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Genetic and environmental influences on the development of allergic pulmonary disease

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Title: Genetic and environmental influences on the development of allergic pulmonary disease
Authors: Sherburn, Rebekah
Item Type: Thesis or dissertation
Abstract: Allergic airway disease is a growing health concern and despite extensive research, mechanisms underlying allergen sensitisation are not fully understood. By utilising experimental mouse models of intra-nasal (i.n) allergen exposure the role of a number of factors in the onset and progression of allergic airway disease (AAD) were investigated including age, allergen type and genetic background. Age at first allergen exposure was found to be a critical determinant of the severity of AAD. Neonatal mice exposed to i.n. house dust mite (HDM) extract developed enhanced AAD compared to adult mice. A period of non-responsiveness to HDM exposure was also identified between the ages of day 14 and 21 of life which corresponded to a natural nadir in both IL-13+ CD4+T cells and IL-13+ innate lymphoid cells (ILCs). The type of allergen to which mice were exposed was also revealed as a determinant of the severity of AAD that developed. The fungal allergen Alternaria alternata (Alt) was associated with a more severe disease phonotype, characterised by elevated IL-13 levels and steroid resistance. Investigation of the genetic contribution to the development of AAD focussed on two genes identified by large-scale genome wide association studies (GWAS) as associated with childhood onset asthma - IL-33 and ST2. ST2, but not IL-33, was determined to be critical for sensitisation with HDM. However, neither IL-33 nor ST2 were required for the development of AAD in response to Alt exposure. Investigation of short-term exposure to Alt identified ST2 as having a critical role in early inflammatory responses to Alt but not in the development of Alt specific T cells and IgE. Overall, work conducted in this thesis identified the age-dependent development of allergic disease, the likely existence of an alternative ligand for ST2 and provided a mechanistic explanation for the association of Alt sensitisation and steroid resistance.
Content Version: Open Access
Issue Date: Jan-2015
Date Awarded: Jun-2015
URI: http://hdl.handle.net/10044/1/46042
DOI: https://doi.org/10.25560/46042
Supervisor: Lloyd, Clare
Saglani, Sejal
Sponsor/Funder: Medical Research Council
Asthma UK
Wellcome Trust (London, England)
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses



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