Effect of beta_2-glycoprotein I null mutation on reproductive outcome and antiphospholipid antibody-mediated pregnancy pathology in mice

摘要

beta_2-Glycoprotein I (beta2GPI) is a principal target antigen for antiphospholipid antibodies associated with recurrent pregnancy loss and fetal growth restriction in women. The significance of disrupted beta_2GPI activity in contributing to pregnancy pathology in antiphospholipid syndrome (APS) is "hot clear. In this study the physiological requirement for functional beta_2GPI in pregnancy was investigated by evaluating reproductive outcomes in beta_2GPI null mutant (beta_2GPI-/-) mice. p2GPI-/- mice were fertile and carried viable fetuses to term. However, there was an 18% reduction in the number of viable implantation sites in p2GPI-/-mice and reduced fetal weight and fetal:placental weight ratio in late gestation, suggesting compromised placental function. Placental architecture was altered in beta_2GPI-/- implantation sites with a 24% increase in the junctional zone: labyrinthine ratio, but placentae showed no evidence of increased thrombosis in the absence of beta_2GPI. The effect of beta_2GPI genotype on pregnancy success after passive transfer of human and mouse antibodies reactive with beta_2GPI was also explored. Two of five anti-beta_2GPI antibodies induced pregnancy loss in beta_2GPI+/+ mice but beta_2GPI-/- mice were refractory to antibody-induced pregnancy failure. We conclude that functional beta_2GPI is not essential for successful pregnancy in mice, but optimal placental development and fetal growth require this molecule. Together these data are consistent with pathogenic mechanisms in antiphospholipid syndrome involving both neutralization of beta_2GPI function and beta_2GPI-immunoglobulin complex formation.