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| 9. |
- Erjefält, Jonas
(författare)
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Mast cells in human airways: the culprit?
- 2014
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Ingår i: European Respiratory Review. - : European Respiratory Society (ERS). - 1600-0617 .- 0905-9180. ; 23:133, s. 299-307
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Forskningsöversikt (refereegranskat)abstract
- By virtue of their undisputed role in allergy, the study of airway mast cells has focused on nasal and bronchial mast cells and their involvement in allergic rhinitis and asthma. However, recent mechanistic and human studies suggest that peripheral mast cells also have an important role in asthma, as well as chronic obstructive pulmonary disease, respiratory infections and lung fibrosis. Pathogenic roles include immune-modulatory, pro-inflammatory and pro-fibrotic activities. Importantly, mast cells also actively downregulate inflammation and participate in the defence against respiratory infections. Another complicating factor is the notorious mast cell heterogeneity, where each anatomical compartment of the lung harbours site-specific mast cell populations. Alveolar mast cells stand out as they lack the cardinal expression of the high affinity IgE receptor. Supporting the emerging concept of alveolar inflammation in asthma, alveolar mast cells shift to a highly FcϵRI-expressing phenotype in uncontrolled asthma. Site-specific and disease-associated mast cell changes have also recently been described in most other inflammatory conditions of the lung. Thus, in the exploration of new anti-mast cell treatment strategies the search has widened to include the lung periphery and the delicate task of identifying which of the countless potential roles are the critical disease modifying ones in a given clinical situation.
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| 10. |
- Erjefält, Jonas
(författare)
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The airway epithelium as regulator of inflammation patterns in asthma
- 2010
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Ingår i: Clinical Respiratory Journal. - 1752-6981. ; 4:s1, s. 9-14
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Asthma is a complex, heterogeneous and mutifactorial disease and represents a major health problem in Westernised countries. The airway epithelium, with its direct physical contact with luminal triggers, has a major role in determining the nature of inflammation that develops in asthmatic airways. Objective: The present review aims to provide a brief overview of the numerous ways the airway epithelium can affect and influence the histopathological picture in asthma. Results and Conclusion: The ways the epithelium aggravates inflammation range from acute responses to luminal triggers such as allergens and infections to the multipathogenic events occurring as a consequence of repeated epithelial damage-repair responses. The airway epithelium also facilitates the selective migration of leukocytes into the airway lumen, a process that is important in regulating inflammatory cell homeostasis. The fact that only some of the important leukocyte subtypes participate in this process cause translational problems and difficulties in the interpretation of luminal samples. To further reveal the nature of the multifaceted involvement of the airway epithelium in inflamed asthmatic airways emerges as a promising goal for identifying new therapeutic strategies. Please cite this paper as: Erjefalt JS. The airway epithelium as regulator of inflammation patterns in asthma. Clin Respir J 2010; 4 (Suppl. 1): 9-14.
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