Abstract
Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, pregnancy morbidity in the presence of circulating “anti-phospholipid antibodies” (aPL). One of the main target antigens of aPL is β2-glycoprotein I (β2-GPI). APS may occur as a primary syndrome or associated with Systemic Lupus Erythematosus (SLE). High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein which is secreted from different type of cells during activation and/or cell death and may act as a proinflammatory mediator through ligation to its receptors, including RAGE. There is accumulating evidence that HMGB1 contributes to the pathogenesis of inflammatory and autoimmune diseases, especially SLE. In a previous study we demonstrated increased serum levels of HMGB1 in both primary and secondary APS patients. In this work we analyzed: (i) in vitro whether anti-β2-GPI antibodies from APS patients may induce both a HMGB1 cellular relocation by activation of its putative receptor RAGE in platelets and monocytes and, (ii) ex vivo, serum levels of HMGB1/soluble RAGE (sRAGE) in APS patients and their possible correlation with clinical manifestations. Platelets and monocytes from healthy donors were incubated with affinity purified anti-β2-GPI antibodies. HMGB1 and RAGE expression were analyzed by Western Blot. Sera from 60 consecutive APS patients (primary or secondary), diagnosed according to the Sydney Classification Criteria, were enrolled. As a control, 30 matched healthy subjects were studied. Serum levels of HMGB1 and sRAGE were analyzed by Western Blot. In vitro results showed that anti-β2-GPI antibodies were able to induce RAGE activation and HMGB1 cellular relocation in both monocytes and platelets. HMGB1 and sRAGE serum levels were significantly increased in APS patients in comparison with healthy subjects (p<0.0001). Interestingly, APS patients with spontaneous recurrent abortion showed significantly higher levels of sRAGE; moreover, in APS patients a direct correlation between serum levels of HMGB1 and disease duration was detected. Our observations suggest that anti-β2-GPI antibodies may trigger RAGE activation and HMGB1 cellular relocation during APS. Monitoring these molecules serum levels may represent an useful tool to evaluate the pathogenesis and risk stratification of clinical manifestations in APS.
Highlights
Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, pregnancy morbidity in the presence of “antiphospholipid antibodies” namely lupus anticoagulant (LA), anticardiolipin antibodies, or anti-β2−glycoprotein I antibodies [1]
In order to evaluate whether autoantibodies in APS may be able to elicit the alarmin response, we preliminary analyzed in vitro whether anti-β2-GPI antibodies from APS patients may induce both a High Mobility Group Box 1 (HMGB1) relocation to cytosol and an activation of its putative receptor Receptor for Advanced Glycation End products (RAGE) in monocytes from healthy donors
Since extracellular HMGB1 is known to be able to interact with RAGE, and in turn participate to the cell activation, i.e., inducing proinflammatory phenotype [12], we investigated whether HMGB1 was secreted from monocytes treated with anti-β2-GPI antibodies from APS patients
Summary
Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, pregnancy morbidity in the presence of “antiphospholipid antibodies” (aPL) namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2−glycoprotein I antibodies (aβ2-GPI) [1]. There is accumulating evidence that High Mobility Group Box 1 (HMGB1), an endogenous danger signal released when immune cells are activated or cell death occurs [7], contributes to the pathogenesis of inflammatory and autoimmune diseases, especially SLE [8, 9]. HMGB1 is a 30 kDa nuclear protein which was purified from nuclei for the first time in 1970 [10]. In the nucleus it works as a chromatin structural protein, organizing DNA, stabilizing nucleosome formation and regulating transcription; it was found in cytosol, mitochondria and cell plasma membrane, where it can be released to the extracellular milieu [11]. The C-truncated secretory isoform of RAGE, termed soluble RAGE (sRAGE), can be shedded by several cell types, including monocytes, and may neutralize the AGEs-mediated damage by acting as a decoy [18,19,20]
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