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Long-Term Exposure to Interleukin-8, Lung Remodelling and Altered T Cell

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Long-Term Exposure to Interleukin-8, Lung Remodelling and Altered T Cell Long-term exposure to interleukin-8, lung remodelling and altered T cell immunity in the context of chronic infection with Pseudomonas aeruginosa in chronic lung disease. Kathryn Jane Quigley A thesis submitted for the degree of Doctor of Philosophy Lung Immunology Group Infectious Diseases and Immunity Department of Medicine Imperial College London August 2014 1 Declaration I hereby declare that the research submitted in this thesis is my own and describes my own work under the supervision of Dr. Rosemary Boyton, at the Department of Medicine, Imperial College, except where the work of others has been acknowledged at the point of use. All sources of information have been appropriately cited and accompanied with a full list of references. Copyright Declaration ‘The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work.’ 2 Abstract In the lung, the fine balance between an appropriate immune response that defends against incoming pathogens while avoiding excessive inflammation leading to collateral tissue damage is dependent on appropriate and effective immune regulation. Lung disease can result in situations where the balance is tipped and excessive or inappropriate inflammation results in acute or chronic lung damage and impaired lung function. This is the case in non-CF bronchiectasis where enhanced inflammation and chronic lung infection are associated with irreversible tissue damage. Bronchiectasis is a pathological endpoint with several causes. It is often associated with chronic Pseudomonas aeruginosa infection and elevated levels of interleukin (IL)-8, a neutrophil chemoattractant, in bronchoalveolar lavage (BAL) and sputum. This thesis investigates the following hypotheses: 1) long-term exposure to high levels of IL-8 causes lung-remodeling and alters susceptibility to Pseudomonas aeruginosa infection; 2) individuals with bronchiectasis that are chronically infected with Pseudomonas aeruginosa have altered T cell immunity to the pathogen. To investigate the impact of long-term exposure to IL-8 on lung-remodelling and susceptibility to Pseudomonas, a transgenic model made by the Boyton lab was used. IL-8 transgenic mice show enhanced mucus secretion, lung fibrosis and remodelling with leaky tight junctions, but effectively clear Pseudomonas aeruginosa compared to controls. Differences in T cell immunity were tested in a cohort of patients with non-CF bronchiectasis, with or without Pseudomonas aeruginosa, to the outer membrane porin F (OprF) protein. A narrowed repertoire of T cell epitopes and different adaptive immune responses were observed in patients chronically infected with Pseudomonas aeruginosa. HLA-restricted OprF T cell epitopes were identified in HLA class II transgenics. The Boyton 3 lab has previously identified a genetic susceptibility to idiopathic bronchiectasis associated with the presence of the HLA-Cw*03. In this thesis, the association between HLA-Cw*03 and functional immunity was investigated. 4 Acknowledgements I wish to start by thanking my supervisor Dr. Rosemary Boyton for giving me the opportunity to carry out a PhD project and for all her support and advice that has helped me drive my project forward over the past four years. Several individuals have helped with a number of aspects of the work that went into this thesis. Many thanks must go to Dr. Michael Poidinger (Singapore Immunology Network) for help with the pathway analysis, Dr. Scott Brouilette for his time and advice on using Partek, Ruhena Sergeant of the HLA-typing facility (Hammersmith Hospital) for efficiently processing all patient samples and to Ivan Andrew at the CSC genomics laboratory, Imperial College for running the Affymetrix assay. A special thanks must go to Dr. Andrew Quigley and Dr. Rod Chalk at the University of Oxford for not only confirming my protein by mass spectrometry, but also for their guidance, help and willingness to discuss my ideas. In addition, thanks must be given to Chrysoula Panethymitaki and Bernadette Byrne for helping me in the initial stages of my protein work. I would also like to thank Dr. Stefan Worgall for providing the OprF plasmid. A thanks must also go to the CBS staff that maintained and looked after the transgenic lines. This project would not have been possible without the dedication of Catherine Hennessy and Dr. Michael Loebinger at the Royal Brompton Hospital for co-ordinating, recruiting and collecting blood samples for use in this project. I would also particularly like to thank all the patients that took part and donated blood. I am very grateful for all the help, support and time that Dr. Catherine Reynolds gave me throughout my time at Imperial, but also to her never failing encouragement and for putting 5 up with my constant questioning. I would also like to thank all past and present members of the Lung Immunology Group and Human Disease and Immunogenetics Group. In addition thanks go to the members of the 8th floor that have helped me along the way. I would particularly like to thank Debs, Cheryl, Julia, Janet, Jitin and Malcolm. Janet, you are my rock! Thanks are also extended to the MRC and Asthma UK Centre for the financial backing enabling me to do this PhD. A big big big thank you to all my friends and family, in particular my parents and those that were phoned every few days for a chat during my write up to keep me sane. Lastly I am indebted to Chris who lived this thesis almost as much as I did but also for his love, continuous support and motivation throughout. 6 Contents Page Declaration ........................................................................................................... 2 Copyright Declaration ........................................................................................ 2 Abstract ................................................................................................................ 3 Acknowledgements.............................................................................................. 5 Table of Tables .................................................................................................. 13 Table of Figures ................................................................................................. 15 CHAPTER 1: Introduction .............................................................................. 29 1.1. Interleukin 8................................................................................................................. 31 1.2. IL-8 receptors and signalling ..................................................................................... 35 1.3. Biological activity of IL-8 ........................................................................................... 37 1.4. Neutrophils ................................................................................................................... 40 1.5. Characteristics of airway remodelling and lung damage associated with chronic respiratory disease.............................................................................................................. 41 1.5.1. Mucus production ............................................................................................................... 42 1.5.2. Fibrosis ................................................................................................................................ 43 1.5.3. Smooth muscle .................................................................................................................... 46 1.6. Tight junctions and epithelial permeability in respiratory disease ........................ 47 1.7. hIL-8 transgenic model of chronic respiratory disease ........................................... 52 1.8. Chronic respiratory disease and infection ................................................................ 52 1.9. Pseudomonas aeruginosa............................................................................................. 53 1.9.1. The innate immune response to P. aeruginosa ................................................................... 58 1.9.2. The adaptive immune response to P. aeruginosa ............................................................... 62 1.10. Current treatment strategies for P. aeruginosa infections .................................... 65 1.11. Outer membrane porin F (OprF) ............................................................................ 68 1.12. T cells .......................................................................................................................... 70 1.12.1. T cell development ............................................................................................................ 71 1.12.2. Central and peripheral tolerance mechanisms ................................................................... 72 1.12.3. CD4+ T cell Subsets .......................................................................................................... 74 1.12.4. Th1 and Th2 cells .............................................................................................................. 74 1.12.5. CD4+ T cell populations ...................................................................................................
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