Abstract
Domain I (DI) of beta-2-glycoprotein I (β2GPI) 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 β2GPI. The majority of circulating β2GPI is biochemically reduced with two free thiols in Domain V. However, increased levels of oxidised β2GPI are found in patients with antiphospholipid syndrome (APS). It is not known whether oxidation of β2GPI favours the linear form of the molecule and thus promotes development of anti-DI antibodies. We investigated whether the proportion of oxidised β2GPI 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-β2GPI, anti-cardiolipin (anti-CL) and biochemically reduced β2GPI. A negative correlation was found between the proportion of β2GPI 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 β2GPI 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 β2GPI was no different between patients who were positive or negative for IgG, IgM and IgA anti-β2GPI or anti-CL. This study demonstrates that oxidised β2GPI lacking free cysteine-thiol groups most closely associates with IgG anti-DI positivity compared to IgG anti-CL and anti-β2GPI. Future studies are required to ascertain the directionality of this association to define causation.
Highlights
A significant negative correlation was obtained between the proportion of β2GPI in the reduced form and IgG anti-Domain I (DI) levels (r = -0.54, p = 0.0002), but not with IgM or IgA antibodies targeting β2GPI-DI (anti-DI) (r = 0.08, p = 0.59 and r = -0.19, p = 0.21, respectively)
Anti-DI antibodies represent a sub-population of anti-β2GPI, no significant correlation was found between the reduced proportion of β2GPI and IgG, IgM or IgA anti-β2GPI (r = -0.17, p = 0.25; r = -0.09, p = 0.56; r = -0.01, p = 0.94 respectively) and no significant difference existed dividing the samples according to IgG anti-β2GPI positivity (p = 0.89)
In this study we report, for the first time, a statistically significant negative correlation between levels of IgG anti-DI antibodies and proportion of β2GPI in the reduced form in patients with Antiphospholipid syndrome (APS)
Summary
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis and recurrent pregnancy morbidity in the presence of serum antiphospholipid. Giannakopoulos and Krilis showed that affinity-purified antiphospholipid antibodies from patients with APS bound more strongly to oxidised than to reduced β2GPI [10]. It is not known, whether the circular form of β2GPI is primarily reduced and whether oxidation of β2GPI favours linearization of the protein with exposure of antigenic epitopes on DI. Can be used to test the hypothesis that the proportion of oxidised β2GPI in serum of patients with APS correlates with the level of anti-DI antibodies.
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