Circulating Truncated Alpha-1 Antitrypsin Glycoprotein in Patient Plasma Retains Anti-Inflammatory Capacity

• Published in: The Journal of immunology (1950) Vol. 202; no. 8; pp. 2240 - 2253
• Main Authors: Reeves, Emer P, Dunlea, Danielle M, McQuillan, Karen, O'Dwyer, Ciara A, Carroll, Tomás P, Saldova, Radka, Akepati, Prithvi Reddy, Wormald, Mark R, McElvaney, Oliver J, Shutchaidat, Vipatsorn, Henry, Michael, Meleady, Paula, Keenan, Joanne, Liberti, Derek C, Kotton, Darrell N, Rudd, Pauline M, Wilson, Andrew A, McElvaney, Noel G
• Format: Journal Article
• Language: English
• Published: United States AAI 15-04-2019
• Subjects: Adult; Alleles; alpha 1-Antitrypsin - blood; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - immunology; alpha 1-Antitrypsin Deficiency - blood; alpha 1-Antitrypsin Deficiency - genetics; alpha 1-Antitrypsin Deficiency - immunology; Codon, Nonsense; Female; Humans; Immune Regulation; Induced Pluripotent Stem Cells - immunology; Induced Pluripotent Stem Cells - metabolism; Liver - immunology; Liver - metabolism; Male
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1801045

Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune-regulatory and anti-inflammatory functions independent of antiprotease activity. AAT deficiency (AATD) is associated with early-onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed null or Q0), the majority of which arise from premature termination codons in the mRNA coding region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton allele (
) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0
-AAT. A low-abundance, truncated AAT protein was confirmed in plasma of a Q0
-AATD patient and was secreted by patient-derived induced pluripotent stem cell-hepatic cells. Functional assays confirmed the ability of purified Q0
-AAT protein to bind neutrophil elastase and to inhibit protease activity. Q0
-AAT bound IL-8 and leukotriene B
, comparable to healthy control M-AAT, and significantly decreased leukotriene B
-induced neutrophil adhesion (
= 0.04). Through a mechanism involving increased mRNA stability (
= 0.007), ataluren treatment of HEK-293 significantly increased
mRNA expression (
= 0.03) and Q0
-AAT truncated protein secretion (
= 0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0
-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.