David A. Bergin

Coupling endoplasmic reticulum stress to neutrophil dysfunction in Alpha-1-Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic disorder that affects approximately one in 2000 individuals in Ireland. AATD is clinically associated with early-onset emphysema and severe hepatic disease. AAT is mainly produced in the liver and disease symptoms arise due to accumulation of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes. The most frequent mutation that causes severe AATD arises in the SERPINA 1 gene and gives rise to the Z-allele. The ‘Z' variant is responsible for >95% cases of AATD. Misfolded ZAAT is also expressed by cells of the lung and is a contributory factor to the lung inflammation experienced by those with AATD. Our preliminary data supports previous observations that circulating blood neutrophils express the AAT gene. As neutrophils play an important role in the pathological manifestations of AATD lung disease, the primary goal of this innovative project is to determine the functional importance of polymerization and ER localization of ZAAT in circulating neutrophils. Cytosolic free calcium (Ca2+) concentration, in circulating neutrophils is an important determinant of cellular activity. In resting neutrophils Ca2+ is low (approximately 100 nM), but in response to occupation of cell surface receptors, it rises to micromolar levels, thereby activating a variety of cellular functions. To date we have observed quantitative changes in AATD (ZZ) neutrophil function and have recorded enhanced NADPH-oxidase and migratory activity, indicative of a sub-activated cellular state. We believe these to be important results as increased chemotaxis and reactive oxygen species production can contribute to more rapid lung disease progression. As the ER functions as a Ca2+ storage organelle, we hypothesize that ER accumulation of misfolded ZAAT impacts upon Ca2+ regulation in circulating AATD (ZZ) neutrophils. Accordingly, the aim of this project is to evaluate whether efflux of Ca2+ from ZAAT-sensitive endoplasmic reticulum plays a role in the observed defective activation of AATD (ZZ) neutrophils.

Curriculum Vitae of David A. Bergin
Dr David Bergin has been a post-doctoral fellow at the Royal College of Surgeons at the Beaumont Hospital in Ireland since 2005. He has completed his PhD in Immunology and Microbiology at the University of Ireland in Maynooth. Dr Bergin has extensive experience in the field of alpha-1 antitrypsin and related serpins and has been a regular speaker on this topic at the meetings of the American Thoracic Society (ATS). In addition to other prizes, Dr Bergin was awarded the ATS' Genentech/Novartis Award in 2008.

Dr Bergin's research interests include proinflammatory properties of pulmonary proteases, regulation of inflammation and innate immunity in airway epithelium and neutrophil immune responses and NADPH oxidase activity. His research in these areas has resulted in a number of peer-reviewed publications. The primary goal of his eALTA project "Coupling endoplasmic reticulum stress to neutrophil dysfunction in alpha-1 antitrypsin deficiency" was to determine the functional importance of polymerisation and ER localisation of z-AAT in circulating neutrophils.

David A. Bergin, PhD
Respiratory Research Division
Department of Medicine
Royal College of Surgeons in Ireland
Education and Research Centre
Beaumont Hospital
Dublin 9