Role of infection in obstetric antiphospholipid syndrome

Women with antiphospholipid syndrome (APS) have an increased risk for adverse pregnancy outcomes (APO). There is a need to better understand the underlying mechanisms by which antiphospholipid antibodies (aPL) impact pregnancy so that improved predictive and therapeutic approaches may be identified. Obstetric APS arises from insufficient placentation and inflammation, rather than thrombosis. Our group demonstrated that aPL trigger human trophoblast to produce elevated inflammatory IL-1ß and anti-angiogenic sEndoglin, while disrupting their ability to migrate and interact with endothelial cells. Furthermore, aPL induce trophoblast IL-1ß via activation of Toll-like receptor 4 (TLR4) and the Nalp3 inflammasome. We found that the Nod2 agonist, bacterial MDP, sensitizes the trophoblast to aPL, generating an augmented IL-1ß response. Thus, a woman with APS may be at increased risk for APO if she has an infection. Our central hypothesis is that infection exacerbates human trophoblast responses to aPL by synergizing innate immune TLR4, Nod2 and Nalp3 inflammasome signaling. Our specific aims are to determine the:
1. Mechanism by which bacterial MDP sensitizes the trophoblast to aPL-induced IL-1ß.
2. Effect of bacterial MDP on trophoblast migration, angiogenic factor production and endothelial interactions in the presence of aPL.
3. Impact aPL and bacterial MDP have on pregnancy outcome.