Novel Assays of Thrombogenic Pathogenicity in the Antiphospholipid Syndrome Based on the Detection of Molecular Oxidative Modification of the Major Autoantigen β2-Glycoprotein I

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Abstract

Objective

Beta-2-glycoprotein I (β ₂GPI) constitutes the major autoantigen in the antiphospholipid syndrome (APS), a common acquired cause of arterial and venous thrombosis. We recently described the novel observation that β ₂GPI may exist in healthy individuals in a free thiol (biochemically reduced) form. The present study was undertaken to quantify the levels of total, reduced, and posttranslationally modified oxidized β ₂GPI in APS patients compared to various control groups.

Methods

In a retrospective multicenter analysis, the proportion of β ₂GPI with free thiols in serum from healthy volunteers was quantified. Assays for measurement of reduced as well as total circulating β ₂GPI were developed and tested in the following groups: APS (with thrombosis) (n = 139), autoimmune disease with or without persistent antiphospholipid antibodies (aPL) but without APS (n = 188), vascular thrombosis without APS or aPL (n = 38), and healthy volunteers (n = 91).

Results

Total β ₂GPI was significantly elevated in patients with APS (median 216.2 μg/ml [interquartile range 173.3–263.8]) as compared to healthy subjects (median 178.4 μg/ml [interquartile range 149.4–227.5] [ P < 0.0002]) or control patients with autoimmune disease or vascular thrombosis (both P < 0.0001). The proportion of total β ₂GPI in an oxidized form (i.e., lacking free thiols) was significantly greater in the APS group than in each of the 3 control groups (all P < 0.0001).

Conclusion

This large retrospective multicenter study shows that posttranslational modification of β ₂GPI via thiol-exchange reactions is a highly specific phenomenon in the setting of APS thrombosis. Quantification of posttranslational modifications of β ₂GPI in conjunction with standard laboratory tests for APS may offer the potential to more accurately predict the risk of occurrence of a thrombotic event in the setting of APS.

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Most cited references 24

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Author and article information

Journal

Journal ID (nlm-ta): Arthritis Rheum

Journal ID (iso-abbrev): Arthritis Rheum

Journal ID (publisher-id): art

Title: Arthritis and Rheumatism

Publisher: Wiley Subscription Services, Inc., A Wiley Company (Hoboken )

ISSN (Print): 0004-3591

ISSN (Electronic): 1529-0131

Publication date (Print): September 2011

Volume: 63

Issue: 9

Pages: 2774-2782

Affiliations

[1 ]simpleSt. George Hospital and University of New South Wales Sydney, New South Wales, Australia

[2 ]simpleSt. George Hospital and University of New South Wales Sydney, New South Wales, Australia

[3 ]simpleSt. George Hospital and University of New South Wales Sydney, New South Wales, Australia

[4 ]simpleMetabolic Disease Hospital and Tianjin Medical University Tianjin, China

[5 ]simpleNational University of Athens Medical School Athens, Greece

[6 ]simpleUniversity College London London, UK

[7 ]simpleHokkaido University School of Medicine Sapporo, Japan

[8 ]simpleThe George Institute for Global Health and Sydney University Sydney, New South Wales, Australia

Author notes

Address correspondence to Bill Giannakopoulos, MBBS, PhD, FRACP, Departments of Immunology, Rheumatology, and Medicine, St. George Hospital, University of New South Wales, Gray Street, Kogarah 2217, Sydney, New South Wales, Australia (e-mail: bill.giannakopoulos@ 123456unsw.edu.au ); or to Steven A. Krilis, MBBS, PhD, FRACP, Department of Immunology, Allergy and Infectious Diseases, St. George Hospital, University of New South Wales, 2 South Street, Kogarah 2217, Sydney, New South Wales, Australia (e-mail: s.krilis@ 123456unsw.edu.au ).

Dr. Ioannou's work was supported by Arthritis Research UK (Clinician Scientist Fellowship award, grant 17821). Dr. Zhang's work was supported by Tianjin Medical University, Tianjin, China. Dr. Pericleous' work was supported by Arthritis Research UK (project grant 18491). Dr. Krilis' work was supported by grants from the National Health and Medical Research Council of Australia.

Drs. Giannakopoulos and Krilis contributed equally to this work.

Dr. Atsumi has received consulting fees, speaking fees, and/or honoraria from Mitsubishi Tanabe, Takeda, Pfizer, Bristol-Myers Squibb, Chugai, Eisai, Abbott Japan, and MBL (less than $10,000 each). Dr. Koike has received consulting fees, speaking fees, and/or honoraria from Abbott Immunology, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe, Takeda, Pfizer, and Eisai (less than $10,000 each).

Article

DOI: 10.1002/art.30383

PMC ID: 3328749

PubMed ID: 21618459

SO-VID: dd917fe8-3a38-4410-9075-0b1ecc1c25bb

License:

Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.