The Significance of Antibodies against Domain I of Beta-2 Glycoprotein I in Antiphospholipid Syndrome

AbstractThe antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Progress is being made in understanding the pathogenesis of the syndrome, but difficulties persist in the identification of patients at risk for thrombosis and/or pregnancy morbidity. Beta-2 glycoprotein I (β2GPI), a plasma protein consisting of five sushi domains, is thought to be the main antigenic target of aPLs. Antibodies recognizing domain I of β2GPI are predominantly present in patients with an elevated risk of thrombosis, whereas antidomain IV/V antibodies are found in nonthrombotic autoimmune diseases. Indeed, domain I antibodies proved to be pathogenic in multiple studies. Retrospective studies have provided evidence for an added clinical value of antidomain I antibodies in the risk stratification of patients with APS. Still, wide ranges of odds ratio exist between studies, probably due to differences in the study and control population, and detection methods used. Despite the proven pathogenicity of antidomain I antibodies and their correlations with clinical manifestations of APS, heterogeneity of the current studies has prohibited their acceptance in the official diagnostic criteria. Well-designed large longitudinal prospective studies with available and new, preferentially functional, assays for the risk stratification of patients with APS are required.

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Is There an Additional Value in Detecting Anticardiolipin and Anti-β2 glycoprotein I IgA Antibodies in the Antiphospholipid Syndrome?

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714653 ◽

2020 ◽

Vol 120 (11) ◽

pp. 1557-1568

Author(s):

Walid Chayoua ◽

Dong-mei Yin ◽

Hilde Kelchtermans ◽

Gary W. Moore ◽

Jean-Christophe Gris ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Immunoglobulin A ◽

Clinical Manifestations ◽

Pregnancy Morbidity ◽

Medical Centers ◽

Glycoprotein I ◽

Iga Antibodies ◽

Obstetric Aps ◽

Current Criterion ◽

Additional Value

Abstract Background Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin A (IgA) antiphospholipid antibodies (aPL) have shown to associate with thrombosis and pregnancy morbidity. However, inclusion of IgA aPL in the classification criteria of the antiphospholipid syndrome (APS) has been debated. We investigated the value of aCL and aβ2GPI IgA aPL in the detection of thrombosis and pregnancy morbidity in addition to the current aPL panel for APS. Methods We included 1,068 patients from eight European medical centers: 259 thrombotic APS patients, 122 obstetric APS patients, 204 non-APS thrombosis patients, 33 non-APS obstetric patients, 60 APS patients with unspecified clinical manifestations, 196 patients with autoimmune diseases, and 194 controls. aCL and aβ2GPI IgG/M/A were detected with four commercial assays and lupus anticoagulant was determined by the local center. Results Positivity for IgA aPL was found in 17 to 26% of the patients with clinical manifestations of APS and in 6 to 13% of the control population. Both aCL and aβ2GPI IgA were significantly associated with thrombosis and pregnancy morbidity. Isolated IgA positivity was rare in patients with clinical manifestations of APS (0.3–5%) and not associated with thrombosis and/or pregnancy morbidity. Addition of IgA to the current criterion panel did not increase odds ratios for thrombosis nor pregnancy morbidity. Conclusion aCL and aβ2GPI IgA are associated with clinical manifestations of APS. However, isolated IgA positivity was rare and not associated with thrombosis or pregnancy morbidity. These data do not support testing for aCL and aβ2GPI IgA subsequent to conventional aPL assays in identifying patients with thrombosis or pregnancy morbidity.

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Pathophysiological insights into the antiphospholipid syndrome

Hämostaseologie ◽

10.5482/hamo-16-07-0020 ◽

2017 ◽

Vol 37 (03) ◽

pp. 202-207 ◽

Cited By ~ 1

Author(s):

Davit Manukyan ◽

Nadine Müller-Calleja ◽

Karl Lackner

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Manifestations ◽

Future Research ◽

Scientific Debate ◽

Pregnancy Morbidity ◽

Anionic Phospholipids ◽

The Third ◽

Glycoprotein I ◽

Underlying Mechanisms

SummaryThe antiphospholipid syndrome (APS) is characterized by venous and/or arterial thrombosis and severe pregnancy morbidity in presence of antiphospholipid antibodies (aPL). While there is compelling evidence that aPL cause the clinical manifestations of APS, the underlying mechanisms are still a matter of scientific debate. This is mainly related to the broad heterogeneity of aPL. There are three major types of aPL: The first one binds to (anionic) phospholipids, e.g. cardiolipin, in absence of other factors (cofactor independent aPL). The second type binds to phospholipids only in presence of protein cofactors, e.g. ß2-glycoprotein I (ß2GPI) (cofactor dependent aPL). The third type binds to cofactor proteins directly without need for phospholipids. It is widely believed that cofactor independent aPL (type 1) are associated with infections and, more importantly, non-pathogenic, while pathogenic aPL belong to the second and in particular to the third type. This view, in particular with regard to type 1 aPL, has not been undisputed and novel research data have shown that it is in fact untenable. We summarize the available data on the pathogenetic role of aPL and the implications for diagnosis of APS and future research.

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The clinical value of assays detecting antibodies against domain I of β2-glycoprotein I in the antiphospholipid syndrome

Autoimmunity Reviews ◽

10.1016/j.autrev.2018.06.011 ◽

2018 ◽

Vol 17 (12) ◽

pp. 1210-1218 ◽

Cited By ~ 12

Author(s):

Dongmei Yin ◽

Bas de Laat ◽

Katrien M.J. Devreese ◽

Hilde Kelchtermans

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Value ◽

Glycoprotein I ◽

Domain I

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IgG Autoantibodies againstβ2-Glycoprotein I Complexed with a Lipid Ligand Derived from Oxidized Low-Density Lipoprotein are Associated with Arterial Thrombosis in Antiphospholipid Syndrome

Clinical and Developmental Immunology ◽

10.1080/10446670310001642113 ◽

2003 ◽

Vol 10 (2-4) ◽

pp. 203-211 ◽

Cited By ~ 40

Author(s):

Daniel Lopez ◽

Kazuko Kobayashi ◽

Joan T. Merrill ◽

E. Matsuura ◽

Luis R. Lopez

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Syndrome ◽

Arterial Thrombosis ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Clinical Manifestations ◽

Density Lipoprotein ◽

Healthy Individuals ◽

Pregnancy Morbidity ◽

Glycoprotein I

We recently reported [J. Lipid Res.42(2001), 697;43(2002), 1486;44(2003), 716] thatβ2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship ofβ2GPI/oxLDL complexes and IgG autoantibodies againstβ2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. Theβ2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-β2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation withβ2GPI in SLE and APS patients. In contrast, anti-β2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies againstβ2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

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AB0619 Isotypes of Anti-Beta 2- Glycoprotein I in Systemic Lupus Erythematosus Patients: Correlation with Clinical Manifestations, Laboratory Features and Association with Antiphospholipid Syndrome

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-eular.6396 ◽

2015 ◽

Vol 74 (Suppl 2) ◽

pp. 1106.2-1106

Author(s):

D. Attia ◽

T.A. Gheita ◽

A. El Awar ◽

A. Abd Alaal ◽

M. Ayoub

Keyword(s):

Systemic Lupus Erythematosus ◽

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Clinical Manifestations ◽

Systemic Lupus ◽

Glycoprotein I ◽

Laboratory Features ◽

Beta 2

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Current Promising Biomarkers and Methods in the Diagnostics of Antiphospholipid Syndrome: A Review

Biomedicines ◽

10.3390/biomedicines9020166 ◽

2021 ◽

Vol 9 (2) ◽

pp. 166

Author(s):

Pavla Bradacova ◽

Ludek Slavik ◽

Jana Ulehlova ◽

Adela Skoumalova ◽

Jana Ullrychova ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Lupus Anticoagulant ◽

Wide Spectrum ◽

Clinical Manifestations ◽

Annexin V ◽

Protein S ◽

Point Of View ◽

Laboratory Diagnostics ◽

Glycoprotein I ◽

Domain I

Antiphospholipid syndrome (APS) is a hypercoagulation condition associated with the incidence of heterogenic antiphospholipid antibodies (aPLs), which non-specifically affect hemostasis processes. APS is clinically manifested by recurrent arterial and venous thromboses and reproduction losses. The aPL antibodies, which may induce clinical manifestations of APS, include criteria antibodies anti-cardiolipin, anti-β2-glycoprotein-I, and lupus anticoagulant, but also non-criteria antibodies, for example anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-annexin V, and many others. APS occurs mostly in patients of younger and middle age, most frequently in females. Laboratory diagnostics of APS are quite difficult, as they include a wide spectrum of examining methods, which are based on various principles of detection and are performed using various laboratory techniques. The objective of the review is to describe the current state of potentially examined biomarkers and methods in APS diagnostics. The aforementioned biomarkers are lupus anticoagulant, anti-β2-glycoprotein-I, anti-cardiolipin, anti-β2-glycoprotein-I domain I, anti-phosphatidylserine/prothrombin, anti-β2-glycoprotein-I IgA, anti-cardiolipin IgA, anti-annexin V and II, anti-prothrombin, anti-cardiolipin/vimentin, anti-protein S/protein C, and antibodies against phospholipid antigens for whose diagnostics we may use some of the methods established for a long time and some of the modern methods—the coagulation method for the determination of lupus anticoagulant (LA), enzyme-linked imunosorbent assay (ELISA), chemiluminescence analysis (CLIA), multiplex fluorescence flow immunoassay (MFFIA), fluorescence enzyme immunoassay (EliA), line immunoassay (LIA), multiline dot assay (MLDA), and thin-layer chromatography (TLC). Conclusion: Antibodies against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, cardiolipin/vimentin complex, and annexin V are currently the most studied new markers. However, these assays have not been standardized until now, both from the laboratory and clinical point of view. In this review we summarize the evidence of the most studied aPL markers and their potential clinical significance in seronegative APS (SN-APS).

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PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome

Frontiers in Immunology ◽

10.3389/fimmu.2018.02413 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Thomas C. R. McDonnell ◽

Rohan Willis ◽

Charis Pericleous ◽

Vera M. Ripoll ◽

Ian P. Giles ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Glycoprotein I ◽

Beta 2 ◽

Domain I

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Challenges in the Diagnosis of the Antiphospholipid Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2009.133678 ◽

2010 ◽

Vol 56 (6) ◽

pp. 930-940 ◽

Cited By ~ 55

Author(s):

Katrien Devreese ◽

Marc F Hoylaerts

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Complex Disease ◽

Clinical Manifestations ◽

Clinical Role ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Coagulation Tests

Abstract Background: The antiphospholipid syndrome (APS) is an important cause of acquired thromboembolic complications and pregnancy morbidity. Its diagnosis is based on clinical and laboratory criteria, defined by strict guidelines. The original clinical and laboratory criteria for the identification of APS patients were published in 1999, in the so-called Sapporo criteria. In 2006 these criteria were revised, and recently more precise guidelines for analysis of the lupus anticoagulant have been provided. However, several questions related to the diagnosis of APS remain unanswered. Content: In addition to providing a historical perspective, this review covers several challenges in the diagnosis of APS with respect to clinical and laboratory features, while highlighting pathogenic pathways of the syndrome. We discuss ongoing dilemmas in the diagnosis of this complex disease. Although antiphospholipid antibodies are found in association with various clinical manifestations, the older established clinical criteria were not substantively altered in the 2006 update. Several laboratory tests recommended in the latest criteria, including phospholipid-dependent coagulation tests for the detection of the lupus anticoagulant and ELISAs for measuring anticardiolipin and β2-glycoprotein I antibodies, still show methodological and diagnostic shortcomings. In addition, antiphospholipid antibodies have been described against other antigens, but their clinical role remains uncertain. Conclusions: Despite updated APS criteria, diagnosis of this syndrome remains challenging. Further research on clinically relevant antibodies and standardization of their detection are needed to improve clinical risk assessment in APS.

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