Antigenic structures recognized by anti-β2-glycoprotein I auto-antibodies

Abstract

Beta2-glycoprotein I (beta2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D193-K246, D222-K317 and E228-K308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta2-GPI auto-antibodies to solid-phase beta2-GPI was significantly reduced either by L replacement for W235, a common amino acid component for the epitopes, or by V replacement for all of D193, D222 and E228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W235 and that epitope spreading occurred in the region surrounding W235. Thus, epitopic structures recognized by anti-beta2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.

β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome

“…It has been reported that domains IV and V of b2GPI are involved in EY2C9 mAb binding. 48,49 Conversely, mutational analyses of domain I suggested that domain I is also involved in EY2C9 mAb recognition of b2GPI.…”

“…It has been suggested that domains I, IV, and V of b2GPI are involved in EY2C9 mAb binding. [48][49][50] Indeed, when domain I-deleted b2GPI and HLA-DR were cotransfected, EY2C9 mAb failed to recognize the domain I-deleted b2GPI complexed with HLA-DR7, although the mutant b2GPI complexed with HLA-DR7 was well recognized by anti-b2GPI domain IV-V antibody (supplemental Figure 3). These data suggested that domain I plays a critical role for EY2C9 mAb recognition of the b2GPI/HLA-DR7 complexes and that domain I is not involved in the association of b2GPI with HLA-DR7.…”

Immunoreactivity and avidity of IgG anti-β2-glycoprotein I antibodies from patients with autoimmune diseases to different peptide clusters of β2-glycoprotein I

“…Due to their polyclonal nature, subpopulations of anti-b2GPI vary in epitope recognition [8,[20][21][22][23], avidity [24][25][26][27] and mechanisms of action [7,8,28], which results in their different pathogenicity and clinical relevance [8,22,23,25,29,30]. A subset of IgG anti-b2GPI directed against domain I on b2GPI seems to have a prominent role in the pathology of thrombotic complications in patients with APS [19].…”

The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis

“…We have recently demonstrated that oxLDL interacts with b2GPI and the presence of oxLDL/b2GPI complexes circulating in patients with atherosclerotic and inflammatory diseases, such as systemic lupus erythematosus, APS, DM, and chronic nephritis (4,6,10). High levels of oxLDL/ b2GPI complexes were also present in atherosclerosis-prone mice with apoe 2/2 and ldlr 2/2 genotypes, especially those fed a high-cholesterol diet (unpublished observations).…”

“…Antiphospholipid Abs are directed against epitopes that include proteins such as b2-glycoprotein I (b2GPI) (4)(5)(6), lipids, and protein-lipid complexes. We have demonstrated that anti-b2GPI autoAbs also recognize oxLDL/b2GPI complexes (4,(7)(8)(9)(10).…”