Autoantibodies to domain 1 of beta 2 glycoprotein 1: A promising candidate biomarker for risk management in antiphospholipid syndrome

doi:10.1016/j.autrev.2012.05.006

Autoimmunity Reviews

Volume 12, Issue 2, December 2012, Pages 313-317

https://doi.org/10.1016/j.autrev.2012.05.006 Get rights and content

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by frequent clotting in arteries and veins and/or miscarriages. Autoantibodies to phospholipids and to beta 2 glycoprotein 1 (β₂GP1) play an important role in the pathogenesis of APS. Antibodies to the domain 1 of β₂GP1 (β₂GP1-D1) have been suggested as a risk marker for thrombosis and to a lesser extent for pregnancy complications in patients suffering from APS. Despite significant interest in anti-β₂GP1-D1 antibodies and a considerable research history, the number of studies is still limited and acceptance of the clinical significance of this biomarker is still evolving. The present review summarizes the current knowledge of anti-β₂GP1-D1 antibodies and provides insights on recent discoveries. Moreover, we present a suggested guideline for future studies to better understand and verify the clinical utility of anti-β₂GP1-D1 antibodies.

Introduction

The creation of domain-specific recombinant beta 2 glycoprotein 1 (β₂GP1) molecules by Iverson et al. in 2002 [1] led to significant effort directed towards understanding the precise significance of autoantibodies to each of the 5 domains of β₂GP1. Domain 1 of beta 2 glycoprotein 1 (β₂GP1-D1) was identified as the primary target of autoantibodies for patients with antiphospholipid syndrome (APS) [2] and considerable research has since focused on the functional and clinical significance of anti-β₂GP1-D1 antibodies. Despite wide interest in the potential diagnostic value of anti-β₂GP1-D1 antibodies, the number of studies is still limited and acceptance of their potential clinical utility is still evolving [3]. The present review article summarizes the current knowledge of anti-β₂GP1-D1 antibodies (Table 1) and suggests a guideline for future studies.

Section snippets

Clinical picture of APS

APS, also known as the Hughes syndrome, is an autoimmune disorder which can cause frequent clotting in arteries and veins and/or miscarriages (see Fig. 1a) [4]. The clotting is caused by anti-phospholipid (commonly called aPL), anti-β₂GP1 or related autoantibodies which interfere with coagulation, leading to increased clot formation or thrombosis, or with placenta tissues affecting pregnancy [4]. In addition to thrombosis and pregnancy complications (early and late miscarriage, and

Biomarkers in APS

Antibodies to cardiolipin (CL) [9] and to β₂GP1 are a serological hallmark for the diagnosis of APS and are included in the classification criteria of the disease [10]. β₂GP1, (also called apolipoprotein H) is a 326 amino acid (aa) protein [11] synthesized by endothelial cells, hepatocytes, and trophoblast cells [12]. The protein consists of 5 homologous domains of approximately 60 aa each (see Fig. 1b) [1]. Domain 5, located at the C terminus, contains a hydrophobic core surrounded by 14

Classification criteria for APS

The classification of APS requires that at least 1 clinical criterion and 1 laboratory criterion be fulfilled (see Fig. 1a) [10]. The clinical criteria include vascular thrombosis (arterial or venous in any organ or tissue) and pregnancy morbidity (unexplained foetal death, premature birth, severe preeclampsia, or placental insufficiency). Other clinical manifestations often associated with APS are not included in the classification criteria. The laboratory classification criteria for APS

Epitope recognition patterns of anti-β₂GP1 antibodies

Several studies investigated the epitope distribution of anti-β₂GP1 antibodies using different approaches [21], [22]. The majority of the antibodies studied have been of the IgG isotype and have been reported to bind to epitopes located in β₂GP1-D1 [1], [23], D4, and D5 [21], [24]. IgA antibodies have also been detected and in addition to being present in some APS patients negative for APS-relavant IgG antibodies, they have been associated with cardiovascular disease and thrombotic events [25].

Detection of anti-β₂GP1-D1 antibodies

Although no commercial assays are currently available for the detection of anti-β₂GP1-D1 antibodies, several research methods have been described [3]. The majority of studies used a two-step approach using β₂GP1-D1 coated to hydrophobic and hydrophilic microtiter plates [3], [31], [32]. This method is based on the assumption that on hydrophilic plates, only the epitope of β₂GP1-D1 is exposed to the surface and thus accessible for autoantibody binding [31]. It has been demonstrated that about

Clinical association of anti-β₂GP1-D1 antibodies

Only a few studies have investigated the sero-clinical correlation of anti-β₂GP1-D1 antibodies [27], [31]. In an international multi-centre evaluation, a strong association between anti-β₂GP1-D1 antibodies and history of (mostly venous) thrombosis has been found [31]. To a lesser extent anti-β₂GP1-D1 antibodies were also associated with pregnancy complications [31]. Although the data presented by Bas De Laat et al. [31] are promising, part of the presented data are controversial. In his study,

Take-home messages

•
The hypothesis of anti-β₂GP1-D1 antibodies as promising biomarker in diagnosis / risk assessment of APS is scientifically sound, but needs further verification
•
Efforts are needed to standardize assays to detect β₂GP1-D1 antibodies
•
Prospective, multi-centric, longitudinal studies are necessary to clearly define the clinical utility of anti-β₂GP1-D1 antibodies

Competing interest

Michael Mahler and Gary L. Norman are employees of INOVA Diagnostics, Inc. Pier Luigi Meroni and Munther Khamashta have received consultant fees from INOVA Diagnostics.

Acknowledgements

We thank Roger Albesa, Navid Zohoury, and Zakera Shums for support with the immunoassays.

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ReviewAutoantibodies to domain 1 of beta 2 glycoprotein 1: A promising candidate biomarker for risk management in antiphospholipid syndrome

Abstract

Introduction

Section snippets

Clinical picture of APS

Biomarkers in APS

Classification criteria for APS

Epitope recognition patterns of anti-β2GP1 antibodies

Detection of anti-β2GP1-D1 antibodies

Clinical association of anti-β2GP1-D1 antibodies

Take-home messages

Competing interest

Acknowledgements

Lancet

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

J Thromb Haemost

J Thromb Haemost

J Thromb Haemost

J Thromb Haemost

Autoimmun Rev

Blood

J Autoimmun

Blood

J Thromb Haemost

J Autoimmun

Thromb Res

Clin Chim Acta

Blood

Autoimmun Rev

Autoimmun Rev

Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies

J Immunol

Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H)

Proc Natl Acad Sci U S A

Review
Autoantibodies to domain 1 of beta 2 glycoprotein 1: A promising candidate biomarker for risk management in antiphospholipid syndrome

Epitope recognition patterns of anti-β₂GP1 antibodies

Detection of anti-β₂GP1-D1 antibodies

Clinical association of anti-β₂GP1-D1 antibodies