Autoantibodies directed against domain I of beta2-glycoprotein I

Abstract

Patients diagnosed with the antiphospholipid syndrome typically suffer from vascular thrombosis, pregnancy morbidity, or a combination of the two. Due to the high prevalence of these clinical symptoms, the diagnosis of antiphospholipid syndrome is almost completely dependent on the detection of antiphospholipid antibodies in patient plasma. However, not every individual with antiphospholipid antibodies in his or her plasma suffers from thrombosis and/or pregnancy morbidity, which suggests the existence of different populations of antiphospholipid antibodies. Although many antigens have been identified in relation to the antiphospholipid syndrome, β2-glycoprotein I is regarded as clinically most significant. During the past decade, evidence has accumulated to suggest the presence of a dominant epitope on the first domain of β2-glycoprotein I. Several studies have detected a specific population of antibodies recognizing a cryptic epitope on domain I, at least comprising arginine 39 to arginine 43. In contrast to antibodies recognizing other domains of β2-glycoprotein I, anti-domain I antibodies are found to be highly associated with clinical symptoms. This review discusses several studies that have investigated a role for domain I within the antiphospholipid syndrome on a predominantly diagnostic level.

Fig. 1

Model for conformational change in different published β2-glycoprotein I (β2GPI)-based structures. The crystal structure of β2GPI was first found and showed β2GPI in a fishhook-like shape [20, 21]. Interestingly, using small x-ray scattering, β2GPI was found to be in an S-shape conformation, with a carbohydrate chain on top of the interface between domains I and II [22]. Agar et al. [••] recently found a circular shape of β2GPI in the absence of anionic phospholipids when applying electron microscopy. This circular conformation could be transformed into a fishhook-like shape by adding anionic phospholipids to the β2GPI preparation. It can be hypothesized that all three conformations exist in the human body. Based on this hypothesis, a model can be designed in which β2GPI exists in a circular conformation in solution. Although domain V and domains I and II have a predominantly positively charged surface, they can interact due to the fact that a negative carbohydrate chain lies in between and serves as a sort of glue. Upon binding to phospholipids, β2GPI transitions from a circular conformation into an S-shaped conformation. This conformation is based on the fact that both the surface (anionic phospholipids) and the carbohydrate on top of domains I and II are negatively charged, thereby causing domains I and II to dissociate from domain V, which has a higher affinity for phospholipids. Subsequently, the whole molecule erects, making epitope arginine 39-arginine 43 available to react with anti-domain I antibodies