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dc.contributor.advisorHill, Adam
dc.contributor.advisorRossi, Adriano
dc.contributor.authorChalmers, James Duncan
dc.date.accessioned2018-10-16T11:37:46Z
dc.date.available2018-10-16T11:37:46Z
dc.date.issued2014-07-05
dc.identifier.urihttp://hdl.handle.net/1842/33117
dc.description.abstractBronchiectasis is a chronic inflammatory lung disease associated with failure of the normal mucociliary escalator, chronic bacterial colonisation of the airways, neutrophil mediated inflammation and a resulting clinical syndrome of respiratory infections, lung damage and symptoms such as cough, sputum production and shortness of breath. These are few effective treatments and the cause of bronchiectasis is unknown in the majority of patients. It is hypothesised that unrecognised immune defects may predispose to bronchiectasis or affect the severity of lung disease. Ficolin-2 is a circulating innate immune protein able to activate the lectin pathway of complement through interaction with mannose binding lectin associated serine protease-2. Through its structural and functional similarity to complement component C1q and mannose binding lectin, it is hypothesised that ficolin-2 may be involved in opsonophagocytosis of pathogens. A number of single nucleotide polymorphisms in the ficolin-2 gene have been described causing considerable variation in human ficolin-2 serum concentrations in healthy individuals. In this thesis, the role of the key lectin pathway components ficolin-2 and mannose binding lectin, are investigated in patients with bronchiectasis. We demonstrate a significant association between single nucleotide polymorphisms in the FCN2 gene and disease severity in bronchiectasis. Specifically, patients with low expressing FCN2 haplotypes have a higher frequency of chronic colonisation, colonisation with P. aeruginosa, more frequent exacerbations and worse health related quality of life. An association between MBL deficient genotypes and disease severity is also demonstrated suggesting an important role for the lectin pathway of complement in modifying disease severity in bronchiectasis. In-vitro studies identify that ficolin-2 is the major lectin pathway component responsible for complement activation on P. aeruginosa and that ficolin-2 binds to a wide range of clinically relevant pathogens. Neutrophils isolated from the sputum of patients with bronchiectasis showed significant alterations in surface receptor expression and function compared to peripheral blood neutrophils, with a novel effect of neutrophil elastase cleavage of CD88 contributing to reduced phagocytosis by airway neutrophils. Despite loss of phagocytic receptors from sputum neutrophils, opsonisation by ficolin-2/MASP-2 complexes still enhanced phagocytosis of P. aeruginosa by sputum neutrophils, suggesting that ficolin-2 may be relevant in the clearance of P. aeruginosa in the airway. In summary, ficolin-2 was found to be an important modifier of disease severity in bronchiectasis.en
dc.contributor.sponsorMedical Research Council (MRC)en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionChalmers JD, Hill AT. Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis. Molecular Immunology 2013; 55(1):27-34.en
dc.relation.hasversionChalmers JD, Fleming GB, Hill AT, Kilpatrick DC. Impact of mannose binding lectin (MBL) insufficiency on the course of cystic fibrosis: a review and metaanalysis. Glycobiology 2011;21(3):271-82.en
dc.relation.hasversionKilpatrick DC, Chalmers JD. Human L-ficolin (ficolin-2) and its clnical significance. J Biomed Biotechnol. 2012:2012:138797.en
dc.relation.hasversionChalmers JD, Smith MP, McHugh B, Doherty C, Govan JRW, Hill AT. Short and long term antibiotic therapy reduces airway and systemic inflammation in non-CF bronchiectasis. Am J Respir Crit Care Med. 2012; 186(7):657-65.en
dc.relation.hasversionChalmers JD, McHugh BJ, Doherty CJ, Govan JRW, Kilpatrick DC, Hill AT. Mannose binding lectin deficiency and disease severity in non-CF bronchiectasis: a prospective study. Lancet Respiratory Medicine; 1(3):175-274.en
dc.subjectbronchiectasisen
dc.subjectficolin-2en
dc.subjectMBLen
dc.titleLectin pathway of complement and bacterial colonisation in bronchiectasisen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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