240 results found
Invernizzi R, Lloyd CM, Molyneaux PL, 2020, Respiratory microbiome and epithelial interactions shape immunity in the lungs., Immunology, ISSN: 0019-2805
The airway epithelium represents a physical barrier to the external environment acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens. However, lung epithelial cells are increasingly recognised as active effectors of microbial defence, contributing to both innate and adaptive immune function in the lower respiratory tract. These cells express an ample repertoire of pattern-recognition receptors with specificity for conserved microbial and host motifs. Modern molecular techniques have uncovered the complexity of the lower respiratory tract microbiome. The interaction between the microbiota and the airway epithelium is key to understanding how stable immune homeostasis is maintained. Loss of epithelial integrity following exposure to infection can result in the onset of inflammation in susceptible individuals and may culminate in lung disease. Here we discuss the current knowledge regarding the molecular and cellular mechanisms by which the pulmonary epithelium interacts with the lung microbiome in shaping immunity in the lung. Specifically, we focus on the interactions between the lung microbiome and the cells of the conducting airways in modulating immune cell regulation and how defects in barrier structure and function may culminate in lung disease. Understanding these interactions is fundamental in the search for more effective therapies for respiratory diseases.
Branchett W, Stoelting H, Oliver R, et al., 2020, A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma, Journal of Allergy and Clinical Immunology, Vol: 145, Pages: 666-678.e9, ISSN: 0091-6749
BackgroundAlthough originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly severe disease. IL-10 regulates T helper (Th) cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthma are unclear. Objective: Determine how IL-10 regulates the balance of Th cell responses to inhaled allergen.MethodsAllergic airway disease (AAD) was induced in wild-type, IL-10 reporter and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice, by repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signalling were disrupted using blocking antibodies.ResultsRepeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10-producing FoxP3- effector CD4+ T cells in the lungs. Ablation of T cell-derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c+ myeloid cells or local IL-10Rα blockade. Disruption of the T cell-myeloid IL-10 axis resulted in elevated pulmonary monocyte-derived dendritic cell numbers and increased IFN-γ-dependent expression of CXCR3 ligands by airway macrophages, suggestive of a feedforward loop of Th1 cell recruitment. Augmented IFN-γ responses in the HDM AAD model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ.ConclusionsIL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.
Foster W, Grime C, Tan H-L, et al., Enhanced frequency and function of follicular T cells in the tonsils of house dust mite sensitized children, Allergy, ISSN: 0105-4538
Invernizzi R, Barnett J, Rawal B, et al., 2020, Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent, European Respiratory Journal, ISSN: 0903-1936
Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.Increased bacterial burden significantly associated with disease progression (hazard ratio 2.1; 95% confidence interval 1.287–3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.
Entwistle L, Gregory L, Oliver R, et al., 2020, Pulmonary group 2 innate lymphoid cell phenotype is context specific: Determining the effect of strain, location and stimuli, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224
Group 2 innate lymphoid cells (ILC2s) are enriched at mucosal sites, including the lung, and play a central role in type 2 immunity and maintaining tissue homeostasis. As a result, since their discovery in 2010, research into ILC2s has increased markedly. Numerous strategies have been used to define ILC2s by flow cytometry, often utilizing different combinations of surface markers despite their expression being variable and context-dependent. In this study, we sought to generate a comprehensive characterization of pulmonary ILC2s, identifying stable and context specific markers from different pulmonary compartments following different airway exposures in different strains of mice. Our analysis revealed that pulmonary ILC2 surface marker phenotype is heterogeneous and is influenced by mouse strain, pulmonary location, in vivo treatment/exposure and ex vivo stimulation. Therefore, we propose that a lineage negative cell expressing CD45 and Gata3 defines an ILC2, and subsequent surface marker expression should be used to describe their phenotype in context-specific scenarios.
Byrne A, powell J, O'Sullivan B, et al., 2020, Dynamics of human monocytes and airway macrophages during healthy aging and post-transplant, Journal of Experimental Medicine, Vol: 217, Pages: 1-9, ISSN: 0022-1007
The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2–12 yr), maturity (20–50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood and bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.
Abeler-Dorner L, Laing AG, Lorenc A, et al., 2020, High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation, NATURE IMMUNOLOGY, Vol: 21, Pages: 86-+, ISSN: 1529-2908
Turnbull A, Pyle C, Patel D, et al., 2020, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993
BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.
Entwistle LJ, Puttur F, Gregory LG, et al., 2020, Group 2 ILC Functional Assays in Allergic Airway Inflammation., Methods Mol Biol, Vol: 2121, Pages: 99-114
ILC2s are a rare innate cell population capable of rapidly producing type 2 cytokines prior to the recruitment and expansion of adaptive type 2 T helper cells. As a result, they are implicated in the pathogenesis of many type-2 immune-mediated diseases, including allergic airway inflammation. Here we describe methods for interrogating and analyzing ILC2 biology in the context of allergic airway inflammation, such as flow cytometric analysis of mouse and human ILC2s as well as live imaging of pulmonary ILC2s.
Broadbent L, Manzoor S, Zarcone MC, et al., 2020, Comparative primary paediatric nasal epithelial cell culture differentiation and RSV-induced cytopathogenesis following culture in two commercial media., PLoS One, Vol: 15
The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.
Patel DF, Peiro T, Bruno N, et al., 2019, Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation, Science Immunology, Vol: 4, ISSN: 2470-9468
Neutrophil mobilization, recruitmentand clearancemust be tightly regulated asover-exuberant neutrophilic inflammation isimplicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophilstherapeutically have failed to consider theirpleiotropic functions and theimplications of disrupting fundamental regulatory pathways that govern their turnover duringhomeostasisand inflammation.Using thehouse dust mite(HDM)model of allergic airways disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated TH2 inflammation, epithelial remodelling and airway resistance. Mechanistically, this was attributable to astriking increase insystemic G-CSF concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increasedG-CSF augmented allergic sensitization in HDM exposed animals bydirectly acting on airway ILC2s toelicitcytokine production.Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool.By modelling the effects of neutrophil depletion, our studies have therefore uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly,they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.
Lloyd CM, Saglani S, 2019, Opening the Window of Immune Opportunity: Treating Childhood Asthma, TRENDS IN IMMUNOLOGY, Vol: 40, Pages: 786-798, ISSN: 1471-4906
Allden SJ, Ogger PP, Ghai P, et al., 2019, The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 200, ISSN: 1073-449X
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease.
Oksel C, Granell R, Haider S, et al., 2019, Distinguishing wheezing phenotypes from infancy to adolescence: a pooled analysis of five birth cohorts, Annals of the American Thoracic Society, Vol: 16, Pages: 868-876, ISSN: 2329-6933
RATIONALE: Pooling data from multiple cohorts and extending the time-frame across childhood should minimize study-specific effects, enabling better characterization of the childhood wheezing. OBJECTIVE: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. METHODS: We used latent class analysis to derive wheeze phenotypes among 7719 participants from five birth cohorts with complete report of wheeze at five time-periods. We tested the association of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. RESULTS: We identified five phenotypes: Never/Infrequent wheeze (52.1%), Early-onset pre-school remitting (23.9%), Early-onset mid-childhood remitting (9%), Persistent (7.9%) and Late-onset wheeze (7.1%). Compared to the Never/infrequent wheeze, all phenotypes had higher odds of asthma and lower FEV1 and FEV1/FVC in adolescence. The association with asthma was strongest for Persistent wheeze (adjusted odds ratio 56.54, 95%CI 43.75-73.06). We observed considerable within-class heterogeneity at individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in Persistent and Never/infrequent, and lowest in Late-onset wheeze (with 51% of participants having membership probabilities<0.80). Individual wheezing patterns were particularly heterogeneous in Late-onset wheeze, while many children assigned to Early-onset pre-school remitting class reported wheezing at later time points. CONCLUSIONS: All wheeze phenotypes had significantly diminished lung function in school-age, suggesting that the notion that early-life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.
Singhania A, Graham CM, Gabrysova L, et al., 2019, Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases, Nature Communications, Vol: 10, ISSN: 2041-1723
Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.
Patel DF, Gaggar A, Blalock JE, et al., 2019, Response to Comment on "An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness", SCIENCE TRANSLATIONAL MEDICINE, Vol: 11, ISSN: 1946-6234
Lloyd C, Puttur F, Denney L, et al., 2019, Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans, Science Immunology, Vol: 4, ISSN: 2470-9468
Group 2 innate lymphoid cells (ILC2s) are enriched in mucosal tissues (e.g., lung) and respond to epithelial cell–derived cytokines initiating type 2 inflammation. During inflammation, ILC2 numbers are increased in the lung. However, the mechanisms controlling ILC2 trafficking and motility within inflamed lungs remain unclear and are crucial for understanding ILC2 function in pulmonary immunity. Using several approaches, including lung intravital microscopy, we demonstrate that pulmonary ILC2s are highly dynamic, exhibit amoeboid-like movement, and aggregate in the lung peribronchial and perivascular spaces. They express distinct chemokine receptors, including CCR8, and actively home to CCL8 deposits located around the airway epithelium. Within lung tissue, ILC2s were particularly motile in extracellular matrix–enriched regions. We show that collagen-I drives ILC2 to markedly change their morphology by remodeling their actin cytoskeleton to promote environmental exploration critical for regulating eosinophilic inflammation. Our study provides previously unappreciated insights into ILC2 migratory patterns during inflammation and highlights the importance of environmental guidance cues in the lung in controlling ILC2 dynamics.
Nagakumar P, Puttur F, Gregory LG, et al., 2019, Pulmonary type2 innate lymphoid cells in paediatric severe asthma: phenotype and response to steroids, European Respiratory Journal, Vol: 54, Pages: 1-14, ISSN: 0903-1936
Children with severe therapy resistant asthma (STRA) have poor control despite maximal treatment, while those with difficult asthma (DA) have poor control from failure to implement basic management including adherence to therapy. Although recognised as clinically distinct, the airway molecular phenotype, including the role of ILCs and their response to steroids in DA and STRA is unknown.Immunophenotyping of sputum and blood ILCs and T cells from STRA, DA and non-asthmatic controls was undertaken. Leukocytes were analysed longitudinally pre and post intramuscular triamcinolone in children with STRA. Cultured ILCs were also evaluated to assess steroid responsiveness in vitroAirway eosinophils, Th2 cells and ILC2s were significantly higher in STRA patients compared to DA and disease controls, while IL-17+ lymphoid cells were similar. ILC2s and Th2 cells were significantly reduced in vivo following intramuscular triamcinolone and in vitro with steroids. Asthma attacks and symptoms also reduced after systemic steroids despite persistence of steroid resistant IL-17+ cells and eosinophils.Paediatric STRA and DA have distinct airway molecular phenotypes with STRA characterised by elevated type2 cells. Systemic corticosteroids but not maintenance inhaled steroids resulted in improved symptom control and exacerbations concomitant with a reduction in functional ILC2s despite persistently elevated IL-17+ lymphoid cells.
Davies ER, Denney L, Wandel M, et al., 2019, Regulation of ectodomain shedding of ADAM33 in vitro and in vivo, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 2281-2284.e3, ISSN: 0091-6749
Oksel C, Custovic A, Granell R, et al., 2019, Causes of variability in latent phenotypes of childhood wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1783-1790.e11, ISSN: 0091-6749
BackgroundLatent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.ObjectiveWe sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.MethodsWe used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years.ResultsA relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers.ConclusionsSample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.
Robinson PFM, Pattaroni C, Cook J, et al., 2019, Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1607-1610.e, ISSN: 0091-6749
Uwadiae F, Pyle C, Walker S, et al., 2019, Targeting the ICOS/ICOS-L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease, Allergy, Vol: 74, Pages: 650-662, ISSN: 0105-4538
BackgroundAllergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (TFH) are crucial in T‐dependent B cell responses and have been implicated in allergic airway disease (AAD). TFH, unlike other CD4+ T cells are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T cell priming, therefore disrupting this signal can impair TFH responses. However, the contribution of TFH to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells has not been evaluated.MethodsTo establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of TFH on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS‐Ligand targeted antibodies, 3 times for the last 2 weeks.ResultsTFH were first observed in the lung draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH but did not affect the differentiation of other CD4+ T cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness.ConclusionsTFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma.
Branchett W, Lloyd C, 2019, Regulatory cytokine function in the respiratory tract, Mucosal Immunology, Vol: 12, Pages: 589-600, ISSN: 1933-0219
The respiratory tract is an important site of immune regulation; required to allow protective immunity against pathogens, while minimizing tissue damage and avoiding aberrant inflammatory responses to inhaled allergens. Several cell types work in concert to control pulmonary immune responses and maintain tolerance in the respiratory tract, including regulatory and effector T cells, airway and interstitial macrophages, dendritic cells and the airway epithelium. The cytokines transforming growth factor β (TGF-β), interleukin (IL-) 10, IL-27 and IL-35 are key coordinators of immune regulation in tissues such as the lung. Here, we discuss the role of these cytokines during respiratory infection and allergic airway disease, highlighting the critical importance of cellular source and immunological context for the effects of these cytokines in vivo.
Gregory L, Lloyd C, Puttur F, 2019, Airway macrophages as the guardians of tissue repair in the lung, Immunology and Cell Biology, ISSN: 1440-1711
Zhang Y, Willis-Owen S, Spiegel S, et al., 2019, The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 478-488, ISSN: 1073-449X
Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.
Saglani S, Lloyd CM, Bush A, 2019, Biology and Assessment of Airway Inflammation, Kendig's Disorders of the Respiratory Tract in Children, Pages: 101-119.e4, ISBN: 9780323448871
© 2019 Elsevier Inc. All rights reserved. The nature and development airway inflammation may be driven by numerous factors, including pathogenic infections, pollution, or even relatively innocuous inhaled particles, such as allergens. A robust inflammatory response is essential to fight pathogens, but both active inflammation and efficient resolution are equally important. The failure of resolution or persistent proinflammatory immune responses results in chronic inflammatory airway diseases. These may be characterized by persistent neutrophilic inflammation, as is the case in cystic fibrosis and chronic suppurative lung diseases, or persistent eosinophilia, as is seen in allergic asthma. It is essential to accurately undertake an assessment of the airway inflammatory phenotype in chronic airways diseases to allow an understanding of the mechanisms mediating disease and identify appropriate therapeutic targets. It is also becoming increasingly important to phenotype airway inflammation in individual patients to allow targeted treatment as we move towards personalized therapies. This chapter will discuss what is known about the mechanisms driving chronic inflammatory airways diseases in children and provide an update on the methods used to investigate airway inflammation invasively and noninvasively in patients to allow phenotype driven and targeted therapies.
Saglani S, Lloyd CM, 2019, 43 - The Immunopathogenesis of Asthma, Kendig's Disorders of the Respiratory Tract in Children, Pages: 665-676.e3, ISBN: 9780323448871
© 2019 Elsevier Inc. All rights reserved. Asthma occurs as a result of the interplay of genetic susceptibility and environmental influences on the developing lungs and immune system. Asthma in children is predominantly associated with the development of allergic sensitization and the pathological features of eosinophilic airway inflammation and structural airway wall changes, collectively termed airway remodeling. The clinical manifestation of disease is heterogeneous but includes symptoms of breathlessness and wheeze, which result from bronchoconstriction. Acute attacks in children commonly result from respiratory infection, with repeated episodes of infection with rhinovirus and respiratory syncytial virus in early life being especially associated with the risk of recurrent wheezing and asthma in children who also develop early allergic sensitization and have a genetic susceptibility. The focus of this chapter is to discuss the basic immunological mechanisms that drive the pathophysiology of asthma, with specific focus on the close interactions between innate and adaptive immune responses in driving disease. The immunopathology of specific clinical manifestations of disease, including exacerbations and preschool wheezing disorders, will also be discussed, and mechanisms that are unique to the developing pediatric airway and that cannot be extrapolated from adult disease will be highlighted.
Robinson PF, Pattaroni C, Cook J, et al., 2019, Lower Airway Microbiota Associates with Inflammatory Phenotype in Severe Preschool Wheeze, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Snelgrove RJ, Patel DF, Patel T, et al., 2018, The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?, Clinical and Experimental Allergy, Vol: 48, Pages: 1275-1285, ISSN: 0954-7894
Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.
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