AbstractAnti–β2–glycoprotein I antibodies are known to have a heterogeneous reactivity against β2–glycoprotein I. We performed this study to characterize the epitope on β2–glycoprotein I to which pathologic anti–β2–glycoprotein I antibodies are directed. Plasma samples from 198 patients with various systemic autoimmune diseases were tested for the presence of lupus anticoagulant and anti–β2–glycoprotein I immunoglobulin G (IgG) antibodies. The reactivity of the anti–β2–glycoprotein I–positive samples was further tested by coating recombinant full-length β2–glycoprotein I and 8 deletion mutants of β2–glycoprotein I onto hydrophilic and hydrophobic enzyme-linked immunosorbent assay (ELISA) plates. Full-length β2–glycoprotein I with point mutations in domain I at positions 8, 40, and 43 were used in inhibition experiments. Fifty-two patients with anti–β2–glycoprotein I IgG antibodies could be divided into 2 patterns. Type A antibodies only recognize domain I when coated onto hydrophobic plates; they do not recognize domain I coated onto hydrophilic plates. Type B antibodies have heterogeneous reactivity for all domains. Type A antibodies recognize the epitope around amino acids Gly40-Arg43 and cause lupus anticoagulant activity. In contrast to type B antibodies, those of type A strongly correlated with thrombosis. In conclusion, antibodies directed at domain I (epitope comprising Gly40 and Arg43) have lupus anticoagulant activity and strongly associate with thrombosis.
Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of 2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis