Anti-cardiolipin antibodies induce pregnancy failure by impairing embryonic implantation.

Abstract

The antiphospholipid syndrome is characterized by thrombocytopenia, thrombosis, and recurrent fetal loss in association with anti-cardiolipin antibodies (ACAs) or lupus anti-coagulants. However, the causal role of these antibodies in the disease and the mechanisms by which the ACA may induce the syndrome are not clear. Recently, we have established an experimental mouse antiphospholipid syndrome induced by the mouse IgM monoclonal ACA designated 2C4C2. In the present study, we focused on the effects of immunization with the monoclonal ACA 2C4C2 on the outcome of pregnancies in BALB/c female mice. Four weeks after active immunization with the monoclonal ACA, a severe gestational failure with low pregnancy rates, low number of fetuses, and a high rate of resorptions was observed. Moreover, embryos obtained from the ACA-immunized females on day 3.5 of pregnancy were severely impaired, demonstrating developmental delay and abnormal morphology. These abnormal embryos failed also to develop in-an in vitro implantation model. Furthermore, specifiic binding of the 2C4C2 ACA to the trophectoderm cell lineage of in vitro implanting normal embryos was observed. Thus, our studies demonstrate that the severe ACA-induced gestational failure results from an impairment of implantation and suggest that the ACA may react directly with the preimplantation embryos.

Prenatal Diagnosis of ‘True Tail’ with Cartilage Content?

“…In a murine model, immunization with monoclonal aPL antibodies resulted in low pregnancy rates as well as in embryos demonstrating developmental delays and abnormal morphology [14]. A variety of congenital malformations have been reported in association with APS such as kidney atresia, oromandibular hypogenesis, aplasia cutis congenita, and congenital heart disease [13,15,16].…”

Management of Women with Recurrent Pregnancy Losses and Antiphospholipid Antibody Syndrome

“…aPL has been shown to have a direct effect on trophoblasts unrelated to thrombosis and may induce direct cellular injury, apoptosis, inhibition of proliferation and syncytia formation, decreased human chorionic gonadotropin production, and defective invasiveness. 35,36,52,53 All of these aPL-mediated effects might play a role in defective placentation. Heparin was reported to suppress some of these aPL-related pathology but not all.…”

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

“…Early experiments incubating aPL with human placental trophoblast cells showed inhibition of proliferation and secretory activity was elicited by antibodies reacting with h 2 GPI, confirming the involvement of h 2 GPI in APS-related pregnancy loss, and suggesting that h 2 GPI contains the critical antigenic determinants for anticardiolipin antibodies [48]. Alternative hypotheses have also been formulated: (1) aPL may prevent in vitro implantation, after binding to trophectoderm of preimplantation embryos [49]; (2) aPL may interfere with the ability of h 2 GPI to mediate the activity of lipoprotein lipase [50], for placental prostaglandin synthesis from maternal membrane phospholipids [51]; and (3) h 2 GPI could react with oxidized-LDL, facilitating the binding of aPL [52]; this induces the uptake of oxidized-LDL by macrophages triggering atherogenesis [53], and acute atherosis is a common finding in the placental bed of complicated pregnancies [54].…”