The role of autoantibodies in fibrotic lung conditions
Autoimmunity in COPD was first hypothesised as early as 1976, when circulating antinuclear autoantibodies (ANAs) were demonstrated to be increased in patients with COPD. In COPD autoantibodies are mainly produced against extracellular matrix components, of which have been shown to correlate with disease severity. For example, autoantibodies produced against elastin, bronchial endothelial cells, as well as carbonylated proteins have each been documented in recent studies compared to healthy controls. Characteristics of some of these autoantibodies found in COPD are associated with disease manifestations, and have been demonstrated to mediate antibody-dependent cell cytotoxicity. In addition, immune complexes and in situ complement deposition have also been documented within severe disease, both of which are typically direct evidence of immune activation. Two main theories exist to explain the occurrence of autoantibodies in COPD. Emphysema results in fragments of extracellular matrix (ECM) proteins being released in to the circulation, as well as revealing normally hidden ECM moieties. Both have the ability to be immunogenic and are commonly referred to as cryptic antigens. Inflammation results in the production of oxidative chemicals which can oxidatively modify existing ECM (eg chlorinated or carbonylated proteins). These changes result in an altered tertiary structure, and as such also act as neo antigens. Collectively, it is increasingly likely that autoimmunity plays a role in the pathogenesis of COPD, but surprisingly we don’t know what autoantibodies are produced against.
We have developed a novel solid phase assay which allows us to detect and quantify autoantibodies in serum. Using this we have confirmed that there are increased autoantibodies to both Collagen V and K-alpha-1 tubulin in serum from patients with COPD including those with alpha-1 antitrypsin deficiency (fig 1).
In this project you will use proteomics techniques to profile the range of lung antigens that autoantibodies bind to in health and disease.
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