title: Acute-phase protein α1-anti-trypsin: diverting injurious innate and adaptive immune responses from non-authentic threats.
abstract: One would assume that the anti-inflammatory activity of α1-anti-trypsin (AAT) is the result of inhibiting neutrophil enzymes. However, AAT exhibits tolerogenic activities that are difficult to explain by serine-protease inhibition or by reduced inflammatory parameters. Targets outside the serine-protease family have been identified, supporting the notion that elastase inhibition, the only functional factory release criteria for clinical-grade AAT, is over-emphasized. Non-obvious developments in the understanding of AAT biology disqualify it from being a straightforward anti-inflammatory agent: AAT does not block dendritic cell activities, nor does it promote viral and tumour susceptibilities, stunt B lymphocyte responses or render treated patients susceptible to infections; accordingly, outcomes of elevated AAT do not overlap those attained by immunosuppression. Aside from the acute-phase response, AAT rises during the third trimester of pregnancy and also in advanced age. At the molecular level, AAT docks onto cholesterol-rich lipid-rafts and circulating lipid particles, directly binds interleukin (IL)-8, ADAM metallopeptidase domain 17 (ADAM17) and danger-associated molecular pattern (DAMP) molecules, and its activity is lost to smoke, high glucose levels and bacterial proteases, introducing a novel entity - 'relative AAT deficiency'. Unlike immunosuppression, AAT appears to help the immune system to distinguish between desired responses against authentic threats, and unwanted responses fuelled by a positive feedback loop perpetuated by, and at the expense of, inflamed injured innocent bystander cells. With a remarkable clinical safety record, AAT treatment is currently tested in clinical trials for its potential benefit in a variety of categorically distinct pathologies that share at least one common driving force: cell injury.
authors.affiliation: Ben-Gurion University of the Negev, Faculty of Health Sciences, Department of Clinical Biochemistry and Pharmacology, Beer-Sheva, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Guttman
authors.forename: B M
authors.initials: BM
authors.lastname: Baranovski
authors.forename: R
authors.initials: R
authors.lastname: Schuster
authors.forename: Z
authors.initials: Z
authors.lastname: Kaner
authors.forename: G S
authors.initials: GS
authors.lastname: Freixo-Lima
authors.forename: N
authors.initials: N
authors.lastname: Bahar
authors.forename: N
authors.initials: N
authors.lastname: Kalay
authors.forename: M I
authors.initials: MI
authors.lastname: Mizrahi
authors.forename: I
authors.initials: I
authors.lastname: Brami
authors.forename: D E
authors.initials: DE
authors.lastname: Ochayon
authors.forename: E C
authors.initials: EC
authors.lastname: Lewis
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D000072198:ADAM17 Protein; D056704:Adaptive Immunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007113:Immunity, Innate; D007165:Immunosuppression Therapy / Q000379:methods*; D011247:Pregnancy; D000515:alpha 1-Antitrypsin / Q000276:immunology / Q000627:therapeutic use*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: acute-phase proteins; diabetes; transplantation