Long-term exposure to cigarette smoke (CS) is the major risk factor in the development of chronic obstructive pulmonary disease (COPD). COPD, which includes chronic bronchitis and emphysema, is a major global health burden and morbidity and mortality are expected to expand in the next decades. Recent studies demonstrate oligoclonal expansions of T and B cells in emphysema patients, persistent oligoclonal CD4 T cell expansions following smoking cessation in a mouse model of COPD, and the presence of autoantibodies against lung components in COPD. Presently, it is unknown whether autoreactivity against pulmonary tissue contributes to disease pathogenesis. Given the limitations of associative clinical findings, the development of novel animal models to investigate autoimmune components in COPD is necessary to investigate the mechanisms whereby CS exposure leads to the development of autoreactivity. Our goal is to identify potential lung antigens and isolate autoreactive T cell clones in a mouse model of COPD. The CENTRAL HYPOTHESIS is that long-term exposure to CS induces aberrant expansions of T cells that are reactive against lung components which contribute to tissue destruction and pulmonary remodeling. This hypothesis is supported by preliminary evidence demonstrating i) excessive accumulation of IgG in the lungs of CS-exposed mice, ii) serum from CS- exposed mice recognizes unique antigens in naive lung, and iii) transfer of IgG from CS-exposed mice, leads to an emphysema-like pathology. We will achieve the objective of this proposal by pursuing two aims: 1) Identify relevant antigens that specifically react with IgG from CS-exposed mice. Using serum from CS-exposed mice, we will perform immunoprecipitation against lung antigens followed by 2D gel electrophoresis and mass spectroscopy analyses, and 2) Isolate autoreactive T cell clones that develop in response a mouse model of COPD. We will also generate T cell hybridomas and screen for reactivity against putative antigens. The concept of self-reactive T cells developing in response to CS exposure is supported by extensive preliminary data from our lab and a growing body of literature. Isolating these reagents will allow us to examine the expanded T cell populations in the lung and define their role in the development of pulmonary changes pathognomonic of COPD. Successful completion of this project will lead to novel reagents (novel T cell clones, autoreactive T cell receptor sequences, and putative antigens) which are critically needed to investigate the complex pathophysiology of COPD. A more complete understanding of autoreactive T cell effector function in COPD will open new frontiers into specific approaches towards therapeutic development in this devastating disease.
The proposed research is relevant to public health because it represents a fundamental shift in the investigation of immune function in the context of cigarette smoke exposure. The successful completion of this project is expected to lead to the development of novel reagents that are required to substantively advance the study of autoimmune mechanisms in the progression of disease. This contribution would decrease the morbidity and mortality, and enhance the quality of life in persons exposed to cigarette smoke.
|Hassett, Daniel J; Borchers, Michael T; Panos, Ralph J (2014) Chronic obstructive pulmonary disease (COPD): evaluation from clinical, immunological and bacterial pathogenesis perspectives. J Microbiol 52:211-26|
|Eppert, Bryan L; Wortham, Brian W; Flury, Jennifer L et al. (2013) Functional characterization of T cell populations in a mouse model of chronic obstructive pulmonary disease. J Immunol 190:1331-40|