Anti-microbial immune profiles in obstructive lung diseases

Jaat, Fathia (2017) Anti-microbial immune profiles in obstructive lung diseases. Doctoral thesis, Northumbria University.

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Abstract

Obstructive lung diseases are major causes of morbidity and mortality globally. The most common, chronic obstructive pulmonary disorder (COPD), is caused by smoke inhalation, whilst bronchiectasis (BR) is often caused by lung infection, and cystic fibrosis (CF) is due to the defective passage of fluids through lung epithelial cells. Whilst it is now recognised that the healthy lung harbours a microbial flora, obstructive lung diseases are characterised by periodic or persistent heavy bacterial colonization that can be determined using microbiological cultures of patient sputum as well as by novel genomic analysis, the most common species identified being Pseudomonas aeruginosa and Haemophilus influenzae. Adaptive immune responses generated against such organisms, in the form of antigen-specific antibodies and T cells, may be protective against infection but may also contribute to the inflammatory disease mechanism such as through IL-17-mediated neutrophil recruitment. This thesis asks whether such immune responses can serve as biomarkers of microbial colonization and of disease; whether levels of antibodies and T cells indicate lung infection and exacerbations frequency. However, high levels may simply indicate exposure to microbes. Thus, the aim of this study was to measure antibody and T cell responses against a range of lung-colonizing microbes in patients with BR (n=119), COPD (n=58), CF (n=30), asthma (n=14), and in healthy controls (n=28). Patients were clinically characterised in terms of exacerbations, lung function, sputum microbiology and underlying disease. Enzyme linked immunosorbent assays (ELISAs) were set up to measure specific antibodies in serum, whilst T cell responses in peripheral blood mononuclear cells (PBMCs) were measured by specific Enzyme-linked ImmunoSpot assay (ELIspot), flow cytometry and multiplex cytokine ELISA. Typical microbial colonization for the given disease was seen in the sputum-producing patients. The results showed that in BR, specific IgG responses against P. aeruginosa increased according to episodes of colonization, whilst T cell responses in the form of antigen-specific IFNY showed the opposite effect, suggesting T cell dysregulation. As well as IFNY, T cells were shown to secrete IL-17 and IL-22 in response to microbial antigens and to possess activation and homing receptors. Antibody responses were also further characterised for cross-reactivity and Ig isotype, confirming specificity and isotype switching. In CF patients that harboured P. aeruginosa, high anti-pseudomonas IgG titres were detected, and T cell IFNY responses were similar to healthy controls and were associated with greater disease stability and FEV1. In conclusion, immune responses were successfully characterised in patients with obstructive lung diseases, and specific antibody and T cells showed some associations with colonization and clinical disease, respectively, depending upon the disease and the microbe.

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