Anders Bergqvist

Mast cell–associated alveolar inflammation in patients with atopic uncontrolled asthma

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 μg/d; n = 14) were processed for immunohistochemical identification of mast cell subtypes and mast cell expression of FcεRI 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 (MC(T)) numbers decreased compared with controls (P ≤ .05), whereas tryptase and chymase positive mast cells (MC(TC)) increased (P ≤ .05). In the alveolar parenchyma from patients with asthma, an increased density was found for both MC(T) (P ≤ .05) and MC(TC) (P ≤ .05). The increased alveolar mast cell densities were paralleled by an increased mast cell expression of FcεRI (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, FcεRI 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 MC(T) and MC(TC) populations with increased expression of FcεRI and surface-bound IgE compared with atopic and nonatopic controls.

Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: Clinical and histopathologic correlations

Background: The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma, yet its effect on different bronchial structures remains unknown. Objective: We sought to examine the effect of BT on bronchial structures and to explore the association with clinical outcome in patients with severe refractory asthma. Methods: Bronchial biopsy specimens (n = 300) were collected from 15 patients with severe uncontrolled asthma before and 3 months after BT. Immunostained sections were assessed for airway smooth muscle (ASM) area, subepithelial basement membrane thickness, nerve fibers, and epithelial neuroendocrine cells. Histopathologic findings were correlated with clinical parameters. Results: BT significantly improved asthma control and quality of life at both 3 and 12 months and decreased the numbers of severe exacerbations and the dose of oral corticosteroids. At 3 months, this clinical benefit was accompanied by a reduction in ASM area (median values before and after BT, respectively: 19.7% [25th‐75th interquartile range (IQR), 15.9% to 22.4%] and 5.3% [25th‐75th IQR], 3.5% to 10.1%, P < .001), subepithelial basement membrane thickening (4.4 &mgr;m [25th‐75th IQR, 4.0‐4.7 &mgr;m] and 3.9 &mgr;m [25th‐75th IQR, 3.7‐4.6 &mgr;m], P = 0.02), submucosal nerves (1.0 ‰ [25th‐75th IQR, 0.7‐1.3 ‰] immunoreactivity and 0.3 ‰ [25th‐75th IQR, 0.1‐0.5 ‰] immunoreactivity, P < .001), ASM‐associated nerves (452.6 [25th‐75th IQR, 196.0‐811.2] immunoreactive pixels per mm2 and 62.7 [25th‐75th IQR, 0.0‐230.3] immunoreactive pixels per mm2, P = .02), and epithelial neuroendocrine cells (4.9/mm2 [25th‐75th IQR, 0‐16.4/mm2] and 0.0/mm2 [25th‐75th IQR, 0‐0/mm2], P = .02). Histopathologic parameters were associated based on Asthma Control Test scores, numbers of exacerbations, and visits to the emergency department (all P ≤ .02) 3 and 12 months after BT. Conclusion: BT is a treatment option in patients with severe therapy‐refractory asthma that downregulates selectively structural abnormalities involved in airway narrowing and bronchial reactivity, particularly ASM, neuroendocrine epithelial cells, and bronchial nerve endings.

Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease

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.

Mapping of TLR5 and TLR7 in central and distal human airways and identification of reduced TLR expression in severe asthma.

The toll‐like receptors, TLR5 and TLR7, have recently been proposed in asthma immunopathogenesis. While supporting data come from animal or in vitro studies, little is known about TLR5 and TLR7 expression in human asthmatic airways.

Alveolar mast cells shift to an FcεRI-expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology.

To cite this article: Andersson CK, Tufvesson E, Aronsson D, Bergqvist A, Mori M, Bjermer L, Erjefält JS. Alveolar mast cells shift to an FcεRI‐expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology. Allergy 2011; 66: 1590–1597.

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome

Background Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti‐inflammatory treatment. Objective We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid‐free patients with asthma and healthy control subjects. Methods Bronchoalveolar lavage fluid was collected from 23 steroid‐free nonsmoking patients with asthma and 10 healthy control subjects. Bacterial DNA was extracted from and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and neutrophils in the submucosa were quantified by means of immunohistochemical identification and computerized image analysis. Induced sputum was obtained, and airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide values were measured. Relationships between airway microbial diversity and composition and inflammatory profiles were analyzed. Results In asthmatic patients airway microbial composition was associated with airway eosinophilia and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients with the lowest levels of eosinophils had an altered bacterial abundance profile, with more Neisseria, Bacteroides, and Rothia species and less Sphingomonas, Halomonas, and Aeribacillus species compared with asthmatic patients with more eosinophils and healthy control subjects. Conclusion The level of eosinophilic airway inflammation correlates with variations in the microbiome across asthmatic patients, whereas neutrophilic airway inflammation does not. This warrants further investigation on molecular pathways involved in both patients with eosinophilic and those with noneosinophilic asthma.

Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control

Real-world evaluation studies have shown that many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICSs). As conventional ICSs have poor access to the peripheral airways, the aim of the present paper was to study the relationship between peripheral airway inflammation and clinical control in allergic asthma. Consequently, bronchial and transbronchial biopsies were obtained from patients with poorly controlled asthma [n=12, asthma control test (ACT) score<20], patients with well-controlled asthma (n=12, ACT score≥20) and healthy controls (n=8). Tissue sections were immunostained to assess multiple leucocyte populations. To determine the degree of T-helper type-2 (Th2) immunity, the logarithmic value of the ratio between Th2 cells/mm2 and Th1 cells/mm2 was used as a surrogate score for Th2-skewed immunity. In the bronchi, the leucocyte infiltration pattern and the Th2-score were similar between patients with well-controlled asthma and those with poorly controlled asthma. In contrast, in the alveolar parenchyma, the expression of T-helper cells was significantly higher in patients with poorly controlled asthma than in patients with well-controlled asthma (P<0.01). Furthermore, the alveolar Th2-score was significantly higher in patients with poorly controlled asthma (median 0.4) than in the controlled patients (median -0.10, P<0.05). In addition, in contrast with bronchial Th2-score, the alveolar Th2-score correlated significantly with ACT score (rs=-0.62, P<0.01) in the pooled asthma group. Collectively, our data reveal an alveolar Th2-skewed inflammation, specifically in asthmatic patients who are poorly controlled with ICSs, and suggest that pharmacological targeting of the peripheral airways may be beneficial in this large patient category.

Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation.

Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell‐associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol.

Marked Epithelial Cell Pathology and Leukocyte Paucity in Persistently Symptomatic Severe Asthma

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IL‐33 is related to innate immune activation and sensitization to HDM in mild steroid‐free asthma

IL‐33 represents a potential link between the airway epithelium and induction of a Th2‐type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid‐free asthma.