Altered lipid raft cholesterol content contributes to the dysregulated activity of neutrophils in alpha-1 antitrypsin deficiency

Alpha-1-antitrypsin (AAT) deficiency (AATD) is largely unrecognized and under diagnosed. This hereditary disorder results in the rapid progression of lung disease, especially in smokers. Specific treatment for this disorder is available in the form of weekly intravenous injections of AAT. This is referred to as augmentation therapy and studies have shown that augmentation therapy restores the concentration of AAT in the blood and slows down the course of lung disease and leads to reduced exacerbation and lung infections.
White blood cells called neutrophils are the primary cells responsible for the development of AATD lung disease and for this reason they are an important cell to study. The question that this innovative study will address is; are neutrophils circulating in the blood stream of AATD individuals structurally and functionally altered thereby exposing AATD individuals to increased bacterial infections?
The principle investigator and co-applicants of this proposal have an excellent track record in medical based research and have published widely in the areas of AATD and lung inflammation. Now the focus of their research is to investigate impaired structure and function of neutrophils in AATD as a result of lack of circulating AAT.
Our central hypothesis is that systemic inflammation in individuals with AATD triggers major changes in the structure of the circulating neutrophil involving reduced cholesterol content and disruption of specialized signalling regions on the neutrophil plasma membrane called lipid-rafts. This is very important as lipid rafts determine the bacterial killing ability of neutrophils. The long-term objective of this research proposal is to improve the quality of life for individuals with AATD. This innovative study will focus on the clinical relevance of AAT augmentation therapy. With respect to assigning an AAT anti-inflammatory role, this project aims to challenge the hypothesis that infused AAT in AATD individuals effectively corrects neutrophil lipid raft structure thereby improving the bacterial killing ability of this important immune cell.

Award Date

19 June 2014

Award Value

€138,000

Principal Investigator

Ms Kitty O'Connor

Host Institution

Alpha One Foundation

Scheme

MRCG-HRB Joint Funding Scheme