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Title: Genetic and environmental influences on the development of allergic pulmonary disease
Author: Sherburn, Rebekah
ISNI:       0000 0004 6346 833X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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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.
Supervisor: Lloyd, Clare ; Saglani, Sejal Sponsor: Medical Research Council ; Asthma UK ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral