Clinical relevance of nitrated beta 2-glycoprotein I in antiphospholipid syndrome: Implications for thrombosis risk

M Krilis; M Qi; Y Ioannou; J Y Zhang; Z Ahmadi; J W H Wong; P G Vlachoyiannopoulos; H M Moutsopoulos; T Koike; A D Sturgess; B H Chong; S A Krilis; B Giannakopoulos

doi:10.1016/j.jaut.2021.102675

Clinical relevance of nitrated beta 2-glycoprotein I in antiphospholipid syndrome: Implications for thrombosis risk

J Autoimmun. 2021 Aug:122:102675. doi: 10.1016/j.jaut.2021.102675. Epub 2021 Jun 5.

Authors

M Krilis¹, M Qi², Y Ioannou³, J Y Zhang⁴, Z Ahmadi⁵, J W H Wong⁶, P G Vlachoyiannopoulos⁷, H M Moutsopoulos⁸, T Koike⁹, A D Sturgess¹⁰, B H Chong¹¹, S A Krilis¹², B Giannakopoulos¹³

Affiliations

¹ Department of Infectious Disease, Immunology and Sexual Health, St George Hospital and Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia. Electronic address: matthewkrilis@gmail.com.
² Department of Infectious Disease, Immunology and Sexual Health, St George Hospital and Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia. Electronic address: fanmangren@hotmail.com.
³ Department of Infectious Disease, Immunology and Sexual Health, St George Hospital and Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia; Division of Medicine, Centre for Rheumatology Research, University College London, London, UK. Electronic address: j.ioannou@ich.ucl.ac.uk.
⁴ Department of Infectious Disease, Immunology and Sexual Health, St George Hospital and Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia. Electronic address: zhangjingyun7903@hotmail.com.
⁵ Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: z.ahmadi@unsw.edu.au.
⁶ Prince of Wales Clinical School and Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia. Electronic address: jason.wong@unsw.edu.au.
⁷ Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: pvlah@med.uoa.gr.
⁸ Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: hmoutsop@med.uoa.gr.
⁹ Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University School of Medicine, Sapporo, Japan. Electronic address: tkoike@med.hokudai.ac.jp.
¹⁰ Department of Rheumatology, St George Hospital, University of New South Wales, Sydney, NSW, Australia. Electronic address: allan.sturgess@health.nsw.gov.au.
¹¹ Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: beng.chong@unsw.edu.au.
¹² Department of Infectious Disease, Immunology and Sexual Health, St George Hospital and Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia. Electronic address: s.krilis@unsw.edu.au.
¹³ Department of Infectious Disease, Immunology and Sexual Health, St George Hospital and Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia; Department of Rheumatology, St George Hospital, University of New South Wales, Sydney, NSW, Australia. Electronic address: bill.giannakopoulos@unsw.edu.au.

PMID: 34098405
DOI: 10.1016/j.jaut.2021.102675

Abstract

Β₂-Glycoprotein I (β₂GPI) is an important anti-thrombotic protein and is the major auto-antigen in the antiphospholipid syndrome (APS). The clinical relevance of nitrosative stress in post translational modification of β₂GPI was examined.The effects of nitrated (n)β₂GPI on its anti-thrombotic properties and its plasma levels in primary and secondary APS were determined with appropriate clinical control groups. β2-glycoprotein I was nitrated at tyrosines 218, 275 and 309. β₂-glycoprotein I binds to lipid peroxidation modified products through Domains IV and V. Nitrated β₂GPI loses this binding (p < 0.05) and had diminished activity in inhibiting platelet adhesion to vWF under high shear flow (p < 0.01). Levels of nβ₂GPI were increased in patients with primary APS compared to patients with either secondary APS (p < 0.05), autoimmune disease without APS (p < 0.05) or non-autoimmune patients with arterial thrombosis (p < 0.01) and healthy individuals (p < 0.05).In conclusion tyrosine nitration of plasma β₂GPI is demonstrated and has important implications with regards to the pathophysiology of platelet mediated thrombosis in APS. Elevated plasma levels of nβ₂GPI in primary APS may be a risk factor for thrombosis warranting further investigation.

Keywords: Antiphospholipid syndrome; Nitration; Nitrosative stress; Post-translational modification; Thrombosis; βeta-2-glycoprotein I.

Publication types

Multicenter Study
Observational Study

MeSH terms

Antiphospholipid Syndrome / blood
Antiphospholipid Syndrome / complications*
Antiphospholipid Syndrome / immunology
Case-Control Studies
Healthy Volunteers
Humans
Lipid Peroxidation
Nitrates / metabolism
Platelet Aggregation / immunology
Protein Processing, Post-Translational / immunology
Risk Factors
Thrombosis / blood
Thrombosis / immunology*
beta 2-Glycoprotein I / blood
beta 2-Glycoprotein I / immunology*
beta 2-Glycoprotein I / metabolism

Substances

Nitrates
beta 2-Glycoprotein I