Monocyte Tissue Factor Induction by Activation of β2-Glycoprotein-I-Specific T Lymphocytes Is Associated with Thrombosis and Fetal Loss in Patients with Antiphospholipid Antibodies

Abstract

Antiphospholipid (aPL) syndrome (APS) is characterized by thromboembolic events, thrombocytopenia, or recurrent miscarriage associated with aPL Abs with specificity for β2-glycoprotein-I (β2GPI). We recently reported that at least 44% of patients with the APS possess circulating type 1 (Th1) CD4+ T cells that proliferate and secrete IFN-γ when stimulated with β2GPI in vitro. In this study, we show that stimulation of PBMCs from 20 APS patients with β2GPI induced substantial monocyte tissue factor (TF) (80 ± 11 TF stimulation index (TF-SI)), whereas no induction was observed using PBMCs from 13 patients with aPL Abs without APS (6 ± 1 TF-SI) or 7 normal and 7 autoimmune controls (5 ± 1 and 3 ± 1 TF-SI, respectively) (p < 0.0001). TF induction on monocytes by β2GPI was dose dependent and required CD4+ T lymphocytes and class II MHC molecules. Because monocyte TF induction by β2GPI was observed in all patients with APS, but not in any patient with aPL Abs without APS, this response is a potentially useful predictor for APS in patients with aPL Abs, as well as providing mechanistic insight into thrombosis and fetal loss in these patients.

Clinical manifestations of chronic inflammatory demyelinating polyneuropathy with anti-cardiolipin antibodies

“…However, clinical manifestations of APS do not occur in patients with these infectious diseases. Thus, anti-b2-GPI antibodies were detected in patients with APS, but not in patients with those infectious diseases (32). The main difference appears to be an absolute requirement for b2-GPI, a plasma protein, in detection of antiphospholipid antibodies in APS (29,30).…”

Beta-2-glycoprotein I expression on monocytes is increased in anti-phospholipid antibody syndrome and correlates with tissue factor expression

“…Indeed, circulating monocytes of patients with primary APS display tissue factor overexpression that may contribute to the prothrombotic state [27]. Stimulation of peripheral blood mononuclear cells of these patients with β 2 ‐GPI induces substantial monocyte tissue factor, which was shown to be dose‐dependent and requiring CD4+ T lymphocytes and class II MHC molecules to be expressed [28]. These findings suggested that patients with APS may have chronic stimulation of β 2 ‐GPI‐specific T lymphocytes which leads to persistently high monocyte tissue factor expression and consequently to a prothrombotic diathesis [28].…”

Molecular Pathogenesis of the Antiphospholipid Syndrome

“…97 Stimulation of monocytes from aPL syndrome patients with ␤ 2 GPI induced substantial monocyte tissue factor, whereas no induction was observed with cells from patients having aPL antibodies without clinical problems; this effect required CD4 ϩ T lymphocytes and class II MHC molecules. 98 In one study, the ability of IgG to stimulate monocyte tissue factor expression was associated with the presence of decreased free protein S and increased prethrombotic markers. 99,100 Another means by which aPL antibodies may increase tissue factor activity and resultant Xa generation is via antibody-mediated inhibition of tissue factor pathway inhibitor activity.…”