ORCID Profile
0000-0002-0017-3433
Current Organisations
The University of Auckland
,
University of Queensland
,
Metro South Health
,
Princess Alexandra Hospital
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Terrestrial Ecology | Ecology |
Ecosystem Adaptation to Climate Change | Expanding Knowledge in the Biological Sciences | Flora, Fauna and Biodiversity at Regional or Larger Scales
Publisher: Wiley
Date: 24-03-2018
DOI: 10.1002/PPUL.23984
Abstract: Protracted bacterial bronchitis (PBB) is a common cause of prolonged cough in young children, and may be a precursor of bronchiectasis. Bacteria are often present in the lower airways in both PBB and bronchiectasis and may cause persistent infections. However, there is a paucity of information available on the pathogenesis of PBB and the factors associated with persistent bacterial infection and progression to bronchiectasis. This study hypothesised that lung immune cells in recurrent PBB and bronchiectasis differentially express genes related to immune cell dysfunction compared to lung immune cells from control subjects. Cells isolated from bronchoalveolar lavage (adult-control and PBB BAL cells) were stimulated with nontypeable Haemophilus influenzae (NTHi), and expression of genes involved in various inflammatory pathways was assessed. NTHi induced production of large amounts of IL-1β, IL-6, and IL-8 in adult-control BAL cells, however BAL cells from PBB airways appeared refractory to NTHi stimulation. BAL cells from PBB and bronchiectasis showed differential expression of several genes relative to control cells, including CCL20, MARCO, CCL24, IL-10, PPAR-γ, CD200R, TREM2, RelB. Expression of genes involved in resolution of inflammation and anti-inflammation response, such as CD200R and IL-10, was associated with the number of pathogenic bacteria found in the airways. In summary, we have shown that the expression of genes related to macrophage function and resolution of inflammation are similar in PBB and bronchiectasis. Lung immune cell dysfunction in PBB and bronchiectasis may contribute to poor bacterial clearance and prolonged resolution of inflammation.
Publisher: The American Association of Immunologists
Date: 09-2004
DOI: 10.4049/JIMMUNOL.173.5.3084
Abstract: A number of laboratories have reported cord blood T cell responses to ubiquitous environmental Ags, including allergens, by proliferation and cytokine secretion. Moreover, the magnitude of these responses has been linked with risk for subsequent expression of allergy. These findings have been widely interpreted as evidence for transplacental priming and the development of fetal T memory cells against Ags present in the maternal environment. However, we present findings below that suggest that neonatal T cell responses to allergens (and other Ags) differ markedly from those occurring in later life. Notably, in contrast to allergen-responsive adult CD4+ T cell cultures, responding neonatal T cell cultures display high levels of apoptosis. Comparable responses were observed against a range of microbial Ags and against a parasite Ag absent from the local environment, but not against autoantigen. A notable finding was the appearance in these cultures of CD4+CD25+CTLA4+ T cells that de novo develop MLR-suppressive activity. These cells moreover expressed CD45RA and CD38, hallmarks of recent thymic emigrants. CFSE-labeling studies indicate that the CD4+CD25+ cells observed at the end of the culture period were present in the day 0 starting populations, but they were not suppressive in MLR responses. Collectively, these findings suggest that a significant component of the reactivity of human neonatal CD4+ T cells toward nominal Ag (allergen) represents a default response by recent thymic emigrants, providing an initial burst of short-lived cellular immunity in the absence of conventional T cell memory, which is limited in intensity and duration via the parallel activation of regulatory T cells.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.CHEST.2015.10.066
Abstract: Children with recurrent protracted bacterial bronchitis (PBB) and bronchiectasis share common features, and PBB is likely a forerunner to bronchiectasis. Both diseases are associated with neutrophilic inflammation and frequent isolation of potentially pathogenic microorganisms, including nontypeable Haemophilus influenzae (NTHi), from the lower airway. Defective alveolar macrophage phagocytosis of apoptotic bronchial epithelial cells (efferocytosis), as found in other chronic lung diseases, may also contribute to tissue damage and neutrophil persistence. Thus, in children with bronchiectasis or PBB and in control subjects, we quantified the phagocytosis of airway apoptotic cells and NTHi by alveolar macrophages and related the phagocytic capacity to clinical and airway inflammation. Children with bronchiectasis (n = 55) or PBB (n = 13) and control subjects (n = 13) were recruited. Alveolar macrophage phagocytosis, efferocytosis, and expression of phagocytic scavenger receptors were assessed by flow cytometry. Bronchoalveolar lavage fluid interleukin (IL) 1β was measured by enzyme-linked immunosorbent assay. For children with PBB or bronchiectasis, macrophage phagocytic capacity was significantly lower than for control subjects (P = .003 and P < .001 for efferocytosis and P = .041 and P = .004 for phagocytosis of NTHi PBB and bronchiectasis, respectively) median phagocytosis of NTHi for the groups was as follows: bronchiectasis, 13.7% (interquartile range [IQR], 11%-16%) PBB, 16% (IQR, 11%-16%) control subjects, 19.0% (IQR, 13%-21%) and median efferocytosis for the groups was as follows: bronchiectasis, 14.1% (IQR, 10%-16%) PBB, 16.2% (IQR, 14%-17%) control subjects, 18.1% (IQR, 16%-21%). Mannose receptor expression was significantly reduced in the bronchiectasis group (P = .019), and IL-1β increased in both bronchiectasis and PBB groups vs control subjects. A reduced alveolar macrophage phagocytic host response to apoptotic cells or NTHi may contribute to neutrophilic inflammation and NTHi colonization in both PBB and bronchiectasis. Whether this mechanism also contributes to the progression of PBB to bronchiectasis remains unknown.
Publisher: Wiley
Date: 07-2017
DOI: 10.1111/IMJ.13403
Abstract: There are limited data on outcomes of hypoxaemic respiratory failure (HRF), especially in non-intensive care unit (ICU) settings. To assess outcomes in HRF (without multi-system disease and not requiring early intubation) of patients directly admitted to a Respiratory High-dependency Unit (R-HDU). This is a retrospective cohort study of HRF compared to hypercapnic respiratory failure (HCRF) in a R-HDU (2007-2011). Patient characteristics (age, gender, pre-morbid status, diagnoses) and outcomes (non-invasive ventilation (NIV) use, survival, ICU admission) were assessed. There were 1207 R-HDU admissions in 2007-2011, 205 (17%) with HRF and 495 (41%) with HCRF. The proportion with HRF increased from 12.2% in 2007 to 20.1% in 2011 (P < 0.05). HRF patients were younger, more often male and had better pre-morbid performance. Compared to HCRF, HRF was more frequently associated with lung consolidation (61% vs 15%, P < 0.001), interstitial lung disease (12% vs 1%, P < 0.001) and pulmonary hypertension (7% vs 0%, P < 0.001) and less frequently with chronic obstructive pulmonary disease (24% vs 65%, P < 0.001) and obstructive sleep apnoea (8% vs 26%, P < 0.001). Fewer patients with HRF were treated with NIV (28% vs 87%, P < 0.001), but NIV was discontinued early more often (28% vs 7%, P < 0.001). A total of 18% with HRF was transferred to ICU compared to 6% with HCRF (P = 0.06). More patients with HRF died (19.5% vs 12.3%, P = 0.02). Interstitial lung disease, consolidation, shock, malignancy and poorer pre-morbid function were associated with increased mortality. Initial R-HDU management is an effective option in selected HRF to reduce ICU demand, although mortality and clinical deterioration despite NIV are more common than in HCRF.
Publisher: Wiley
Date: 03-2017
DOI: 10.1111/RESP.13014
Abstract: Biomarkers may be a key foundation for the precision medicine of the future. In this article, we review current knowledge regarding biomarkers in difficult‐to‐treat asthma and their ability to guide the use of both conventional asthma therapies and novel (targeted) therapies. Biomarkers (as measured by tests including prednisolone and cortisol assays and the fractional exhaled nitric oxide ( NO ) suppression test) show promise in the assessment and management of non‐adherence to inhaled and oral corticosteroids. Multiple markers of type 2 inflammation have been developed, including eosinophils in sputum and blood, exhaled NO , serum IgE and periostin. Although these show potential in guiding the selection of novel interventions for refractory type 2 inflammation in asthma, and in determining if the desired response is being achieved, it is becoming clear that different biomarkers reflect distinct components of the complex type 2 inflammatory pathways. Less progress has been made in identifying biomarkers for use in difficult‐to‐treat asthma that is not associated with type 2 inflammation. The future is likely to see further biomarker discovery, direct measurements of in idual cytokines rather than surrogates of their activity and the increasing use of biomarkers in combination. If the promise of biomarkers is to be fulfilled, they will need to provide useful information that aids clinical decision‐making, rather than being ‘just another test’ for clinicians to order.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.PHARMTHERA.2011.01.002
Abstract: Asthma treatment goals focus on disease control rather than remission as a therapeutic aim. This is in contrast to diseases where remission is frequently discussed and has well-defined criteria. In this review, we consider the similarities and differences between remission in asthma and another chronic inflammatory disease, rheumatoid arthritis, where new therapies have made remission a realistic treatment goal. Clinical remission of asthma is often defined as prolonged absence of asthma symptoms without requirement for medication while others insist on the demonstration of normal lung function and airway responsiveness. Even in those who develop a symptomatic remission of asthma, persistent physiological abnormalities and airway inflammation are common. There is a clear need to develop a precise, internationally accepted, definition of asthma remission that can be used as a therapeutic endpoint in studies of new asthma treatments. Spontaneous remission of asthma symptoms is relatively common, especially during adolescence. It is more likely in males, those with mild symptoms and normal lung function and in those who quit smoking, and may be linked to normalisation of immune function. Remission is less likely in severe asthma, atopy, eosinophilia, airflow obstruction, continued smoking and weight gain. Studies of spontaneous remissions may provide insight into how remission might be induced with therapy. Remission is not identical to cure, there remains a risk of subsequent symptomatic relapse of asthma and there is little evidence that current asthma treatments can induce remission. Long-term remission should be regarded as the next therapeutic frontier in asthma management.
Publisher: Wiley
Date: 13-01-2011
DOI: 10.1111/J.1365-2222.2010.03670.X
Abstract: Grass pollens are major triggers of allergic rhinitis and asthma, but the immunological relationships between pollen allergens of the subtropical Bahia grass, Paspalum notatum, and temperate grasses are unresolved. To assess serum IgE cross-reactivity between subtropical P. notatum and temperate Lolium perenne (Ryegrass) pollen allergens. Serum IgE reactivities of grass pollen-allergic patients with P. notatum, L. perenne and Cynodon dactylon (Bermuda grass) pollen extracts and their respective purified group 1 allergens, Pas n 1, Lol p 1 and Cyn d 1, were compared by immunoblotting, ELISA and basophil activation. In a cohort of 51 patients from a temperate region, a high frequency of IgE reactivity with each grass pollen was detected, but reactivity with L. perenne pollen was substantially greater than with P. notatum and C. dactylon pollen. Similarly, serum IgE reactivity with Lol p 1 was greater than with Pas n 1 or Cyn d 1. For seven of eight sera studied in detail, asymmetric serum IgE cross-reactivity was observed L. perenne pollen inhibited IgE reactivity with P. notatum pollen but not the converse, and IgE reactivity with Pas n 1 was inhibited by Lol p 1 but IgE reactivity with Lol p 1 was not inhibited by Pas n 1 or Cyn d 1. Importantly, P. notatum pollen and Pas n 1 activated basophils in grass pollen-allergic patients from a temperate region, although stimulation was greater by pollen of L. perenne than P. notatum or C. dactylon, and by Lol p 1 than Pas n 1 or Cyn d 1. In contrast, a cohort of 47 patients from a subtropical region showed similar IgE reactivity with P. notatum and L. perenne pollen, and reciprocal cross-inhibition of IgE reactivity between L. perenne and P. notatum. Pollen allergens of the subtropical P. notatum, including Pas n 1, show clinically relevant IgE cross-reactivity with pollen allergens of L. perenne but also species-specific IgE reactivity.
Publisher: Wiley
Date: 23-12-2016
DOI: 10.1111/CEA.12634
Abstract: Non-eosinophilic asthma (NEA) is a distinct, often corticosteroid-resistant inflammatory asthma phenotype. NK and NKT-like cells are effector lymphocytes that we have shown, like CD28null T cells, to be relatively resistant to steroids and major sources of pro-inflammatory/cytotoxic mediators. We hypothesized that these cells and mediators would be increased in peripheral blood in NEA. Adults with severe asthma and variable airflow obstruction, poorly controlled despite maintenance therapy with inhaled glucocorticosteroids and long-acting bronchodilators, were recruited. Blood was assessed in those with eosinophilic asthma (n = 12), NEA (n = 25) and healthy non-smoking controls (n = 30). We applied flow cytometry to measure T, CD28null, NK and NKT-like cells and their expression of granzyme B, perforin, and killer inhibitory/activating receptors CD94(Kp43), CD158b and CD107A. Intracellular pro-inflammatory cytokine production (IFN-γ and TNF-α) was assessed in 18 controls and 10 patients with asthma/group. In NEA, there was increased expression of granzyme B by CD8+ T cells vs. There was increased expression of granzyme B and CD158 and decreased CD94 on NK cells, vs. healthy controls and those with eosinophilic asthma. IFN-γ production by NK cells and TNF-α production by NKT-like cells in NEA were significantly increased vs. In both eosinophilic and NEA phenotypes, there were significant increases in CD4+28null T cells (72% and 81% increases, respectively, vs. controls) and their expression of pro-inflammatory cytokines. Significant correlations were noted between blood CD4+28null T cells and neutrophil numbers in induced sputum, and between corticosteroid dose and blood NKT-like cells, and their production of granzyme B and TNF-α and NK IFN-γ. In poorly controlled asthma, altered expression of cytotoxic ro-inflammatory mediators can be seen on a variety of lymphocyte subsets in the peripheral blood these changes are most apparent in NEA. Whether this pattern of expression is a marker of treatment responsiveness and future risk of exacerbations remains to be determined.
Publisher: BMJ
Date: 08-1995
DOI: 10.1136/THX.50.8.887
Publisher: Elsevier BV
Date: 12-2010
Publisher: Frontiers Media SA
Date: 29-05-2017
Publisher: European Respiratory Society (ERS)
Date: 07-2010
DOI: 10.1183/09031936.00029310
Abstract: The soluble receptor for advanced glycation end-products (sRAGE) has anti-inflammatory properties, and deficiency of circulating sRAGE is associated with various human diseases. Whether sRAGE concentrations are reduced in chronic obstructive pulmonary disease (COPD) has not been determined. The aim of this study was to determine plasma levels of sRAGE in COPD patients and establish whether sRAGE varies in relation to forced expiratory volume in 1 s (FEV(1)) and other inflammatory markers. 61 COPD patients and 42 healthy controls were recruited. Plasma sRAGE, C-reactive protein (CRP) and serum amyloid A (SAA) were measured in patients with stable COPD. A subgroup had measurements during acute exacerbations of COPD (AECOPD). sRAGE was significantly lower in stable COPD than in healthy controls (p<0.001), while CRP (p<0.001) and SAA (p = 0.015) were higher in stable COPD than in healthy controls. Multiple linear regression confirmed that COPD was negatively associated with sRAGE (p<0.001). Plasma sRAGE was positively correlated with FEV(1) (r(2) = 0.530, p<0.001), while CRP and SAA were inversely proportional to FEV(1). Multiple linear regression analysis showed that only sRAGE was a strong predictor of FEV(1). AECOPD were associated with even lower sRAGE levels that increased with convalescence. Circulating sRAGE is lower in COPD and shows a strong correlation to the degree of airflow limitation.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.JACI.2005.04.017
Abstract: The term asthma refers to a spectrum of wheezing syndromes resulting from airways inflammation triggered by a range of environmental stimuli, the most important of which are aeroallergens and viruses. We describe below a model for the cause of atopic asthma in which discrete sets of developmental factors governing the postnatal maturation of the immune and respiratory systems play central and complementary roles in disease causality. Within the immune system, the relevant developmental processes involve maturation of TH1 and associated innate immune functions that combat infection and concomitantly antagonize the early programming of TH2-polarized immunologic memory against inhalant allergens. Within the respiratory system, the relevant developmental processes involve intensive lung growth and airway remodeling during infancy. We hypothesize that delayed maturation of TH1-associated functions during early postnatal life increases the risk for sensitization to aeroallergens and for severe respiratory infection, resulting in airway inflammation at a crucial stage in lung development and precipitating changes in lung growth that are the harbingers of susceptibility to persistent asthma. We further hypothesize that protection of the growing lung against the effects of inflammation during infancy and early childhood has unique potential as a generic strategy for asthma prophylaxis.
Publisher: Wiley
Date: 02-02-2015
DOI: 10.1111/ALL.12563
Publisher: Elsevier BV
Date: 10-2014
Abstract: Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. This study investigates the IL-1 pathway and a neutrophil gene expression signature in PBB. BAL was collected from children in an experimental cohort (n = 21, PBB n = 33, control subjects), and a second validation cohort (n = 36, PBB n = 11, control subjects). IL-1β, IL-1 receptor antagonist (IL-1RA), and α-defensins 1-3 were assayed by enzyme-linked immunosorbent assay, western blot, and quantitative real-time polymerase chain reaction, together with selected IL-1 pathway members and neutrophil-related molecules. In the experimental cohort, children with symptomatic PBB had significantly higher levels of IL-1β and α-defensin gene and protein expression. Expression of the neutrophil chemokine receptor C-X-C motif receptor 2 was also higher in PBB. IL-1RA protein was higher, however, the IL-1RA:IL-1β ratio was lower in children with PBB than control subjects. In the validation cohort, protein and gene expression of IL-1β and α-defensins 1-3 were confirmed higher, as was gene expression of IL-1 pathway members and C-X-C motif receptor 2. IL-1β and α-defensin 1-3 levels lowered when PBB was treated and resolved. In children with recurrent PBB, gene expression of the IL-1β signaling molecules pellino-1 and IL-1 receptor-associated kinase 2 was significantly higher. IL-1β protein levels correlated with BAL neutrophilia and the duration and severity of cough symptoms. IL-1β and α-defensin 1-3 levels were highly correlated. PBB is characterized by increased IL-1β pathway activation. IL-1β and related mediators were associated with BAL neutrophils, cough symptoms, and disease recurrence, providing insight into PBB pathogenesis.
Publisher: Informa UK Limited
Date: 07-2022
DOI: 10.2147/POR.S360044
Publisher: BMJ
Date: 05-1998
DOI: 10.1136/THX.53.5.437
Publisher: Wiley
Date: 06-02-2018
DOI: 10.1111/ALL.13415
Abstract: In mouse models of allergic asthma, exposure to different allergens can trigger distinct inflammatory subtypes in the airways. We investigated whether this observation extends to humans. We compared the frequency of sputum inflammatory subtypes between mild allergic asthma subjects (n = 129) exposed to different allergens in inhalation challenge tests. These tests were performed using a standardized protocol as part of clinical trials of experimental treatments for asthma, prior to drug randomization. Five allergen types were represented: the house dust mites Dermatophagoides pteronyssinus and Dermatophagoides farinae, ragweed, grass, and cat. Of 118 in iduals with a sputum s le collected before allergen challenge (baseline), 45 (38%) had paucigranulocytic, 51 (43%) eosinophilic, 11 (9%) neutrophilic, and 11 (9%) mixed granulocytic sputum. Of note, most in iduals with baseline paucigranulocytic sputum developed eosinophilic (48%) or mixed granulocytic (43%) sputum 7 hours after allergen challenge, highlighting the dynamic nature of sputum inflammatory subtype in asthma. Overall, there was no difference in the frequency of sputum inflammatory subtypes following challenge with different allergen types. Similar results were observed at 24 hours after allergen challenge. Unlike reported in mice, in humans the sputum inflammatory subtype observed after an allergen-induced asthma exacerbation is unlikely to be influenced by the type of allergen used.
Publisher: Elsevier BV
Date: 10-2015
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000369341
Abstract: b i Background: /i /b Pollens of the Panicoideae subfamily of grasses including Bahia i (Paspalum notatum) /i are important allergen sources in subtropical regions of the world. An assay for specific IgE to the major molecular allergenic component, Pas n 1, of Bahia grass pollen (BaGP) would have immunodiagnostic utility for patients with pollen allergy in these regions. b i Methods: /i /b Biotinylated Pas n 1 purified from BaGP was coated onto streptavidin ImmunoCAPs. Subjects were assessed by clinical history of allergic rhinitis and skin prick test (SPT) to aeroallergens. Serum total, BaGP-specific and Pas n 1-specific IgE were measured. b i Results: /i /b Pas n 1 IgE concentrations were highly correlated with BaGP SPT (r = 0.795, p 0.0001) and BaGP IgE (r = 0.915, p 0.0001). At 0.23 kU/l Pas n 1 IgE, the diagnostic sensitivity (92.4%) and specificity (93.1%) for the detection of BaGP allergy was high (area under receiver operator curve 0.960, p 0.0001). The median concentrations of Pas n 1 IgE in non-atopic subjects (0.01 kU/l, n = 67) and those with other allergies (0.02 kU/l, n = 59) showed no inter-group difference, whilst grass pollen-allergic patients with allergic rhinitis showed elevated Pas n 1 IgE (6.71 kU/l, n = 182, p 0.0001). The inter-assay coefficient of variation for the BaGP-allergic serum pool was 6.92%. b i Conclusions: /i /b Pas n 1 IgE appears to account for most of the BaGP-specific IgE. This molecular component immunoassay for Pas n 1 IgE has potential utility to improve the sensitivity and accuracy of diagnosis of BaGP allergy for patients in subtropical regions.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.VACCINE.2014.11.024
Abstract: Endobronchial infections related to non-typeable Haemophilus influenzae (NTHi) are common in children and adults with suppurative airway disease such as bronchiectasis and COPD. Impaired cell mediated immune responses to NTHi have been described in these patients. Currently there are no interventions known to correct the deficiency in cell mediated immune responses to NTHi. The aim of this study was to determine if receipt of a conjugate vaccine containing protein D from H. influenzae is associated with improvement in NTHi-specific cytokine responses in children with chronic suppurative lung disease. Blood mononuclear cells from 107 young children with chronic suppurative lung disease and 32 healthy control children were stimulated in vitro with NTHi. We compared the cytokine production of stimulated mononuclear cells from children who had received the pneumococcal H. influenzae protein D conjugate vaccine with cells from children who received pneumococcal vaccines without protein D. Protein D-specific IgG1 was quantified in plasma. Children with chronic suppurative lung disease who received ≥ 3 doses of the protein D conjugate vaccine produced significantly more IFNγ than children who received the alternative vaccines without protein D (median 939 versus 338 pg/ml p = 0.007). Importantly, the amount of IFNγ produced by those vaccinated with the conjugate vaccine approached the levels observed in cells from healthy children. The conjugate vaccine was also associated with small but significant increases in IL-13 (p < 0.001) and IL-5 (p = 0.007). Protein D-specific IgG1 levels correlated with the number of PHiD-CV doses (p = 0.02). Vaccination with PHiD-CV is associated with improvements in NTHi-specific cell-mediated and humoral immune responses in children with chronic suppurative lung disease.
Publisher: American Thoracic Society
Date: 08-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
DOI: 10.1097/00130832-200402000-00009
Abstract: The central importance of respiratory tract dendritic cells in the regulation of adaptive immune responses to inhaled antigens is now well established. Dendritic cells are not merely a conduit for the transfer of antigen to regional lymph nodes, but rather function as a sophisticated information transfer system linking the airway micro-environment to the adaptive immune system. Evidence from both animal models and clinical studies points to a critical role for dendritic cells in both allergic sensitization and the pathogenesis of chronic airway inflammation. This article reviews recent information on the distribution and function of dendritic cells in healthy in iduals, the responsiveness of these cells to external stimuli, and the factors regulating their activation and turnover within the lung. Animal models of allergic airway inflammation continue to shed new light on the role of lung dendritic cells in T helper 1/T helper 2 switching, and the ability of these cells to direct regulatory T-cell development and immune tolerance. Recent studies have further characterized circulating dendritic cell populations, highlighting important functional differences between dendritic cells from atopic and nonatopic in iduals, and have delineated the involvement of these cells in the late phase response to inhaled allergen. Because of the immunoregulatory properties of dendritic cells, the future is likely to see a concerted effort to further define the role that these cells play in allergic sensitization, as a basis for the development of new treatments for asthma and other atopic disorders.
Publisher: American Society for Microbiology
Date: 12-2002
DOI: 10.1128/IAI.70.12.6583-6588.2002
Abstract: Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy in iduals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5- and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR + cells that lacked B-cell- and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.
Publisher: Public Library of Science (PLoS)
Date: 18-11-2011
Publisher: Wiley
Date: 19-03-2012
DOI: 10.1002/PPUL.22544
Abstract: Some pediatric centers perform flexible bronchoscopy (FB) routinely when bronchiectasis is suspected. However, there are no published data evaluating this practice. To evaluate the contribution of FB and bronchoalveolar lavage (BAL) to the initial management of children newly diagnosed with non-cystic fibrosis (CF) bronchiectasis. We examined FB and BAL data collected prospectively in 56 children aged 0.8-9.8 years during initial investigations for bronchiectasis. Investigations contributed to management if any of the following were identified: (1) airway obstruction requiring additional intervention, (2) lower airway eosinophilia (BAL eosinophils >2.5%), or (3) BAL fluid culture >10(4) colony-forming units/ml of a respiratory bacterial pathogen requiring change from usual empiric antibiotics. Of the 56 children undergoing FB, there were 25 occasions in 23 children where these procedures altered empiric treatment. Lower airway eosinophilia was identified in 19 (34%) children, BAL microbiology results led to antibiotic changes in 5 (9%) and an unsuspected foreign body was found in another (2%). Strongyloides serology was performed in 38 children, including 12 of the 19 with airway eosinophilia, and was positive in 5 of these 12 children (42%). Contrary to some expert recommendations that FB should only be performed when bronchiectasis is localized, our data suggest that FB with BAL should at least be included in the initial investigations of Indigenous children with non-CF bronchiectasis.
Publisher: Wiley
Date: 15-06-2011
Publisher: Wiley
Date: 21-08-2014
DOI: 10.1111/CEA.12345
Abstract: In asthma, the airway inflammatory phenotype influences clinical characteristics and treatment response. Although induced sputum is the gold standard test for phenotyping asthma, a more accessible method is needed for clinical practice. To investigate whether white blood cell counts and/or their derived ratios can predict sputum eosinophils or neutrophils in uncontrolled asthma. This cross-sectional study evaluated 164 treated but uncontrolled asthmatic patients with sputum induction and blood collection. Receiver-operating characteristic (ROC) curves were used to assess the relationship between blood and sputum parameters. There was a significant positive relationship between blood eosinophil parameters and the percentage of sputum eosinophil count. A weak but significant correlation was found between sputum neutrophil percentage and blood neutrophil percentage (r = 0.219, P = 0.005). ROC curve analysis identified that blood eosinophil percentage count was the best predictor for eosinophilic asthma, with an area under the curve (AUC) of 0.907 (P < 0.001). The optimum cut-point for blood eosinophil percentage was 2.7%, and this yielded a sensitivity of 92.2% and a specificity of 75.8%. The absolute blood eosinophil count was also highly predictive with an AUC of 0.898 (P < 0.0001) at a blood eosinophil cut-off of 0.26 × 10(9) /L. The blood eosinophil/lymphocyte ratio (ELR) and eosinophil/neutrophil ratio (ENR) were increased in eosinophilic asthma, and the neutrophil/lymphocyte ratio (NLR) was increased in neutrophilic asthma. Neutrophilic asthma could also be detected by blood neutrophil percentages and NLR, but with less accuracy. Blood eosinophil counts and derived ratios (ELR and ENR) can accurately predict eosinophilic asthma in patients with persistent uncontrolled asthma despite treatment. Blood neutrophil parameters are poor surrogates for the proportion of sputum neutrophils. Blood counts may be a useful aid in the monitoring of uncontrolled asthma.
Publisher: Wiley
Date: 30-11-2017
DOI: 10.1111/RESP.12957
Abstract: Asthma is a chronic respiratory disease characterized by respiratory symptoms, airway inflammation, airway obstruction and airway hyper-responsiveness. Asthma is common and directly affects 10% of Australians, 1-5% of adults in Asia and 300 million people worldwide. It is a heterogeneous disorder with many clinical, molecular, biological and pathophysiological phenotypes. Current management strategies successfully treat the majority of patients with asthma who have access to them. However, there is a subset of an estimated 5-10% of patients with asthma who have severe disease and are disproportionately impacted by symptoms, exacerbations and overall illness burden. The care required for this relatively small proportion of patients is also significant and has a major impact on the healthcare system. A number of new therapies that hold promise for severe asthma are currently in clinical trials or are entering the Australian and international market. However, recognition of severe asthma in clinical practice is variable, and there is little consensus on the best models of care or how to integrate emerging and often costly therapies into current practice. In this article, we report on roundtable discussions held with severe asthma experts from around Australia, and make recommendations about approaches for better patient diagnosis and assessment. We assess current models of care for patient management and discuss how approaches may be optimized to improve patient outcomes. Finally, we propose mechanisms to assess new therapies and how to best integrate these approaches into future treatment.
Publisher: Wiley
Date: 04-12-2016
DOI: 10.1002/PPUL.23351
Publisher: The American Association of Immunologists
Date: 15-06-2012
Abstract: Human rhinoviruses (RV) cause only minor illness in healthy in iduals, but can have deleterious consequences in people with asthma. This study sought to examine normal homeostatic mechanisms regulating adaptive immunity to RV in healthy humans, focusing on effects of IFN-αβ and plasmacytoid dendritic cells (pDC) on Th2 immune responses. PBMC were isolated from 27 healthy in iduals and cultured with RV16 for up to 5 d. In some experiments, IFN-αβ was neutralized using a decoy receptor that blocks IFN signaling, whereas specific dendritic cell subsets were depleted from cultures with immune-magnetic beads. RV16 induced robust expression of IFN-α, IFN-β, multiple IFN-stimulated genes, and T cell-polarizing factors within the first 24 h. At 5 d, the production of memory T cell-derived IFN-γ, IL-10, and IL-13, but not IL-17A, was significantly elevated. Neutralizing the effects of type-I IFN with the decoy receptor B18R led to a significant increase in IL-13 synthesis, but had no effect on IFN-γ synthesis. Depletion of pDC from RV-stimulated cultures markedly inhibited IFN-α secretion, and led to a significant increase in expression and production of the Th2 cytokines IL-5 (p = 0.02), IL-9 (p & 0.01), and IL-13 (p & 0.01), but had no effect on IFN-γ synthesis. Depletion of CD1c+ dendritic cells did not alter cytokine synthesis. In healthy humans, pDC and the IFN-αβ they secrete selectively constrain Th2 cytokine synthesis following RV exposure in vitro. This important regulatory mechanism may be lost in asthma deficient IFN-αβ synthesis and/or pDC dysfunction have the potential to contribute to asthma exacerbations during RV infections.
Publisher: Wiley
Date: 02-1992
DOI: 10.1111/J.1445-5994.1992.TB01707.X
Abstract: To assess the place of bronchoscopy in the investigation of pleural effusion, 245 patients presenting during a two year period were reviewed. Of the 46 patients who had bronchoscopy, a positive yield was obtained in 13, though in five of these a second pleural aspiration was also diagnostic. Bronchoscopy was more likely to be diagnostic in patients presenting with a cough (12/24) than in those with no cough (1/22) (p less than 0.001), and in those whose chest X-ray revealed significant radiological abnormalities such as hilar enlargement, lung mass or persisting consolidation (12/29), than in those without such changes (1/17) (p less than 0.01). Bronchoscopy has a limited role in the investigation of pleural effusion. The presence or absence of cough, and the appearance of the chest X-ray, are both important considerations when planning the investigation of an undiagnosed pleural effusion.
Publisher: The American Association of Immunologists
Date: 07-2007
DOI: 10.4049/JIMMUNOL.179.1.132
Abstract: Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the 299Gly and 399Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence (299Asp/399Thr), or the 299Gly or 399Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing 299Gly or 399Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-κB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-α. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus.
Publisher: American Thoracic Society
Date: 09-2004
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.COI.2010.10.019
Abstract: Airway epithelial cells act through multiple mechanisms to function as an important component of the pulmonary defence strategy that is crucial to the maintenance of immune homeostasis. Dendritic cells are uniquely potent inducers of immune responses and it is increasingly clear that epithelium has the capacity to modulate the functional activity of dendritic cells, and vice versa, through production of a erse array of mediators. Bidirectional interactions between epithelial cells and dendritic cell networks can thus impact upon the development and progression of immunity/tolerance in respiratory tissues. In this brief review we highlight the most recent advances in understanding how airway epithelial/dendritic cell interactions contribute to allergic disorders.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.JACI.2008.09.009
Abstract: Dendritic cells (DCs) are important in allergic diseases such as asthma, although little is known regarding the mechanisms by which DCs induce T(H)2-polarized responses in atopic in iduals. It has been suggested that intrinsic properties of allergens can directly stimulate T(H)2 polarizing functions of DCs, but little is known of the underlying mechanisms. To identify novel genes expressed by house dust mite (HDM) allergen-exposed DCs. We screened for allergen-induced gene expression by microarray, and validated differentially expressed genes at the mRNA and protein levels. Thrombomodulin (CD141, blood dendritic cell antigen 3) expression by microarray was higher on HDM-stimulated DCs from atopic (relative to nonatopic) in iduals. These findings were confirmed at both the mRNA and protein levels in an independent group. Purified thrombomodulin(+) DCs induced a strongly T(H)2-polarized cytokine response by allergen-specific T cells compared with DCs lacking thrombomodulin. In vivo, thrombomodulin(+) circulating DCs were significantly more frequent in subjects with HDM allergy and asthma, compared with control subjects. Furthermore, thrombomodulin expression in blood leukocytes was higher in children with acute asthma than at convalescence 6 weeks later. Thrombomodulin expression on DCs may be involved in the pathogenesis of atopy and asthma.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2022
DOI: 10.1038/S41541-021-00422-4
Abstract: Though clinical guidelines recommend influenza vaccination for chronic obstructive pulmonary disease (COPD) patients and other high-risk populations, it is unclear whether current vaccination strategies induce optimal antibody responses. This study aimed to identify key variables associated with strain-specific antibody responses in COPD patients and healthy older people. 76 COPD and 72 healthy participants were recruited from two Australian centres and inoculated with influenza vaccine. Serum strain-specific antibody titres were measured pre- and post-inoculation. Seroconversion rate was the primary endpoint. Antibody responses varied between vaccine strains. The highest rates of seroconversion were seen with novel strains (36–55%), with lesser responses to strains included in the vaccine in more than one consecutive year (27–33%). Vaccine responses were similar in COPD patients and healthy participants. Vaccine strain, hypertension and latitude were independent predictors of seroconversion. Our findings reassure that influenza vaccination is equally immunogenic in COPD patients and healthy older people however, there is room for improvement. There may be a need to personalise the yearly influenza vaccine, including consideration of pre-existing antibody titres, in order to target gaps in in idual antibody repertoires and improve protection.
Publisher: Springer Science and Business Media LLC
Date: 30-04-2016
Publisher: Public Library of Science (PLoS)
Date: 09-09-2014
Publisher: Bentham Science Publishers Ltd.
Date: 12-2016
Publisher: Public Library of Science (PLoS)
Date: 16-07-2013
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.HUMIMM.2012.03.004
Abstract: Measles virus causes severe morbidity and mortality, despite the availability of measles vaccines. Successful defence against viral pathogens requires early recognition of virus-specific patterns by innate receptors like Toll-like receptor (TLR)3 and the RNA helicase, retinoic acid inducible gene-I (RIG-I). Genetic differences in these receptors may influence the primary immune responses to measles and the efficacy of measles vaccine. In 1-year-old Australian infants after their first measles vaccine dose, we investigated functional effects of TLR3 and RIG-I polymorphisms on intracellular protein expression using flow cytometry, cytokine responses to receptor ligands and measles lysate, and post-vaccination measles IgG levels. We found that TLR3 Leu412Phe was significantly associated with IFN-α/β response after stimulation with TLR3 ligand, poly(I:C) (P=0.024). Downregulation of TLR3 protein expression in NK cells after poly(I:C) was also associated with this variant (P=0.011). In contrast, measles-specific expression, cytokine responses and antibody responses were not associated with TLR3 polymorphisms. No associations were found with RIG-I variants. These results suggest that a TLR3 polymorphism has functional effects on receptor expression and cytokine response. However, this did not translate to an effect on specific responses to measles virus or vaccine. We found no evidence that RIG-I polymorphisms were involved in measles immune responses.
Publisher: BMJ
Date: 03-2005
Publisher: Wiley
Date: 20-06-2014
DOI: 10.1002/PPUL.22792
Abstract: Wet cough is a common feature of many disease processes affecting children. Our aim was to examine the relationships between cough nature, lower airway infection (bacterial, viral, and viral-bacterial) and severity of neutrophilic airway inflammation. We hypothesized that viral-bacterial co-infection of the lower airway would be associated with wet cough and heightened neutrophilic airway inflammation. We prospectively recruited 232 children undergoing elective flexible bronchoscopy. Participants were grouped using a cough nature symptom-based approach, into wet, dry or no cough groups. Broncho-alveolar lavage (BAL) and clinical data, including presence, nature, and duration of cough and key demographic factors, were collected. Children with wet cough (n = 143) were more likely to have lower airway bacterial infection (OR 2.6, P = 0.001), viral infection (OR 2.04, P = 0.045) and viral-bacterial co-infection (OR 2.65, P = 0.042) compared to those without wet cough. Wet cough was associated with heightened airway neutrophilia (median 19%) as compared to dry or no cough. Viral-bacterial co-infection was associated with the highest median %neutrophils (33.5%) compared to bacteria only, virus/es only and no infection (20%, 18%, and 6%, respectively, P < 0.0001). Children with wet cough had higher rates of lower airway infection with bacteria and viruses. Maximal neutrophilic airway inflammation was seen in those with viral-bacterial co-infection. Cough nature may be a useful indicator of infection and inflammation of the lower airways in children.
Publisher: Wiley
Date: 02-2022
DOI: 10.1111/IMJ.15049
Abstract: Several recent randomised controlled trials (RCT) have investigated the use of direct oral anticoagulants (DOAC) in the treatment of malignancy‐associated venous thromboembolism (VTE). This meta‐analysis combines all RCT data to determine the risks of recurrent VTE and bleeding with DOAC in patients with malignancy‐associated VTE compared with low‐molecular‐weight heparin (LMWH). The study followed PRISMA guidelines. MEDLINE, EMBASE and CENTRAL were systematically searched from inception to 1 April 2020. References of reviews and relevant conference proceedings were searched by hand. Two authors independently evaluated study eligibility, extracted data and assessed risk of bias. Direct and indirect meta‐analyses were performed. In four RCT with low risk of bias (2907 patients), high certainty evidence suggested that DOAC had a 37% reduction in risk of recurrent VTE compared with LMWH (direct pooled risk ratio (RR) 0.63 95% confidence interval (CI) 0.44–0.91 I 2 = 28%). No significant difference was observed in the risk of major bleeding with DOAC compared with LMWH (RR 1.31 95% CI 0.83–2.07 I 2 = 22% moderate certainty evidence), including in patients in gastrointestinal and genitourinary malignancy. An increased risk of combined major or clinically relevant non‐major bleeding was seen with DOAC (RR 1.52 95% CI 1.09–2.12 I 2 = 51% low certainty evidence). Apixaban had the highest probability of being ranked the most effective and least bleeding risk among the DOAC. DOAC are effective in treating malignancy associated VTE however, caution is required in patients with high risk of bleeding. Apixaban had lower risk of bleeding compared to other DOAC in this population.
Publisher: Wiley
Date: 24-07-2012
DOI: 10.1038/ICB.2012.39
Abstract: Several studies provided evidence of innate interferons (IFNs) regulating T(H)2 cytokine production using purified CD4(+) memory cells and T(H)2 polarisation via interleukin-4 (IL-4). Vitally, none of these previous studies examined IFN attenuation of T(H)2 responses to allergen or antigen. This study therefore sought to investigate the abrogation of specific allergen- and antigen-stimulated T(H)2 response in peripheral blood mononuclear cells (PBMC) derived from 12 sensitised in iduals by IFN-β and IFN-λ. PBMC were cultured in the presence of house dust mite (HDM) allergen, rhinovirus (RV), influenza vaccine and tetanus toxoid (TT)±either IFN-β or IFN-λ for 3 and 5 days. IFN-γ, IL-5 and IL-13 protein levels were measured by ELISA. Quantitative PCR (qPCR) was used to investigate induction of genes involved in control of T(H)2 cytokines. No alteration in T(H)1 IFN-γ allergen/antigen response was observed with addition of IFN-β or IFN-λ. Consistent abrogation of T(H)2 response to HDM and influenza was observed with IFN-β at both time points attenuation was observed by day 5 with RV and TT. IFN-λ had no consistent effect on T(H)2 production except in the presence of RV (multiplicity of infection=5) a decrease in IL-5 alone was observed in the presence of trivalent inactivated influenza vaccine. GATA binding protein 3 (GATA3) and suppressors of cytokine signalling3 mRNA were differentially regulated in HDM and influenza-stimulated cultures±IFN-β. We concluded that IFN-β produced a strong and consistent abrogation of T(H)2 cytokine production in the presence of a range of allergen and antigen stimulants.
Publisher: Wiley
Date: 03-04-2019
DOI: 10.1111/RESP.13553
Publisher: Wiley
Date: 15-03-2022
DOI: 10.1111/RESP.14244
Publisher: European Respiratory Society (ERS)
Date: 13-10-2022
DOI: 10.1183/23120541.00641-2021
Abstract: COPD patients are more susceptible to viral respiratory infections and their sequelae, and have intrinsically weaker immune responses to vaccinations against influenza and other pathogens. Prime-boost, double-dose immunisation has been suggested as a general strategy to overcome weak humoral response to vaccines, such as seasonal influenza vaccination, in susceptible populations with weak immunity. However, this strategy, which may also provide fundamental insights into the nature of weakened immunity, has not been formally studied in COPD. We conducted an open-label study of seasonal influenza vaccination in 33 vaccine-experienced COPD patients recruited from established cohorts (mean age 70 (95% CI 66.9–73.2) years mean forced expiratory volume in 1 s/forced vital capacity ratio 53.4% (95% CI 48.0–58.8%)). Patients received two sequential standard doses of the 2018 quadrivalent influenza vaccine (15 μg haemagglutinin per strain) in a prime-boost schedule 28 days apart. We measured strain-specific antibody titres, an accepted surrogate of likely efficacy, and induction of strain-specific B-cell responses following the prime and boost immunisations. Whereas priming immunisation induced the expected increase in strain-specific antibody titres, a second booster dose was strikingly ineffective at further increasing antibody titres. Similarly, priming immunisation induced strain-specific B-cells, but a second booster dose did not further enhance the B-cell response. Poor antibody responses were associated with male gender and cumulative cigarette exposure. Prime-boost, double-dose immunisation does not further improve influenza vaccine immunogenicity in previously vaccinated COPD patients. These findings underscore the need to design more effective vaccine strategies for COPD patients for influenza.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S0163-7258(03)00094-9
Abstract: Increasing evidence points to the role of antigen-presenting dendritic cells (DC) in regulating adaptive immune responses. DC are especially sensitive to signals derived from microbes, allergens, and the airway tissue microenvironment, can polarize naïve T-cells into either Th1 or Th2 effector cells, and are increasingly recognized as having a central role in the establishment of T-cell memory and tolerance to inhaled antigens. DC form a closely meshed network within the respiratory mucosa and are rapidly recruited from the circulation in response to a variety of proinflammatory stimuli. Studies using animal models have highlighted the role of DC in both initiation and maintenance of allergic airway inflammation. Increased numbers of airway mucosal DC are found in both allergic rhinitis and asthma, and an increasing number of investigators have highlighted important functional differences between DC from atopic and normal in iduals. This article reviews recent information on the involvement of DC in the pathogenesis of allergic airway disease and the means by which DC could be exploited as targets for therapy in asthma and allergic rhinitis.
Publisher: Wiley
Date: 12-1993
DOI: 10.1111/J.1445-5994.1993.TB04727.X
Abstract: Malignant mesothelioma is a tumour which is generally resistant to chemotherapy. While the addition of interferon to chemotherapy improves response rates in some other malignancies, such a combination has not been evaluated in the treatment of mesothelioma. To assess the anti-tumour effects and toxicity of interferon-alpha combined with doxorubicin in the treatment of pleural mesothelioma. Twenty five patients (mean age 54 +/- 11 years) were enrolled in a phase II study. All patients had a confirmed histological diagnosis, measurable tumour, a life expectancy of at least three months, and no prior chemotherapy or interferon. Interferon alpha-2a, 9 x 10(6) U sc daily, was administered together with doxorubicin 25 mg per m2 i.v. weekly, for 12 weeks. Response status was assessed by tumour measurements on clinical examination and thoracic CT scans before and after treatment. A partial response was observed in four patients (16% 90% CI, 8-30%), 11 remained stable, while six had progressive disease. Four patients withdrew within the first month because of toxicity. The median survival of all patients was 11 months (95% CI, 3-19). Dose modification as a result of toxicity was required in all patients. Lethargy, weight loss, leukopenia and vomiting were the most common side effects. The combination of interferon-alpha and doxorubicin showed only modest activity and was associated with significant toxicity. It cannot be recommended in the treatment of malignant pleural mesothelioma.
Publisher: Springer Science and Business Media LLC
Date: 12-2010
Abstract: Rhinoviruses (RV) are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age. Blood mononuclear cells were isolated from 63 healthy in iduals and grouped by sex and age (≤50 years old and ≥52 years old). Cells were cultured with rhinovirus 16 at a multiplicity of infection of 1. The chemokine IP-10 was measured at 24 h as an index of innate immunity while IFNγ and IL-13 were measured at 5 days as an index of adaptive immunity. Rhinovirus induced IFNγ and IL-13 was significantly higher in ≤50 year old women than in age matched men (p 0.02 and p 0.05) and ≥52 year old women (p 0.02 and p 0.005). There was no sex or age based difference in rhinovirus induced IP-10 expression. Both IFNγ and IL-13 were negatively correlated with age in women but not in men. This study suggests that pre-menopausal women have a stronger adaptive immune response to rhinovirus infection than men and older people, though the mechanisms responsible for these differences remain to be determined. Our findings highlight the importance of gender and age balance in clinical studies and in the development of new treatments and vaccines.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2011
DOI: 10.1007/S00251-011-0574-0
Abstract: Successful defence against viral pathogens requires the rapid recognition of virus-specific "danger signals" and the activation of both innate and adaptive immunity. Toll-like receptors (TLR) 7 and 8 play a critical role in the elimination of viruses by recognising the common viral component, single stranded (ss)RNA. Measles virus, an ssRNA virus, continues to cause serious morbidity and mortality worldwide despite available measles vaccines. TLR7 and TLR8 genetic variation may cause functional alterations that result in impaired responses to measles. In a population of 12-month-old Australian infants, receptor protein expression was examined to assess the functionality of TLR7 and TLR8 polymorphisms, and the effects of these polymorphisms on cellular and antibody responses after the first measles vaccine dose were investigated. TLR7 Leu11Gln showed associations with TNF-α responses after ligand (imiquimod) stimulation in males only (P = 0.040), and non-responders were more likely to be Gln males (P = 0.044). TNF-α non-responders after imiquimod also had higher percentages of TLR8 -4284TT (69.6%) (P = 0.001) and TLR8 -558CC (69.6%) (P = 0.002) in females. Receptor protein expression after imiquimod or measles stimulation was not significantly altered compared with baseline, nor was it affected by genotype. None of the TLR7 or TLR8 polymorphisms studied were associated with measles-specific cytokine levels or with measles IgG levels. In conclusion, we report gender-specific associations with TLR7 and TLR8 polymorphisms and TNF-α cellular responses to its ligand. However, we found no evidence of any functional effects of TLR7 or TLR8 polymorphisms on receptor expression, measles-specific cellular responses or measles vaccine antibody responses.
Publisher: Wiley
Date: 17-05-2018
DOI: 10.1111/CEA.13153
Abstract: Severe asthma affects quality of life however, its impact on workplace productivity is poorly understood. To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.
Publisher: Informa UK Limited
Date: 08-01-2013
DOI: 10.1517/17425255.2013.754009
Abstract: The process of drug disposition in the lung after pulmonary delivery is complex involving absorptive and non-absorptive mechanisms. The lung has also been suggested to be a trapping and metabolizing organ, especially after intravenous administration of drug. A key challenge is to define the most suitable models for the evaluation of pulmonary drug disposition. This review provides an overview of the anatomy and physiology of the lung and sites of action. The authors follow this with a description of the processes associated with pulmonary disposition (deposition, absorption, distribution, metabolism, and non-absorptive clearance). The article also summarizes and compares models and techniques for the assessment of drug disposition in the lung, in terms of characteristic features, advantages and disadvantages. Finally, the authors review pharmaceutical science implications of these findings. In vivo models are preferred for studying drug deposition, absorption, disposition, and response in the lung. In vitro models may be useful in the initial screening for new compounds and in drug lead optimization. The labor-intensive isolated perfused lung models are most suitable for in-depth studies on drug pulmonary disposition for lead compounds. In the future, engineered lungs may become a more convenient means of evaluating drug disposition in the lung.
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0091-6749(99)70381-7
Abstract: Recent findings point to an association between allergic asthma in adults and increased responsiveness of myeloid progenitor cells to certain hemopoietic growth factors. However, it is not clear at what age these changes in progenitor cells first become manifest, although increasing evidence suggests that the allergic phenotype may begin to emerge in very early life. We sought to compare expression of hemopoietic cytokine receptors on CD34(+) progenitor cells in cord blood from normal infants ("low risk" for subsequent atopy) and infants with at least one atopic first degree relative ("at risk" for subsequent atopy). Cord blood was obtained from 21 neonates. Nonadherent mononuclear cells were stained with mAbs directed against CD45, CD34, and the alpha-chains of the GM-CSF, IL-3, and IL-5 receptors and analyzed by flow cytometry. No differences in absolute CD34(+) numbers were observed between the 2 groups. However, expression of GM-CSF receptor on CD34(+) cells was reduced in the "at-risk" compared with the "low- risk" group (P =.021), although no significant differences were noted between the 2 groups with respect to IL-3 and IL-5 receptor expression. The functional sequelae of reduced GM-CSF receptor expression on CD34(+) cells remain to be determined. Nonetheless, these findings show an association between genetic risk for atopy and changes in the expression of hemopoietic cytokine receptors on cord blood progenitor cells and support the notion that the allergic phenotype may begin to evolve in the perinatal period.
Publisher: Public Library of Science (PLoS)
Date: 11-09-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-11-2012
Publisher: S. Karger AG
Date: 2001
DOI: 10.1159/000053724
Abstract: We and others have shown that IL-5 plays a central role in eosinophil and basophil differentiation, exerting its effects through the IL-5 receptor (IL-5R). Little is currently known concerning regulation of IL-5Rα gene transcription in the context of commitment of hemopoietic progenitor cells to the eosinophil and basophil lineages recent studies have indicated that IL-5 itself can regulate IL-5Rα expression on mature eosinophils. We now provide evidence to indicate that IL-5 can upregulate IL-5Rα on bone marrow CD34+ progenitors in vitro, as we have demonstrated in vivo in atopic asthmatics. Given that all- i trans /i retinoic acid (ATRA) is known to modulate some granulopoiesis, causing neutrophilic differentiation, we examined the effects of ATRA on eosinophil/basophil differentiation and IL-5Rα expression. In cultures of normal human bone marrow, ATRA selectively suppressed eosinophil/basophil differentiation. Similarly, ATRA inhibited eosinophil/basophil differentiation of cord blood CD34+ cells, while neutrophil differentiation proceeded without impediment. Most importantly, these effects of ATRA on CD34+ cells were associated with selective, dose-dependent inhibition of membrane-bound IL-5Rα, upregulation of soluble IL-5Rα transcription, but no change in GM-CSF receptor expression. These findings indicate that retinoids can differentially regulate membrane and soluble isoforms of IL-5Rα, and that these effects have functional consequences in vitro on eosinophil and basophil differentiation. ATRA may be of therapeutic benefit in allergic inflammatory disorders in which eosinophil differentiation and membrane-bound IL-5R are upregulated.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.RMED.2022.106928
Abstract: Accuracy of right heart strain (RHS) measured on computed tomography pulmonary angiogram (CTPA) scans by non-radiologists is unknown. We assessed inter-observer variability of four RHS features and determined the accuracy of measurements by respiratory physicians. 1560 consecutive patients with acute PE were identified, and those who had a CTPA and an echocardiogram within 24-h included. CTPAs were independently scored prospectively by two radiologists, two thoracic physicians and a specialist registrar. Inter-observer variability was assessed, and diagnostic accuracy compared to echocardiography. 182 patients (median age 62.8 years, IQR 49.8-71.5) with acute PE (7.7% high-risk, 40.7% intermediate high-risk, 31.3% intermediate low-risk and 20.3% low-risk) were included. Right ventricle to left ventricle diameter ratio (RV:LV) measurement had low inter-observer variability among the radiologists and non-radiologists with interclass correlation coefficient (ICC) of 0.95 (95%CI 0.92-0.97) and 0.96 (95%CI 0.94-0.97) respectively. RV:LV ratio had high diagnostic accuracy compared to RV dilatation on echocardiography (AUC 0.89, 95%CI 0.84-0.94 for radiologists and AUC 0.84, 95%CI 0.77-0.90 for non-radiologists). Main pulmonary artery to ascending aorta diameter ratio (MPA:Ao) measurement also had excellent agreement amongst the radiologists and non-radiologists (ICC 0.93 (95%CI 0.88-0.96) and 0.92 (95%CI 0.81-0.96) respectively). Significant variability was seen in the assessment of subjective features of RHS (leftward bowing of interventricular septum and contrast reflux into inferior vena cava) amongst the non-radiologists. RV:LV and MPA:Ao diameter ratios on CTPA measured by non-radiologists have low inter-observer variability and good agreement with radiologists, and can be reliably used where an expert report is unavailable.
Publisher: European Respiratory Society
Date: 09-2017
Publisher: Wiley
Date: 23-12-2014
DOI: 10.1111/RESP.12213
Abstract: The non-eosinophilic phenotype of asthma (NEA) is associated with chronic airway inflammation and airway neutrophilia. An accumulation of apoptotic airway epithelial cells, if not efficiently cleared by efferocytosis, can undergo secondary necrosis, with the potential for inflammation of surrounding tissues. Apoptosis may occur via the T cell granzyme B pathway. The role of granzyme B in NEA is not known. The aim of this study was to investigate production of granzyme B and its inhibitor proteinase inhibitor (PI)-9 by T cells from induced sputum and compare expression between eosinophilic, NEA and healthy controls. We investigated T cell intracellular granzyme B and its inhibitor, PI-9, in sputum from healthy control subjects (n = 10), and patients with NEA (n = 22) or eosinophilic asthma (EA) (n = 15) using flow cytometry. Granzyme B expression and the ratio of granzyme B to PI-9 positive cells were highest in those with NEA for both CD3+ and CD4+ T cells. The expression of granzyme B was not statistically different between patients with NEA and EA however, the ratio of granzyme B to PI-9 positive cells for CD3+ T cells was significantly higher in those with NEA compared with EA. Induced sputum provides a non-invasive tool for investigating T cell cytotoxic mediators in the various asthma subtypes. Granzyme B expression is increased in NEA and the contribution of granzyme B to chronic inflammation requires further study.
Publisher: Wiley
Date: 12-2018
DOI: 10.1111/IMJ.14103
Abstract: Severe asthma leads to debilitating symptoms for patients and excessive socioeconomic burden for the community. Comprehensive models of care are required to address complex issues, risk factors and comorbidities in patients with severe asthma, and to identify patients most appropriate for specialised treatments. Dedicated severe asthma services improve asthma control, reduce asthma exacerbations and hospital admissions, and improve quality of life. Currently, erse models of care exist for managing severe asthma across Australia. Most referrals to severe asthma services are from respiratory physicians seeking a second opinion or from primary care for poorly controlled asthma. Despite benefits of specialised severe asthma services, many patients are not referred and resources are limited, often resulting in long waiting times. Patient referral is often unstructured and there are considerable variations in the management of severe asthma with limited access to other health care professionals such as speech pathologists and dieticians, and restricted scope to optimise patient work-up before referral. Ongoing communication between the specialist and referring clinician is essential for continuity of care but is often lacking. Referral pathways can be optimised by developing referral criteria and guidelines to triage patients with severe asthma and to improve resource efficiency. Additional education and tools for assessing and managing severe asthma are needed, and mechanisms should be developed for involving primary care in the management of stabilised patients. Strategies to increase patient access to multidisciplinary services are recommended.
Publisher: European Respiratory Society (ERS)
Date: 31-08-2011
Publisher: Wiley
Date: 19-09-2019
DOI: 10.1111/RESP.13389
Abstract: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.
Publisher: Wiley
Date: 17-08-2010
DOI: 10.1002/PPUL.21230
Abstract: Lung disease in patients with cystic fibrosis (CF) is characterized by recurrent bacterial respiratory infections and intense airway inflammation. Pattern recognition receptors such as Toll-like receptor 2 (TLR2) and TLR4 identify bacterial pathogens and activate the innate immune response. We therefore hypothesized that increased expression of these receptors would be found on circulating immune cells from children with CF. A cohort of 66 young children (median age 3 years) with CF was studied and compared to both healthy controls (n = 14) and children without CF who were being investigated for recurrent respiratory infections (non-CF disease controls n = 17) of a similar age. Surface expression of TLR2 and TLR4 on peripheral blood monocytes was analyzed using flow cytometry. TLR4 expression was significantly higher in patients with CF compared to healthy controls (P = 0.017) and non-CF disease controls (P = 0.025) but did not vary according to the presence or absence of pulmonary infection with Gram-negative or Gram-positive bacteria (P = 0.387) in the CF group. In contrast, TLR2 expression was similar across all three study groups (P = 0.930). The increased surface expression of TLR4 seen in young children with CF appears to be related to having CF per se and not related to current pulmonary infection.
Publisher: Wiley
Date: 06-1997
Publisher: Wiley
Date: 10-2015
DOI: 10.1038/CTI.2015.27
Publisher: European Respiratory Society (ERS)
Date: 22-04-2009
DOI: 10.1183/09031936.00178508
Abstract: Airway inflammation is an important component of cystic fibrosis (CF) lung disease. We sought to determine whether alveolar macrophages were involved in early CF lung disease. Children with CF (median age 3.1 yrs) participated in a surveillance programme that included annual bronchoalveolar lavage (BAL). Control s les were obtained from non-CF children (median age 3.1 yrs n = 24) investigated for persistent respiratory symptoms. Pulmonary infection was detected in 31% (16 out of 51) and 38% (nine out of 24) of children from the CF and non-CF groups, respectively. Alveolar macrophages in BAL were increased in CF compared with non-CF in the absence of infection (223x10(3) versus 85x10(3) cells.mL(-1) p = 0.001) and were associated with elevations in the CC chemokines (macrophage inflammatory protein (MIP)-3alpha (chemokine (C-C motif) ligand (CCL)20 355.8 versus 46.0 pg.mL(-1) p<0.001), monocyte chemotactic protein-1 (CCL2 263.5 versus 25.3 pg.mL(-1) p<0.001), MIP-1alpha (CCL3 38.2 versus 4.9 pg.mL(-1) p<0.001) and MIP-1beta (CCL4 326.6 versus 27.5 pg.mL(-1) p<0.001)). Total cell counts and neutrophil numbers increased in the presence of infection however, there was no additional effect of CF. Alveolar macrophages and CC chemokines are elevated in the lungs in young children with CF even in the absence of pulmonary infection. Longitudinal studies are required to determine the clinical relevance of these findings.
Publisher: BMJ
Date: 09-1997
DOI: 10.1136/THX.52.9.786
Abstract: Alveolar macrophages are thought to play an important part in regulating lung immune responses. While it is clear that human alveolar macrophages suppress T cell proliferation in vitro, the mechanisms by which this is achieved are not clear, nor is it known whether alveolar macrophages also inhibit other aspects of T cell function. Peripheral blood mononuclear cells were stimulated with phytohaemagglutinin or house dust mite allergen, and cultured with variable numbers of autologous alveolar macrophages obtained by bronchoalveolar lavage from 20 normal subjects. Alveolar macrophages induced a reversible inhibition of T cell proliferation in response to both mitogen and allergen stimulation, with the latter being considerably more susceptible to inhibition. This was achieved via heterogenous mechanisms, involving both soluble factors derived from alveolar macrophages and cell-cell contact. Despite inhibiting proliferation, alveolar macrophages had little or no effect on T cell calcium flux, the characteristic changes in CD3, CD2, CD28 and interleukin-2 (IL-2) receptor expression which accompany normal T cell activation, and IL-2 and interferon gamma secretion. In contrast, alveolar macrophages inhibited the tyrosine phosphorylation of proteins which may be involved in IL-2 receptor-associated signal transduction. The immunoregulatory properties of alveolar macrophages are relatively selective, allowing T cell activation and cytokine secretion while inhibiting T cell proliferation within the lung.
Publisher: American Thoracic Society
Date: 06-1994
DOI: 10.1164/AJRCCM.149.6.7911708
Abstract: Functional analysis of T cells from the bronchial mucosa has been limited by difficulties in extracting T cells from this tissue. Because interleukin-2 (IL-2) is chemotactic for T cells, we determined whether this cytokine could be used to extract T cells from human bronchial wall (BW). Fresh tissue was obtained from 21 patients undergoing surgery for malignancy. Within the BW, 95% of T cells stained for the memory/activation marker CD45RO. When BW sections were incubated with IL-2 for 24 h, 88 to 91% of T cells emigrated into the culture medium. Compared with autologous blood T cells (also exposed to IL-2), these BW T cells expressed CD2 at a greater intensity and showed a fourfold reduction in cloning efficiency in response to phytohemagglutinin, and T-cell clones derived from the BW population displayed a tendency for higher interferon-gamma production. Furthermore, we were also able to extract and clone T cells from bronchoscopic biopsies in four subjects, suggesting that this method will provide a new avenue for examining T-cell function in airway inflammatory diseases.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2018
Publisher: Wiley
Date: 04-04-2008
Publisher: Informa UK Limited
Date: 12-2014
DOI: 10.2147/COPD.S53590
Publisher: Wiley
Date: 06-04-2016
DOI: 10.1111/ALL.12891
Abstract: Both systemic inflammation and sex hormones have been proposed as potential mediators of the obese-asthma phenotype. The aim of this study was to examine the associations between sex hormones, oral contraceptive pill (OCP) use, systemic inflammation and airway inflammation in adults with asthma. Obese (n = 39) and nonobese (n = 42) females and obese (n = 24) and nonobese (n = 25) males with asthma were recruited. Females were further categorized as reproductive-aged ( 50 years old n = 45). Thirteen (36.1%) reproductive-aged females were using the OCP. Participants had induced sputum cell counts measured and blood analysed for sex hormones and inflammatory markers. Obese reproductive-aged females had higher sputum %neutrophils than nonobese reproductive-aged females (45.4 ± 24.3% vs 27.5 ± 17.5%, P = 0.016) however, there was no difference in sputum neutrophils in obese compared with nonobese males (P = 0.620) or older females (P = 0.087). Multiple linear regression analysis found testosterone and OCP use to be negative predictors of sputum %neutrophils, while C-reactive protein and IL-6 were positive predictors of sputum %neutrophils. BMI and age were not significant predictors in the multivariate model. Reproductive-aged females using the OCP had significantly lower sputum %neutrophils than those not using the OCP (23.2 ± 12.6% vs 42.1 ± 23.8%, P = 0.015). This study suggests that sex hormones and systemic inflammation may be mediating the obese-asthma phenotype. The observation that OCP use was associated with lower sputum %neutrophils in reproductive-aged females warrants further investigation.
Publisher: Wiley
Date: 05-1995
DOI: 10.1111/J.1399-3038.1995.TB00264.X
Abstract: The study below comprises prospective analysis of patterns of allergen-specific T-cell reactivity in a cohort of 23 children bled at regular intervals from 6-10 weeks to 2 years of age, together with cross sectional studies on panels of cord and adult blood s les. The results indicate reciprocal patterns of responses to dietary and inhalant allergens, the former being frequent in infancy but rare in adults, whereas the latter are preserved and expand between infancy and adulthood. These findings are consistent with a recently proposed model for the development of immunity to environmental allergens which involves allergen-driven T-cell "selection" during early life leading to deletion of food allergen-specific T-cells via the induction of specific anergy, with concomitant selection and ultimately expansion of mutually exclusive TH-1-like or TH-2-like reactivity to inhalant allergens via Immune Deviation mechanisms.
Publisher: Wiley
Date: 08-07-2003
DOI: 10.1034/J.1600-0463.2003.11107806.X
Abstract: The large quantities and complex mixtures of antigens encountered daily at airway mucosal and alveolar surfaces pose a major challenge to maintenance of immunological homeostasis in the respiratory tract. Amongst this myriad of antigens, the immune system must discriminate between innocuous components that can be tolerated by the host and potentially life‐threatening pathogens that require a rapid immune response. Dendritic cells (DC) represent the principal cell type at these sites capable of processing antigens and delivering signals that initiate tolerogenic or immunogenic immune responses. This review will discuss the role of DC at the “front‐line” of immune surveillance and homeostasis within the respiratory tract and their role in the pathogenesis of respiratory disease.
Publisher: Frontiers Media SA
Date: 25-10-2017
Publisher: European Respiratory Society (ERS)
Date: 21-02-2013
DOI: 10.1183/09031936.00203412
Abstract: The onset, progression and exacerbations of asthma are frequently associated with viral infections of the lower respiratory tract. An emerging paradigm suggests that this relationship may be underpinned by a defect in the host's antiviral response, typified by the impaired production of type I and type III interferons (IFNs). The failure to control viral burden probably causes damage to the lung architecture and contributes to an aberrant immune response, which together compromise lung function. Although a relatively rare cell type, the plasmacytoid dendritic cell dedicates much of its transcriptome to the synthesis of IFNs and is pre-armed with virus-sensing pattern recognition receptors. Thus, plasmacytoid dendritic cells are specialised to ensure early viral detection and the rapid induction of the antiviral state to block viral replication and spread. In addition, plasmacytoid dendritic cells can limit immunopathology, and promote peripheral tolerance to prevent allergic sensitisation to harmless antigens, possibly through the induction of regulatory T-cells. Thus, this enigmatic cell may lie at an important intersection, orchestrating the immediate phase of antiviral immunity to effect viral clearance while regulating tolerance. Here, we review the evidence to support the hypothesis that a primary defect in plasmacytoid dendritic function may underlie the development of asthma.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JACI.2016.02.039
Abstract: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-α and IFN-λ production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-α production. We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
Publisher: European Centre for Disease Control and Prevention (ECDC)
Date: 28-07-2016
DOI: 10.2807/1560-7917.ES.2016.21.30.30301
Abstract: The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance programme operating in all states and territories in Australia. We summarise the epidemiology of children hospitalised with laboratory-confirmed influenza in 2014 and reports on the effectiveness of inactivated trivalent inactivated vaccine (TIV) in children. In this observational study, cases were defined as children admitted with acute respiratory illness (ARI) with influenza confirmed by PCR. Controls were hospitalised children with ARI testing negative for influenza. Vaccine effectiveness (VE) was estimated as 1 minus the odds ratio of vaccination in influenza positive cases compared with test-negative controls using conditional logistic regression models. From April until October 2014, 402 children were admitted with PCR-confirmed influenza. Of these, 28% were aged 1 year, 16% were Indigenous, and 39% had underlying conditions predisposing to severe influenza. Influenza A was detected in 90% of cases of influenza influenza A(H1N1)pdm09 was the most frequent subtype (109/141 of subtyped cases) followed by A(H3N2) (32/141). Only 15% of children with influenza received antiviral therapy. The adjusted VE of one or more doses of TIV for preventing hospitalised influenza was estimated at 55.5% (95% confidence intervals (CI): 11.6–77.6%). Effectiveness against influenza A(H1N1)pdm09 was high (91.6% , 95% CI: 36.0–98.9%) yet appeared poor against H3N2. In summary, the 2014 southern hemisphere TIV was moderately effective against severe influenza in children. Significant VE was observed against influenza A(H1N1)pdm09.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-10-2016
DOI: 10.1126/SCITRANSLMED.AAF8807
Abstract: A secreted hookworm protein in recombinant form acts on dendritic cells to drive the expansion and mucosal homing of regulatory T cells that protect against airway inflammation in mice, and also d ens human dendritic cell and T cell activation.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.JPEDS.2012.03.049
Abstract: To determine bronchoalveolar lavage (BAL) levels of 3 innate immunity components (human β-defensin-2 [hBD2], mannose-binding lectin [MBL], and surfactant protein-A [SP-A]), the relationship with airway neutrophilia and infection, and cytokine production of stimulated BAL cells in children with current protracted bacterial bronchitis (PBB), children with resolved PBB (PBB well), and controls. BAL of 102 children (mean age 2.8 years) fulfilling predefined criteria of current PBB (n = 61), PBB well (n = 20), and controls (n = 21) was cultured (quantitative bacteriology) and viruses examined by polymerase chain reaction. hBD2, MBL, and SP-A were measured, and cytokine production by lipopolysaccharide-stimulated BAL cells was determined. Median hBD2 and MBL levels were significantly higher in the current PBB group (hBD2 = 164.4, IQR 0-435.5 pg/mL MBL = 1.7, 0.4-4 ng/mL) than in the PBB well group (hBD2 = 0, IQR 0-85.2 MBL = 0.6, IQR 0.03-2.9) and controls (hBD2 = 3.6, IQR 0-126 MBL = 0.4, IQR 0.02-79). hBD2 was significantly higher in children with airway infection (n = 54 median 76.9, IQR 0-397.3) compared with those without (n = 48 0, IQR 0-236.3), P= .04. SP-A levels and cytokine production of stimulated BAL cells were similar between groups. In children's airways, hBD2, but not MBL and SP-A, relates to inflammation and infection. In children with PBB, mechanisms involving airway hBD2 and MBL are augmented. These pulmonary innate immunity components and the ability of BAL cells to respond to stimuli are unlikely to be deficient.
Publisher: European Respiratory Society (ERS)
Date: 02-12-2016
DOI: 10.1183/13993003.00405-2015
Abstract: Asthma is a chronic inflammatory disorder of the airways where bacteria may act as protagonists of chronic inflammation. Little is known about the relation of airway inflammation to the presence of specific bacterial taxa. We sought to describe the sputum microbiome in adults with poorly controlled asthma. DNA was extracted from induced sputum and microbial communities were profiled using 16S rRNA pyrosequencing. Bacterial species were characterised, and the relationship between microbial populations, asthma inflammatory subtypes and other covariates was explored. Real-time PCR was used to identify Tropheryma whipplei and Haemophilus influenzae in sputum. Adults with neutrophilic asthma had reduced bacterial ersity and species richness. Tropheryma was identified and confirmed with real-time PCR in 12 (40%) participants. Haemophilus occurred most often in a group of younger atopic males with an increased proportion of neutrophils. PCR confirmed the presence of H. influenzae in 35 (76%) participants with poorly controlled asthma. There are phenotype-specific alterations to the airway microbiome in asthma. Reduced bacterial ersity combined with a high prevalence of H. influenzae was observed in neutrophilic asthma, whereas eosinophilic asthma had abundant T. whipplei .
Publisher: Wiley
Date: 24-12-2013
DOI: 10.1111/J.1365-2222.2012.04075.X
Abstract: Many patients with non-eosinophilic asthma have increased numbers of neutrophils in the airways. The explanation for this chronic inflammation remains unclear, but may result from an impaired ability of alveolar macrophages to phagocytose apoptotic cells (a process termed 'efferocytosis'), as we have shown in chronic obstructive pulmonary disease (COPD). To examine induced sputum as a non-invasive technique to characterize efferocytosis in chronic lung diseases and to compare efferocytosis in patients with non-eosinophilic asthma, eosinophilic asthma and COPD. Participants with stable asthma (20 with eosinophilic and 30 with non-eosinophilic) and COPD (n = 11) underwent clinical assessment including allergy skin tests, saline challenge and sputum induction. Sputum cells were dispersed using dithiothreitol and resuspended in culture medium. Efferocytosis of apoptotic bronchial epithelial cells by sputum-derived macrophages was determined using flow cytometry. There were no significant differences in efferocytosis between paired sputum and bronchoalveolar lavage macrophages from three subjects. Efferocytosis was significantly impaired in patients with non-eosinophilic asthma [mean (SD) 0.95 (0.24)] compared with eosinophilic asthma [1.17 (0.19)] and to a similar degree as patients with COPD [1.04 (0.16)]. Sputum neutrophils were significantly higher in patients with COPD and non-eosinophilic asthma compared with eosinophilic asthma. Induced sputum provides a reliable and non-invasive method for studying macrophage efferocytosis in chronic lung disease. Macrophage efferocytosis is impaired in non-eosinophilic asthma to a similar degree as that in COPD and may explain the persistent airway neutrophilia and chronic inflammation that characterizes this asthma subtype.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JIM.2018.11.001
Abstract: Plasmacytoid dendritic cells (pDC) are an important type I interferon producer that play an important role in the first line of host defence during viral infection. Abnormalities in pDC numbers and function have been associated with several health conditions. Quantifying pDC is important for understanding pDC related immune responses in viral infections and other diseases, however the current methods for quantifying pDC using flow cytometry have limited utility in large cohort studies involving multiple centres with limited access to flow cytometry. We reasoned that examining gene expression of the pDC marker C-type lectin domain family 4 member C (CLEC4C, also known as CD303 and BDCA2) in combination with pDC exclusive leukocyte immunoglobulin like receptor A4 (LILRA4, also known as CD85g and ILT7) might provide a more practical method that could be applied to multi-centre studies. Our results show a moderate correlation between pDC numbers measured by surface staining and CLEC4C gene expression in whole blood (rho = 0.39, P = .037, as well as a high correlation between CLEC4C gene expression in whole blood and peripheral blood mononuclear cells (rho = 0.79, P < .001). LILRA4 gene expression did not provide additional useful information. Our results indicate that measuring CLEC4C gene expression can provide an alternative method for quantifying pDC numbers in human s les.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.VACCINE.2015.10.016
Abstract: We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A/H1N1 dm09 strain predominated. This was performed using a case-test negative study design as part of a national sentinel surveillance system in Australia. Vaccine effectiveness was estimated as (1-OR)×100% where the odds ratio of vaccination in cases vs test negative participants was estimated from a conditional logistic regression. Between April and November, 1692 adult patients were admitted with laboratory-confirmed influenza. Vaccine effectiveness was estimated from 1283 patients with influenza and 1116 test negative patients where vaccination status was ascertained. Vaccination was associated with a reduction in the risk of hospitalisation with influenza of 51.5% (95% CI: 41.6%, 59.7%) in all patients, and a reduction of 50.7% (95% CI: 40.1%, 59.3%) in the target population for vaccination. We estimate that the influenza vaccine was moderately protective against hospitalisation with laboratory-confirmed influenza during the 2014 influenza season in Australia.
Publisher: Wiley
Date: 12-11-2020
DOI: 10.1111/RESP.13730
Publisher: American Thoracic Society
Date: 15-03-2016
Publisher: Elsevier BV
Date: 02-2014
Publisher: Massachusetts Medical Society
Date: 12-05-2016
Publisher: Springer Science and Business Media LLC
Date: 10-2002
DOI: 10.1038/NI1002-885
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.AJPATH.2014.02.026
Abstract: Human metapneumovirus (hMPV) is a leading cause of respiratory tract disease in children and is associated with acute bronchiolitis, pneumonia, and asthma exacerbations, yet the mechanisms by which the host immune response to hMPV is regulated are poorly understood. By using gene-deleted neonatal mice, we examined the contributions of the innate receptor signaling molecules interferon (IFN)-β promoter stimulator 1 (IPS-1), IFN regulatory factor (IRF) 3, and IRF7. Viral load in the lungs was markedly greater in IPS-1(-/-) > IRF3/7(-/-) > IRF3(-/-), but not IRF7(-/-), mice compared with wild-type mice. IFN-β and IFN-λ2/3 (IL-28A/B) production was attenuated in the bronchoalveolar lavage fluid in all factor-deficient mice compared with wild-type mice at 1 day after infection, although IFN-λ2/3 was greater in IRF3/7(-/-) mice at 5 days after infection. IRF7(-/-) and IRF3/7(-/-) mice presented with airway eosinophilia, whereas only IRF3/7(-/-) mice developed an exaggerated type 1 and 17 helper T-cell response, characterized by natural killer T-cell and neutrophilic inflammation. Despite having the highest viral load, IPS-1(-/-) mice did not develop a proinflammatory cytokine or granulocytic response to hMPV infection. Our findings demonstrate that IFN-β, but not IFN-λ2/3, produced via an IPS-1-IRF3 signaling pathway, is important for hMPV clearance. In the absence of a robust type I IFN-α/β response, targeting the IPS-1 signaling pathway may limit the overexuberant inflammatory response that occurs as a consequence of viral persistence.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2015
Publisher: Elsevier BV
Date: 02-2002
Abstract: IL-5 plays a central role in eosinophil and basophil differentiation, exerting its effects through the IL-5 receptor (IL-5Ralpha). Currently, little is known concerning regulation of IL-5Ralpha expression in the context of commitment of hemopoietic progenitor cells to the eosinophil and basophil lineages. Because all-trans retinoic acid (ATRA) is known to modulate some aspects of hemopoietic differentiation, we examined the effects of ATRA on eosinophil-basophil differentiation and IL-5Ralpha expression. Progenitor cells were obtained from bone marrow aspirates and cord blood s les. Enriched populations of CD34(+) cells were isolated by means of positive immunomagnetic selection with MACS beads. In semisolid methylcellulose cultures of normal human bone marrow, ATRA (10(-6) mol/L) selectively suppressed eosinophil-basophil colony-forming units but had no effect on granulocyte-macrophage colony-forming units. Similarly, ATRA (10(-6) mol/L) inhibited eosinophil-basophil differentiation of cord blood CD34(+) cells in liquid culture, whereas neutrophil differentiation proceeded without impediment. Most importantly, these effects of ATRA (10(-8) to 10(-6) mol/L) on CD34(+) cells were associated with a dose-dependent inhibition of IL-5Ralpha but no change in GM-CSF receptor expression, as detected with flow cytometry. These findings indicate that retinoids can differentially regulate expression of IL-5Ralpha, but not GM-CSF receptor, and that these effects have functional consequences in vitro on eosinophil and basophil differentiation.
Publisher: Wiley
Date: 09-2016
DOI: 10.1111/IMJ.13166
Abstract: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway however, effectiveness data in a population with significant comorbidities are limited. To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 ≥ 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.
Publisher: Oxford University Press (OUP)
Date: 18-04-2014
DOI: 10.1093/CID/CIU225
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JACI.2017.03.044
Abstract: Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly understood. We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β- ersity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less erse (P = .022) and more dissimilar (P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these ersity measures (α- ersity: Spearman r = -0.374, P < .001 β- ersity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus, Gemella, and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Public Library of Science (PLoS)
Date: 11-08-2014
Publisher: John Wiley & Sons, Ltd
Date: 21-01-2009
Publisher: Bentham Science Publishers Ltd.
Date: 05-2006
DOI: 10.2174/138945006776818647
Abstract: Airway epithelial cells (AEC) and dendritic cells (DC) are situated in close proximity within the airway epithelium, and are the first cells to encounter inhaled pathogens, allergens and environmental pollutants. AEC and DC interact through the release of cytokines and other soluble mediators and through direct cell-cell contact, and these interactions are likely to play an important role in maintaining immune homeostasis. Increasing evidence indicates that both AEC and DC from asthmatic in iduals exhibit distinct functional properties, compared with AEC and DC from healthy in iduals. Both animal models, and novel co-culture models for directly studying human AEC/DC interactions are providing new insight into the cross-talk between these two important cells types, as a foundation for the development of new drug targets for use in asthma, cystic fibrosis and chronic obstructive pulmonary disease.
Publisher: Wiley
Date: 04-2005
DOI: 10.1111/J.1365-2222.2005.02171.X
Abstract: Maternal allergy confers stronger allergy risk (than paternal allergy) suggesting that maternal patterns of immune response can directly influence immune development in offspring. Women prone to allergic immune responses to allergens may also have altered immune responses to other antigens including fetal antigens. This exploratory study examines relationships between maternal immune responses to fetal antigens and the subsequent risk of allergy. Mononuclear cells (MNC) were collected from 36 mother-infant pairs to compare maternal (and fetal) cellular immune responses to alloantigens (fetal, maternal or unrelated donor [URD]), and allergens in allergic (18 pairs) and non-allergic (18 pairs) mothers. Thirty children had documented allergic outcomes at 6 years of age. In this population, allergic outcomes in the offspring were associated more strongly with materno-fetal immune interactions than with a maternal family history of allergy. Specifically, allergic disease at 6 years of age was associated with significantly higher maternal responses to fetal alloantigens (lymphoproliferation, P=0.008 IL-13, P=0.02 and IFN-gamma, P=0.015), whereas associations with maternal allergy did not reach significance (P=0.07). Fetal IFN-gamma alloantigen responses were significantly correlated with the degree of human lymphocyte antigen (HLA) mismatch (maternal HLA class II antibodies) (tau=0.3, P=0.03). The capacity of the fetus to produce IL-13 (tau=0.4, P=0.001) and IL-10 (tau=0.3, P=0.029) was directly related to the level of these cytokines produced by the mother in response to fetal antigens. Allergic mothers showed a non-significant trend for stronger lymphoproliferation to fetal alloantigens. The number of previous pregnancies (gravidity) was associated with stronger maternal responses to fetal alloantigens, as shown by lymphoproliferation (Kendall tau=0.3, P=0.04) and IFN-gamma (tau=0.3, P=0.04) synthesis, but did not affect fetal responses to the various stimuli. Maternal responses to fetal antigens were related to fetal immune responses and subsequent allergy. This novel observation suggests that events at the materno-fetal interface have an important influence on early immune development and should be investigated further.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.VACCINE.2011.07.087
Abstract: We aimed to estimate the effectiveness of H1N1/09 containing influenza vaccines against hospitalization from influenza in Australia. We performed a test-negative case control study in patients hospitalized in 15 sentinel Australian hospitals between March and November 2010, comparing influenza vaccination (H1N1/09 monovalent or 2010 seasonal trivalent) in hospitalized patients with PCR-confirmed influenza compared to PCR-negative controls. Between March and November 2010, 1169 hospitalized patients were tested for suspected influenza, of which influenza vaccine status was ascertained in 165/238 patients with H1N1/09 influenza, 40/64 with seasonal influenza and 558/867 test negative controls 24% of H1N1/09 cases, 43% of seasonal influenza cases and 54% of controls were vaccinated. VE against hospitalisation with H1N1/09 influenza after adjusting for age, medical comorbidities and pregnancy status was estimated at 49% (95% CI: 13%, 70%). Influenza vaccination was associated with a reduction in hospitalisation caused by H1N1/09 influenza in the 2010 southern hemisphere winter season.
Publisher: American Thoracic Society
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 19-11-2021
DOI: 10.1007/S40519-021-01326-X
Abstract: Intuitive Eating (IE) is an approach to eating designed to facilitate a positive relationship with food. Its use in clinical settings and in the community is rapidly growing in popularity. The Intuitive Eating Scale 2 (IES-2) is a widely used measure that indexes intuitive eating motivations and behaviour, however evidence of its validity in populations with clinical eating disorders remains scarce. The objective of the proposed study was thus to evaluate the factor structure of the IES-2 in a large s le of in iduals seeking treatment for eating disorders in private practice. Data collected from 569 women and men aged 12-68 years seeking treatment for an eating disorder in one of eight specialist private outpatient eating disorder clinics were examined using confirmatory factor analysis (CFA). Relationships between IES-2 scores and measures of psychopathology were also examined. Results were relatively consistent with the purported four-factor structure of the IES-2. The measure displayed strong construct validity and good internal consistency. Scores on the IES-2 were inversely associated with scores of depression, anxiety, and disordered eating, providing evidence for ergent validity of the measure. Clinical norms are provided for anorexia nervosa (AN) spectrum disorders and bulimia nervosa (BN) spectrum disorders, as well as for the clinical s le as a whole. Findings suggest that the IES-2 may be an appropriate measure for evaluating behaviours relating to IE in community outpatient eating disorder settings, and provide further evidence for the association between IE and positive health outcomes. III, evidence obtained from well-designed cohort or case-control analytic studies.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2003
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Wiley
Date: 26-06-2012
DOI: 10.1111/J.1440-1843.2012.02174.X
Abstract: The soluble receptor for advanced glycation end products (sRAGE) plays an important role in inflammation. Few studies have looked at sRAGE levels in human lungs, and there is no information in children. Therefore, this study aimed to compare bronchoalveolar lavage fluid (BALF) and plasma sRAGE concentrations in children in relation to age and inflammation. BAL was performed in 76 children, and BALF and plasma sRAGE levels were determined by enzyme-linked immunosorbent assay. sRAGE levels were fourfold higher in BALF than in plasma (P < 0.001). BALF sRAGE was inversely proportional to age (r = -0.333, P = 0.008) and serum immunoglobulin A (r = -0.283, P = 0.028). Plasma sRAGE showed a positive correlation to the percentage of BAL macrophages and negative correlation to the percentage of neutrophils and lymphocytes (P < 0.05). Multivariate linear regression analysis identified that the percentage of BAL lymphocytes and neutrophils were significant independent predictors of plasma sRAGE levels, while age and the percentage of BAL macrophages independently predicted BALF sRAGE levels. In children, sRAGE is present at higher concentrations in the lung compared with blood. It appears that sRAGE varies with age, and hence future studies of sRAGE in paediatric lung disease require age matching. The significant relationship between sRAGE and lung inflammation warrants further research.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Wiley
Date: 03-2015
DOI: 10.1111/RESP.12494_7
Publisher: Elsevier BV
Date: 02-2012
Publisher: Elsevier BV
Date: 08-2017
Publisher: American Thoracic Society
Date: 11-2018
Publisher: Elsevier BV
Date: 05-1992
DOI: 10.1016/S0954-6111(06)80055-7
Abstract: Squamous cell carcinoma antigen (SCC Ag), a recently developed tumour marker, has shown some promise, particularly in squamous cell carcinoma (SCC) of the uterine cervix. To evaluate its usefulness in SCC of the lung, serum SCC Ag levels were measured in 52 patients with a variety of respiratory diseases (both benign and malignant), 17 patients with renal failure and 56 healthy controls. SCC Ag was elevated in 11 of 25 patients with SCC lung and one patient with a mixed adeno-squamous tumour, but in no patients with other malignancies or benign respiratory disease. SCC Ag levels appeared unrelated to either tumour stage or the degree of differentiation. False-positive results were noted in patients with renal failure, with six of eight patients with a plasma creatinine greater than 0.7 mmol l-1 having an elevated SCC Ag level. Because SCC Ag was highly specific in the presence of normal renal function, an elevated level would support early investigation of a patient with suspected pulmonary malignancy. The potential of SCC Ag in typing large cell lung carcinomas (where light microscopic features of SCC are uncertain) warrants further investigation.
Publisher: eLife Sciences Publications, Ltd
Date: 18-01-2017
DOI: 10.7554/ELIFE.21199
Abstract: Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of in iduals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
Publisher: Wiley
Date: 02-2004
DOI: 10.1111/J.1440-1711.2004.01213.X
Abstract: Prostaglandins (PG) are well known lipid mediators with important immunoregulatory properties. While exogenous PGE2 has the ability to modulate the function and maturation of antigen presenting cells, such as dendritic cells (DC), it is not clear whether human DC have the capacity to synthesize PGE2 and other prostaglandins themselves. We therefore examined the expression of inducible cyclo-oxygenase (COX-2) by monocyte derived DC and the production of PGE2 and PGD2. Both monocyte derived DC and freshly isolated blood myeloid DC expressed little COX-2 constitutively, though COX-2 expression was rapidly but transiently upregulated in response to lipopolysaccharide stimulation. COX-2 mRNA was detectable within 1 h of LPS exposure, peaked at 4-6 h, and rapidly declined thereafter. COX-2 expression was accompanied by DC synthesis of PGE2, with peak levels present at 6-18 h post-stimulation. In contrast, PGD2 synthesis was not detected at any time point. When DC were activated with LPS in the presence of nimesulide, a COX-2 selective inhibitor, IL-10 synthesis was inhibited, indicating that endogenous prostaglandins regulate DC cytokine production. PGE2 production by DC may therefore modulate DC and T-cell function, thereby shaping the character of the immune response.
Publisher: S. Karger AG
Date: 1999
DOI: 10.1159/000024040
Abstract: b Background: /b Following consistent demonstrations of the clinical relevance of fluctuations in eosinophil–basophil (Eo–B) progenitors in the blood of patients with a variety of allergic airway disorders, we have turned our attention recently to hemopoietic events occurring in the bone marrow of allergic asthmatic subjects, utilizing a model of airway allergen challenge. b Methods: /b Flow–cytometric analyses of CD34/45+ progenitors for coexpression of surface α–receptor subunits for IL–3, IL–5 and GM–CSF, as well as in situ hybridization and in situ PCR methodologies to detect mRNA for IL–5 and GM–CSF in developing Eo–B in colony and liquid culture assays were employed before and after in vivo allergen challenge. b Results: /b An early, specific upregulation of IL–5R α expression on CD34/45 progenitors was observed after allergen challenge, concomitant with the development of the late–phase asthmatic response. Protein and mRNA for both GM–CSF and IL–5 were expressed in a time–dependent manner ex vivo, in developing (β 7–integrin–positive), colony–derived Eo–B after allergen challenge in vivo. Both retinoic acid and corticosteroids were able to downregulate IL–3– and IL–5–induced expression of IL–5R on cord–blood–derived as well as HL–60 cloned Eo–B progenitors. b Conclusion: /b These studies indicate the critical involvement of IL–5 and IL–5R in the induction of Eo–B differentiation and eosinophilic airway inflammation in allergic asthmatics, and point to these events as potential targets for long–term therapy of atopic disease.
Publisher: Elsevier BV
Date: 02-2009
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.CHEST.2015.12.018
Abstract: Asthma is a heterogeneous chronic inflammatory disease in which host defense against respiratory viruses such as human rhinovirus (HRV) may be abnormal. This is a matter of some controversy, with some investigators reporting reduced type I interferon (IFN) synthesis and others suggesting that type I IFN synthesis is relatively normal in asthma. The objective of this study was to examine the responsiveness of circulating mononuclear cells to HRV in a large cohort of participants with poorly controlled asthma and determine whether IFN-α and IFN-β synthesis varies across different inflammatory phenotypes. Eligible adults with asthma (n = 86) underwent clinical assessment, sputum induction, and blood s ling. Asthma inflammatory subtypes were defined by sputum cell count, and supernatant assessed for IL-1β. Peripheral blood mononuclear cells (PBMCs) were exposed to HRV serotype 1b, and IFN-α and IFN-β release was measured by enzyme-linked immunosorbent assay. Participants (mean age, 59 years atopy, 76%) had suboptimal asthma control (mean asthma control questionnaire 6, 1.7). In those with neutrophilic asthma (n = 12), HRV1b-stimulated PBMCs produced significantly less IFN-α than PBMCs from participants with eosinophilic (n = 35) and paucigranulocytic asthma (n = 35). Sputum neutrophil proportion and the dose of inhaled corticosteroids were independent predictors of reduced IFN-α production after HRV1b exposure. Antiviral type I IFN production is impaired in those with neutrophilic airway inflammation and in those prescribed high doses of inhaled corticosteroids. Our study is an important step toward identifying those with poorly controlled asthma who might respond best to inhaled IFN therapy during exacerbations.
Publisher: Hong Kong STM Publishing Co., Ltd.
Date: 2014
DOI: 10.7178/JEIT.25
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JACI.2017.07.051
Abstract: Rhinovirus infection triggers acute asthma exacerbations. IL-33 is an instructive cytokine of type 2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic patients. We sought to determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vitro human primary airway epithelial cells (AECs). Mice were exposed to pneumonia virus of mice and cockroach extract in early and later life and then challenged with rhinovirus to model disease onset, progression, and chronicity. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic patients and healthy subjects and treated with anti-IL-33 after rhinovirus infection. Anti-IL-33 decreased type 2 inflammation in all phases of disease however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high, and rhinovirus challenge exacerbated the type 2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity, and anti-IL-33, but not dexamethasone, promoted antiviral interferon expression and decreased viral load. Rhinovirus replication was higher and IFN-λ levels were lower in AECs from asthmatic patients compared with those from healthy subjects. Anti-IL-33 decreased rhinovirus replication and increased IFN-λ levels at the gene and protein levels. Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.
Publisher: OMICS Publishing Group
Date: 2012
Publisher: Wiley
Date: 02-2021
DOI: 10.1111/IMJ.14806
Publisher: Wiley
Date: 25-08-2023
DOI: 10.1111/ALL.15867
Abstract: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. This observational study included 453 severe asthma patients (41% male mean age ± SD 55.7 ± 14.7 years) from two real‐world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5‐item Asthma Control Questionnaire (ACQ‐5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post‐bronchodilator FEV1 ≥80%) or stabilization (post‐bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut‐offs of ACQ‐5/FEV1 scores. The predictors of clinical remission were identified. 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. Biologic treatment with mepolizumab or omalizumab for severe asthma‐induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.
Publisher: Wiley
Date: 2019
DOI: 10.1002/CTI2.1044
Publisher: Hogrefe Publishing Group
Date: 2006
Publisher: Elsevier BV
Date: 04-2017
Publisher: Public Library of Science (PLoS)
Date: 10-08-2015
Publisher: Public Library of Science (PLoS)
Date: 13-07-2020
Publisher: AMPCo
Date: 07-2018
DOI: 10.5694/MJA18.00175
Abstract: The treatment landscape in severe asthma is changing rapidly, with multiple new therapies emerging that promise to transform patient outcomes. In a patient who is not responding to conventional therapy with inhaled corticosteroids and long-acting β2-agonists, it is important to first consider if the diagnosis of asthma is correct and, second, to reflect on whether readily modifiable factors are contributing to poor asthma control. In selected patients it may be appropriate to consider a modified n-of-1 trial of add-on therapies such as long-acting anti-muscarinic agents, leukotriene blockers, theophylline or low dose macrolide antibiotics. A number of monoclonal antibodies are now available that target the molecular pathways that contribute to asthma pathogenesis, and more such agents are likely to emerge in the near future. These biologicals can be transformative in selected patients, markedly reducing the frequency of asthma exacerbations, and allowing many patients to reduce or eliminate their use of long term oral corticosteroids. If the promise of personalised treatment is to be fully realised, it is important that better methods are developed to target these new and expensive treatments to patients most likely to respond. The ultimate goal of inducing remission or cure of asthma is still some distance away.
Publisher: Frontiers Media SA
Date: 13-02-2015
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.MOLIMM.2010.12.013
Abstract: Bahia grass, Paspalum notatum, is an important pollen allergen source with a long season of pollination and wide distribution in subtropical and temperate regions. We aimed to characterize the 55 kDa allergen of Bahia grass pollen (BaGP) and ascertain its clinical importance. BaGP extract was separated by 2D-PAGE and immunoblotted with serum IgE of a grass pollen-allergic patient. The amino-terminal protein sequence of the predominant allergen isoform at 55 kDa had similarity with the group 13 allergens of Timothy grass and maize pollen, Phl p 13 and Zea m 13. Four sequences obtained by rapid lification of the allergen cDNA ends represented multiple isoforms of Pas n 13. The predicted full length cDNA for Pas n 13 encoded a 423 amino acid glycoprotein including a signal peptide of 28 residues and with a predicted pI of 7.0. Tandem mass spectrometry of tryptic peptides of 2D gel spots identified peptides specific to the deduced amino acid sequence for each of the four Pas n 13 cDNA, representing 47% of the predicted mature protein sequence of Pas n 13. There was 80.6% and 72.6% amino acid identity with Zea m 13 and Phl p 13, respectively. Reactivity with a Phl p 13-specific monoclonal antibody AF6 supported designation of this allergen as Pas n 13. The allergen was purified from BaGP extract by ammonium sulphate precipitation, hydrophobic interaction and size exclusion chromatography. Purified Pas n 13 reacted with serum IgE of 34 of 71 (48%) grass pollen-allergic patients and specifically inhibited IgE reactivity with the 55 kDa band of BaGP for two grass pollen-allergic donors. Four isoforms of Pas n 13 from pI 6.3-7.8 had IgE-reactivity with grass pollen allergic sera. The allergenic activity of purified Pas n 13 was demonstrated by activation of basophils from whole blood of three grass pollen-allergic donors tested but not control donors. Pas n 13 is thus a clinically relevant pollen allergen of the subtropical Bahia grass likely to be important in eliciting seasonal allergic rhinitis and asthma in grass pollen-allergic patients.
Publisher: Wiley
Date: 05-2000
DOI: 10.1002/(SICI)1097-0320(20000501)40:1<50::AID-CYTO7>3.0.CO;2-P
Abstract: Recognition of the importance of dendritic cells (DC) in the initiation of T-cell-dependent immune responses has led to increasing interest in methods for the identification of DC within the circulation. We sought to develop a flow cytometric method that would allow the reliable enumeration of absolute myeloid DC counts in minimally manipulated blood s les. Myeloid DC were identified by three-color staining of whole blood leukocytes as a discrete population of mononuclear cells expressing high levels of HLA-DR and CD33, yet having little or no expression of CD14 and CD16. This method was analyzed for reproducibility and variation in blood DC number during typical clinical day hours and after exercise. The new method was compared to an established commercial kit method. FACS sorting of the CD33(+) DC showed that they morphologically resembled immature DC, and developed cytoplasmic projections typical of mature DC following overnight culture in granulocyte macrophage-colony stimulating factor (GM-CSF). Within peripheral blood, these DC were found at a mean concentration of 17. 4 +/- 5.4 x 10(6) per liter, corresponding to 0.93 +/- 0.27% of mononuclear cells. Comparison of duplicate s les stained and analyzed in parallel showed that the intras le variability was very low, with an intraclass correlation coefficient of 0.95. The frequency of CD33(+) myeloid DC and their light scatter characteristics were similar to that of CD11c(+) myeloid cells. Four-color FACS analysis revealed complete identity of CD11c(hi), HLA-DR(+) DC with CD33(+), HLA-DR(+) DC. Only rare CD33(+) DC coexpressed CD123 and HLA-DR. Numbers of blood myeloid DC, identified by CD33 staining, showed no significant variation during standard laboratory hours. However, their numbers rose significantly during vigorous exercise, in parallel to other blood cells. The method described herein is rapid, reproducible, requires only small volumes of blood, can be readily used by a clinical immunology laboratory, and requires fewer antibodies than a currently available commercial method.
Publisher: MDPI AG
Date: 16-06-2022
Abstract: Wildfires are increasing and cause health effects. The immediate and ongoing health impacts of prolonged wildfire smoke exposure in severe asthma are unknown. This longitudinal study examined the experiences and health impacts of prolonged wildfire (bushfire) smoke exposure in adults with severe asthma during the 2019/2020 Australian bushfire period. Participants from Eastern/Southern Australia who had previously enrolled in an asthma registry completed a questionnaire survey regarding symptoms, asthma attacks, quality of life and smoke exposure mitigation during the bushfires and in the months following exposure. Daily in idualized exposure to bushfire particulate matter (PM2.5) was estimated by geolocation and validated modelling. Respondents (n = 240) had a median age of 63 years, 60% were female and 92% had severe asthma. They experienced prolonged intense PM2.5 exposure (mean PM2.5 32.5 μg/m3 on 55 bushfire days). Most (83%) of the participants experienced symptoms during the bushfire period, including: breathlessness (57%) wheeze/whistling chest (53%) and cough (50%). A total of 44% required oral corticosteroid treatment for an asthma attack and 65% reported reduced capacity to participate in usual activities. About half of the participants received information/advice regarding asthma management (45%) and smoke exposure minimization strategies (52%). Most of the participants stayed indoors (88%) and kept the windows/doors shut when inside (93%), but this did not clearly mitigate the symptoms. Following the bushfire period, 65% of the participants reported persistent asthma symptoms. Monoclonal antibody use for asthma was associated with a reduced risk of persistent symptoms. Intense and prolonged PM2.5 exposure during the 2019/2020 bushfires was associated with acute and persistent symptoms among people with severe asthma. There are opportunities to improve the exposure mitigation strategies and communicate these to people with severe asthma.
Publisher: Wiley
Date: 05-2003
DOI: 10.1046/J.1365-2222.2003.01659.X
Abstract: A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. In this study we examined the relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years. The capacity of circulating neonatal (and maternal) APC to produce IL-12 p70 in response to LPS (and IFN-gamma) stimulation was assessed in a group of 60 children with previously well-characterized immune responses to allergens and atopic outcomes. The IL-12 responses were compared with allergen-induced lymphoproliferation (to house dust mite (HDM) ovalbumin (OVA), cat and beta-lactoglobulin (BLG)) and IL-13 and IFN-gamma cytokine responses (to OVA, HDM and phytohaemaglutinin (PHA)) in the neonatal and postnatal periods. IL-12 responses were also compared according to atopic risk and atopic outcomes (doctor-diagnosed asthma, eczema, food allergies and sensitization as evidenced by skin prick testing) at 6 years clinical follow-up. Maternal peripheral blood mononuclear cells (PBMC) synthesized significantly greater amounts of IL-12 than neonatal PBMC, though within maternal-infant pairs IL-12 responses were significantly correlated (r = 0.4, P = 0.019). Moreover, neonatal IL-12 responses were positively correlated with neonatal allergen proliferation for HDM (r = 0.6, P < 0.0001), OVA (r = 0.55, P < 0.0001), cat (r = 0.5, P = 0.003) and BLG (r = 0.55, P = 0.001), but negatively correlated with neonatal IL-13 responses to both allergens tested (HDM: r = - 0.4, P = 0.03 and OVA: r = - 0.5, P = 0.001). Both neonatal and maternal IL-12 responses were positively correlated with postnatal IFN-gamma responses to HDM at 12, 18 and 24 months of age (responses after age of 2 years were not assessed). There was no relationship between atopic risk and IL-12 capacity in the neonatal period, but there was a (non-significant) trend for neonatal IL-12 responses to be lower in the high-risk children who developed clinical allergy at 6 years (compared with the low risk group) although the number in this analysis was small. Reduced APC IL-12 production in the perinatal period was associated with reduced T cell activation (lymphoproliferation), stronger neonatal Th2 responses, and weaker Th1 responses to allergen in the postnatal period. This supports the notion that variations in APC function in early life may contribute to altered allergen-specific cytokine responses associated with later allergy.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CHEST.2016.09.030
Abstract: Dendritic cells (DCs) are potent antigen-presenting cells. Because of their particular ability to initiate and regulate cell mediated and humoral immune responses, there is considerable interest in the role that DCs play in the pathogenesis of various lung diseases, especially those in which there is an excessive immune response to specific antigens (as in asthma) or a deficient immune response (as in lung cancer). A number of DC subpopulations have been defined in the lungs, including myeloid or conventional DCs that initiate T-cell immunity and antibody production and plasmacytoid DCs that have an important role in antiviral immunity and immune tolerance. Although an extensive body of literature has documented the role that DCs play in experimental models of lung disease, this review will highlight recent advances in our understanding of DC function in human disease, including asthma, COPD, antimicrobial immunity, and lung cancer. The future is likely to see new approaches whereby antigens and small molecules are targeted to receptors on particular DC subpopulations in order to modify pulmonary immune responses.
Publisher: Wiley
Date: 22-07-2016
DOI: 10.1111/CEA.12774
Abstract: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2022
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.JACI.2004.06.051
Abstract: The specific mechanisms regulating priming of T-cell immunity to common allergens during early childhood remain to be elucidated, though increasing evidence indicates that antigen-presenting cell function is impaired in childhood. Examine the relationship between HLA-DR expression on monocytes and B cells, allergen-specific T-cell responses at birth, and clinical outcomes at 2 years of age. Blood mononuclear cells were obtained from 36 healthy neonates who were followed up clinically to the age of 2 years. Expression of HLA-DR by monocytes and B cells was determined at baseline and after in vitro exposure to IFN-gamma, a cytokine that is known to upregulate the expression of HLA-DR. Mononuclear cells were stimulated with endotoxin or a panel of inhalant and food allergens, and cytokine responses and lymphoproliferation were determined after 1 and 5 days, respectively. The magnitude of HLA-DR upregulation on IFN-gamma-stimulated cord blood CD14 + monocytes was consistently correlated with allergen-induced, but not mitogen-induced, lymphoproliferation at birth. HLA-DR upregulation on monocytes was also positively associated with endotoxin-induced IL-12 p70 synthesis (tau = 0.46 P < .001) but inversely related to mite- and ovalbumin-induced IL-13 synthesis ( P = .0006 and P < .003, respectively). HLA-DR expression on unstimulated cord blood monocytes was inversely associated with symptoms of atopic disease at the 2-year follow-up ( P = .015). In contrast, HLA-DR expression on B cells was not associated with these parameters of immune function. These findings suggest that the maturity of neonatal monocytes and their responsiveness to external stimuli are linked to differing patterns of immune reactivity at birth and to the risk of allergic symptoms in early childhood.
Publisher: Wiley
Date: 09-05-2003
DOI: 10.1046/J.1440-1843.2003.00465.X
Abstract: Dendritic cells (DC) are potent antigen presenting cells that display an extraordinary capacity to present antigen to naïve T-cells and initiate primary immune responses. In the context of the lung and upper airway it is clear that DC play a key role in the regulation of adaptive immune responses to inhaled antigen. DC are particularly sensitive to signals derived from microbes, allergens and the airway tissue microenvironment. By the nature of the signals they provide at the time of antigen presentation, DC can polarize naïve T-cells into either T-helper type 1 (Th1) or Th2 effector cells, and are increasingly recognized as having a central role in the establishment of T-cell memory and peripheral immune tolerance. DC form a network within the upper airway and lung, and are rapidly recruited from the circulation in response to a variety of proinflammatory stimuli. Studies using animal models have highlighted the role of DC in both the initiation and maintenance of allergic airway inflammation. In early childhood, human DC are functionally immature, and this is thought to contribute to the development of allergic sensitization in those children who are genetically at risk for the development of atopy. Increased numbers of airway mucosal DC are found in both allergic rhinitis and asthma, while studies of blood-derived DC have emphasized important differences between the function of DC from atopic and normal in iduals. This article reviews recent information on the involvement of DC in allergic airway disease, and the mechanisms by which DC could be exploited as targets for therapy in asthma and allergic rhinitis.
Publisher: European Respiratory Society (ERS)
Date: 10-2017
DOI: 10.1183/23120541.00025-2017
Abstract: Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1β signature, the contribution of the IL-1β pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway. Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1β, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3 + T cells and CD56 + NK cells. Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.
Publisher: MDPI AG
Date: 19-10-2022
DOI: 10.3390/NU14204392
Abstract: Research suggests exercise may reduce eosinophilic airway inflammation in adults with asthma. The Dietary Inflammatory Index (DII®) quantifies the inflammatory potential of the diet and has been associated with asthma outcomes. This study aimed to determine whether the DII of a meal consumed either before or after exercise influences exercise-induced changes in airway inflammation. A total of 56 adults with asthma were randomised to (1) 30–45 min moderate–vigorous exercise, or (2) a control group. Participants consumed self-selected meals, two hours pre- and two hours post-intervention. Energy-adjusted DII (E-DIITM) was determined for each meal, with meals then characterised as “anti-inflammatory” or “pro-inflammatory” according to median DII. Induced sputum cell counts were measured pre- and four hours post-intervention. Participants consuming an anti-inflammatory meal two hours post-exercise had a decrease in sputum %eosinophils (−0.5 (−2.0, 0.3)%) compared with participants who consumed a pro-inflammatory meal two hours post-exercise (0.5 (0, 3.0)%, p = 0.009). There was a positive correlation between the E-DII score of the post-exercise meal and change in sputum %eosinophils (rs = 0.478, p = 0.008). The E-DII score of the meal consumed two hours pre-exercise had no effect on sputum %eosinophils (p = 0.523). This study suggests an anti-inflammatory meal two hours post-exercise augments exercise-induced improvements in eosinophilic airway inflammation in adults with asthma.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-05-2018
DOI: 10.1126/SCITRANSLMED.AAO0052
Abstract: Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal s les from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2005
DOI: 10.1097/01.ALL.0000162310.79555.ED
Abstract: Asthma and other atopic disorders are the result of complex interactions between genetic predisposition and multiple environmental influences. However, the marked increase in asthma prevalence over recent decades is unlikely to be due to genetic changes, highlighting the contribution of environmental factors to the process of allergic sensitization. This article reviews recent information on environmental influences on the development of atopy in children. Both observational and interventional studies continue to shed new light on the critical influence of early life events--such as events in pregnancy, exposure to allergens and endotoxin, pet ownership, infections, family size--and have highlighted important gene-environment interactions that modify the relationships between environmental exposures and atopic outcomes. The future is likely to see a concerted effort to further define the role that these environmental exposures play in allergic sensitization and the expression of atopic diseases, in order to provide a rational platform on which to develop new methods of allergy prevention that can be targeted at high-risk children.
Publisher: Wiley
Date: 24-03-2016
DOI: 10.1111/ALL.12869
Publisher: Springer Science and Business Media LLC
Date: 11-2007
Publisher: Public Library of Science (PLoS)
Date: 12-06-2015
Publisher: Springer Science and Business Media LLC
Date: 31-07-2012
Abstract: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are often linked to respiratory infections. However, it is unknown if COPD patients who experience frequent exacerbations have impaired humoral immunity. The aim of this study was to determine if antibodies specific for common respiratory pathogens are associated with AECOPD. Plasma was obtained from COPD patients when clinically stable. AECOPD requiring hospitalisation were recorded. IgG 1 antibodies to H. Influenzae outer membrane protein 6 (P6), pneumococcal surface protein C (PspC) and the VP1 viral capsid protein of rhinovirus were measured. COPD patients who had an AECOPD (n = 32) had significantly lower anti-VP1 IgG 1 antibody levels when stable compared to COPD patients who did not have an AECOPD (n = 28, p = 0.024). Furthermore, the number of hospitalisations was inversely proportional to anti-VP1 antibody levels (r = −0.331, p = 0.011). In contrast, antibodies specific for P6 and PspC were present at similar concentrations between groups. Plasma IL-21, a cytokine important for B-cell development and antibody synthesis, was also lower in COPD patients who had an AECOPD, than in stable COPD patients (p = 0.046). Deficient humoral immunity specific for rhinoviruses is associated with AECOPD requiring hospitalisation, and may partly explain why some COPD patients have an increased exacerbation risk following respiratory viral infections.
Publisher: Elsevier BV
Date: 02-2015
Publisher: Wiley
Date: 03-2005
DOI: 10.1111/J.1365-2222.2005.02187.X
Abstract: The T-helper type 1 (Th1) trophic properties of bacterial cytosine-phosphate-guanine (CpG) motifs have made them logical adjuvants both for the suppression of Th2-mediated allergic disease in early life and for promoting vaccine responses in neonates who have relatively immature Th1 function. However, little is known about their effects on immature immune responses in this period. To compare the effects of CpG on adult and neonatal cellular immune responses to various stimuli. The immune responses of mononuclear cells (MC) derived from neonates (n=25) and their mothers (n=25) were compared in vitro. These were stimulated with house dust mite (HDM), CpG B, CpG C, non-CpG oligodeoxynucleotides (ODN) or diphtheria toxoid (DT) in optimized conditions. In parallel cultures, CpGs were combined with HDM or DT antigens to assess the effect of the various ODN on these antigen-specific responses. Lymphoproliferation and cytokine responses IL-13, IFN-gamma, IL-6, IL-10, TNF-alpha) were measured for all of the cultures described above. Although neonates showed attenuated lymphoproliferation to CpG, the production of antigen-presenting cell-derived cytokines such as IL-6 and IL-10 and the up-regulation of major histocompatibility complex class II (HLA-DR) were detected at adult levels. T cell-derived cytokines (IL-13 and IFN-gamma) were not detectable in response to CpG alone. Most neonates also failed to produce detectable IFN-gamma to HDM or DT (unlike adults), but readily produced IL-13 to these stimuli. The addition of CpG resulted in an increase in neonatal IFN-gamma production in response to HDM (P=0.011) and a similar but non-significant trend with DT. However, rather than inhibiting Th2 IL-13 responses, the addition of CpGs was associated with a significant increase in the IL-13 responses to HDM (P=0.016) and DT (P=0.03), effects not seen in adults. This study provides further evidence that neonatal MC responses to CpG are functionally different from adults, and do not show clear Th1 polarization. The CpG associated increase in Th2 responses may reflect a potentiation of the normal neonatal Th2 propensity, or non-specific activation of neonatal MC.
Publisher: Wiley
Date: 07-1995
DOI: 10.1111/J.1365-2222.1995.TB01111.X
Abstract: It is widely held that in vitro T cell responses to allergens are more prominent in atopic than in normal in iduals, though this conclusion is based upon culture techniques which fail to detect proliferative responses in a significant minority of atopics and many normals. Study allergen-specific proliferative responses of T cells cultured in serum-free medium (SFM). Examine associations between atopic status, age and T cell reactivity. Initially, peripheral blood mononuclear cells were stimulated with allergens or antigens in SFM, and compared with cells cultured in RPMI + 10% fetal calf serum or human AB serum. Subsequently, T cell reactivity was studied in 34 adults (20-49 years), 27 children (2-13 years), and 19 infants (< or = 10 weeks) using SFM alone. Compared with serum-supplemented medium, SFM enhanced net T cell proliferation, both in bulk culture and when cloning at limiting dilution. In many subjects, SFM unmasked T cell reactivity to allergens which was not otherwise evident, and lowered the threshold allergen levels required for in vitro T cell triggering. For most allergens, T cell proliferative responses did not differ between adults who had specific IgE, and those who did not. The most vigorous responses observed were to ubiquitous inhalant allergens, which stimulated T cells from close to 100% of adults and children, and over 60% of infants. In contrast, responses to the 'vaccine' antigen tetanus toxoid were completely absent in the latter age group, but present in the majority of adults and children. These findings suggest that the extent of active T cell recognition of environmental allergens has been hitherto underestimated, and further that these responses may frequently be initiated in very early life. Additionally, these findings reinforce the notion that qualitative (as opposed to quantitative) variations in specific T cell reactivity ultimately determine allergen responder phenotype.
Publisher: Wiley
Date: 26-01-2010
Publisher: BMJ
Date: 11-10-2017
DOI: 10.1136/ARCHDISCHILD-2017-312982
Abstract: To describe the point prevalence of respiratory viruses/atypical bacteria using PCR and evaluate the impact of respiratory viruses/atypical bacteria and atopy on acute severity and clinical recovery in children with hospitalised and non-hospitalised asthma exacerbations. This was a prospective study performed during 2009–2011. The study was performed in the emergency departments of two hospitals. 244 children aged 2–16 years presenting with acute asthma to the emergency departments were recruited. A nasopharyngeal aspirate and allergen skin prick test were performed. The outcomes were ided into (1) acute severity outcomes (Australian National Asthma Council assessment, hospitalisation, Functional Severity Scale, Acute Asthma Score, asthma quality of life questionnaires for parents (PACQLQ) on presentation, asthma diary scores (ADS) on presentation and length of hospitalisation) and (2) recovery outcomes (PACQLQ for 21 days, ADS for 14 days and representation for asthma for 21 days). PCR for viruses/atypical bacteria was positive in 81.7% of children (75.1% human rhinovirus, codetection in 14.2%). Mycoplasma pneumoniae and Chlamydophila pneumoniae were rarely detected. The presence of micro-organisms had little impact on acute asthma or recovery outcomes. Children with atopy were significantly more likely to relapse and represent for medical care by day 14 (OR 1.11, 95% CI 1.00 to 1.23). The presence of any viruses is associated with asthma exacerbations but does not appear to influence asthma recovery. In contrast, atopy is associated with asthma relapse. M. pneumoniae and C. pneumoniae are rare triggers of acute asthma in young children.
Publisher: BMJ
Date: 03-04-2015
Publisher: BMJ
Date: 07-2023
DOI: 10.1136/BMJRESP-2023-001637
Abstract: Data on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE. We prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation–perfusion (VQ) scan at 3 months follow-up. Thirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO 2 ) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO 2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV–PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease. In our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications.
Publisher: American Society for Microbiology
Date: 02-2006
DOI: 10.1128/IAI.74.2.1106-1112.2006
Abstract: The capacity of the immune system in infants to develop stable T-cell memory in response to vaccination is attenuated, and the mechanism(s) underlying this developmental deficiency in humans is poorly understood. The present study focuses on the capacity for expression of in vitro recall responses to tetanus and diphtheria antigens in lymphocytes from 12-month-old infants vaccinated during the first 6 months of life. We demonstrate that supplementation of infant lymphocytes with “matured” dendritic cells (DC) cultured from autologous CD14 + precursors unmasks previously covert cellular immunity in the form of Th2-skewed cytokine production. Supplementation of adult lymphocytes with comparable prematured autologous DC also boosted vaccine-specific T-cell memory expression, but in contrast to the case for the infants, these cytokine responses were heavily Th1 skewed. Compared to adults, infants had significantly fewer circulating myeloid DC ( P 0.0001) and plasmacytoid DC ( P 0.0001) as a proportion of peripheral blood mononuclear cells. These findings suggest that deficiencies in the numbers of antigen-presenting cells and their functional competence at 12 months of age limit the capacity to express effector memory responses and are potentially a key factor in reduced vaccine responsiveness in infants.
Publisher: Wiley
Date: 18-07-2002
DOI: 10.1046/J.1365-3083.2002.01117.X
Abstract: Increasing levels of proinflammatory cells, including eosinophils and basophils, are seen at the site of allergen challenge in allergic disease of the airways. Mechanisms for the recruitment of these cell types could involve either specific upregulation of adhesion molecule and chemoattraction, or the initiation of proliferation and differentiation of inflammatory cell progenitors derived from the bone marrow. In this study, we demonstrate, in two systems of eosinophilic-basophilic lineage-committed granulocytes of relative immaturity, that eosinophilic differentiation in vivo implies the induction of a distinct adhesion phenotype, characterized by the upregulation of beta(7) integrin and downregulation of beta(1) and alpha(5) integrins. Moreover, the eosinophilic differentiation induced an upregulation of complement receptor type 1 and type 3, and the expression was further enhanced upon a short-course in vitro activation with ionomycin. These data indicate a sequential alteration of disparate members of the integrin family during eosinophilic-basophilic differentiation, which may attribute to specific adhesion requirements at distinct stages of cell maturation.
Publisher: Cold Spring Harbor Laboratory
Date: 10-11-2017
DOI: 10.1101/217547
Abstract: In children with hospitalised and non-hospitalised asthma exacerbations, to: (a) describe the point prevalence of respiratory viruses/atypical bacteria using polymerase chain reaction (PCR) and (b) evaluate the impact of respiratory viruses/atypical bacteria and atopy on acute severity and clinical recovery. This was a prospective study performed during 2009-2011. The study was performed in the Emergency Departments of 2 hospitals. 244 children aged 2-16 years presenting with acute asthma to the Emergency Departments were recruited. A nasopharyngeal aspirate and allergen skin prick test were performed. The outcomes were ided into (a) acute severity outcomes [Australian National Asthma Council assessment, hospitalisation, Functional Severity Scale, acute asthma score, asthma quality of life questionnaires for parents (PACQLQ) on presentation, asthma diary scores (ADS) on presentation and length of hospitalisation] and (b) recovery outcomes (PACQLQ for 21 days, ADS for 14 days and representation for asthma for 21 days). PCR for viruses/atypical bacteria was positive in 81.7% of children (75.1% human rhinovirus, co-detection in 14.2%). M. pneumoniae and C. pneumoniae were rarely detected. The presence of micro-organisms had little impact on acute asthma or recovery outcomes. Children with atopy were significantly more likely to relapse and represent for medical care by day-14 (OR 1.11, 95%CI 1.00,1.23). The presence of any viruses is associated with asthma exacerbations but does not appear to influence asthma recovery. In contrast, atopy is associated with asthma relapse. M. pneumoniae and C. pneumoniae are rare triggers of acute asthma in young children.
Publisher: European Respiratory Society
Date: 09-2017
Publisher: Frontiers Media SA
Date: 16-08-2018
Publisher: BMJ
Date: 11-2001
Abstract: Airway dendritic cells (DC) play an important role in chronic allergic airway inflammation in experimental animals, but a similar role for DC in human allergic asthma has been difficult to define. This pilot study was undertaken to elucidate the role of DC in allergic asthma by examining their potential to migrate to the lower airways in response to bronchial challenge with specific allergen. Bronchial biopsy specimens were obtained from seven patients with allergic asthma before and 4-5 hours after allergen challenge. Multicolour immunofluorescence staining was performed on mucosal cryosections to identify changes in the number and phenotypes of DC. A dramatic increase in the number of CD1c+HLA-DR+ DC were observed in the lamina propria after challenge compared with baseline (22.4 v 7.8 cells/mm(2)). The rapid accumulation (within 4-5 hours) of these cells strongly suggests that they were directly recruited from peripheral blood. We have shown for the first time that a specific DC subset rapidly emigrates into the human bronchial mucosa during allergic inflammation. While this study is based on relatively few patients, the consistency of the overall results strongly suggests that the rapid population dynamics of human airway DC closely parallel those in animal models of acute inflammation. These findings support suggestions that DC have an important role in human airway allergy.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.JACI.2009.07.009
Abstract: It has been proposed that immune dysfunction during early childhood plays an important role in asthma pathogenesis. However, it is not known specifically whether changes in dendritic cells (DCs) during infancy antedate the development of respiratory tract infections, asthma, and related clinical phenotypes. We sought to assess the association between the level of blood DCs during the first year and the subsequent development of respiratory tract infections, wheezing, and allergic sensitization. A community-based cohort of children with a family history of atopy was followed to age 5 years. Children were monitored intensively for respiratory tract infections. History of wheeze and asthma was collected annually, atopy was documented at 5 years, and flow cytometry was used to identify DC subsets in blood s les collected when children were well. Levels of plasmacytoid DCs (pDCs) during infancy were inversely correlated with symptoms of lower respiratory tract infections, parent-reported wheezing, and the cumulative rate of physician-diagnosed asthma up to age 5 years. These relationships were independent of atopy, as determined by allergy skin test results and total and specific IgE levels. In contrast, levels of myeloid DCs were not associated with respiratory tract infections, asthma, or wheezing but were associated with total IgE levels at age 5 years. In children with a family history of atopy, relative deficiency of circulating pDCs during infancy appears to be a risk factor for more frequent and more severe respiratory tract infections, wheezing, and a diagnosis of asthma. Infants with higher numbers of pDCs are protected against these outcomes.
Publisher: Wiley
Date: 2012
Publisher: Wiley
Date: 27-01-2016
Publisher: John Wiley & Sons, Ltd
Date: 14-04-2010
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1103
Publisher: The American Association of Immunologists
Date: 2009
DOI: 10.4049/JIMMUNOL.182.1.72
Abstract: Atopic asthma pathogenesis is driven by the combined effects of airway inflammation generated during responses to viral infections and aeroallergens, and both these pathways are regulated by dendritic cells (DC) that differentiate locally from monocytic precursors. These DCs normally exhibit a sentinel phenotype characterized by active Ag s ling but attenuated presentation capability, which limits the intensity of local expression of adaptive immunity. How this tight control of airway DC functions is normally maintained, and why it breaks down in some atopics leading to immunopathological changes in airway tissues, is unknown. We postulated that signals from adjacent airway epithelial cells (AEC) contribute to regulation of local differentiation of DC. We tested this in a coculture model containing both cell types in a GM-CSF-IL-4-enriched cytokine milieu characteristic of the atopic asthmatic airway mucosa. We demonstrate that contact with AEC during DC differentiation up-regulates expression of the function-associated markers MHC class II, CD40, CD80, TLR3, and TLR4 on DCs with concomitant up-regulation of Ag uptake rocessing. Moreover, the AEC-conditioned DCs displayed increased LPS responsiveness evidenced by higher production of IL-12, IL-6, IL-10, and TNF-α. The Th2 memory-activating properties of AEC-conditioned DCs were also selectively attenuated. Data from microarray and blocking experiments implicate AEC-derived type 1 IFNs and IL-6 in modulation of DC differentiation. Collectively, these findings suggest that resting AECs modulate local DC differentiation to optimize antimicrobial defenses in the airways and in the process down-modulate capacity for expression of potentially damaging Th2 immunity.
Publisher: American Thoracic Society
Date: 15-09-2009
Publisher: Elsevier BV
Date: 06-2014
Publisher: Wiley
Date: 24-03-2014
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.JACI.2006.02.014
Abstract: There is intense interest in the interaction between microbial compounds and allergy. Although Toll-like receptor (TLR)-2 ligands derived from Gram-positive bacteria alter allergic sensitization in animal models, it is not clear what effect TLR2 ligands have on allergen-specific T-cell memory in human beings. To determine whether in vitro exposure to TLR2 ligands modifies the immune response to house dust mite allergen (HDM). Blood mononuclear cells were obtained from in iduals both allergic (n = 23) and not allergic (n = 22) to HDM, and stimulated with HDM in the presence or absence of TLR2 ligands. In subjects allergic to HDM, IL-5 and IL-13 responses to HDM were inhibited by heat-killed Staphylococcus aureus, staphylococcal lipoteichoic acid, and the synthetic lipoprotein Pam3CSK4 (P < .005 all stimuli). Although the whole staphylococcal bacteria increased IFN-gamma responses, the purified TLR2 ligands lipoteichoic acid and Pam3CSK4 inhibited HDM-specific IFN-gamma synthesis. In contrast, TLR2 ligands had minimal effects on responses to HDM in subjects without allergy. TLR2 ligands induced upregulation of HLA-DR expression but did not inhibit antigen uptake or processing by antigen-presenting cells. Toll-like receptor 2 ligands inhibit allergen-specific T(H)2 responses in sensitized in iduals. This effect appears to be mediated by the actions of TLR2 ligands on antigen-presenting cells, and at least for the purified TLR2 ligands does not involve the induction of a strong T(H)1 immune response. These findings provide an impetus for further preclinical studies examining the potential use of TLR2 ligands in allergic disease.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.ANAI.2015.04.002
Abstract: Although exercise has multiple health benefits, relatively little attention has been paid to its potential therapeutic effects in those with asthma. To examine the effects of acute exercise on inflammation in physically inactive and active adults with asthma. Fourteen adults with asthma (n = 6 physically inactive, n = 8 physically active) completed (1) 30 minutes of moderate-intensity exercise on a treadmill and (2) 30 minutes of rest in random order, with 4 weeks between sessions. Exhaled nitric oxide (eNO) was measured before and after the intervention (0, 0.5, 1, 2, 4, and 24 hours). Blood inflammatory mediators were measured before and after the intervention (0, 2, and 24 hours). Physically inactive participants had a significant decrease in eNO 4 hours after exercise (-4.8 ppb, -6.4 to -0.5 ppb, P = .028), which was not observed in physically active participants (P = .362). Interluekin-1 receptor antagonist increased in the physically inactive group 2 hours after exercise, with this increase strongly correlated with the decrease in eNO at 4 hours (R = -0.685, P = .007) and 24 hours (R = -0.659, P = .014) after exercise. Interleukin-6 was increased significantly 2 hours after exercise in physically inactive participants. Blood neutrophils and nuclear factor erythroid 2-like 2 gene expression were increased 2 hours after exercise in the overall cohort. This study demonstrates that acute moderate-intensity exercise is associated with decreased eNO in physically inactive adults with asthma and suggests that interluekin-1 receptor antagonist could have a role in mediating this effect. The attenuated response in physically active participants might be due to the sustained anti-inflammatory effects of exercise training. Future studies should investigate the impact of exercise intensity and exercise training on airway inflammation in those with asthma. Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), registration number ACTRN12613001014741.
Publisher: Rockefeller University Press
Date: 22-12-2017
DOI: 10.1084/JEM.20170298
Abstract: Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2022
Publisher: Wiley
Date: 30-05-2002
DOI: 10.1046/J.1365-2222.2002.01375.X
Abstract: Dendritic cells (DC) are thought to play a key role in the initiation and maintenance of T cell immunity to inhaled antigens. While the density of DC within the bronchial mucosa is increased in stable asthma, there is little information currently available concerning the effects of allergen inhalation on DC in subjects with asthma. To enumerate changes in the numbers of circulating CD33(+) myeloid DC in asthmatics, before and after allergen challenge. Blood DC numbers were enumerated by flow cytometry before and at 3, 6 and 24 h after inhaled allergen and diluent in 10 mild, allergic asthmatic subjects. Blood DC numbers rapidly fell from 3.42 +/- 0.30 x 10(7)/L at baseline, to 2.10 +/- 0.17 x 10(7)/L by 3 h post-challenge (P < 0.01), and remained significantly below baseline values at both 6 and 24 h following allergen challenge. No such changes in DC numbers were noted after diluent challenge. A similar, early fall in circulating lymphocytes was also noted post-allergen challenge, whereas changes in circulating eosinophil and neutrophil numbers occurred more slowly. A significant proportion of myeloid DC rapidly 'disappear' from the circulation following allergen inhalation, suggesting that margination of circulating myeloid DC, and their recruitment into the airway mucosa, is an important feature of the immune response to inhaled allergen.
Start Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2011
End Date: 2014
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 04-2012
End Date: 12-2015
Amount: $300,000.00
Funder: Australian Research Council
View Funded Activity