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Open AccessArticle

Potential Roles of Antiphospholipid Antibodies in Generating Platelet-C4d in Systemic Lupus Erythematosus

by Chau-Ching Liu, Travis Schofield, Amy Tang, Susan Manzi and Joseph M. Ahearn

Antibodies 2017, 6(3), 9; https://doi.org/10.3390/antib6030009 - 02 Jul 2017

Cited by 2 | Viewed by 6153

Premature, accelerated onset of atherothrombotic disease is prevalent in patients with systemic lupus erythematosus (SLE). Most, if not all, atherothrombotic diseases are likely to involve platelets and complement. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in SLE [...] Read more.

Premature, accelerated onset of atherothrombotic disease is prevalent in patients with systemic lupus erythematosus (SLE). Most, if not all, atherothrombotic diseases are likely to involve platelets and complement. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in SLE patients, and are significantly associated with antiphospholipid (aPL) antibody positivity and stroke in SLE patients. The goal of the present study was to further elucidate the role of aPL and other platelet-reactive autoantibodies in the generation of P-C4d. To determine the association between P-C4d and aPL antibodies, the serum levels of aPL antibodies and P-C4d of 180 SLE patients were measured by enzyme-linked immunoassays and flow cytometry, respectively. To investigate the role of aPL antibodies, and possibly other autoantibodies as well, in mediating the generation of P-C4d, in vitro 2-step P-C4d induction experiments were performed. The results showed that the presence and levels of aPL antibodies in the serum were specifically elevated in SLE patients with positive P-C4d. The plasma and immunoglobulins purified from SLE patients who were positive for P-C4d and aPL were capable of inducing C4d deposition on normal platelets in vitro. The capacity of SLE plasma in inducing P-C4d appeared to correlate proportionately to the serum aPL levels. Collectively, the results demonstrate that both aPL and other platelet-reactive autoantibodies may participate in mediating the generation of P-C4d in SLE patients. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessArticle

Dimerized Domain V of Beta2-Glycoprotein I Is Sufficient to Upregulate Procoagulant Activity in PMA-Treated U937 Monocytes and Require Intact Residues in Two Phospholipid-Binding Loops

by Alexey Kolyada, David A. Barrios and Natalia Beglova

Antibodies 2017, 6(2), 8; https://doi.org/10.3390/antib6020008 - 02 Jun 2017

Cited by 6 | Viewed by 5718

Abstract

Upregulation of the procoagulant activity of monocytes by antibodies to beta2-glycoprotein I (β2GPI) is one of the mechanisms contributing to thrombosis in antiphospholipid syndrome. Current knowledge about receptors responsible for the upregulation of procoagulant activity by β2GPI/anti-β2GPI complexes and their binding sites on [...] Read more.

Upregulation of the procoagulant activity of monocytes by antibodies to beta2-glycoprotein I (β2GPI) is one of the mechanisms contributing to thrombosis in antiphospholipid syndrome. Current knowledge about receptors responsible for the upregulation of procoagulant activity by β2GPI/anti-β2GPI complexes and their binding sites on β2GPI is far from complete. We quantified the procoagulant activity expressed by phorbol 12-myristate 13-acetate (PMA)-differentiated U937 cells by measuring clotting kinetics in human plasma exposed to stimulated cells. Cells stimulated with anti-β2GPI were compared to cells treated with dimerized domain V of β2GPI (β2GPI-DV) or point mutants of β2GPI-DV. We demonstrated that dimerized β2GPI-DV is sufficient to induce procoagulant activity in monocytes. Using site-directed mutagenesis, we determined that the phospholipid-binding interface on β2GPI is larger than previously thought and includes Lys308 in β2GPI-DV. Intact residues in two phospholipid-binding loops of β2GPI-DV were important for the potentiation of procoagulant activity. We did not detect a correlation between the ability of β2GPI-DV variants to bind ApoER2 and potentiation of the procoagulant activity of cells. The region on β2GPI inducing procoagulant activity in monocytes can now be narrowed down to β2GPI-DV. The ability of β2GPI-DV dimers to come close to cell membrane and attach to it is important for the stimulation of procoagulant activity. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessArticle

A Clinical Approach for Defining the Threshold between Low and Medium Anti-Cardiolipin Antibody Levels for QUANTA Flash Assays

by Gabriella Lakos, Chelsea Bentow and Michael Mahler

Antibodies 2016, 5(2), 14; https://doi.org/10.3390/antib5020014 - 25 May 2016

Cited by 10 | Viewed by 6566

Abstract

The threshold between low and medium antibody levels for anticardiolipin (aCL) and anti-β2 glycoprotein I antibodies (aβ2GPI) for the diagnosis of antiphospholipid syndrome (APS) remains a matter of discussion. Our goal was to create a protocol for determining the low/medium antibody cut-off for [...] Read more.

The threshold between low and medium antibody levels for anticardiolipin (aCL) and anti-β2 glycoprotein I antibodies (aβ2GPI) for the diagnosis of antiphospholipid syndrome (APS) remains a matter of discussion. Our goal was to create a protocol for determining the low/medium antibody cut-off for aCL antibody methods based on a clinical approach, and utilize it to establish the clinically-relevant low/medium threshold for QUANTA Flash aCL chemiluminescent immunoassay (CIA) results. The study included 288 samples from patients with primary APS (n = 70), secondary APS (n = 42), suspected APS (n = 36), systemic lupus erythematosus (SLE) without APS (n = 96) and other connective tissue diseases (n = 44). All samples were tested for IgG and IgM aCL antibodies with QUANTA Flash CIA, along with traditional enzyme-linked immunosorbent assays (ELISAs) (QUANTA Lite). The assay specific low/medium threshold for QUANTA Flash aCL IgG and IgM assays (i.e., the equivalent of 40 GPL and MPL units) was established as 95 and 31 chemiluminescent units (CU), respectively, based on clinical performance and comparison to QUANTA Lite ELISAs. Agreement between CIA and ELISA assay results improved substantially when the platform-specific low/medium antibody threshold was used, as compared to agreement obtained on results generated with the assay cutoff: Cohen’s kappa increased from 0.85 to 0.91 for IgG aCL, and from 0.59 to 0.75 for IgM aCL results. This study describes a clinical approach for establishing the low/medium antibody threshold for aPL antibody assays, and successfully employs it to define 95 and 31 CU, respectively, as the low/medium cut point for QUANTA Flash aCL IgG and IgM results. This study can serve as a model for labs wishing to establish the appropriate low/medium aPL antibody threshold when implementing new aPL antibody assays. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Review

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Open AccessReview

Neutrophil Extracellular Traps, Antiphospholipid Antibodies and Treatment

by Jessica Bravo-Barrera, Maria Kourilovitch and Claudio Galarza-Maldonado

Antibodies 2017, 6(1), 4; https://doi.org/10.3390/antib6010004 - 06 Mar 2017

Cited by 12 | Viewed by 10404

Abstract

Neutrophil extracellular traps (NETs) are a network of extracellular fibers, compounds of chromatin, neutrophil DNA and histones, which are covered with antimicrobial enzymes with granular components. Autophagy and the production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are [...] Read more.

Neutrophil extracellular traps (NETs) are a network of extracellular fibers, compounds of chromatin, neutrophil DNA and histones, which are covered with antimicrobial enzymes with granular components. Autophagy and the production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are essential in the formation of NETs. There is increasing evidence that suggests that autoantibodies against beta-2-glycoprotein-1 (B2GP1) induce NETs and enhance thrombosis. Past research on new mechanisms of thrombosis formation in antiphospholipid syndrome (APS) has elucidated the pharmacokinetics of the most common medication in the treatment of the disease. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessReview

Current Controversies in Lupus Anticoagulant Detection

by Gary W. Moore

Antibodies 2016, 5(4), 22; https://doi.org/10.3390/antib5040022 - 02 Dec 2016

Cited by 22 | Viewed by 8355

Abstract

Antiphospholipid syndrome is an autoimmune, acquired thrombophilia diagnosed when vascular thrombosis or pregnancy morbidity are accompanied by persistent antiphospholipid antibodies. Lupus anticoagulants (LA) are one of the criteria antibodies but calibration plasmas are unavailable and they are detected by inference based on antibody [...] Read more.

Antiphospholipid syndrome is an autoimmune, acquired thrombophilia diagnosed when vascular thrombosis or pregnancy morbidity are accompanied by persistent antiphospholipid antibodies. Lupus anticoagulants (LA) are one of the criteria antibodies but calibration plasmas are unavailable and they are detected by inference based on antibody behaviour in a medley of coagulation-based assays. Elevated screening tests suggest the presence of a LA, which is confirmed with mixing tests to evidence inhibition and confirmatory tests to demonstrate phospholipid-dependence. At least two screening tests of different principle must be used to account for antibody heterogeneity and controversy exists on whether assays, in addition to dilute Russell’s viper venom time and activated partial thromboplastin time, should be employed. A variety of approaches to raw data manipulation and interpretation attract debate, as does inclusion or exclusion of mixing studies in circumstances where the presence of a LA is already evident from other results. Therapeutic anticoagulation compromises coagulation-based assays but careful data interpretation and use of alternative reagents can detect or exclude LA in specific circumstances, and this aspect of LA detection continues to evolve. This review focuses on the main areas of debate in LA detection. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessReview

Antiphospholipid Antibodies: From General Concepts to Its Relation with Malignancies

by José A. Gómez-Puerta, Gerard Espinosa and Ricard Cervera

Antibodies 2016, 5(3), 18; https://doi.org/10.3390/antib5030018 - 02 Aug 2016

Cited by 12 | Viewed by 5375

Abstract

Antiphospholipid syndrome (APS) is an adquired autoimmune pro-thrombotic disease characterized by arterial and/or venous thrombosis and/or fetal losses associated with the persistent presence of antiphospholipid antibodies (aPL) detectable by solid phase assays (anticardiolipin (aCL) and anti-β2 glycoprotein I, β2GPI) and/or functional coagulation test [...] Read more.

Antiphospholipid syndrome (APS) is an adquired autoimmune pro-thrombotic disease characterized by arterial and/or venous thrombosis and/or fetal losses associated with the persistent presence of antiphospholipid antibodies (aPL) detectable by solid phase assays (anticardiolipin (aCL) and anti-β2 glycoprotein I, β2GPI) and/or functional coagulation test (lupus anticoagulant (LA)). Most patients with typical APS manifestations have the presence of one or more of conventional aPL, but, some patients might exhibit clinical features related with APS but with persistent negative determinations of “classic” aPL (seronegative APS). Expanding the network of autoantibodies in patients highly suspected of having APS but who have normal results from a conventional test using new antibodies (i.e., phosphatidylserine/prothrombin and β2GPI domain 1) would increase the diagnosis. Thrombosis is one of the leading causes of death among patients with cancer, representing up to 15% of all deaths. Cancer increases the risk of thrombosis and chemotherapy is further associated with a higher risk of thrombosis. In addition, aPL may contribute to an increased risk of thrombosis in patients with malignancies, although the levels do not seem to reflect their pathogenicity. Several malignancies, particularly hematological and lymphoproliferative malignancies, may indeed be associated with the generation of aPL but do not necessarily enhance the thrombophilic risk in these patients. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessReview

Antiphospholipid Syndrome and Kidney Involvement: New Insights

by José A. Martínez-Flores, Manuel Serrano, Jose M. Morales and Antonio Serrano

Antibodies 2016, 5(3), 17; https://doi.org/10.3390/antib5030017 - 11 Jul 2016

Cited by 4 | Viewed by 7380

Abstract

Antiphospholipid syndrome is an autoimmune disorder characterized by vascular thromboses and pregnancy morbidity associated with antiphospholipid antibodies: lupus anticoagulant, IgG or IgM anticardiolipin or anti-beta 2-glycoprotein I. The kidney is one of the major target organs in antiphospholipid syndrome (APS). However, beyond the [...] Read more.

Antiphospholipid syndrome is an autoimmune disorder characterized by vascular thromboses and pregnancy morbidity associated with antiphospholipid antibodies: lupus anticoagulant, IgG or IgM anticardiolipin or anti-beta 2-glycoprotein I. The kidney is one of the major target organs in antiphospholipid syndrome (APS). However, beyond the known involvement of the kidney in primary and associated APS, we may be observing a new form of APS within the context of renal failure. This review describes the classical kidney manifestations of APS and provides new considerations to be taken into account. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessReview

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

by Anna Brusch

Antibodies 2016, 5(2), 16; https://doi.org/10.3390/antib5020016 - 08 Jun 2016

Cited by 23 | Viewed by 9029

Abstract

Antiphospholipid syndrome (APS) is a thrombophilic disorder that classically presents with vascular thrombosis and/or obstetric complications. APS is associated with antiphospholipid antibodies: a heterogeneous group of autoantibodies that are directed against membrane phospholipids in complex with phospholipid-binding proteins. Beta-2-glycoprotein I (B2GPI) binds anionic [...] Read more.

Antiphospholipid syndrome (APS) is a thrombophilic disorder that classically presents with vascular thrombosis and/or obstetric complications. APS is associated with antiphospholipid antibodies: a heterogeneous group of autoantibodies that are directed against membrane phospholipids in complex with phospholipid-binding proteins. Beta-2-glycoprotein I (B2GPI) binds anionic phospholipids and is considered to be the predominant antigen in APS and antibodies against B2GPI (anti-B2GPI) are recognised in the laboratory criteria for APS diagnosis. This review focuses on the part played by anti-B2GPI in the pathogenesis of APS, their associations with different clinical phenotypes of the disorder and new avenues for refining the diagnostic potential of anti-B2GPI testing. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessReview

Antiphospholipid Antibodies: Their Origin and Development

by Karl J. Lackner and Nadine Müller-Calleja

Antibodies 2016, 5(2), 15; https://doi.org/10.3390/antib5020015 - 02 Jun 2016

Cited by 12 | Viewed by 6315

Abstract

Antiphospholipid antibodies (aPL) are a hallmark of the antiphospholipid syndrome (APS), which is the most commonly acquired thrombophilia. To date there is consensus that aPL cause the clinical manifestations of this potentially devastating disorder. However, there is good evidence that not all aPL [...] Read more.

Antiphospholipid antibodies (aPL) are a hallmark of the antiphospholipid syndrome (APS), which is the most commonly acquired thrombophilia. To date there is consensus that aPL cause the clinical manifestations of this potentially devastating disorder. However, there is good evidence that not all aPL are pathogenic. For instance, aPL associated with syphilis show no association with the manifestations of APS. While there has been intensive research on the pathogenetic role of aPL, comparably little is known about the origin and development of aPL. This review will summarize the current knowledge and understanding of the origin and development of aPL derived from animal and human studies. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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Open AccessReview

β₂GP1, Anti-β₂GP1 Antibodies and Platelets: Key Players in the Antiphospholipid Syndrome

by Yik C. Ho, Kiran D. K. Ahuja, Heinrich Körner and Murray J. Adams

Antibodies 2016, 5(2), 12; https://doi.org/10.3390/antib5020012 - 06 May 2016

Cited by 22 | Viewed by 11719

Abstract

Anti-beta 2 glycoprotein 1 (anti-β₂GP1) antibodies are commonly found in patients with autoimmune diseases such as the antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Their presence is highly associated with increased risk of vascular thrombosis and/or recurrent pregnancy-related complications. Although [...] Read more.

Anti-beta 2 glycoprotein 1 (anti-β₂GP1) antibodies are commonly found in patients with autoimmune diseases such as the antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Their presence is highly associated with increased risk of vascular thrombosis and/or recurrent pregnancy-related complications. Although they are a subtype of anti-phospholipid (APL) antibody, anti-β₂GP1 antibodies form complexes with β₂GP1 before binding to different receptors associated with anionic phospholipids on structures such as platelets and endothelial cells. β₂GP1 consists of five short consensus repeat termed “sushi” domains. It has three interchangeable conformations with a cryptic epitope at domain 1 within the molecule. Anti-β₂GP1 antibodies against this cryptic epitope are referred to as ‘type A’ antibodies, and have been suggested to be more strongly associated with both vascular and obstetric complications. In contrast, ‘type B’ antibodies, directed against other domains of β₂GP1, are more likely to be benign antibodies found in asymptomatic patients and healthy individuals. Although the interactions between anti-β₂GP1 antibodies, β₂GP1, and platelets have been investigated, the actual targeted metabolic pathway(s) and/or receptor(s) involved remain to be clearly elucidated. This review will discuss the current understanding of the interaction between anti-β₂GP1 antibodies and β₂GP1, with platelet receptors and associated signalling pathways. Full article

(This article belongs to the Special Issue Antiphospholipid Antibodies and Syndrome)

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