Beyond antibodies: Beta-2 glycoprotein I as the unsung guardian of pregnancy

The physiological function of beta 2 glycoprotein I (β2GPI) itself is not well understood, other than that it is a primary antigen to anti-phospholipid antibodies in the autoimmune disease antiphospholipid syndrome. β2GPI is a soluble blood protein that is predominantly synthesized in hepatocytes. Why is the expression of β2GPI observed in the placenta despite its abundance in the circulating blood of healthy individuals? Does the placenta produce a specific-acting β2GPI?. β2GPI was recently shown to adopt two interconvertible biochemical confirmations based on the integrity of disulfide bonds: oxidized and reduced. The present study investigates the physiological function of β2GPI in trophoblast cells, with a focus on the reduced and oxidized forms of β2GPI under the hypothesis that placental β2GPI has a different activity from circulating β2GPI. Endogenous β2GPI secretion in trophoblast cells were predominantly in the reduced form, while those in HepG2 liver cells were mainly in the oxidized form. Progesterone increased reduced-β2GPI in both the trophoblast and liver cells. Oxidized-β2GPI significantly inhibited trophoblast cell migration and increased placental soluble fms-like tyrosine kinase-1 (sFlt-1). Furthermore, excess sFlt-1 significantly increased oxidized-β2GPI secretion in HepG2 cells. Circulating oxidized-β2GPI levels were significantly higher in women with pre-eclampsia than in those without pre-eclampsia. Therefore, oxidized-β2GPI may contribute to the pathogenesis of pre-eclampsia. Under oxidative stress, the excessive oxidation of β2GPI and/or excessive placental sFlt-1 may trigger a negative spiral between trophoblast and liver cells.