Effect of β₂-glycoprotein I null mutation on reproductive outcome and antiphospholipid antibody-mediated pregnancy pathology in mice

β₂-Glycoprotein I (β₂GPI) is a principal target antigen for antiphospholipid antibodies associated with recurrent pregnancy loss and fetal growth restriction in women. The significance of disrupted β₂GPI activity in contributing to pregnancy pathology in antiphospholipid syndrome (APS) is not clear. In this study the physiological requirement for functional β₂GPI in pregnancy was investigated by evaluating reproductive outcomes in β ₂GPI null mutant (β₂GPI-/-) mice. β ₂GPI-/- mice were fertile and carried viable fetuses to term. However, there was an 18% reduction in the number of viable implantation sites in β₂GPI-/- mice and reduced fetal weight and fetal:placental weight ratio in late gestation, suggesting compromised placental function. Placental architecture was altered in β₂GPI-/- implantation sites with a 24% increase in the junctional zone: labyrinthine ratio, but placentae showed no evidence of increased thrombosis in the absence of β₂GPI. The effect of β₂GPI genotype on pregnancy success after passive transfer of human and mouse antibodies reactive with β ₂GPI was also explored. Two of five anti-β ₂GPI antibodies induced pregnancy loss in β ₂GPI+/+ mice but β₂GPI-/- mice were refractory to antibody-induced pregnancy failure. We conclude that functional β₂GPI 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 β₂GPI function and β ₂GPI-immunoglobulin complex formation.