BETA 2-GLYCOPROTEIN I-DEPENDENT ANTICARDIOLIPIN ANTIBODIES PREFERENTIALLY BIND THE AMINO TERMINAL DOMAIN OF BETA 2-GLYCOPROTEIN 1

McNeeley PA1, Dlott JS2, Furie RA3, Jack RM4, Ortel TL5, Triplett DA2, Victoria EJ1, Linnik MD1.

1. La Jolla Pharmaceutical Company, San Diego, CA
2. Midwest Hemostasis and Thrombosis Laboratories, Medical Education Department, Ball Memorial Hospital, Muncie, IN
3. Division of Rheumatology and Allergy-Clinical Immunology, North Shore University Hospital-NYU School of Medicine, Manhasset, NY
4. Triad Therapeutics, San Diego, CA
5. Department of Medicine, Duke University Medical Center, Durham, NC.

Many of the autoantibodies in antiphospholipid syndrome (APS) are directed against beta2-glycoprotein I (beta2-GPI). Recent studies from our laboratories have indicated that the immunodominant binding epitope(s) for high titer, affinity purified antibodies from 11 APS patients are localized to the amino terminal domain (domain 1) of beta2-GPI. The present study employed surface plasmon resonance to localize the immunodominant domain in serum samples from a large cohort of patients with GPL values ranging from 21 to 230 units (n = 106 patients). Eighty-eight percent of patients showed > or = threefold selectivity for beta2-GPI containing domain 1 relative to the domain deletion mutant that lacked domain 1. The domain 1 binding activity in patient serum was abolished by removing the IgG fraction from the serum and the binding activity could be fully reconstituted with the IgG fraction. Thus, analysis of serum samples from a large cohort of APS patients indicates that the immunodominant binding epitope(s) for anti-beta2 antibodies are localized to the amino terminal domain of beta2-GPI.

Published in Thrombosis and Haemostasis, 2001;86: 590-595