Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Abstract

Anticardiolipin (aCL) autoantibodies are associated with thrombosis, recurrent fetal loss, and thrombocytopenia. Only aCL found in autoimmune disease require the participation of the phospholipid binding plasma protein ␤2 glycoprotein I (␤2GPI) for antibody binding and now are called anti-␤2GPI. The antigenic specificity of aCL affinity purified from 11 patients with high titers was evaluated in an effort to better understand the pathophysiology associated with aCL. Seven different recombinant domain-deleted mutants of human ␤2GPI, and full length human ␤2GPI (wildtype), were used in competition assays to inhibit the autoantibodies from binding to immobilized wild-type ␤2GPI. Only those domain-deleted mutants that contained domain 1 inhibited the binding to immobilized wild-type ␤2GPI from all of the patients. The domain-deleted mutants that contained domain 1 inhibited all aCL in a similar but not identical pattern, suggesting that these aCL recognize a similar, but distinguishable, epitope(s) present on domain 1.

How do antiphospholipid antibodies bind β2‐glycoprotein I?

“…If domain IV does contain the major epitope for aPL, then the DMs for domains II-V, III-V, and IV-V would be expected to bind aPL to variable degrees. These mutants were either not examined (80,81) or found to be unable to bind aPL (57). Thus, the data from Iverson et al complements and extends the findings from the other two groups, and clearly implicates domain I in the binding of aPL, particularly since they found that the domains I-II and domain I DMs both bound aPL (57).…”

“…Iverson et al (57) studied the reactivity of aPL with various ␤ 2 GPI domain-deleted mutants (DM) expressed in insect cells. The expression vectors were designed such that expression products contained carboxyl-terminal Gly/His-6 tags for binding to nickel chelate plates.…”

Receptors involved in cell activation by antiphospholipid antibodies

“…β2GP1 is composed of five "sushi" domains. Domain V mediates the binding of the molecule to anionic phospholipids while domain I seems to be the main target of antibodies associated with an increased risk of thrombosis [24,25]. At least two different conformations are known for β2GP1: a circular plasma conformation in which domain I interacts with domain V and an "activated" fishhook-like conformation [26].…”

Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human β2‐glycoprotein I: Mutation studies including residues R39 to R43

“…The bulk of the evidence favors aPL binding immunodominant epitopes located within the N-terminal (domain I) (13)(14)(15). The ability of anti-␤ 2 GPI antibodies purified from patients with autoimmune disease to bind domain I of ␤ 2 GPI has been shown to be strongly correlated with the occurrence of thrombosis in those patients (16).…”