Acute‐phase protein α1‐anti‐trypsin: diverting injurious innate and adaptive immune responses from non‐authentic threats. (February 2015)

• Record Type: Journal Article
• Authors: Guttman, O.; Baranovski, B. M.; Schuster, R.; Kaner, Z.; Freixo‐Lima, G. S.; Bahar, N.; Kalay, N.; Mizrahi, M. I.; Brami, I.; Ochayon, D. E.; Lewis, E. C.
• Is Part Of: Clinical and experimental immunology. Volume 179:Number 2(2015:Feb.)
• Page Start: 161
• Page End: 172
• Publication Date: 2015-02
• Subjects: Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12476
• Languages: English
• ISSNs: 0009-9104

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>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.</p> </abstract>