Elucidating the Role of Complement Activation in the Pathogenesis of Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) is characterised by low circulating levels of alpha-1 antitrypsin (AAT) and is associated with neutrophil-driven chronic obstructive pulmonary disease (COPD), liver disease and other autoimmune comorbidities including vasculitis and panniculitis. Complement C3 has recently been identified as a binding partner of AAT. The aim of this study was to evaluate the significance of the lack of this binding event in AATD.
A significant link between AATD manifestations and those which are reported to occur as a result of complement activation was observed, suggesting complement activation may represent a novel system involved in the pathogenesis of AATD. In line with this, C3d, a cleavage product of C3 produced during complement activation was increased in the plasma of AATD individuals. Increased NE activity on neutrophil membranes of AATD individuals was demonstrated to result in increased cleavage of neutrophil bound C3, leading to the production of C3d. CR2, the C3d receptor was confirmed to be present on neutrophils by a number of methods including FACs analysis, Western blotting, confocal microscopy and RT-PCR.
Increased C3d bound to CR2 on the ZZ-AATD neutrophil membrane resulted in increased release of primary, secondary and tertiary granules. C3d also induced the release of IL-8, a key neutrophil chemoattractant from HL-60 cells. C3d neutrophil membrane levels significantly correlated with FEV1(% predicted), providing evidence that complement activation aligns with the presence of obstructive pulmonary disease in AATD individuals. AAT augmentation therapy was demonstrated to augment AAT plasma levels, subsequently reducing C3d production and preventing this cycle of events.
In conclusion, this study presents a novel player in the pathogenesis of AATD and provides a novel mechanism of action for AAT augmentation therapy.
Alpha-1 Foundation Ireland
First SupervisorDr. Emer P. Reeves
Second SupervisorDr. Tomás P. Carroll
Third SupervisorProfessor Noel G. McElvaney
CommentsA thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2019.
Published CitationFee L. Elucidating the Role of Complement Activation in the Pathogenesis of Alpha-1 Antitrypsin Deficiency [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2019.
Degree NameDoctor of Philosophy (PhD)
Date of award30/11/2019
- Doctor of Philosophy (PhD)