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Title: The Th17 pathway in cystic fibrosis lung disease
Author: Tan, Hui-leng
ISNI:       0000 0004 2723 9759
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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In contrast to the neutrophilic inflammation found in the airway lumen, lymphocytes predominate in the airway wall of Cystic fibrosis (CF) patients. The Th17 pathway could play an important role in CF, as IL-17, secreted by Th17 lymphocytes, is proinflammatory, stimulates neutrophil recruitment and has been detected in CF sputum. This thesis investigates the hypothesis that T lymphocytes, in particular Th17 lymphocytes, are present in the CF airway wall and activation of the Th17 pathway is CF specific. Lymphocyte populations were characterised in endobronchial biopsies of children with CF, non-CF bronchiectasis and controls and related to clinical status, microbiological cultures and inflammation (cells and soluble factors) in bronchoalveolar lavage fluid (BALF). In parallel, lymphoid aggregates seen in the nasal mucosa of CF mice were investigated. Immunohistochemistry was performed on these endobronchial biopsies, staining for CD4, CD8 and IL-17. Cellular sources of IL-17 were determined following development of a novel immunofluorescence double staining protocol. Cells and cytokine levels were measured in BALF. Flow cytometry analysis of the nasal mucosa of CF and wild type mice was performed. Significant differences in T helper (CD4+) cells but not cytotoxic (CD8+) T cells were found between patient groups. Established CF and non-CF bronchiectasis samples had higher numbers of IL-17+ cells than controls; newly diagnosed CF patients had intermediate counts. Double staining confirmed there were Th17 lymphocytes in the submucosa of these biopsies. IL-17+ neutrophils, !"T cells and natural killer T cells were also identified. CF mice were also shown to have CD4+IL-17+ cells in their nasal mucosa. In conclusion, Th17 lymphocytes are present in the airway submucosa in CF and represent one of a number of sources of IL-17. Non-CF bronchiectasis patients had similar numbers of IL-17+ cells, suggesting activation of the Th17 pathway is not CF specific.
Supervisor: Bush, Andrew ; Davies, Jane ; Lloyd, Clare Sponsor: National Heart and Lung Institute
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral