title: The circulating proteinase inhibitor α-1 antitrypsin regulates neutrophil degranulation and autoimmunity.
abstract: 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.
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: David A
authors.initials: DA
authors.lastname: Bergin
authors.forename: Emer P
authors.initials: EP
authors.lastname: Reeves
authors.forename: Killian
authors.initials: K
authors.lastname: Hurley
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wolfe
authors.forename: Ramia
authors.initials: R
authors.lastname: Jameel
authors.forename: Sean
authors.initials: S
authors.lastname: Fitzgerald
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000502:physiology*; D015550:Cell Degranulation / Q000502:physiology*; D005260:Female; D006801:Humans; D007781:Lactoferrin / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000097:blood* / Q000502:physiology
chemical_list: D001323:Autoantibodies; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D007781:Lactoferrin