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

Autoantibodies characteristic for antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are anti-β2 -glycoprotein I (β2 GPI) antibodies and anti-DNA antibodies, respectively, and nearly half of APS cases occur in SLE. Anti-β2 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-β2 GPI antibodies to cell surface β2 GPI in monocytes and endothelial cells triggers the TLR4-MyD88 signaling pathway which leads to activation of p38 MAPK, MEK-1/ERK, and/or NF-κB, and expression of tissue factor (TF). However resting cells do not express substantial amounts of TLR4. Previously, we generated a mouse monoclonal anti-β2 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 TNF-α, which in turn stimulated endothelial cells to express ICAM-I and VCAM-I. These results suggest a possibility that a subset of anti-β2 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. This article is protected by copyright. All rights reserved.

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