Date of Award


Document type


Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Emer P. Reeves

Second Supervisor

Professor Noel G McElvaney




Alpha 1 - Antitrypsin Deficiency, Alpha 1 - Binding Protein 1, Inflammation


The findings of this thesis demonstrate that individuals with alpha-1 antitrypsin deficiency (AATD) and a more severe clinical phenotype, characterized by worsening pulmonary emphysema, have evidence of persistent inflammation despite clinical stability. The binding of alpha-1 antitrypsin (AAT) to proteins of various systems in the circulation is an important mechanism through which AAT mediates its anti-inflammatory properties. A key finding of this thesis is that AAT binds to complement component C3 and can prevent its dysregulated cleavage by neutrophil-derived proteases, in particular NE. Complement activation may be one mechanism through which the perpetuation of inflammation is mediated in AATD through an axis of neutrophil recruitment and activation, protease release, complement degradation, generation of chemotactic complement peptides, and consequently further neutrophilic inflammation.

The discovery of a relationship between the observed clinical phenotype in AATD individuals, homozygous for the Z-allele, and complement activation implicates this pathophysiological process in pulmonary disease progression. The ratio of the complement cleavage product C3d to total C3 may also serve as a biomarker of pulmonary disease severity. Furthermore, the role of C3d as an innate immune adjuvant to the adaptive immune response cannot be overlooked. This bridge between innate and adaptive immunity has implications for the pathogenesis of pulmonary emphysema, a mechanism that warrants further investigation in the future.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

30.5 MB


A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2016.