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.

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.

Pathophysiology of β2-glycoprotein I in antiphospholipid syndrome

Lupus ◽  
2010 ◽  
Vol 19 (4) ◽  
pp. 379-384 ◽  
Author(s):  
E. Matsuura ◽  
L. Shen ◽  
Y. Matsunami ◽  
N. Quan ◽  
M. Makarova ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Antiphospholipid Syndrome ◽  
Mechanism Of Action ◽  
Antiphospholipid Antibodies ◽  
Physiological Role ◽  
Therapeutic Strategies ◽  
Physiological Functions ◽  
Glycoprotein I ◽  
The Impact

Since β2-glycoprotein I (β2GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of β2GPI and anti-β2GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of β2GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. β2GPI’s epitopes for anti-β2GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-β2GPI antibodies are pathogenic. The pathophysiologic role of β2GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of β2GPI, its metabolites and autoantibodies to β2GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease. Lupus (2010) 19, 379—384.

Anticardiolipin Antibodies Block the Inhibition by β2-Glycoprotein I of the Factor Xa Generating Activity of Platelets

1993 ◽  
Vol 70 (02) ◽  
pp. 342-345 ◽  
Author(s):  
Wei Shi ◽  
Beng H Chong ◽  
Philip J Hogg ◽  
Colin N Chesterman
Keyword(s):  
Antiphospholipid Antibodies ◽  
Lupus Anticoagulant ◽  
Fetal Loss ◽  
Factor Xa ◽  
Anticardiolipin Antibodies ◽  
Recurrent Fetal Loss ◽  
Glycoprotein I ◽  
Activated Platelets ◽  
Inhibit Factor

SummaryAntiphospholipid antibodies, defined either by lupus anticoagulant (LA) activity or positive anticardiolipin immunoabsorbent assay (ACA) are associated with a predisposition to thromboses, recurrent fetal loss or thrombocytopenia. The mechanisms for these predispositions remain undefined. We have enriched immunoglobulin fractions from two patient plasmas to obtain antibodies with LA activity but no ACA, or conversely, with ACA positivity but no LA, in order to investigate in vitro characteristics which might explain a thrombotic propensity. β2-glycoprotein I (β2-GPI), the plasma cofactor required for ACA binding to negatively charged phospholipid, has previously been shown to inhibit prothrombinase generation in the presence of activated platelets (8). We now report that β2-GPI, at physiological concentrations, inhibits the generation of factor Xa in the presence of activated gel-filtered platelets. Further, ACA interferes with this inhibition, resulting in protracted, unopposed factor Xa generation. This interference with β2-GPI, a natural anticoagulant component of plasma, is potentially prothrombotic. LA immunoglobulins behave differently and inhibit factor Xa generation in a manner similar to β2-GPI. These findings provide the basis for a previously unsuspected mechanism for thrombosis in patients with aPL.

scholarly journals Epidemiological, clinical and immune factors that influence the persistence of antiphospholipid antibodies in leprosy

2019 ◽  
Vol 59 (1) ◽  
Author(s):  
Sandra Lúcia Euzébio Ribeiro ◽  
Helena Lúcia Alves Pereira ◽  
Antonio Luiz Boechat ◽  
Neusa Pereira Silva ◽  
Emilia Ionue Sato ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Specific Treatment ◽  
Binary Logistic Regression ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Leprosy Patients ◽  
Immunological Factors ◽  
Bacterial Index

Abstract Introduction Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. Objectives To determine whether epidemiological, clinical and immunological factors played a role in the long-term persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. Methods The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. Results Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-β2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82–0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0–0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03–7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. Conclusion Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.

Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3495-3500 ◽  
Author(s):  
Elena Raschi ◽  
Cinzia Testoni ◽  
Daniela Bosisio ◽  
Maria O. Borghi ◽  
Takao Koike ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Fetal Loss ◽  
Endothelial Activation ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Signaling Cascade ◽  
Glycoprotein I ◽  
Tnf Α ◽  
Factor Α

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPLs) and recurrent thrombosis or fetal loss. The thrombophilic state has been partially related to the induction of a proinflammatory and procoagulant endothelial cell (EC) phenotype induced by anti–β2-glycoprotein I (β2-GPI) antibodies that bind β2-GPI expressed on the EC surface. Anti–β2-GPI antibody binding has been shown to induce nuclear factor-κB (NF-κB) translocation leading to a proinflammatory EC phenotype similar to that elicited by interaction with microbial products (lipopolysaccharide [LPS]) and proinflammatory cytokines (interleukin 1β [IL-1β], tumor necrosis factor α [TNF-α]). However, the upstream signaling events are not characterized yet. To investigate the endothelial signaling cascade activated by anti–β2-GPI antibodies, we transiently cotransfected immortalized human microvascular endothelial cells (HMEC-1) with dominant-negative constructs of different components of the pathway (ΔTRAF2, ΔTRAF6, ΔMyD88) together with reporter genes (NF-κB luciferase and pCMV-β-galactosidase). Results showed that both human anti–β2-GPI IgM monoclonal antibodies as well as polyclonal affinity-purified anti–β2-GPI IgG display a signaling cascade comparable to that activated by LPS or IL-1. ΔTRAF6 and ΔMyD88 significantly abrogate antibody-induced as well as IL-1– or LPS-induced NF-κB activation, whereas ΔTRAF2 (involved in NF-κB activation by TNF) does not affect it. Moreover, anti– β2-GPI antibodies and LPS followed the same time kinetic of IL-1 receptor–activated kinase (IRAK) phosphorylation, suggesting an involvement of the toll-like receptor (TLR) family. Our findings demonstrate that anti–β2-GPI antibodies react with their antigen likely associated to a member of the TLR/IL-1 receptor family on the EC surface and directly induce activation.

scholarly journals An Efficient Method to Identify Conditionally Activated Transcription Factors and their Corresponding Signal Transduction Pathway Segments

2009 ◽  
Vol 3 ◽  
pp. BBI.S3485
Author(s):  
Haiyan Hu
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
Efficient Method ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Signal Transduction Pathway ◽  
Protein Interaction Data ◽  
Transduction Pathway ◽  
Binding Data ◽  
Microarray Datasets

A signal transduction pathway (STP) is a cascade composed of a series of signal transferring steps, which often activate one or more transcription factors (TFs) to control the transcription of target genes. Understanding signaling pathways is important to our understanding of the molecular mechanisms of disease. Many condition-annotated pathways have been deposited in public databases. However, condition-annotated pathways are far from complete, considering the large number of possible conditions. Computational methods to assist in the identification of conditionally activated pathways are greatly needed. In this paper, we propose an efficient method to identify conditionally activated pathway segments starting from the identification of conditionally activated TFs, by incorporating protein-DNA binding data, gene expression data and protein interaction data. Applying our methods on several microarray datasets, we have discovered many significantly activated TFs and their corresponding pathway segments, which are supported by evidence in the literature.

Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view

Lupus ◽  
2010 ◽  
Vol 19 (4) ◽  
pp. 453-456 ◽  
Author(s):  
PL Meroni ◽  
F. Tedesco ◽  
M. Locati ◽  
A. Vecchi ◽  
N. Di Simone ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Antiphospholipid Antibodies ◽  
Clinical Manifestations ◽  
Fetal Loss ◽  
Neutrophil Infiltration ◽  
Point Of View ◽  
Pathogenic Mechanisms ◽  
Inhibition Of Growth ◽  
Glycoprotein I ◽  
Open Question

Antiphospholipid antibodies (aPL) are associated with recurrent miscarriages and pregnancy complications, however their pathogenic mechanisms are still matter of research. Thrombotic events at the placental level cannot explain all of the clinical manifestations. It has been suggested that aPL may be responsible for a local acute inflammatory response mediated by complement activation and neutrophil infiltration eventually leading to fetal loss. However histological and immunohistological studies on human placental samples do support such a mechanism only in part and with no any clear relationship with the pregnancy outcome. A direct effect of aPL on both maternal and fetal placental tissues has been reported through the reactivity of the antibodies with beta2 glycoprotein I (β2GPI) expressed on the cell membranes. These events do not require an inflammatory response and can be in part related to the inhibition of growth factors favouring a physiological placentation. Understanding the different pathogenic mechanisms of aPL-associated miscarriages may help in improving our therapeutic approach particularly in recurrent cases not responsive to the usual treatment. Lupus (2010) 19, 453—456.

Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2322-2332 ◽  
Author(s):  
Nadine Prinz ◽  
Natascha Clemens ◽  
Dennis Strand ◽  
Inge Pütz ◽  
Mareike Lorenz ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antiphospholipid Antibodies ◽  
Ex Vivo ◽  
Fetal Loss ◽  
Signal Transduction Pathway ◽  
Plasmacytoid Dendritic Cells ◽  
Systemic Autoimmunity ◽  
Subsequent Activation ◽  
Inappropriate Expression ◽  
Increase Mrna Expression

Abstract The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thromboembolic events and/or fetal loss in the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the pathogenicity of aPLs are still poorly understood. Here we show that 3 human monoclonal aPLs as well as IgG fractions from patients with the APS increase mRNA expression of the intracellular toll-like receptor (TLR) 7 in plasmacytoid dendritic cells and TLR8 in monocytes. Simultaneously they induce the translocation of TLR7 or TLR8 from the endoplasmic reticulum to the endosome. These effects depend on the uptake of aPLs into the endosome, subsequent activation of endosomal NADPH oxidase, and generation of superoxide. As a consequence cells are dramatically sensitized to ligands for TLR7 and TLR8. This observation delineates a novel signal transduction pathway in innate immunity originating from the endosome. Because the overexpression of TLR7 can also be detected in plasmacytoid dendritic cells from patients with the APS ex vivo, our results provide an explanation for proinflammatory and procoagulant effects of aPLs. Because inappropriate expression of TLR7 has been implicated in the development of systemic autoimmunity, these findings may also be relevant for the understanding of autoimmunity.

scholarly journals Anti-Phosphatidylserine/Prothrombin Antibodies in Healthy Women with Unexplained Recurrent Pregnancy Loss

2021 ◽  
Vol 10 (10) ◽  
pp. 2094
Author(s):  
Daniel E. Pleguezuelo ◽  
Oscar Cabrera-Marante ◽  
Magdalena Abad ◽  
Edgard Alfonso Rodriguez-Frias ◽  
Laura Naranjo ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Odds Ratio ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Fetal Death ◽  
Fetal Loss ◽  
Healthy Women ◽  
Glycoprotein I ◽  
Early Miscarriage ◽  
Beta 2

Recurrent pregnancy loss (RPL) affects up to 6% of couples. Although chromosomal aberrations of the embryos are considered the leading cause, 50% of cases remain unexplained. Antiphospholipid Syndrome is a known cause in a few cases. Antiphospholipid antibodies (aPL) anticardiolipin, anti-Beta-2-Glycoprotein-I and Lupus Anticoagulant (criteria aPL) are recommended studies in RPL workup. We tested healthy women with unexplained RPL for criteria aPL and anti-Phosphatidylserine/Prothrombin antibodies (aPS/PT). Patients were classified into three groups according to the number and pregnancy week of RPL: Extra-Criteria (EC), with 2 miscarriages, Early Miscarriage (EM), with ≥3 before pregnancy at week 10 and Fetal Loss (FL), with ≥1 fetal death from pregnancy at week 10. Circulating criteria aPL were absent in 98.1% of EM, 90.9% of FL and 96.6% of EC groups. In contrast, aPS/PT were positive in 15.4% of EM, 15.1% of FL, 16.6% of EC patients and 2.9% in controls. aPS/PT posed a risk for RPL, with an odds ratio of 5.96 (95% confidence interval (CI): 1.85–19.13. p = 0.002) for EM, 7.28 (95% CI: 2.07–25.56. p = 0.002) for FL and 6.56. (95% CI: 1.77–24.29. p = 0.004) for EC. A successful live birth was achieved in all pregnant patients positive for aPS/PT who received treatment with heparin, aspirin and/or hydroxychloroquine.

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