Sejal Saglani

Imperial College London, Londinium, England, United Kingdom

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Publications (60)468.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Associations between vitamin D status and childhood asthma are increasingly reported, but direct causation, and mechanisms underlying an effect remain unknown. We investigated the effect of early life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD).
    Allergy 06/2014; · 5.88 Impact Factor
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    ABSTRACT: 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 disease. The neonatal immune system matures during this period, 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 colonization(10) 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.
    Nature medicine 05/2014; · 27.14 Impact Factor
  • Sejal Saglani, Clare M Lloyd
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    ABSTRACT: The importance and functional contribution of eosinophils to the pathogenesis of severe asthma was questioned when adult studies reported neutrophilic inflammation and Th17 cells were central to disease. Eosinophilic inflammation, atopic sensitization and airway remodelling are the hallmark features of severe asthma in children. Contrary to adult reports, neutrophils, Th17 and Th2 cytokines are rarely detected in children with severe disease who are prescribed high-dose steroids. Type 2 innate lymphoid cells (ILCs), which are induced by the epithelial cytokine interleukin (IL)-33, and also release the Th2 cytokines IL-5 and IL-13, have been shown to be important in mediating asthma, and specifically, ILCs have a role in mediating eosinophil homeostasis. A direct link between IL-33, airway remodelling and steroid resistance in paediatric severe asthma suggests the steroid-resistant eosinophilia may be mediated by ILCs rather than classical Th2 lymphocytes. Data from children with severe asthma have shown that findings from adults cannot be translated to children, and that steroid-resistant eosinophilic inflammation appears central to the pathogenesis of paediatric disease. Age-appropriate experimental models and use of airway samples from children are critical to understanding the underlying mechanisms and identifying novel therapeutic targets.
    Current Opinion in Allergy and Clinical Immunology 02/2014; · 3.40 Impact Factor
  • Andrew Bush, Jonathan Grigg, Sejal Saglani
    BMJ (online) 01/2014; 348:g15. · 17.22 Impact Factor
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    ABSTRACT: Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children. Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1α,25-dihydroxyvitamin D3. Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p<0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p<0.001) and decreasing IL-13 (p<0.001) but unexpectedly enhanced IL-17A production in all groups-most strikingly in the STRA cohort (p<0.001). The inclusion of the active form of vitamin D, 1α,25-dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p<0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p<0.01). These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA.
    Thorax 12/2013; · 8.38 Impact Factor
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    ABSTRACT: Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.
    Allergy 12/2013; 68(12):1520-31. · 5.88 Impact Factor
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    Clare M Lloyd, Sejal Saglani
    Nature medicine 08/2013; 19(8):976-7. · 27.14 Impact Factor
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    Sejal Saglani
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    ABSTRACT: Viral aetiology, host susceptibility (in particular allergic predisposition and sensitization), and illness severity, timing and frequency all appear to contribute as synergistic factors to the risk of developing asthma. Experimental models have shown both innate and adaptive immune responses contribute to this risk with lung inflammatory cells showing marked differences in phenotype and function in young compared with older animals, and these differences are further enhanced following virus infection. Findings to date strongly suggest that the impact of infant and preschool viral infections on the maturing immune system and developing lung that subsequently result in an asthma phenotype occur during a critical susceptibility period, and in a genetically susceptible host. There are currently no therapeutic strategies that allow primary or secondary prevention of asthma following early life viral respiratory infections in high-risk children, thus a focus on understanding the mechanisms of progression from viral wheezing in infants and preschool children to asthma development are urgently needed. This review summarizes the data reporting the role of the two most common viruses, that is, respiratory syncytial virus and human rhinovirus, that result in asthma development, comparing risk factors for disease progression, and providing insight into strategies that might be adopted to prevent asthma development.
    Therapeutic Advances in Infectious Disease. 08/2013; 1(4):139-150.
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    ABSTRACT: BACKGROUND: TH2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown. OBJECTIVE: We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA. METHODS: IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2(-/-) mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified. RESULTS: Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2(-/-) mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA. CONCLUSION: IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.
    The Journal of allergy and clinical immunology 06/2013; · 12.05 Impact Factor
  • Alexandra Adams, Sejal Saglani
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    ABSTRACT: Asthma continues to be one of the greatest burdens to healthcare resources throughout the developed world. In most cases, good symptom control can be achieved with low-dose inhaled corticosteroids, and can be cared for in the primary and secondary healthcare systems. However, there is a group in whom control is not achieved despite high-dose inhaled corticosteroids and maximal add-on therapies; these are children with problematic severe asthma that should be referred to a specialist team for further investigation and management. In this review we aimed to provide an evidence-based guide for pediatricians providing care for children with asthma in secondary healthcare settings. The review focuses on a proposed investigation and management strategy for children aged between 6 and 16 years with problematic severe asthma, and is supported as far as possible by evidence from the literature. We first address recent advances in nomenclature and then discuss our proposed course of investigation and management of these children. Distinction of children with true, severe, therapy-resistant asthma from those with asthma that is difficult to treat because of unaddressed underlying modifiable factors is critical and is discussed in detail.
    Paediatric Drugs 04/2013; · 1.72 Impact Factor
  • Clare M Lloyd, Sejal Saglani
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    ABSTRACT: Asthma is classically considered the archetypal TH2 disease, with increased circulating IgE levels and eosinophilic inflammation being caused by increased levels of TH2-type cytokines. However, this paradigm has been challenged because of the realization that strategies designed to suppress TH2 function are not effective for all patients. The clinical phenotype of asthma is notoriously heterogeneous and is affected by genetic and environmental exposures in addition to interactions between airway structural cells, including epithelial cells, and the immune system, as well as contributions from cells other than TH2 cells. A combination of genetic and environmental factors is thought to influence whether inflammation resolves or progresses, and the pulmonary epithelium is increasingly recognized to play a key role in this process. This complex interplay has made it increasingly apparent that immune responses are tailored to the individual patient and determined by the weight of each influence, and thus the label of asthma as a TH2 disease is too conservative. Indeed, an important concept that needs to be addressed, both in animal models and clinically, is that of T-cell plasticity and how lymphocytic responses are determined by environmental influences.
    The Journal of allergy and clinical immunology 03/2013; · 12.05 Impact Factor
  • European Respiratory Journal 03/2013; 41(3):497-9. · 6.36 Impact Factor
  • Alexandra Adams, Sejal Saglani
    Paediatrics and Child Health. 03/2013; 23(3):133–135.
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    ABSTRACT: BACKGROUND: The inflammatory phenotypes of severe asthma in adults may be reflected in peripheral blood. If this were true in children with severe therapy-resistant asthma (STRA), invasive tests could be avoided. At the moment there is no conclusive evidence in children. METHODS: All patients underwent blood tests, exhaled nitric oxide (FeNO), sputum induction, bronchoalveolar lavage (BAL) and endobronchial biopsy (EB). RESULTS: Sixty-three (71.6%) patients had a normal blood profile and only 1/88 had a combined blood eosinophilia and neutrophilia. 76/88 (86%) had normal blood eosinophils, but of these, 84% had airway eosinophilia in either BAL (n = 43;66%) or EB (n = 41;79%). In children with STRA blood eosinophilia was associated with airway eosinophilia. However, normal blood eosinophil levels did not exclude airway eosinophilic inflammation. CONCLUSIONS: Peripheral blood counts are not reliable in characterising airway inflammation in severe asthmatic children exposed to high dose steroid therapy, therefore bronchoscopy with BAL should be considered.
    Allergy 01/2013; · 5.88 Impact Factor
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    ABSTRACT: Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.Mucosal Immunology advance online publication 5 December 2012; doi:10.1038/mi.2012.118.
    Mucosal Immunology 12/2012; · 7.54 Impact Factor
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    ABSTRACT: Vitamin D deficiency and insufficiency are increasingly being recognized in the general population, and have been largely attributed to lifestyle changes (reduced exposure to sunshine due to working indoors or the use of protective clothing and sunscreen; changes in diet) over the last few decades. The musculoskeletal consequences of severe vitamin D deficiency are well established, however, a number of other disorders have now been linked to vitamin D insufficiency, including asthma. There is growing appreciation of the likely importance of vitamin D as a pleiotrophic mediator that contributes to pulmonary health. Children with asthma appear to be at increased risk of vitamin D insufficiency. Epidemiologic data suggest that low serum vitamin D in children with asthma is associated with more symptoms, exacerbations, reduced lung function, increased medication usage and severe disease. In vitro studies have demonstrated that vitamin D enhances steroid responsiveness in adult asthmatics. Vitamin D may play an important role in pulmonary health by inhibiting inflammation, in part through maintaining regulatory T cells, and direct induction of innate antimicrobial mechanisms. More research is required to fully understand the role of vitamin D in the maintenance of airway homeostasis and address the diagnostic and therapeutic implications vitamin D may have in the future of asthma management. This review summarises the current understanding and uncertainties regarding the effect of vitamin D deficiency and insufficiency in children with asthma.
    Paediatric Respiratory Reviews 12/2012; 13(4):236-43. · 2.77 Impact Factor
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    ABSTRACT: BACKGROUND: Increased airway smooth muscle (ASM) is a feature of established asthma in schoolchildren, but nothing is known about ASM in preschool wheezers. OBJECTIVE: We sought to determine endobronchial biopsy specimen ASM area fraction in preschool wheezers and its association with asthma at school age. METHODS: ASM area, reticular basement membrane thickness, and mucosal eosinophil and ASM mast cell values were quantified in endobronchial biopsy specimens previously obtained from preschool children undergoing clinically indicated bronchoscopy: severe recurrent wheezers (n = 47; median age, 26 months) and nonwheezing control subjects (n = 21; median age, 15 months). Children were followed up, and asthma status was established at age 6 to 11 years. Preschool airway pathology was examined in relation to asthma at school age. RESULTS: Forty-two (62%) of 68 children had 1 or more evaluable biopsy specimens for ASM. At school age, 51 of 68 children were followed up, and 15 (40%) of 37 preschool wheezers had asthma. Children who had asthma and an evaluable biopsy specimen had increased preschool ASM area fraction (n = 8; median age, 8.2 years [range, 6-10.4 years]; median ASM, 0.12 [range, 0.08-0.16]) compared with that seen in children without asthma (n = 24; median age, 7.3 years [range, 5.9-11 years]; median ASM, 0.07 [range, 0.02-0.23]; P = .007). However, preschool reticular basement membrane thickness and mucosal eosinophil or ASM mast cell values were not different between those who did or did not have asthma at school age. CONCLUSION: Increased preschool ASM is associated with those children who have asthma at school age. Thus a focus on early changes in ASM might be important in understanding the subsequent development of childhood asthma.
    The Journal of allergy and clinical immunology 10/2012; · 12.05 Impact Factor
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    Andrew Bush, Sejal Saglani
    Jornal de pediatria 09/2012; 88(5):371-4. · 1.07 Impact Factor
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    ABSTRACT: 1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4(+) T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3(+) regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3(+) and IL-10(+) CD4(+) T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3(+) and IL-10(+) T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3(+) Treg cells over their Foxp3(-) T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3(+) expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4(+) Foxp3(+) T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10(+) and Foxp3(+) Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.
    European Journal of Immunology 08/2012; 42(10):2697-708. · 4.97 Impact Factor
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    European Respiratory Journal 07/2012; 40(1):264-7. · 6.36 Impact Factor

Publication Stats

1k Citations
468.48 Total Impact Points

Institutions

  • 2005–2013
    • Imperial College London
      • Section of Leukocyte Biology
      Londinium, England, United Kingdom
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2012
    • King's College London
      • MRC and Asthma UK Centre in Allergic Mechanisms of Asthma
      London, ENG, United Kingdom
  • 2006–2012
    • Royal Brompton and Harefield NHS Foundation Trust
      Harefield, England, United Kingdom
  • 2007–2010
    • National Heart, Lung, and Blood Institute
      Maryland, United States