ORIGINAL ARTICLE: Antiphospholipid Antibodies Induce a Pro-Inflammatory Response in First Trimester Trophoblast Via the TLR4/MyD88 Pathway


Vikki M. Abrahams, Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, LSOG 305C, New Haven, CT 06510, USA.
E-mail: vikki.abrahams@yale.edu


Problem  Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta2-glycoprotein I (β2GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved.

Method of study  First trimester trophoblast cells were treated with anti-β2GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated.

Results  We report that anti-β2GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-α, and IL-1β, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-β2GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-α, and IL-1β secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-β2GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations.

Conclusion  These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.