Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 2960-2967 ◽  
Author(s):  
Elena Ortona ◽  
Antonella Capozzi ◽  
Tania Colasanti ◽  
Fabrizio Conti ◽  
Cristiano Alessandri ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Surface Membrane ◽  
Clinical Signs ◽  
Nuclear Factor Κb ◽  
Endothelial Cell Surface ◽  
Proteomic Approach ◽  
Cardiolipin Antibodies ◽  
Almost All

AbstractAntiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis, recurrent abortions, and antiphospholipid antibodies (aPL). However, it is possible to find patients with clinical signs of APS who persistently test negative for aPL (seronegative APS, or SN-APS). The aim of this study was to identify new antigenic target(s) of autoantibodies in APS patients, which may also be recognized in SN-APS. We tested sera from patients with SN-APS with a proteomic approach by analyzing endothelial cell-surface membrane proteins. Sera from SN-APS patients revealed 2 reactive spots corresponding to vimentin, a protein that is shown to bind cardiolipin in vitro. Antivimentin/cardiolipin antibodies were tested in 29 SN-APS patients, 40 APS patients, 30 patients with systemic lupus erythematosus, 30 with rheumatoid arthritis, 30 with venous or arterial thrombosis, and 32 healthy control patients. We observed that not only a large proportion of SN-APS patients but also almost all the APS patients displayed the presence of antivimentin/cardiolipin antibodies. To verify the possible pathogenic role of these autoantibodies, we demonstrated that affinity-purified antivimentin/cardiolipin antibodies induced interleukin receptor-associated kinase phosphorylation and nuclear factor-κB activation in endothelial cells. Our results prompt to identify vimentin as a “new” cofactor for aPL, which may represent a useful tool mainly in SN-APS patients.

scholarly journals The Mosaic of “Seronegative” Antiphospholipid Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Fabrizio Conti ◽  
Antonella Capozzi ◽  
Simona Truglia ◽  
Emanuela Lococo ◽  
Agostina Longo ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
Annexin V ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dot Blot ◽  
Cardiolipin Antibodies ◽  
Lysobisphosphatidic Acid ◽  
Methodological Approaches ◽  
Antigenic Targets

In the clinical practice it is possible to find patients with clinical signs suggestive of antiphospholipid syndrome (APS), who are persistently negative for the laboratory criteria of APS, that is, anti-cardiolipin antibodies (aCL), anti-β2-GPI antibodies and lupus anticoagulant. Therefore, it was proposed for these cases the term of seronegative APS (SN-APS). In order to detect autoantibodies with different methodological approaches, sera from 24 patients with SN-APS were analysed for anti-phospholipid antibodies using TLC immunostaining, for anti-vimentin/cardiolipin antibodies by enzyme-linked immunosorbent assay (ELISA), and for anti-annexin V and anti-prothrombin antibodies by ELISA and dot blot. Control groups of our study were 25 patients with APS, 18 with systemic lupus erythematosus (SLE), and 32 healthy controls. Results revealed that 13/24 (54.2%) SN-APS sera were positive for aCL (9 of whom were also positive for lysobisphosphatidic acid) by TLC immunostaining, 11/24 (45.8%) for anti-vimentin/cardiolipin antibodies, 3/24 (12.5%) for anti-prothrombin antibodies, and 1/24 (4.2%) for anti-annexin V antibodies. These findings suggest that in sera from patients with SN-APS, antibodies may be detected using “new” antigenic targets (mainly vimentin/cardiolipin) or methodological approaches different from traditional techniques (mainly TLC immunostaining). Thus, SN-APS represents a mosaic, in which antibodies against different antigenic targets may be detected.

scholarly journals Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation

Blood ◽  
1996 ◽  
Vol 88 (9) ◽  
pp. 3621-3625 ◽  
Author(s):  
HH Euler ◽  
AM Marmont ◽  
A Bacigalupo ◽  
S Fastenrath ◽  
P Dreger ◽  
...  
Keyword(s):  
Stem Cell ◽  
Autoimmune Disease ◽  
Stem Cell Transplantation ◽  
Autoimmune Diseases ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
High Dose

Autologous stem cell transplantation with or without in vitro lymphocyte depletion has been suggested as a new treatment option for severe autoimmune diseases. We describe five patients with autoimmune diseases (CREST syndrome, myasthenia gravis and Hashimoto's thyroiditis, systemic lupus erythematosus, atopic dermatitis, and rheumatoid arthritis) who underwent autologous bone marrow (n = 1) or peripheral blood progenitor cell (n = 4) transplantation with unmanipulated grafts as treatment for the autoimmune disease in one case or as treatment for a malignant disorder with a concomitant autoimmune disorder in four cases. In all patients serological and clinical signs of the autoimmune disease recurred early or persisted. These observations should be regarded as a cautionary note concerning the efficacy of high-dose therapy followed by transplantation of unmanipulated autologous stem cells for treatment of severe autoimmune diseases.

Antiphospholipid syndrome – an update

VASA ◽  
2018 ◽  
Vol 47 (6) ◽  
pp. 451-464 ◽  
Author(s):  
Birgit Linnemann
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Clinical Symptoms ◽  
Heart Valve Disease ◽  
Small Vessels ◽  
Glycoprotein I ◽  
Neurologic Disorders ◽  
Cardiolipin Antibodies ◽  
Obstetric Aps ◽  
Beta 2

Abstract. Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI). Its main manifestations are recurrent vascular thromboses (so-called “thrombotic APS”) and pregnancy complications (“obstetric APS”). According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients. APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure. Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high. For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option. Keywords: Antiphospholipid syndrome, lupus anticoagulants, anti-cardiolipin, anti-beta-2-glycoprotein I, vascular thrombosis, pregnancy complication

scholarly journals Lower Limb Ischemia: Aortoiliac Thrombosis Related to Antiphospholipid Syndrome (APS)—Case Report and Review of the Literature

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Arnaldo Toffon ◽  
Raffaella Piovesan ◽  
Consolato Francesco Minniti ◽  
Omar Caruso ◽  
Paolo Criscenti ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Limb Ischemia ◽  
Elisa Test ◽  
Coagulation Tests ◽  
Cardiolipin Antibodies ◽  
Great Vessels ◽  
Main Determinants ◽  
First Time ◽  
The Brain

Antiphospholipid syndrome (APS) is recognized as one of the main determinants of hypercoagulable conditions. The literature reports the incidence of this syndrome in a third of patients who underwent surgery for peripheral revascularization. Antiphospholipid antibodies are divided into two categories in relation to specific diagnostic tests. The first group is called lupus anticoagulant and consists of immunoglobulins that inhibit the phospholipid dependent coagulation tests in vitro. The second group is defined by their ability to conduct the phospholipid in an ELISA test. The occurrence of thrombotic events in patients with systemic erythematosus lupus (SEL) and anticoagulant antibodies was described for the first time in 1963 by Bowie. The discovery of anti-cardiolipin antibodies in antiphospholipid syndrome is due to Harris et al. who described the syndrome. Primitive APS was consequently defined in the absence of further underlying illnesses. In this disease, arterial thrombosis occurs mainly in the brain. Peripheral arteries are affected less frequently. Thrombosis of the great vessels is reported as anecdotal.

scholarly journals Mechanism of Action of Hydroxychloroquine in the Antiphospholipid Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5023-5023
Author(s):  
Nadine Müller-Calleja ◽  
Davit Manukyan ◽  
Wolfram Ruf ◽  
Karl Lackner
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Laser Scanning ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
In Vivo Model

Abstract Objective. The antiphospholipid syndrome (APS) is characterized by thromboembolic events and/or recurrent abortions in the presence of pathogenic antiphospholipid antibodies (aPL). Hydroxychloroquine (HCQ) is recommended for thromboprophylaxis in patients with systemic lupus erythematosus and aPL. We aimed at identifying mechanisms responsible for the beneficial effects of HCQ in the APS. Methods. Monocytic cells were stimulated with human aPL in vitro and expression of tissue factor (TF) and tumor necrosis factor (TNFα) was quantified by qRT-PCR. For intracellular ROS detection, cells were stained with OxyBurst and analyzed by flow cytometry. Live cell imaging was performed by confocal laser scanning microscopy to show translocation of NADPH oxidase 2 (NOX2) and TLR8 on stimulation. Finally, the effect of HCQ was tested in an in vivo model of venous thrombosis. Results. HCQ prevents the induction of TF and TNFα by aPL in MonoMac1 cells, by blocking the activation of endosomal NOX2. This latter effect is not mediated by direct interference with the previously described uptake of aPL into the endosome but by inhibiting the recruitment of the catalytic subunit of NOX2 (gp91phox) into the endosome. Furthermore, HCQ protects mice from aPL induced and NOX2 mediated thrombus formation in vivo. Conclusion. We propose that interference with the assembly of endosomal NOX2 is a major effect of HCQ responsible for its antithrombotic effect in the APS. Since most if not all APS patients harbor aPL that activate endosomal NOX2 this probably explains the well established efficacy of HCQ in APS patients. Disclosures No relevant conflicts of interest to declare.

TECHNIQUES OF MODIFYING LIPID ANTIGENS FOR SYNTHESIS OF DIAGNOSTIC AND THERPAEUTIC PREPARATIONS IN RHEUMATOLOGY

2019 ◽  
Vol 64 (10) ◽  
pp. 603-606
Author(s):  
I. P. Gontar ◽  
Oiga Ivanovna Emelyanova ◽  
O. A. Rusanova ◽  
I. A. Zborovskay ◽  
N. I. Emelyanov
Keyword(s):  
Emulsion Polymerization ◽  
Sorption Capacity ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Solid Phase ◽  
Particle Diameter ◽  
Healthy Individuals ◽  
Sorptive Capacity ◽  
Clinical Presentations ◽  
Cardiolipin Antibodies

The objective of the study is to enhance sorption capacity of diagnostic agents by using cardiolipin antigens for antiphospholipid syndrome in patients with systemic lupus erythematosus (SLE). A technique of emulsion polimerization was used. Having integrated antigen nanoobjects we developed immobilized magnetocontrollable antigen nanosystems and put them to an evaluation test. The nanosystems are polyacrylamide granules with a built in antigen. To obtain stable immobilized multi-use biopharmaceuticals with targeted properties (shape, particle diameter, pore size, density) we used a modified version of emulsion polymerization method using polyacrylamide carrier gel. This method permitted a greater sorptive capacity, preserving the antigen in maximum native state, and opened up the possibility of controllable modification of nanoobjects. Cardiolipin was used as the antigen in question. Following the method described above we performed sorption of anticardiolipin antibodies from blood plasma of SLE patients who showed clinical presentations of antiphospholipid syndrome. All SLE patoents with signs of antiphospholipid syndrome showed reliably higher levels of cardiolipin antibodies compared with SLE patients without antiphospholipid syndrome signs; the antibody level was 0.365 ± 0.026 and 0.075 ± 0.003 on average, correspondingly (p < 0.001). Blood serum from 10 apparently healthy individuals served as control. The level of cardiolipin antibodies was determined before and after sorption by indirect solid phase immunoenzyme method. In the eluate we estimated total protein by Lowry method. In vitro testing showed that the obtained antigen nanosystems based on immobilized cardiolipin could effectively remove cardiolipin antibodies from whole blood of SLE patients with clinical presentations of APS to achieve the values of healthy individuals (before sorption cardiolipin antibodies 0.328 ± 0.0289; after sorption 0.059 ± 0.0170; p<0,001; sorption capacity 8.00 ± 0.390 mg/ml). The method of emulsion polymerization with consideration to hydrophobic and hydrophilic properties of lipid molecules permits obtaining and modifying biomolecules with certain properties, in a controlled fashion.

The Role of the Tissue Factor Pathway in the Hypercoagulable State in Patients with the Antiphospholipid Syndrome

1998 ◽  
Vol 79 (02) ◽  
pp. 276-281 ◽  
Author(s):  
Olga Amengual ◽  
Tatsuya Atsumi ◽  
Graham Hughes ◽  
Munther Khamashta
Keyword(s):  
Tissue Factor ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Umbilical Vein ◽  
Antigen Expression ◽  
Peripheral Blood Mononuclear ◽  
Tissue Factor Pathway

SummaryThe antiphospholipid syndrome (APS) is characterised by both arterial and venous thrombosis, recurrent pregnancy loss and thrombocytopaenia in association with antiphospholipid antibodies (aPL). To explore further the pathogenesis of thrombosis in APS, we evaluated the behaviour of tissue factor (TF) pathway in patients with APS. Plasma antigen levels of soluble TF and tissue factor pathway inhibitor (TFPI), a physiological regulator of TF dependent coagulation activation, were measured in 57 APS patients (36 primary and 21 secondary to systemic lupus erythematosus). Significantly elevated levels of both TF and TFPI were found in APS patients compared with 25 healthy controls (279 ± 15 vs. 217 ± 17 pg/ml, p = 0.01; 56.24 ± 2.00 vs. 47.92 ± 2.22 ng/ml, p = 0.01, respectively), suggesting in vivo upregulation of TF pathway in patients with APS. By flow-cytometry, monocytes from a healthy donor displayed higher TF antigen expression when incubated in the presence of APS plasmas than in control plasmas (24.23 ± 3.11 vs. 12.78 ± 1.57%, p = 0.002). Peripheral blood mononuclear cells (PBMC) also expressed more procoagulant activity (PCA) when incubated in the presence of APS plasmas than in control plasmas (1.80 ± 0.12 vs. 1.35 ± 0.054, p = 0.001) implying that TF up-regulation in APS was reproducible in vitro. Human monoclonal anticardiolipin antibodies induced PCA on PBMC and also TF mRNA on both PBMC and human umbilical vein endothelial cells shown by reverse-transcription polymerase chain reaction. These data strongly suggest that the TF pathway is implicated in the pathogenesis of aPL related thrombosis.

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