Placentas, Pathways, and Pregnancy Complications

Maria Lee | January 22, 2019

Placentas, Pathways, and Pregnancy Complications

Study of Antiphospholipid Antibody Effect on Human Trophoblasts Reveals Striking Findings

How can a minuscule, Y-shaped biological molecule provoke inflammation so drastic and dangerous as to end a pregnancy? A June study conducted by members in the lab of Vikki Abrahams in the Department of Obstetrics, Gynecology & Reproductive Sciences at the Yale School of Medicine focused on uncovering the ways that antibodies initiate inflammatory processes in certain human cells. The study’s findings are promising for the development of medicinal tactics to prevent placental inflammation.

Antibodies are proteins responsible for recognizing and binding to foreign matter in the body in order to effect an immune response. It has been known that antiphospholipid antibodies (aPls), which bind to fats containing a phosphate group, increase the likelihood of pregnancy complication or loss due to placental inflammation. The Abrahams lab had shown in the past that anti-β2-glycoprotein I, or anti-β2 GPI, antibodies turn on a specific receptor, Toll-like receptor 4 (TLR- 4), in human trophoblasts. A trophoblast refers to a specific layer of cells in the human embryo that later develops into the maternal placenta. TLR activation then turns on inflammatory pathways within the cell.

However, there are negative regulators in the human body that suppress inflammation by inhibiting the TLR receptor. One regulator, growth arrest-specific protein 6, or GAS6, activates TAM receptors that are able to shut down TLR4 expression. Another way to inhibit inflammation is through a cell’s self-degradation, called autophagy. The researchers in this study wished to uncover the ways in which these negative regulators work in the context of aPL-instigated placental inflammation.

In order to do this, the Abrahams lab tested the effects of the anti-GPI antibody on first-trimester trophoblasts. Some samples were also given molecules intended to inhibit inflammation—either GAS6 or rapamycin, a substance that triggers autophagy. The Abrahams lab then measured inflammation, autophagy, and the TAM receptor activity levels.

Results indicated that in the trophoblast sample with anti-β2 GPI antibodies, these antibodies cause the expression of multiple TAM receptor-associated proteins, as well as that of GAS6, to diminish. This expression decrease releases the brakes on the cell, triggering an inflammatory response. When GAS6 was added to this sample, it was only able to suppress one component of the inflammation. The Abrahams lab found that the antibodies also prevent normal levels of trophoblast autophagy. Rapamycin was needed in order to restore proper autophagy function and reduce the inflammatory response. Hence, the authors concluded that anti-β2 GPI aPLs indirectly cause inflammation in human first-trimester trophoblasts by overriding the mechanisms of autophagy and TAM receptor pathways, which in turn enables the expression of TLRs and inflammasomes.

The results of this study have the potential to be the basis of medicinal solutions for placental inflammation. The newfound knowledge that anti-β2 GPI aPLs trigger inflammation in trophoblasts by suppressing negative regulatory mechanisms can be utilized to determine specific targets in the human body for therapies and to study novel biological markers to predict such activity.