Oxidation of β2-glycoprotein I associates with IgG antibodies to domain I in patients with antiphospholipid syndrome

Domain I (DI) of beta-2-glycoprotein I (β 2 GPI) contains the immunodominant epitope for pathogenic antiphospholipid antibodies (aPL). DI is exposed in the linear form of the molecule but not in the circular form that comprises 90% of serum β 2 GPI. The majority of circulating β 2 GPI is biochemically reduced with two free thiols in Domain V. However, increased levels of oxidised β 2 GPI are found in patients with antiphospholipid syndrome (APS). It is not known whether oxidation of β 2 GPI favours the linear form of the molecule and thus promotes development of anti-DI antibodies. We investigated whether the proportion of oxidised β 2 GPI associates with the presence of anti-DI in APS patients. Serum samples from 44 APS patients were screened for IgG, IgM and IgA anti-DI, anti-β 2 GPI, anti-cardiolipin (anti-CL) and biochemically reduced β 2 GPI. A negative correlation was found between the proportion of β 2 GPI in the biochemically reduced form and IgG anti-DI levels (r = -0.54, p = 0.0002), but not with IgM or IgA anti-DI. Moreover, the proportion of β 2 GPI in the reduced form was lower in IgG anti-DI positive than anti-DI negative APS patients (p = 0.02). The relative amount of reduced β 2 GPI was no different between patients who were positive or negative for IgG, IgM and IgA anti-β 2 GPI or anti-CL. This study demonstrates that oxidised β 2 GPI lacking free cysteine-thiol groups most closely associates with IgG anti-DI positivity compared to IgG anti-CL and anti-β 2 GPI. Future studies are required to ascertain the directionality of this association to define causation.