Anti-β2 -glycoprotein I antibody with DNA binding activity enters living monocytes via cell surface DNA and induces tissue factor expression.

Abstract

Autoantibodies characteristic for anti-phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are anti-β2 -glycoprotein I (β2 GPI) antibodies and anti-DNA antibodies, respectively, and almost 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 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-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 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-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.

• Authors: S Virachith, M Saito, Y Watanabe, K Inoue, O Hoshi, T Kubota
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 195 Issue 2 Pg. 167-178 (02 2019) ISSN: 1365-2249 [Electronic] England
• PMID: 30368780 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Antinuclear
• Antibodies, Antiphospholipid
• Antibodies, Monoclonal
• Autoantibodies
• DNA-Binding Proteins
• ITGB1BP1 protein, human
• Intracellular Signaling Peptides and Proteins
• MYD88 protein, human
• Membrane Proteins
• Myeloid Differentiation Factor 88
• NF-kappa B
• TLR4 protein, human
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• VCAN protein, human
• beta 2-Glycoprotein I
• Versicans
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• Deoxyribonuclease I

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Antibodies, Antinuclear (immunology)
• Antibodies, Antiphospholipid (immunology)
• Antibodies, Monoclonal (immunology)
• Antiphospholipid Syndrome (immunology)
• Autoantibodies (immunology)
• Cell Line, Tumor
• DNA-Binding Proteins (immunology)
• Deoxyribonuclease I (pharmacology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Intracellular Signaling Peptides and Proteins (biosynthesis)
• Lupus Erythematosus, Systemic (immunology)
• MAP Kinase Kinase 1 (metabolism)
• Membrane Proteins (biosynthesis)
• Mice
• Monocytes (metabolism)
• Myeloid Differentiation Factor 88 (metabolism)
• NF-kappa B (metabolism)
• Signal Transduction
• THP-1 Cells
• Toll-Like Receptor 4 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Versicans (biosynthesis)
• beta 2-Glycoprotein I (immunology)
• p38 Mitogen-Activated Protein Kinases (metabolism)