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.