title: Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein.
abstract: Thrombosis in the antiphospholipid syndrome has been associated with acquired deficiency of the anticoagulant protein S. We sought evidence that beta2-glycoprotein I, a major target antigen for antiphospholipid antibodies, is involved in regulation of protein S activity. Incubation of purified protein S or plasma with beta2-glycoprotein I reversed functional modulation of protein S by its plasma inhibitor, the C4b-binding protein. In a plasma-free ELISA, beta2-glycoprotein I prevented the binding of protein S and C4b-binding protein when preincubated with immobilized protein S but not when similarly preincubated with C4b-binding protein. beta2-glycoprotein I in fluid phase interfered with precipitation of protein S by sepharose-bound C4b-binding protein. Effects of beta2-glycoprotein I on protein S function were inhibited by one of four monoclonal anti-beta2-glycoprotein 1 antibodies. These data suggest that beta2-glycoprotein I helps maintain adequate plasma levels of circulating free, active protein S. Antiphospholipid (anti-beta2-glycoprotein I) antibodies might cause sporadic thrombosis, at least in part, by impairing this novel regulatory mechanism.
authors.affiliation: Division of Rheumatology, St. Luke's/Roosevelt Hospital Center, New York, NY 10019, USA. JTMmail@aol.com
authors.forename: J T
authors.initials: JT
authors.lastname: Merrill
authors.forename: H W
authors.initials: HW
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Shen
authors.forename: B T
authors.initials: BT
authors.lastname: Butman
authors.forename: E P
authors.initials: EP
authors.lastname: Jeffries
authors.forename: R G
authors.initials: RG
authors.lastname: Lahita
authors.forename: B L
authors.initials: BL
authors.lastname: Myones
mesh_terms: D017152:Antibodies, Antiphospholipid / Q000097:blood / Q000276:immunology; D001777:Blood Coagulation; D003169:Complement Inactivator Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D017293:Protein S / Q000378:metabolism*; D011951:Receptors, Complement / Q000097:blood*; D013927:Thrombosis / Q000097:blood*; D053482:beta 2-Glycoprotein I
chemical_list: D017152:Antibodies, Antiphospholipid; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D017293:Protein S; D011951:Receptors, Complement; D053482:beta 2-Glycoprotein I