Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency
Introduction: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy.
Methods: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5).
Results: Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001).
Discussion: Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD.
The US Alpha-1 Foundation
Medical Research Charities Group/Health Research Board Ireland
European Alpha-1-Antitrypsin Laurell’s Training Award, sponsored by Grifols Inc.
3U Biomedical Research (DCU-NUI Maynooth-RCSI)
Beaumont Hospital Foundation, Dublin, Ireland
Programme for Research in Third Level Institutes (PRTLI) administered by the Higher Education Authority
CommentsThe original article is available at https://thorax.bmj.com
Published CitationO'Brien ME. et al. Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency. Thorax. 2020;75(4):321-330.
Publication Date20 January 2020
- Beaumont Hospital
- Immunity, Infection and Inflammation
- Respiratory Medicine
- Population Health and Health Services
- Published Version (Version of Record)