| 1. |
- Al-Garawi, A., et al.
(author)
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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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In: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 4:6, s. 682-694
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Journal article (peer-reviewed)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.
(author)
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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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In: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 66:12, s. 1590-1597
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Journal article (peer-reviewed)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.
(author)
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Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis
- 2011
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12:139
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Journal article (peer-reviewed)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.
(author)
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Alterations in Lung Mast Cell Populations in Patients with COPD.
- 2010
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In: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 181:3, s. 206-217
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Journal article (peer-reviewed)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.
(author)
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Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma
- 2011
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 127:4, s. 123-905
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Journal article (peer-reviewed)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. |
- Mori, Michiko, et al.
(author)
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Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease
- 2013
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In: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 68:6, s. 521-531
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Journal article (peer-reviewed)abstract
- Rationale The alveolar pathology in chronic obstructive pulmonary disease (COPD) involves antigen-driven immune events. However, the induction sites of alveolar adaptive immune responses have remained poorly investigated. Objectives To explore the hypothesis that interfaces between the alveolar lumen and lymphoid aggregates (LAs) provide a structural basis for increased alveolar antigen uptake in COPD lungs. Methods Lung samples from patients with mild (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I), moderate–severe (GOLD II–III), and very severe (GOLD IV) COPD were subjected to detailed histological assessments of adaptive immune system components. Never smokers and smokers without COPD served as controls. Results Quantitative histology, involving computerised three-dimensional reconstructions, confirmed a rich occurrence of alveolar-restricted LAs and revealed, for the first time, that the vast majority of vascular or bronchiolar associated LAs had alveolar interfaces but also an intricate network of lymphatic vessels. Uniquely to COPD lungs, the interface epithelium had transformed into a columnar phenotype. Accumulation of langerin (CD207)+ dendritic cells occurred in the interface epithelium in patients with COPD but not controls. The antigen-capturing capacity of langerin+ dendritic cells was confirmed by increased alveolar protrusions and physical T cell contact. Several of these immune remodelling parameters correlated with lung function parameters. Conclusions Severe stages of COPD are associated with an emergence of remodelled and dendritic cell-rich alveolar–lymphoid interfaces. This novel type of immune remodelling, which predicts an increased capacity to respond to alveolar antigens, is suggested to contribute to aggravated inflammation in COPD.
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| 8. |
- Mori, Michiko, et al.
(author)
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Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD
- 2013
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 14
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Journal article (peer-reviewed)abstract
- Background: De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking. Methods: Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6. Results: The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p < 0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p < 0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0.05), as well as the alveolar parenchyma (p < 0.001) in patients with advanced COPD compared with never-smoking controls. A similar increase in lymphatic D6 immunoreactivity was observed in bronchioles (p < 0.05) and alveolar parenchyma (p < 0.01). Conclusions: This study shows that severe stages of COPD is associated with increased numbers of alveolar lymphatic vessels and a change in lymphatic vessel phenotype in major peripheral lung compartments. This novel histopathological feature is suggested to have important implications for distal lung immune cell traffic in advanced COPD.
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| 9. |
- Mori, Michiko
(author)
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New Aspects of Alveolar Adaptive Immune Responses in COPD
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in conducting airways and the alveolar parenchyma. The inflammation, which is a consequence of inhalation of noxious gases like tobacco smoke, has traditionally been thought to be driven by innate immune responses. However, more recent studies have revealed an increase in lymphocyte-rich lymphoid aggregates (LAs) and antigen presenting dendritic cells (DCs) in peripheral airways of patients with COPD. These findings suggest that peripheral adaptive immune responses and antigen-driven immune events may contribute to the immunopathology of COPD. However, the involvement of the alveolar compartment has remained unexplored. The aim of this thesis work was to provide new insights into the structural as well as the immunological basis for alveolar antigen uptake and peripheral adaptive immune responses in COPD. To investigate this, detailed immunohistochemical assessments of adaptive immune system components were performed in surgical specimens obtained from patients with different severities of COPD (GOLD stage I-IV), smokers and never-smoking control subjects. Immunohistochemistry and 3D reconstructions of serial sections were used to demonstrate a rich occurrence of alveolar-restricted LAs and reveal that also the vast majority of the bronchiolar- and vascular-associated LAs have alveolar interfaces. Importantly, in COPD patients but not in controls a selective accumulation of langerin+ DCs was observed along the alveolar-lymphoid interfaces. Moreover, these alveolar interface DCs had increased luminal protrusions and more physical contact with lymphoid T cells than the corresponding mucosal DCs. A further investigation of multiple DC subsets in different peripheral lung compartments found that in COPD the most marked increase in DC subsets, including BDCA-2+, CD1a+langerin- and CD11c+CD68-CD163- DCs, was observed in the alveolar tissue. Notably, the DCs in LA interfaces and alveolar tissue differed from airway DCs by a distinct marker expression profile. The 3D analysis revealed an intricate connection between LAs and lymphatic vessels. Further, a marked increase in the number of alveolar lymphatic vessels was detected in patients with advanced COPD. Importantly, in COPD lymphatic vessels had an activated phenotype as revealed by increased lymphatic expression of CCL21 and D6, both of which are involved in DC transport to lymphoid tissues. In conclusion, the studies in this thesis have discovered that the alveolar parenchyma in COPD lungs contain a novel type of DC-rich alveolar-lymphoid epithelium, elevated levels of multiple DC subsets as well as activated lymphatic vessels. Taken together these findings forward the alveolar parenchyma as an important arena for antigen uptake in COPD. This insight calls for future investigations to find out to what extent the resulting adaptive immune responses contribute to the COPD pathogenesis and how they can be pharmacologically targeted.
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