Publications
297 results found
Grime C, Nagakumar P, Tan H-L, et al., 2015, Innate lymphoid cells are proportionally higher in children with atopy, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
De Leeuw R, Irving S, Saglani S, 2015, Addressing current gaps in the clinical utility of lung clearance index (LCI) in school aged children with asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Jochmann A, Robson K, Fleming L, et al., 2015, Sputum induction for assessment of lower airway infection in preschool children, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Jochmann A, Nagakumar P, Hall P, et al., 2015, Improvement in asthma control and airway inflammation during a period of electronic monitoring, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 2
Nagakumar P, Denney L, Fleming L, et al., 2015, Type 2 innate lymphoid cells in induced sputum from children with severe asthma, Journal of Allergy and Clinical Immunology, Vol: 137, Pages: 624-626.e6, ISSN: 1097-6825
Castanhinha S, Sherburn RT, Walker SA, et al., 2015, Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 312-322.e7, ISSN: 1097-6825
Background: The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. Objective: We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Methods: Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n= 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Results: Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P= .006), higher total IgE levels (637 vs 177 IU/mL, P= .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P= .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2-/- mice lacking a functional receptor for IL-33. Conclusion: Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.
Saglani S, Bush A, 2015, Onset of Structural Airway Changes in Preschool Wheezers A Window and Target for Secondary Asthma Prevention?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 192, Pages: 121-122, ISSN: 1073-449X
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- Citations: 8
Gielen V, Sykes A, Zhu J, et al., 2015, Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 177-188e.11, ISSN: 1097-6825
BackgroundRhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.ObjectiveWe sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.MethodsWe assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.ResultsWe report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation–related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.ConclusionWe describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.
Moeller A, Carlsen K-H, Sly PD, et al., 2015, Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation, EUROPEAN RESPIRATORY REVIEW, Vol: 24, Pages: 204-215, ISSN: 0905-9180
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- Citations: 77
Lloyd CM, Saglani S, 2015, Epithelial cytokines and pulmonary allergic inflammation, Current Opinion in Immunology, Vol: 34, Pages: 52-58, ISSN: 1879-0372
The triad of epithelial derived cytokines, IL-25, IL-33 and TSLP are important for the initiation and development of pulmonary immune responses to environmental stimuli. Data from experiments using mouse models provide compelling evidence for their involvement in both innate and adaptive immunity to drive type-2 responses, allergic inflammation and airway remodelling. These cytokines are known to be expressed in human lung tissue and immune cells, however their involvement in mediating allergic pulmonary responses in patients is less clear than in murine models of disease. This article focuses on evidence for the role of IL-25, IL-33 and TSLP in human allergic disease and discusses their potential as therapeutic targets for severe asthma.
Lee DC, Walker SA, Byrne AJ, et al., 2015, Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life., Thorax, ISSN: 1468-3296
Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model.
Pijnenburg MW, Baraldi E, Brand PLP, et al., 2015, Monitoring asthma in children, EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 906-925, ISSN: 0903-1936
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- Citations: 89
Pfeffer PE, Chen Y-H, Woszczek G, et al., 2015, Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33, Journal of Allergy and Clinical Immunology, Vol: 135, Pages: 824-827, ISSN: 0091-6749
Malmstrom K, Malmberg LP, O'Reilly R, et al., 2015, Lung function, airway remodeling, and inflammation in infants: outcome at 8 years, ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, Vol: 114, Pages: 90-U193, ISSN: 1081-1206
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- Citations: 25
Fainardi V, Saglani S, 2015, The need to differentiate between adults and children when treating severe asthma, EXPERT REVIEW OF RESPIRATORY MEDICINE, Vol: 9, Pages: 419-428, ISSN: 1747-6348
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- Citations: 13
Nagakumar P, Denney L, Fleming L, et al., 2015, Type 2 Innate Lymphoid Cells Are Increased In Bal And Induced Sputum But Not Blood In Children With Severe Therapy Resistant Asthma (stra), International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Robson K, Nagakumar P, Collins N, et al., 2014, SAFETY, FEASIBILITY AND QUALITY OF SPUTUM INDUCTION IN PRESCHOOL CHILDREN WITH OBSTRUCTIVE AIRWAYS DISEASE, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A123-A123, ISSN: 0040-6376
Nagakumar P, Hall P, Bracken M, et al., 2014, IS PRESCRIPTION UPTAKE AND MEDICATION ADHERENCE RATING SCALE (MARS) A USEFUL TOOL IN ASSESSING ASTHMA CONTROL IN CHILDREN WITH PROBLEMATIC SEVERE ASTHMA (PSA)?, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A98-A98, ISSN: 0040-6376
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- Citations: 1
Hall P, Bracken M, Winch D, et al., 2014, SMARTINHALERS - A NEW APPROACH TO ASSESSING ADHERENCE IN DIFFICULT ASTHMA, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A182-A182, ISSN: 0040-6376
Collins N, Robson K, Nagakumar P, et al., 2014, SPUTUM INDUCTION REDUCES THE NEED FOR BRONCHOSCOPY IN SCHOOL-AGED CHILDREN WITH CYSTIC FIBROSIS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A123-A124, ISSN: 0040-6376
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- Citations: 1
Ahmad FA, Irving SI, Bush AB, et al., 2014, MULTIPLE BREATH WASHOUTS IN CHILDREN CAN BE SIGNIFICANTLY SHORTENED WITHOUT COMPROMISING MEASUREMENT QUALITY, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A166-A167, ISSN: 0040-6376
Malmström K, Lehto M, Majuri ML, et al., 2014, Bronchoalveolar lavage in infants with recurrent lower respiratory symptoms., Clinical and Translational Allergy, Vol: 4, ISSN: 2045-7022
BACKGROUND: Few data are available about the inflammatory cytokine profile of bronchoalveolar lavage (BAL) from young children with frequent wheeze. The first aim was to investigate the BAL cellular and cytokine profiles in infants with recurrent lower respiratory symptoms in whom bronchoscopy was indicated for clinical symptom evaluation. The second aim was to relate the BAL results with the histological findings of the endobronchial carina biopsies. METHODS: Thirty-nine infants (median age 0.9 years) underwent lung function testing by whole-body plethysmography prior to the bronchoscopy. The BAL differential cell counts and cytokine levels were quantified. These findings were compared with the histological findings of the endobronchial carina biopsies. RESULTS: The differential cytology reflected mainly that described for healthy infants with lymphocyte counts at the upper range level. A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement membrane was found. Detectable levels of pro-inflammatory cytokine proteins IL-1β, IL-17A, IL-18, IL-23, and IL-33 were found, whereas levels of Th2-type cytokine proteins were low. Frequent wheeze was the only clinical characteristic significantly related to detectable combined pro-inflammatory cytokine profile. Lung function did not correlate with any cytokine. CONCLUSIONS: A positive association between BAL CD8+ lymphocytes and neutrophils and endobronchial reticular basement thickness was found. Detectable production of pro-inflammatory cytokines associated positively with frequent wheeze.
Vasiliou JE, Lui S, Walker SA, et al., 2014, Vitamin D deficiency induces Th2 skewing and eosinophilia in neonatal allergic airways disease, ALLERGY, Vol: 69, Pages: 1380-1389, ISSN: 0105-4538
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- Citations: 75
Saglani S, 2014, Innate immunity in paediatric viral wheezers is virus specific and not interferon dependent, THORAX, Vol: 69, Pages: 887-+, ISSN: 0040-6376
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- Citations: 3
Saglani S, 2014, NOVEL THERAPEUTIC TARGETS FOR SEVERE-TREATMENT RESISTANT ASTHMA, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: S9-S10, ISSN: 8755-6863
Saglani S, 2014, ALLERGEN IMMUNOTHERAPY IS USEFUL IN THE TREATMENT OF CHILDHOOD ASTHMA (CON), PEDIATRIC PULMONOLOGY, Vol: 49, Pages: S5-S6, ISSN: 8755-6863
Blok F, Irving S, Bush A, et al., 2014, Positive relationship between offline exhaled nitric oxide and lung clearance index in pre-school wheezers, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Tupker F, Blok F, Irving S, et al., 2014, Non-invasive markers of airway eosinophilic inflammation in pre-school children, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Gollwitzer ES, Saglani S, Trompette A, et al., 2014, Lung microbiota promotes tolerance to allergens in neonates via PD-L1, Nature Medicine, Vol: 20, Pages: 642-647, ISSN: 1078-8956
Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease1,2,3,4,5,6,7,8. The neonatal immune system matures during this period9, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4+Foxp3+CD25+Helios+ regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios− Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization10 or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.
Gupta A, Dimeloe S, Richards DF, et al., 2014, Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma, THORAX, Vol: 69, Pages: 508-515, ISSN: 0040-6376
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- Citations: 64
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