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Adolescent, Adult, Autoantibodies, Autoimmunity, Cell Degranulation, Female, Humans, Lactoferrin, Male, Middle Aged, Neutrophils, Signal Transduction, Tumor Necrosis Factor-alpha, Young Adult, alpha 1-Antitrypsin


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.


The original article is available from the American Association for the Advancement of Science at (this is repository article


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.


Medicine and Health Sciences


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

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