Autoantibody-mediated disruption of the epidermal growth factor system during implantation and pregnancy

Japan has a relatively high incidence of coagulation factor XII (FXII) and protein S deficiencies, which are undeniable risk factors for recurrent pregnancy loss (RPL). FXII and protein S share common epidermal growth factor (EGF)-like domains. Patients with RPL who have protein S and FXII deficiencies carry anti-protein S and anti-FXII antibodies (anti-FXII), respectively. Epitope mapping of these antibodies revealed that they have EGF-like domain epitopes, which cross-react with EGF. EGF plays a role in cell growth and differentiation, and its effects on the reproductive system, particularly in implantation and placental development, are well documented. We developed an anti-EGF antibody detection system to investigate the correlation between anti-EGF antibodies (anti-EGF) and other RPL-associated risk factors. Anti-EGF demonstrated a correlation not only with anti-FXII and anti-protein S but also with anti-phosphatidylserine/prothrombin antibodies (aPS/PT). Although the aPS/PT epitope lies within the thrombin region, which lacks an EGF-like domain, it nevertheless cross-reacts with EGF, indicating their pathogenicity to the EGF system as well as anti-FXII and anti-protein S. This review summarizes the history of antibody discovery and epitope mapping studies and discusses the pathogenic potential of these antibodies in pregnancy morbidity through their effects on reproductive biology.