Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction

Soltész, Pál; Dér, Henriett; Veres, Katalin; Laczik, Renáta; Sipka, Sándor; Szegedi, Gyula; Szodoray, Péter

doi:10.1093/rheumatology/ken349

Cited by 56 publications

(52 citation statements)

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“…Persistent autoantibodies affect endothelial function contributing to thrombosis. [33][34][35][36][37] In order to evaluate antithrombotic properties of A1-A1 in vivo in the setting resembling APS in humans, we used a mouse model of APS.38-41 Male (NZW 3 BXSB)F 1 mice express persistent autoimmune antib2GPI antibodies early in life and develop thrombosis of small coronary vessels causing myocardial microinfarcts.For the first time, we demonstrated that A1-A1 efficiently reduces thrombus size in a laser-induced arterial thrombosis model in vivo in the presence of chronic autoimmune anti-b2GPI antibodies. We have The publication costs of this article were defrayed in part by page charge payment.…”

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confidence: 99%

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Kolyada

Porter

Beglova

2014

Blood

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• A1-A1 inhibits thrombotic properties of anti-b2GPI antibodies in mice.• A1-A1 does not affect thrombus size in the absence of anti-b2GPI antibodies.Antiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy losses. b2-glycoprotein I (b2GPI) is the major antigen for clinically relevant antibodies in APS. We engineered a molecule, A1-A1, which interferes with 2 prothrombotic mechanisms in APS: the binding of b2GPI to negatively charged cellular surfaces and ApoE receptor 2. We studied how A1-A1 affects arterial thrombosis in vivo in lupus-prone (NZW 3 BXSB)F 1 male mice. For the first time, we demonstrated that A1-A1 efficiently reduces thrombus size in vivo in the presence of chronic autoimmune antib2GPI antibodies. We have shown that A1-A1 interferes with thrombotic properties of b2GPI/antibody complexes and does not affect normal thrombus formation in the absence of anti-b2GPI antibodies. A1-A1 inhibits prothrombotic properties of b2GPI/antibody complexes in wild-type mice after acute infusion with anti-b2GPI antibodies, as well as in mice expressing persistent autoimmune anti-b2GPI antibodies. A1-A1 reduced thrombus size in a mouse model of APS in the presence of lupus features, suggesting that A1-A1 might effectively interfere with thrombosis not only in primary APS but also in APS secondary to lupus. Our results suggest that A1-A1 could be a prototype for an antithrombotic drug in APS. (Blood. 2014;123(7):1090-1097) IntroductionAntiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy loss. [1][2][3] It is diagnosed based on the combination of clinical features and laboratory tests for circulating autoantibodies. Thrombotic events in APS nearly equally occur in veins and arteries, and about 30% of patients with thrombosis are men. [4][5][6][7] Thrombosis in APS correlates with the presence of antibodies to b2-glycoprotein I (b2GPI). [8][9][10][11] The physiological function of b2GPI is not well defined 12 and its deficiency in humans or mice does not result in apparent abnormalities. [13][14][15][16] b2GPI acquires prothrombotic properties only after association with antibodies. 10,12 Treatment with anti-b2GPI antibodies or recombinant dimers of b2GPI mimicking b2GPI/antibody complexes results in increased thrombus size in animal models of thrombosis and cellular activation in vitro. 2,3,[17][18][19][20] It was demonstrated both in vitro and in vivo that exposure of endothelial cells, monocytes, and platelets to b2GPI/anti-b2GPI antibody complexes shifts the cellular phenotype to prothrombotic and proinflammatory (reviewed in Giannakopoulos and Krilis,2 Tripodi et al, 3 and Harper et al 20 ). Anionic phospholipids, Toll-like receptors 2 and 4 (TLR2 and TLR4), annexin A2, and ApoER2 are cell-surface molecules involved in binding and activation of endothelial cells and monocytes by b2GPI/antibody complexes. [21][22][23][24][25][26] The binding of b2GPI to anionic phospholipids and the assembly of b2GPI/antibody c...

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confidence: 99%

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Kolyada

Porter

Beglova

2014

Blood

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“…15 The presence of antibodies against neuronal cell surface in patients affected by SC or other chorearelated autoimmune diseases, including aPL-related chorea, suggests the possibility of using immunomodulant treatment in these cases. 3,10 In the literature many studies reported the efficacy and the beneficial use of corticosteroid and intravenous immunoglobulin (IVIG) treatment in autoimmune paediatric diseases.…”

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confidence: 99%

Conventional and intravenous immunoglobulin therapy in paediatric antiphospholipid antibodies-related chorea

Brogna

Mariotti

Manna

2014

Lupus

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“…An abnormal ankle-brachial-index was more common in PAPS (19%) than in healthy controls group (4%) though these findings were not corrected for confounders such as hypertension, obesity and hypercholesterolaemia [18]. Flow mediated vasodilatation was consistently lower in PAPS than in controls particularly in patients with arterial disease [8,9,[19][20][21][22].…”

Section: Atherosclerosis and Endothelial Dysfunctionmentioning

confidence: 91%

“…On the other hand, 3 reports of PAPS patients showed greater IMT with a greater prevalence of plaques (21%) compared to an equal number of age and sex matched non-thrombotic controls (3%) [7][8][9][10]. These studies have some limitations in that PAPS patients, by definition, are characterised by persistence of aPL and thrombosis, and any such study should include both healthy (normal) and thrombotic controls with persistence of the thrombotic risk factor.…”

Section: Evidence For Atherosclerosis In Paps Atherosclerosis Detectementioning

confidence: 99%

“…Early observations suggesting that aPL contributed to atherosclerosis in Systemic Lupus Erythematosus (SLE) lead to testing the atherosclerosis hypothesis in primary APS (PAPS) through the measurement of Intima Media Thickness (IMT) in large enough PAPS series [2][3][4][5][6][7][8][9][10][11]. This review will survey the pathways associated with premature atherosclerosis in PAPS as they temporally appeared in the scientific literature, and will discuss how these reports support the concept of atherosclerosis as a low grade inflammatory and immune process.…”

Section: Introductionmentioning

confidence: 99%

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Atherosclerosis in Primary Antiphospholipid Syndrome: Summary of Clinical and Pathogenic Evidence

Prj

Matsuura³

et al. 2014

J Clin Exp Cardiolog

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The Antiphospholipid Syndrome (APS) was described in the early '80s as a combination of thrombosis, thrombocytopenia and recurrent miscarriages associated with persistent high titers of Antiphospholipid Antibodies (aPL). In subsequent years, it became apparent that aPL were also associated with premature atherosclerosis in Systemic Lupus Erythematosus (SLE) and more recently in primary APS (PAPS). The studies exploring atherosclerosis in PAPS were heterogeneous in conception and size, but overall, provided enough evidence that Intima Media Thickness (IMT) of carotid arteries and endothelial function are abnormal in PAPS. In keeping with the general view that atherosclerosis is a low grade inflammatory and "auto"immune disorder characterised by oxidative and nitrative stress, several studies have confirmed similar findings in PAPS, though a specific relation with the severity of atherosclerosis is lacking. Given its development at an earlier age than average, atherosclerosis should be taken into account in the overall management of PAPS patients as it may significantly add to the vascular risk.

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Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction

Abstract: In APS, the orchestrated pro-inflammatory cascade can eventually result in endothelial dysfunction, leading to the characteristic vascular abnormalities of the disease.

Cited by 56 publications

References 31 publications

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Conventional and intravenous immunoglobulin therapy in paediatric antiphospholipid antibodies-related chorea

Atherosclerosis in Primary Antiphospholipid Syndrome: Summary of Clinical and Pathogenic Evidence

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