Dr. Michael Emmet O'Brien
Defective Neutrophil Degranulation in Individuals with Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin (AAT) is found in abundance in human plasma and is a major physiological inhibitor of a range of serine proteases. Within the lung it can protect the alveolar matrix from destruction by neutrophil elastase and thus maintains a protease-antiprotease balance.
AAT deficiency (AATD) is an autosomal co-dominant disease causing early-onset of emphysema and liver disease in affected individuals. This disorder is characterized by low plasma levels of AAT, resulting in the loss of natural anti-protease screen leading to the pathogenesis of early-onset emphysema. Specific treatment for AATD is available in the form of weekly intravenous injections of AAT. This is referred to as augmentation therapy and such treatment restores the concentration of AAT in the blood and may slow down the course of lung disease. Neutrophils are major effector cells responsible for the pathological manifestations of AATD lung disease and therefore an important immune cell to study. Neutrophils migrate from the bloodstream to sites of tissue inflammation in response to chemotactic signals and induce inflammation by undergoing receptor-mediated reactive oxygen species (ROS) production and degranulation. Degranulation of proteolytic enzymes from neutrophils has been implicated as a major causative factor in pulmonary disorders including severe exacerbations of AATD lung disease. Granule release from neutrophils depends on activation of intracellular signaling pathways involving the small GTPase Rab27a.
Within this proposal Emmet hypothesizes that AAT directly impacts upon the degranulation process of circulating neutrophils.
The goal of this innovative study is to demonstrate that circulating neutrophils of AATD individuals illustrate disproportionate levels of Rab27a activation leading to increased degranulation of granule components. In support of our proposal, preliminary data has clearly demonstrated that AATD patients homozygous for the Z-allele have increased plasma levels of neutrophil released secondary and tertiary granule proteins. This is an extremely important result as the incidence of auto-antibodies directed against lactoferrin, a component of secondary granules, is increased in ZZ-AATD, leading to an enhanced rate of neutrophil ROS production.
This translational research proposal aims to fully characterize the anti-degranulation effect of AAT on the circulating neutrophil. Potential patient benefits include an investigation into whether AAT augmentation therapy corrects the accelerated rate of Rab27a activation and neutrophil degranulation in ZZ-AATD individuals.
The specific aims of this study are threefold:
- To perform a direct comparison of the rates of Rab27a activation in AATD and healthy control neutrophils.
- To uncover the extracellular and / or intracellular mechanism by which AAT modulates neutrophil Rab27a activation.
- To investigate the effect of AAT augmentation therapy on accelerated neutrophil degranulation and Rab27a activation of ZZ-AATD individuals.
The long-term objective of this research is to develop the means to control lung disease associated with AATD. The potential ramifications of AAT as a modulator of neutrophil degranulation will add a new understanding to the role of AAT in health and disease
Curriculum Vitae of Dr. O´Brien
Emmet graduated from the National University of Ireland, Cork in 2006 with a First Class Honours degree in Medicine.
His current position is of Clinical Lecturer & Respiratory Research Specialist at the Royal College of Surgeons in Ireland.
Emmet´s research project "Defective Neutrophil Degranulation in Individuals with Alpha-1 Antitrypsin Deficiency" explores defective neutrophil degranulation in individuals with AAT deficiency. Furthermore he aims to fully characterize the anti-degranulation effect of alpha1 antitrypsin AAT on the circulating neutrophils.
Emmet thus hopes to demonstrate that the neutrophils of AAT deficient individuals have disproportionate levels of activation, resulting in an increase of proteolytic enzymes that have been implicated as a major causative factor in pulmonary disorders that may present as severe exacerbations.
Royal College of Surgeons in Ireland
Respiratory Research Division, Education & Research Centre