Date of Award
Medical Doctor (MD)
Vikki M. Abrahams
Women with antiphospholipid antibody syndrome (APS) are at risk for miscarriage and preeclampsia. Obstetric APS is caused by antiphospholipid antibodies (aPL) targeting the placenta. aPL induce a placental trophoblast cell pro-inflammatory, anti-migratory, and
anti-angiogenic profile. Since infection during pregnancy can also increase a woman’s risk for preeclampsia, this study aimed to characterize the effect of infectious components on trophoblast cellular responses to aPL. To test this, a human first trimester trophoblast cell line was treated with media, aPL or control IgG in the presence or absence of either viral ssRNA, viral dsRNA, or a component of gram-negative bacterial cell walls known as γ-Dglutamyl-meso-diaminopimelic acid (iE-DAP). Supernatants were measured by ELISA for pro-inflammatory IL-8 and IL-1β; anti-angiogenic sFlt-1; and pro-angiogenic VEGF and
PlGF. Inflammasome function was measured by assays for uric acid levels and caspase1 activity. Trophoblast migration was measured using a two-chamber assay. Compared to aPL alone, trophoblast cells treated with viral ssRNA in the presence of aPL significantly reduced IL-1β, PlGF, uric acid levels, caspase-1 activity, while exacerbating the aPLinduced anti-migratory effect. Viral dsRNA significantly and synergistically increased trophoblast IL-1β, IL-8, and caspase-1 activity independent of uric acid. Bacterial iE-DAP additively augmented IL-1β and IL-8 responses to aPL compared to aPL alone. Both viral and bacterial triggers may alter the human trophoblast functional response to aPL. Thus, both viral or bacterial infections may increase the risk of adverse pregnancy events in women with APS by contributing to the pro-inflammatory, anti-angiogenic, and antimigratory affects that aPL exert on placental trophoblast cells.
Nelson, Rachel Anne, "The Modulation Of Antiphospholipid Antibody-Induced Trophoblast Response By Infectious Components" (2020). Yale Medicine Thesis Digital Library. 3937.