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New Insights in the Pathophysiology of Antiphospholipid Syndrome.

ABSTRACT: The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by an elevated risk for arterial and venous thrombosis and pregnancy-related morbidity. Since the discovery of the disease in 1980s, numerous studies in cell culture systems, in animal models, and in patient populations have been reported, leading to a deeper understanding of the pathogenesis of APS. These studies have determined that circulating autoantibodies, collectively called antiphospholipid antibodies (aPL), the majority of which recognize cell surface proteins attached to the plasma membrane phospholipids, play a causal role in the development of the disease. The binding of aPL to the cell surface antigens triggers interaction of the complex with transmembrane receptors to initiate intracellular signaling in critical cell types, including platelets, monocytes, endothelial cells, and trophoblasts. Subsequent alteration of various cell functions results in inflammation, thrombus formation, and pregnancy complications. Apolipoprotein E receptor 2 (apoER2), a lipoprotein receptor family member, has been implicated as a mediator for aPL actions in platelets and endothelial cells. Nitric oxide (NO) is a signaling molecule known to exert potent antithrombotic, anti-inflammatory, and anti-atherogenic effects. NO insufficiency and oxidative stress have been linked to APS pathogenesis. This review will focus on the recent findings on how apoER2 and dysregulation of NO production contribute to aPL-mediated pathologies in APS.

SUBMITTER: Sacharidou A

PROVIDER: S-EPMC6333209 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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New Insights in the Pathophysiology of Antiphospholipid Syndrome.

Sacharidou Anastasia A Shaul Philip W PW Mineo Chieko C

Seminars in thrombosis and hemostasis 20170127 5

The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by an elevated risk for arterial and venous thrombosis and pregnancy-related morbidity. Since the discovery of the disease in 1980s, numerous studies in cell culture systems, in animal models, and in patient populations have been reported, leading to a deeper understanding of the pathogenesis of APS. These studies have determined that circulating autoantibodies, collectively called antiphospholipid antibodies (aPL), the ...[more]

PMID: 28129662

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Project description:Antiphospholipid Syndrome (APS) is an autoimmune disorder, characterized by pregnancy morbidity and/or a hyper coagulable state involving the venous or the arterial vasculature and associated with antiphospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), anti-beta2-glycoprotein I (anti-ß2GPI), and Lupus anticoagulant (LA). In recent years there have been many advances in the understanding of the molecular basis of vascular involvement in APS. APS is of multifactorial origin and develops in genetically predisposed individuals. The susceptibility is determined by major histocompatibility complex (MHC). Different HLA-DR and HLA-DQ alleles have been reported in association with APS. Moreover, MHC II alleles may determine the autoantibody profile and, as such, the clinical phenotype of this disease. Besides, polymorphisms in genes related to the vascular system are considered relevant factors predisposing to clinical manifestations. Antiphospholipid antibodies (aPL) induce genomic and epigenetic alterations that support a pro- thrombotic state. Thus, a specific gene profile has been identified in monocytes from APS patients -related to aPL titres in vivo and promoted in vitro by aPL- explaining their cardiovascular involvement. Regarding epigenetic approaches, we previously recognized two miRNAs (miR-19b/miR-20a) as potential modulators of tissue factor, the main receptor involved in thrombosis development in APS. aPLs can further promote changes in the expression of miRNA biogenesis proteins in leukocytes of APS patients, which are translated into an altered miRNA profile and, consequently, in the altered expression of their protein targets related to thrombosis and atherosclerosis. MicroRNAs are further released into the circulation, acting as intercellular communicators. Accordingly, a specific signature of circulating miRNAs has been recently identified in APS patients as potential biomarkers of clinical features. Genomics and epigenetic biomarkers might also serve as indices for disease progression, clinical pharmacology, or safety, so that they might be used to individually predict disease outcome and guide therapeutic decisions. In that way, in the setting of a clinical trial, novel and specific microRNA-mRNA regulatory networks in APS, modified by effect of Ubiquinol treatment, have been identified. In this review, current and previous studies analyzing genomic/epigenetic changes related to the clinical profile of APS patients, and their modulation by effect of specific therapies, are discussed.

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New Insights in the Pathophysiology of Antiphospholipid Syndrome.

Publications

New Insights in the Pathophysiology of Antiphospholipid Syndrome.

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