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Title: The production and function of IL-17A and IL-22 in chronic pulmonary Pseudomonas aeruginosa infection
Author: Bayes, Hannah Kelly
ISNI:       0000 0004 5347 4955
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2014
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Cystic fibrosis (CF) lung disease typically results in pulmonary infections and inflammation that produces progressive respiratory failure. The most common pathogen in adult patients with CF is Pseudomonas aeruginosa (PA), which in the majority of patients chronically colonises the airways and is associated with a neutrophil-dominated host response. This neutrophilic response fails to clear the infection but contributes to progressive lung injury. Prior to the establishment of chronic PA colonisation, patients experience intermittent pulmonary PA infections that can be cleared either by host responses or antibiotic eradication therapy. Recent attention has focused on the role of the cytokines interleukin-17 (IL-17) produced by T helper 17 (Th17) cells, in anti-microbial defences. IL-17 plays a critical role in the generation and recruitment of neutrophils to sites of infection and has been implicated in responses to PA as well as other pulmonary pathogens. Clinical data has also suggested a potential role for IL-17, Th17 cells, as well as other cellular sources of IL-17 in the pathogenesis of human CF pulmonary disease. An additional Th17-related cytokine IL-22 has previously been shown to hold a critical role in defence against acute pulmonary infections, as well as reparative functions in pulmonary disease. However, the functions of this cytokine are not clear cut, since pro-inflammatory effects are also seen depending on the local environment in which it acts. Given the pivotal role of IL-17 in neutrophilic immune responses, in this thesis I hypothesised that IL-17A is beneficial in early CF lung disease where it aids clearance of PA and delays the onset of chronic PA colonisation. However, as the organism adapts to the hostile environment and/or the lung environment becomes more conducive to bacterial growth then chronic PA infection inevitably develops; in this setting I proposed that IL-17A becomes pathogenic by driving persistent, damaging neutrophilic inflammation. In addition, I hypothesised that Th17 cells are a source of IL-17A in PA infection and that, due to persistent antigenic-stimulation in CF patients the Th17 response may be altered to that seen in healthy controls. I further proposed that IL-22 may have a reparative and protective role in persistent pulmonary PA infection, but that the cytokine's reparative effects become overwhelmed or IL-22 becomes pro-inflammatory and pathogenic in later CF lung disease with chronic PA colonisation. These hypotheses were addressed via the use of both clinical samples from patients with CF and a murine model of persistent PA infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR180 Immunology