The significance of autoantibodies against β2-glycoprotein I

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 266-274 ◽  
Author(s):  
Philip G. de Groot ◽  
Rolf T. Urbanus
Keyword(s):  
Autoimmune Disease ◽  
Infectious Diseases ◽  
Antiphospholipid Syndrome ◽  
Plasma Protein ◽  
Antiphospholipid Antibodies ◽  
Fetal Loss ◽  
Thrombotic Risk ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
History Of

AbstractThe antiphospholipid syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with a history of thrombosis and/or pregnancy morbidity, including fetal loss. APS is an autoimmune disease with a confusing name because the pathologic auto-antibodies are shown to be directed against the plasma protein β2-glycoprotein I and not against phospholipids. In fact, auto-antibodies that recognize phospholipids themselves are not associated with thrombosis but with infectious diseases. One of the intriguing questions is why autoantibodies against β2-glycoprotein I are so commonly found in both patients and the healthy. Several potential mechanisms have been suggested to explain the increased thrombotic risk in patients with these autoantibodies. In this overview, we will summarize our knowledge on the etiology of the autoantibodies, and we will discuss the evidence that identify autoantibodies against β2-glycoprotein I as the culprit of APS.

scholarly journals Molecular Mechanisms of “Antiphospholipid Antibodies” and Their Paradoxical Role in the Pathogenesis of “Seronegative APS”

2020 ◽  
Vol 21 (21) ◽  
pp. 8411
Author(s):  
Roberta Misasi ◽  
Agostina Longo ◽  
Serena Recalchi ◽  
Daniela Caissutti ◽  
Gloria Riitano ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Molecular Mechanisms ◽  
Strong Association ◽  
Fetal Loss ◽  
Signal Transduction Pathway ◽  
Therapeutic Strategies ◽  
Transduction Pathway ◽  
Laboratory Methods ◽  
Pregnancy Morbidity ◽  
Glycoprotein I

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative for conventional laboratory diagnostic criteria, are classified as “seronegative” APS patients (SN-APS). Several findings suggest that aPL, which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), may contribute to thrombotic diathesis by interfering with hemostasis. Despite the strong association between aPL and thrombosis, the exact pathogenic mechanisms underlying thrombotic events and pregnancy morbidity in APS have not yet been fully elucidated and multiple mechanisms may be involved. Furthermore, in many SN-APS patients, it is possible to demonstrate the presence of unconventional aPL (“non-criteria” aPL) or to detect aPL with alternative laboratory methods. These findings allowed the scientists to study the pathogenic mechanism of SN-APS. This review is focused on the evidence showing that these antibodies may play a functional role in the signal transduction pathway(s) leading to thrombosis and pregnancy morbidity in SN-APS. A better comprehension of the molecular mechanisms triggered by aPL may drive development of potential therapeutic strategies in APS patients.

Central serous chorioretinopathy and antiphospholipid syndrome: Three cases report

Lupus ◽  
2020 ◽  
pp. 096120332097973
Author(s):  
Paul Billoir ◽  
Adrien Michon ◽  
Luc Darnige
Keyword(s):  
Autoimmune Disease ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Central Serous Chorioretinopathy ◽  
Pregnancy Morbidity

Antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by recurrent venous or arterial thrombotic events and pregnancy morbidity, with persistently presence of antiphospholipid antibodies (aPL). We report three cases of central serous chorioretinopathy (CSC) associated with APS.

scholarly journals Isolated IgA Anti-β2 Glycoprotein I Antibodies in Patients with Clinical Criteria for Antiphospholipid Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Raquel Ruiz-García ◽  
Manuel Serrano ◽  
José Ángel Martínez-Flores ◽  
Sergio Mora ◽  
Luis Morillas ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Arterial Thrombosis ◽  
Clinical Manifestations ◽  
Diagnostic Systems ◽  
Clinical Criteria ◽  
Glycoprotein I ◽  
Standardized Diagnostic ◽  
Disease Present

Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.

Microparticles: An Alternative Explanation to the Behavior of Vascular Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Daniel Álvarez ◽  
Carolina Rúa ◽  
Ángela P.J. Cadavid
Keyword(s):  
Autoimmune Disease ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Alternative Explanation ◽  
Murine Models ◽  
Vascular Thrombosis ◽  
Pregnancy Morbidity ◽  
Clinical Presentations ◽  
Obstetric Antiphospholipid Syndrome

AbstractAntiphospholipid syndrome is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies, along with occurrence of vascular thrombosis and pregnancy morbidity. The variety of antiphospholipid antibodies and their related mechanisms, as well as the behavior of disease in wide groups of patients, have led some authors to propose a differentiation of this syndrome into two independent entities: vascular and obstetric antiphospholipid syndrome. Thus, previous studies have discussed whether specific autoantibodies may be responsible for this differentiation or, in contrast, how the same antibodies are able to generate two different clinical presentations. This discussion is yet to be settled. The capability of serum IgG from patients with vascular thrombosis to trigger the biogenesis of endothelial cell-derived microparticles in vitro is one of the previously discussed differences between the clinical entities of antiphospholipid syndrome. These vesicles constitute a prothrombotic mechanism as they can directly lead to clot activation in murine models and recalcified human plasma. Nevertheless, other indirect mechanisms by which microparticles can spread a procoagulant phenotype could be critical to understanding their role in antiphospholipid syndrome. For this reason, questions regarding the cargo of microparticles, and the signaling pathways involved in their biogenesis, are of interest in attempting to explain the behavior of this autoimmune disease.

β2-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome

Blood ◽  
2010 ◽  
Vol 116 (8) ◽  
pp. 1336-1343 ◽  
Author(s):  
Çetin Ağar ◽  
Gwendolyn M. A. van Os ◽  
Matthias Mörgelin ◽  
Richard R. Sprenger ◽  
J. Arnoud Marquart ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Partial Thromboplastin Time ◽  
Antiphospholipid Antibodies ◽  
Fetal Loss ◽  
Activated Partial Thromboplastin Time ◽  
Ample Evidence ◽  
Glycoprotein I ◽  
Open Conformation ◽  
Cryptic Epitope ◽  
Major Antigen

Abstract The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that β2-glycoprotein I (β2GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize β2GPI when bound to anionic surfaces and not in solution. We showed that β2GPI can exist in at least 2 different conformations: a circular plasma conformation and an “activated” open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of β2GPI. By changing pH and salt concentration, we were able to convert the conformation of β2GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-β2GPI complex. We also demonstrate that the open conformation of β2GPI prolonged the activated partial thromboplastin time when added to normal plasma, whereas the activated partial thromboplastin time is further prolonged by addition of anti-β2GPI antibodies. The conformational change of β2GPI, and the influence of the autoantibodies may have important consequences for our understanding of the antiphospholipid syndrome.

Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity

2006 ◽  
Vol 96 (09) ◽  
pp. 337-341 ◽  
Author(s):  
Amelia Ruffatti ◽  
Marta Tonello ◽  
Teresa Del Ross ◽  
Anna Cavazzana ◽  
Chiara Grava ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Pregnancy Loss ◽  
Late Pregnancy ◽  
Primary Antiphospholipid Syndrome ◽  
Thromboembolic Events ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
History Of ◽  
Classification Category

SummaryIn women diagnosed as having category I primary obstetric antiphospholipid syndrome, clinical characteristics and the risk of subsequent thromboembolic events and further unsuccessful pregnancy has not been clearly documented. Women with unexplained obstetric complications and no definite autoimmune systemic diseases were tested for lupus anticoagulant (LA), IgG/ IgM anticardiolipin (aCL) and IgG/IgM anti-human β2-Glycoprotein I (aβ2GPI) antibodies and diagnosed as having primary antiphospholipid syndrome (APS) in classification category I on the basis of more than one laboratory criteria present in any combination. Characteristics at the time of diagnosis and risk factors for subsequent clinical events during a mean follow-up of 6.3 years were evaluated. Fifty-three of 600 women studied were found to fulfil obstetric criteria and had more than one positive laboratory test at the time of diagnosis. All the women were a CL and aβ2GPI positive, and 16 were also LA positive. This latter group (triple positivity) had distinct features and had more frequently experienced previous thromboembolism (OR= 122.5, 95% CI 16–957, p<0.001).They also had an increased rate of late pregnancy loss (OR=16.2, 95%CI 0.9–292, p=0.01), and a higher IgG aβ2GPI titer at diagnosis (median, 25th and 75th percentile were 118, 37–962, vs. 23, 18–32, respectively, p<0.0001). During follow-up, the rate of thromboembolic events was significantly higher in the group of women with triple positivity and/ or previous thromboembolism (OR=57.5, 95% CI 2.7–1160, p=0.0004) which were the only independent predictors of TE in the multivariate model. Recurrent pregnancy loss took place in seven out of 47 women who had a new pregnancy. Triple positivity and/or previous thromboembolism were again the only independent markers (OR=34.4, 95% CI 3.5–335.1, p=0.003) of an unsuccessful new pregnancy. In conclusion, in primary APS with pregnancy morbidity in classification category I, quite different groups of patients may be identified on the basis of laboratory tests. Triple positivity and/or a history of thromboembolism predict new TE events and new unsuccessful pregnancies.

Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome

2015 ◽  
Vol 53 (8) ◽  
Author(s):  
Ariela Hoxha ◽  
Amelia Ruffatti ◽  
Elena Mattia ◽  
Lauro Meneghel ◽  
Marta Tonello ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Primary Antiphospholipid Syndrome ◽  
Clinical Criteria ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Coagulation Tests ◽  
Healthy Control ◽  
Independent Risk Factors ◽  
Ig G

AbstractAntiphosphatidylserine/prothrombin complex (aPS/PT) antibodies are emerging as an important marker for antiphospholipid syndrome (APS). We aimed to compare their performance with that of conventional antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2GPI) in APS and to assess their frequency in APS-negative (APS-ne) patients.We considered 160 APS patients and 128 APS-ne patients with clinical criteria for APS but tested negative for conventional aPL. Immunoglobulin (Ig)G/IgM aPS/PT, IgG/IgM aCL, and IgG/IgM anti-β2GPI were detected using ELISA assay and LA with a series of coagulation tests.IgG aPS/PT were significantly associated with IgG aCL, IgG anti-β2GPI, and LA (p<0.0001 for all). IgM aPS/PT were significantly associated only with LA (p<0.0001) instead. There was a significant correlation between IgG aPS/PT and both IgG aCL and IgG anti-β2GPI levels (ρ=0.42 and ρ=0.40, respectively). Both IgG aPS/PT and IgM aPS/PT positivity significantly correlated with LA (ρ=0.44 and ρ=0.5, respectively). IgG and IgM aPS/PT were significantly more frequent in triple than in double and in single positivity (p<0.0001). According to multivariate analysis, IgG and/or IgM aPS/PT were independent risk factors for LA. APS/PT antibodies were found in 9.4% of the APS-ne patients vs. 2% of healthy control (p=0.043); those antibodies were significantly more frequent in the thrombosis with respect to the pregnancy morbidity subset (p=0.01).Our data attribute a clinical relevance to both IgG and IgM aPS/PT antibodies. In particular, the significant prevalence of aPS/PT in APS-ne patients suggests including them as additional laboratory criterion for APS.

scholarly journals Recent advances in understanding antiphospholipid syndrome

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2908 ◽  
Author(s):  
Maria Laura Bertolaccini ◽  
Giovanni Sanna
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Anticardiolipin Antibodies ◽  
Coagulation Cascade ◽  
Systemic Autoimmune Disease ◽  
Vascular Thrombosis ◽  
Clinical Criteria ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Hughes Syndrome

Antiphospholipid syndrome (APS), also known as Hughes Syndrome, is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. A patient with APS must meet at least one of two clinical criteria (vascular thrombosis or complications of pregnancy) and at least one of two laboratory criteria including the persistent presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and/or anti-b2 glycoprotein I (anti-b2GPI) antibodies of IgG or IgM isotype at medium to high titres in patient’s plasma. However, several other autoantibodies targeting other coagulation cascade proteins (i.e. prothrombin) or their complex with phospholipids (i.e. phosphatidylserine/prothrombin complex), or to some domains of β2GPI, have been proposed to be also relevant to APS. In fact, the value of testing for new aPL specificities in the identification of APS in thrombosis and/or pregnancy morbidity patients is currently being investigated.

scholarly journals The antiphospholipid syndrome: still an enigma

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Shruti Chaturvedi ◽  
Keith R. McCrae
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Clinical Manifestations ◽  
Fetal Loss ◽  
Basic Research ◽  
Laboratory Diagnosis ◽  
Pregnancy Morbidity ◽  
Common Causes

Abstract Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being β2-glycoprotein 1 (β2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-β2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS-related events, and for targeted treatment of this common yet enigmatic disorder.

Current concepts on the pathogenesis of the antiphospholipid syndrome

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 422-430 ◽  
Author(s):  
Bill Giannakopoulos ◽  
Freda Passam ◽  
Soheila Rahgozar ◽  
Steven A. Krilis
Keyword(s):  
Experimental Evidence ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Clinical Manifestations ◽  
Fetal Loss ◽  
Peripheral Tolerance ◽  
The Core ◽  
Glycoprotein I ◽  
Antigenic Targets ◽  
Acquired Thrombophilia

Abstract The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (β2-GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in this disorder. Delineating the strengths and limitations of the experimental evidence accumulated thus far will hopefully stimulate further experimentation toward achieving the ultimate goal of precisely defining the dominant pathogenic mechanisms operational in APS. This may pave the way for the development of improved therapies.

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