Cross-reactivity of antigenic binding sites of antiphosphatidylserine/prothrombin antibodies in patients with pregnancy loss and epidermal growth factor

Abstract

BackgroundEpidermal growth factor (EGF) protein family is essential for implantation and maintenance of normal pregnancy. Results of our previous study on the high incidence of autoantibodies to EGF in patients with pregnancy loss indicated a strong association between EGF autoantibodies and antiphosphatidylserine/prothrombin antibodies (aPS/PT), which are observed in the plasma of patients with thrombosis and adverse pregnancy outcomes. ObjectivesTo investigate the association between EGF autoantibodies and aPS/PT in patients with pregnancy loss. Patients and methodsPlasma specimens were analyzed from patients who experienced pregnancy loss. Direct binding studies using recombinant proteins of the fragments were conducted to determine the antigenic binding sites of aPS/PT, before examining the cross-reactivity of EGF and aPS/PT binding sites. ResultsOf the 219 patients with pregnancy loss, 26 (11.9 %) were positive for aPS/PT. Moreover, incidence of antihuman EGF autoantibodies (anti-hEGF) was significantly higher in aPS/PT-positive patients than in aPS/PT-negative patients (18/26, 69.2 % and 58/193, 30.1 %, respectively; p = 0.0003). Of the aPS/PT-positive patients, 42.3 % recognized fragment 1 + 2 (F1 + 2), and 61.5 % recognized α-thrombin. Presence of anti-hEGF was correlated with recognition of α-thrombin but not of F1 + 2. Moreover, polyclonal antibodies against EGF recognized α-thrombin, and those against α- thrombin recognized hEGF. ConclusionsIn patients with pregnancy loss, aPS/PT recognize F1 + 2 and α-thrombin. Furthermore, α-thrombin and hEGF are immunologically cross-reactive.Therefore, autoantibody-associated disruption of the EGF system may be a cause ofpregnancy loss.