Glycosylation modifies the anti-inflammatory effect of alpha-1 antitrypsin

Alpha-1-antitryppsin (AAT) is an acute phase protein, demonstrated to increase within hours of inflammation or post-infection. Moreover, AAT has been shown to possess unique anti-inflammatory properties affecting several cell types and modulating inflammation caused by both host and microbial factors. Indeed, it is now accepted that AAT has a number of functions beyond protease inhibition highlighting the use of AAT augmentation therapy for a range of diseases other than AATD. AAT is post-translationally modified by glycosylation through the
addition of N glycosidically linked oligosaccharides.

No study has previously isolated individual glycoforms to address the fundamental question of whether specific glycoforms have distinct antiinflammatory properties.

Within this innovative project we hypothesize that during acute exacerbations and clinical recovery period, AAT activity differences may arise due to variable glycosylation occupancy.

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 in the circulation of people with AAT deficiency (AATD).

Aim:
Objective 1 To investigate the effect of inflammation on AAT glycoform production we will perform structural analysis of N glycans of AAT purified from healthy MM-donors compared to AAT from MM-individuals during acute episodes of inflammation.

Objective 2 To investigate whether inflammation affects the profile of ZZ AAT glycans and perform detailed structural analysis of N glycans of AAT purified from ZZ AATD donors during acute exacerbation and at recovery.

Objective 3 To determine whether AAT M0 and M2 glycoforms containing strongly fucosylated and sialyl Lewis x residues demonstrate increased antiinflammatory activity.

The long-term objective of this research proposal is to improve the quality of life for individuals with AATD. The significant effect that changes in glycosylation can have raises the question of whether different glycoforms of AAT can be considered for the development of new AAT augmentation products with specific anti-inflammatory properties

Curriculum Vitae Dr. Cormac McCarthy:

Cormac graduated with an honours degree in medicine from the Royal College of Surgeons in Ireland in 2007.

Since then he worked in the field of respiratory medicine for 7 years and gathered xperience in both clinical, laboratory and translational research.

Cormac is currently a specialist registrar training in respiratory medicine and he is in the process of completing a PhD in the field of medicine and glycobiology investigating the role and importance of glycosylation in alpha 1 antitrypsin.

His ALTA project "Glycosylation modifies the anti-inflammatory effect of alpha-1 antitrypsin" aims to 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. This will be done with both Z-AAT from individuals with AATD and M AAT from healthy donors.

Contact:
Dr. Cormac McCarthy
Respiratory Research Division, Department of Medicine
Royal College of Surgeons in Ireland
Education and Research Centre, Beaumont Hospital
Dublin, Ireland