Post-translational modifications modify the anti-inflammatory effect of alpha-1 antitrypsin

Lead Researcher:

Dr Emer Reeves

Award Date:

1 January 2013

Host Institution:

Alpha One Foundation

Scheme:

Medical Research Charities Group Co-Fund Award

Summary:

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.
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. The team have invested significant effort into understanding how different molecules and proteins, capable of inducing an immune response, contribute to development of lung disease in AATD. Recently published work from the laboratory has shown that AAT can lessen the potentially harmful effects of a molecule called interleukin-8 (IL-8). This effect of AAT on IL-8 suggested that AAT may regulate the activity of a number of other immune molecules. To validate this theory, compelling new data from the laboratory showed that AAT blocks a second immune molecule called TNF-alpha. Most excitingly, these studies have also demonstrated that AAT can modulate the activity of an enzyme called ADAM-17, which is a key decision maker for immune cell function within the airways. This protective effect of AAT is beneficial as it has been established that IL-8, TNF-alpha and ADAM-17 play an important role in the development and progression of lung disease.
Now the focus of this research turns to investigating the ability of different forms of AAT to control the activity of immune molecules. What does this mean? Well, when AAT is produced by liver cells a variety of sugars are attached to the core protein. The process of adding sugars to AAT is called glycosylation. This results in the formation of nine different forms of AAT, depending on what type of sugar is attached and also how much is attached. These different sugar coated forms of AAT are referred to as glycoforms. The fundamental question that Dr Reeves and the Respiratory Team asked was "why does AAT exist in nine different glycoforms?" As AAT is an acute-phase protein, which is a protein whose plasma concentrations increase in response to infection and inflammation, we hypothesize that different glycoforms of AAT are produced by the liver to dampen down the immune response and to promote clearance of inflammation.
In support of our theory we discovered that plasma from individuals during acute inflammation illustrated significantly enhanced levels of two glycoforms of AAT (referred to as M0 and M1) which were not apparent in healthy control samples. So why is this important? We believe these results to be very important and suggest that M0/M1 glycoforms of AAT are more heavily glycosylated and loaded with sugars and is therefore more efficient in preventing activity of inflammatory molecules such as IL-8 and TNF-alpha. We propose that specific glycoforms of AAT may function to protect the body by supporting clearance of inflammation and preventing tissue damage caused by excessive inflammation. These glycoforms may also be present on the Z-AAT protein present in the circulation of people with AATD. The research of the present study will compare the anti-inflammatory effect of different glycoforms of AAT, so that a more complete picture can be made of the effects that AAT has in the body. Such studies have not been performed to date, and therefore the overall aim of this study is to purify the different glycoforms of AAT to allow us to investigate their individual anti-inflammatory properties for the first time. This will be done with both Z-AAT from individuals with AATD and M-AAT from healthy donors.
The long-term objective of this research proposal is to improve the quality of life for individuals with AATD. We will strive to create a better future for AATD patients by establishing a clear biochemical understanding of the anti-inflammatory effect of different glycoforms of AAT. The significant effect that changes in glycosylation can have raises the question of whether different glycoforms of AAT can be considered for the manufacture of a new AAT augmentation product with specific anti-inflammatory properties.