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Michael E O'Brien



novel the immune response disease progression medicine and health sciences anti inflammatory inflammation alpha 1 antitrypsin deficiency alpha 1 binding protein 1

The influence of novel alpha-1 antitrypsin protein binding partners on inflammation and the clinical phenotype in alpha-1 antitrypsin deficiency (2016)

Abstract 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PhD theses
Ireland -> Royal College of Surgeons in Ireland -> Theses and Dissertations

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Michael E O'Brien

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M Emmet O'Brien
Royal College of Surgeons in Ireland
Total Publications: 9