Altered programmed cell death of neutrophils in individuals with alpha-1 antitrypsin deficiency

Alpha 1-antitrypsin (AAT) is a secretory protease inhibitor found in abundance within 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 restores the concentration of AAT in the blood and may slow down the course of lung disease. Neutrophils are the primary effector cells responsible for the pathological manifestations of AATD lung disease and therefore an important immune cell to study. Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defense and a safe turnover of these potentially harmful cells. Accelerated neutrophil apoptosis has been previously linked with liver cirrhosis and observed within sputum neutrophils of COPD patients. Within this proposal Killian hypothesizes that AAT directly impacts upon the half life of the circulating neutrophil and the goal of this innovative study is to demonstrate that circulating neutrophils of AATD individuals display accelerated apoptosis. In support of this theory data from his laboratory identified AAT as a membrane protein of circulating neutrophils, which quantitatively regulates the level of membrane bound CD16b. This is important as neutrophil apoptosis is associated with a marked down regulation of CD16b. Of major significance, circulating neutrophils of ZZ-AATD individuals present with low levels of membrane bound AAT and concomitantly reduced levels of CD16b. Moreover, their preliminary data has revealed increased expression of recognised markers of apoptosis in ZZ-AATD neutrophils, including caspase-3 cleavage and annexin-V membrane staining. The observed increased rate of neutrophil apoptosis could have significant inflammatory effects contributing to aberrant lung inflammation in AATD. This translational research proposal aims to fully characterise the anti-apoptotic effect of AAT on the circulating neutrophil and to study the implications for AATD with respect to neutrophil apoptosis. Potential patient benefits include evaluating whether AAT augmentation therapy corrects the accelerated rate of neutrophil apoptosis in ZZ-AATD individuals.

The specific aims of this study are threefold:

1. To perform a direct comparison of the rates of AATD and normal neutrophil apoptosis.

2. To uncover the extracellular and / or intracellular mechanism by which AAT modulates neutrophil cell death.
3. To investigate the effect of AAT augmentation therapy on accelerated neutrophil apoptosis 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 apoptosis will add a new understanding to the role of AAT in health and disease.

Killian completed in 2003 his degree in Medicine from the University College Dublin. After a series of internships he started to work on the field of respiratory medicine in 2006. He is currently a Research Fellow and holds a Clinical Lecturer post at the Royal college of Surgeons in Ireland.
Killian´s areas of research are translational research projects in Alpha-1 antitrypsin deficiency involving as well the impact of augmentation therapy in AATD patients. He also carries out basic research studying altered neutrophil apoptosis in Alpha-1 antitrypsin deficiency.
His eALTA research project "Altered programmed cell death of neutrophils in individuals with alpha-1 antitrypsin deficiency" focuses on comparing the rates of apoptosis in AATD and in normal neutrophils. It also uncovers the extracellular /  intracellular mechanism by which AAT modulates neutrophil cell death. Finally, Killian will investigate the effect of AAT augmentation therapy on accelerated neutrophil apoptosis of ZZ-AATD individuals.

Contact
Royal College of Surgeons in Ireland
Education and Research Centre
Beaumont Hospital
Dublin
Ireland