The circulating proteinase inhibitor ?-1 antitrypsin regulates ne.pdf (1.98 MB)

The circulating proteinase inhibitor α-1 antitrypsin regulates neutrophil degranulation and autoimmunity.

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journal contribution
posted on 22.11.2019, 16:33 by David A. Bergin, Emer P. Reeves, Killian Hurley, Rebecca Wolfe, Ramia Jameel, Sean Fitzgerald, Noel G. McElvaney

Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-α (TNF-α) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum α-1 antitrypsin (AAT) to control TNF-α biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-α-related disease. In vitro studies demonstrate that serum AAT coordinates TNF-α intracellular signaling and neutrophil degranulation of tertiary and secondary granules via modulation of ligand-receptor interactions. AATD patients homozygous for the Z allele were characterized by increased activation of the TNF-α system, as demonstrated by increased membrane TNF-α levels and increased plasma concentrations of TNF receptor 1 and neutrophil-released secondary and tertiary granule proteins. The incidence of autoantibodies directed against degranulated lactoferrin and surface protein accessible to these antibodies was increased in ZZ-AATD, leading to an enhanced rate of neutrophil reactive oxygen species production. Treatment of ZZ-AATD individuals with AAT augmentation therapy resulted in decreased membrane TNF-α expression and plasma levels of granule antigenic proteins and immunoglobulin G class autoantibodies. These results provide a mechanism by which AAT augmentation therapy affects TNF-α signaling in the circulating neutrophil, indicating promising potential of this therapy for other TNF-α-related diseases.

Funding

US Alpha One Foundation, the Medical Research Charities Group/Health Research Board Ireland, the European Alpha-1-Antitrypsin Laurell’s Training Award and the Program for Research in Third Level Institutes (PRTLI) administered by the Higher Education Authority.

History

Comments

The original article is available from the American Association for the Advancement of Science at http://stm.sciencemag.org/content/6/217/217ra1.long (this is repository article http://epubs.rcsi.ie/medart/48/)

Published Citation

Bergin DA, Reeves EP, Hurley K, Wolfe R, Jameel R, Fitzgerald S, McElvaney NG. The circulating proteinase inhibitor alpha-1 antitrypsin regulates neutrophil degranulation and autoimmunity. Sci Transl Med. 2014;6(217):217ra1

Publication Date

01/01/2014

Publisher

American Association for the Advancement of Science

PubMed ID

24382893

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