A non–complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome

Blood ◽  
2014 ◽  
Vol 123 (22) ◽  
pp. 3478-3487 ◽  
Author(s):  
Chiara Agostinis ◽  
Paolo Durigutto ◽  
Daniele Sblattero ◽  
Maria O. Borghi ◽  
Claudia Grossi ◽  
...  
Keyword(s):  
Animal Models ◽  
Antiphospholipid Syndrome ◽  
Recombinant Antibody ◽  
Fetal Loss ◽  
Clot Formation ◽  
Novel Therapy ◽  
Glycoprotein I ◽  
Key Points

Key Points A recombinant antibody recognizing the D1 domain of β2 glycoprotein I induces fetal loss and clot formation in animal models. The CH2-deleted antibody fails to activate complement and prevents the procoagulant and proabortive effects of patient antibodies.

scholarly journals Antiphospholipid syndrome: a clinical and laboratorial challenge

2014 ◽  
Vol 60 (2) ◽  
pp. 181-186 ◽  
Author(s):  
Luci Maria Santana Dusse ◽  
Fernanda Dias e Silva ◽  
Letícia Gonçalves Freitas ◽  
Danyelle Romana Alves Rios ◽  
Sandra Cristina Armond ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Fetal Loss ◽  
Anticardiolipin Antibodies ◽  
Major Protein ◽  
Protein Targets ◽  
Clinical Criteria ◽  
Glycoprotein I ◽  
Increased Sensitivity ◽  
Commercial Kits ◽  
Positive Results

Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia characterized by the presence of a heterogeneous family of antibodies that bind to plasma proteins with affinity for phospholipid surfaces. The two major protein targets of antiphospholipid antibodies are prothrombin and β2-glycoprotein I (β2GPI). APS leads to aprothrombotic state, and it is characterized by the occurrence of arterial, venous or microvascular thrombosis or recurrent fetal loss. The diagnosis of APS is based on a set of clinical criteria and the detection of lupus anticoagulant (LA), anticardiolipin antibodies (ACA) or anti-β2GPI in plasma. Although laboratory tests are essential for APS diagnosis, these tests have limitations associated with the robustness, reproducibility and standardization. The standardization of diagnostic tests for detection of APLAs has been a challenge and a variety of results have been obtained using different commercial kits and in-house techniques. An increased sensitivity of the ELISA kits for detection of ACA effectively has contributed to APS diagnosis. However, the lack of specificity associated with a high number of false-positive results is a clinical and laboratorial challenge, since such results may lead to mistaken clinical decisions, such as prescription of oral anticoagulant, leading to the risk of hemorrhaging. Furthermore, clinicians are often unfamiliar with these tests and have difficulty interpreting them, requiring interaction between clinical and laboratory professionals in order to ensure their correct interpretation.

Anti β2-glycoprotein I antibodies: Clinical significance

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 107-109 ◽  
Author(s):  
A Tincani ◽  
L Spatola ◽  
M Cinquini ◽  
R Cattaneo ◽  
P Meroni ◽  
...  
Keyword(s):  
Antibody Response ◽  
Clinical Significance ◽  
Antiphospholipid Syndrome ◽  
Clinical Evaluation ◽  
Fetal Loss ◽  
Anticardiolipin Antibody ◽  
Apoptotic Bodies ◽  
Glycoprotein I ◽  
Antigenic Complex ◽  
Direct Target

The introduction of anticardiolipin antibody (aCL) assay, described in 1983, was able to focus much attention on the study of patients suffering from thrombosis, repeated fetal loss and thrombocytopenia, and allowing the identification of the so called antiphospholipid syndrome (APS). The identification of β2 glycoprotein I (β22GPI) as an essential component of the antigenic complex recognized by aCL suggested that this molecule could be a direct target of the antibody response. Since then, different groups have described ELISAs for the detection of anti β2GPI antibodies, applied to the clinical evaluation of patients with APS, and showing an overall better specificity. Recently, anti β2GPI were also shown to bind apoptotic bodies resulting in an alteration of their physiological clearance with the triggering of TNFα release. This observation suggests that anti β2GPI may also modify the immunogenicity of apoptotic bodies and of the autoantigens that they contain.

scholarly journals β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome

Blood ◽  
2015 ◽  
Vol 125 (18) ◽  
pp. 2835-2844 ◽  
Author(s):  
Kenji Tanimura ◽  
Hui Jin ◽  
Tadahiro Suenaga ◽  
Satoko Morikami ◽  
Noriko Arase ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Class Ii ◽  
Hla Class Ii ◽  
Glycoprotein I ◽  
Key Points ◽  
Hla Class Ii Molecules

Key Pointsβ2GPI complexed with HLA class II molecules was found to be a target for autoantibodies in APS. More than 80% of patients with APS possess autoantibodies against β2GPI/HLA class II complexes.

Cross-reactivity between annexin A2 and Beta-2-glycoprotein I in animal models of antiphospholipid syndrome

2016 ◽  
Vol 65 (1) ◽  
pp. 355-362 ◽  
Author(s):  
R. Weiss ◽  
A. Bitton ◽  
L. Nahary ◽  
M. T. Arango ◽  
I. Benhar ◽  
...  
Keyword(s):  
Animal Models ◽  
Antiphospholipid Syndrome ◽  
Cross Reactivity ◽  
Annexin A2 ◽  
Glycoprotein I ◽  
Beta 2

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.

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.

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.

The Prevalence of a Non-phospholipid-binding Form of β2-Glycoprotein I in Human Plasma

1998 ◽  
Vol 80 (11) ◽  
pp. 791-797 ◽  
Author(s):  
Erica van Oort ◽  
Mariëlle Tempelman ◽  
Ronald Derksen ◽  
Philip de Groot ◽  
Daniëlle Horbach
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Large Population ◽  
Fetal Loss ◽  
Primary Antiphospholipid Syndrome ◽  
Strongly Correlated ◽  
Gene Encoding ◽  
Phospholipid Binding ◽  
Glycoprotein I ◽  
Low Prevalence

SummaryThe presence of antiphospholipid antibodies (aPL) is strongly correlated with venous and arterial thrombosis, fetal loss and thrombocytopenia. This relation is called the antiphospholipid syndrome (APS). It is well recognized that thrombosis related aPL are not directed against phospholipids alone, but to phospholipid bound plasma proteins like β2-glycoprotein I (β2GPI). aPL that need β2GPI for the binding to negatively charged phospholipids are called anti-β2GPI-antibodies. Recently, a mutation in the gene encoding β2GPI has been described, which results in an amino acid substitution Trp316 into Ser316. This Ser316-β2GPI did not bind to negatively charged phospholipids. Because only phospholipid bound β2GPI is recognized by human anti-β2GPI-antibodies, it might be argued that individuals carrying the Trp316Ser mutation are protected against the development of anti-β2GPI-antibodies.To investigate this hypothesis, the prevalence of the Trp316Ser mutation was measured in 170 systemic lupus erythematosus (SLE) patients and in 18 patients with the primary antiphospholipid syndrome (PAPS) and the mutation was correlated with the presence of anti-β2 GPI-antibodies. In the total patient group 1 homozygous patient and 21 heterozygous patients were found. The allele frequency of the mutation in SLE patients with anti-β2GPI-antibodies (0.063) was comparable to that found in SLE patients without anti-β2-GPI-antibodies (0.062). These results indicate that the heterozygous presence of Trp316Ser mutation does not prevent an individual from developing anti-β2GPI-antibodies. We showed that this can be explained by the concentration of Trp316-β2GPI in heterozygous patients, which is far above the minimal β2GPI level necessary for optimal phospholipid binding. In our single patient homozygous for the Trp316Ser mutation no binding of β2GPI to the phospholipid surface was detected and no anti-β2GPI-antibodies were present in the plasma of this patient.In conclusion, heterozygous Trp316Ser β2GPI persons are not protected against the development of anti-β2GPI-antibodies. To confirm that homozygotes do not develop anti-β2GPI-antibodies a very large population is needed, due to the relatively low prevalence of the mutation.

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study

Blood ◽  
2014 ◽  
Vol 123 (3) ◽  
pp. 404-413 ◽  
Author(s):  
Sylvie Bouvier ◽  
Éva Cochery-Nouvellon ◽  
Géraldine Lavigne-Lissalde ◽  
Érick Mercier ◽  
Tess Marchetti ◽  
...  
Keyword(s):  
Observational Study ◽  
Antiphospholipid Syndrome ◽  
Pregnancy Outcomes ◽  
Pregnancy Complications ◽  
Fetal Loss ◽  
Late Pregnancy ◽  
Key Points ◽  
Obstetric Antiphospholipid Syndrome ◽  
Obstetric Aps

Key PointsAmong women with pure obstetric APS, late pregnancy complications are more frequent in cases of prior fetal loss. Late pregnancy complications are more frequent among women treated for pure obstetric APS than among nontreated controls.

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