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Summary  Autoantibodies characteristic for anti‐phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are anti‐β 2 ‐glycoprotein I (β 2 GPI) antibodies and anti‐DNA antibodies, respectively, and almost half of APS cases occur in SLE. Anti‐β 2 GPI antibodies are recognized to play a pivotal role in inducing a prothrombotic state, but the precise mechanism has not been fully elucidated. In a widely accepted view, binding of anti‐β 2 GPI antibodies to cell surface β 2 GPI in monocytes and endothelial cells triggers the Toll‐like receptor 4‐myeloid differentiation primary response 88 (TLR)‐4‐MyD88) signaling pathway which leads to activation of p38 mitogen‐activated protein kinase (MAPK), mitogen‐activated protein kinase kinase 1/extracellular signal‐regulated kinases (MEK‐1/ERK) and/or nuclear factor kappa B (NF‐κB) and expression of tissue factor (TF). However, resting cells do not express substantial amounts of TLR‐4. Previously, we generated a mouse monoclonal anti‐β 2 GPI antibody WB‐6 and showed that it induced a prothrombotic state – including TF expression on circulating monocytes – in normal mice. In the current study, we aimed to clarify the mechanism of interaction between WB‐6 and resting monocytes, and found that WB‐6 exhibits binding activity to DNA and enters living monocytes or a monocytic cell line and, to a lesser extent, vascular endothelial cells. Treatment of the cells with DNase I reduced the internalization, suggesting the involvement of cell surface DNA in this phenomenon. Monocytes harboring internalized WB‐6 expressed TF and tumor necrosis factor (TNF)‐α which, in turn, stimulated endothelial cells to express intercellular adhesion molecule 1 (ICAM‐I) and vascular cell adhesion molecule 1 (VCAM‐I). These results suggest the possibility that a subset of anti‐β 2 GPI antibodies with dual reactivity to DNA possesses ability to stimulate DNA sensors in the cytoplasm, in addition to the cell surface receptor‐mediated pathways, leading to produce proinflammatory and prothrombotic states.

Anti‐β 2 ‐glycoprotein I antibody with DNA binding activity enters living monocytes via cell surface DNA and induces tissue factor expression