Overall, the work presented in this thesis explored the impact of cigarette smoke on the immunopathogenesis of respiratory disease. This thesis highlighted the determinantal impact of cigarette smoke on (auto)antibody levels and pulmonary macrophage composition. Work completed by Steven P Cass 2016-2021. / Cigarette smoke is an insidious insult that is associated with a spectrum of respiratory diseases that range from cancer to obstructive diseases such as chronic obstructive pulmonary disease (COPD), to restrictive diseases such as idiopathic pulmonary fibrosis (IPF). In this thesis, we explore how cigarette smoke impacts immune components that contribute to respiratory disease.
To begin, we assessed the impact of cigarette smoke on airway antibody and autoantibody levels. We assessed sputum, a non-invasive method to sample the lower airways, to directly assess the presence of antibodies and autoantibodies in COPD. Total immunoglobulin M (IgM), IgG and IgA were detectable in the sputum of subjects. Notably, in patients with mild to moderate COPD, current smoking status was associated with decreased IgM and IgG. Next, using a comprehensive autoantigen array, we measured matched sputum and serum autoantibodies in 224 individuals. Serum autoantibodies were more abundant than sputum autoantibodies and correlated strongly between two independent COPD cohorts. Overall, the autoantibody profile of a patient with COPD was the same as a control subject. A proportion of autoantibody specificities were differentially expressed in patients with COPD with anti-tissue autoantibodies weakly associated with measures of emphysema. Taken together, these data suggested chronic cigarette smoke exposure was associated with limited differential expression of autoantibodies, but these changes were not a reliable method to identify COPD status.
In our third study, we assessed the impact of cigarette smoke exposure on the composition and function of pulmonary macrophage subpopulations. Macrophages perform a central role in respiratory host defence and are implicated in the pathobiology of several respiratory diseases. Using a mouse model of cigarette smoke exposure, we reported cigarette smoke-induced expansion of CD11b+ macrophage subpopulations including monocyte-derived alveolar macrophages and interstitial macrophages. The altered pulmonary macrophage composition following cigarette smoke exposure contributed to attenuated fibrogenesis in a model of bleomycin-induced lung injury. This study offered insight to pulmonary macrophage composition and function following cigarette smoke exposure.
This thesis summarises the original contributions and work completed during the course of this Ph.D., aimed at understanding the impact of cigarette smoke exposure on immune components central to respiratory disease. In conclusion, these findings shed light on the presence of (auto)antibodies in patients with COPD and the composition of macrophage subpopulations following cigarette smoke exposure. / Thesis / Doctor of Philosophy (PhD) / Currently there are 1.3 billion people who use tobacco across the world. The most common method to consume tobacco is by smoking cigarettes. Cigarette smoking is well-known to cause disease; however, smoking rates are still increasing with more daily cigarette smokers in 2012 than there were in 1980. In this thesis, we explore the impact of cigarette smoke upon the immune system. We first assessed whether cigarette smoking impacts the levels of antibodies, proteins that are produced by the immune system to protect against foreign bodies, in healthy individuals, cigarette smokers without disease and patients with chronic obstructive pulmonary disease (COPD). We found that current smokers had decreased antibodies in the airways, thus predisposing cigarette smokers to increased damage. In our second study, we measured the presence of airway and blood autoantibodies. These are antibodies that target self and have the potential to inflict damage. We discovered that patients with COPD had minor changes in autoantibodies and these changes were weakly associated with emphysema. In our third study, we evaluated the impact of cigarette smoke on lung macrophages, cells that eat and destroy foreign bodies, in a mouse model of cigarette smoke exposure. Cigarette smoke increased the number of bone marrow-derived macrophages and this change in macrophage populations was associated with a reduced wound healing ability. Overall, these studies offer insight into how cigarette smoke impairs the function of the immune system and contributes to lung disease.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26772 |
| Date | January 2021 |
| Creators | Cass, Steven P |
| Contributors | Stampfli, Martin, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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