Purified IgG from Patients with Obstetric but not IgG from Non‐obstetric Antiphospholipid Syndrome Inhibit Trophoblast Invasion

Abstract

ProblemSome patients with antiphospholipid syndrome (APS) suffer pregnancy morbidity (PM) but not vascular thrombosis (VT), whilst others suffer VT only. Therefore, we compared the effects of IgG from VT+/PM− and VT−/PM+ subjects on human first-trimester trophoblast (HTR8) cells.Method of studyHTR-8 cells were incubated with APS VT+/PM−, APS VT−/PM+ or healthy control (HC) IgG. We measured trophoblast invasion by cell invasion assay; mRNA expression of TLR4 and adaptor proteins; phosphorylation of p38 MAPK, NFκB and ERK; and expression of interleukin (IL)-8 and IL-6.ResultsVT−/PM+ IgG, but not VT+/PM− IgG significantly reduced HTR-8 invasion. The effects on invasion were blocked by TLR-4 inhibition. Neither VT+/PM− nor VT−/PM+ IgG altered MyD88 mRNA expression, phosphorylation of signalling molecules or cytokine expression.ConclusionsVT−/PM+ IgG exert functionally relevant effects on human trophoblast cells but VT+/PM− IgG do not.

Modulation of antiphospholipid antibodies‐induced trophoblast damage by different drugs used to prevent pregnancy morbidity associated with antiphospholipid syndrome

“…These results were in concordance with a recently published report by Poulton et al. using polyclonal IgG antibodies from patients with APS . Although the FAK pathway is involved in cellular migration and is activated in HTR‐8/SVneo cells (revised in), in our hands no changes were induced by either polyclonal IgGs or other drugs (data not shown).…”

“…We have previously demonstrated that pooled sera from patients with APS impair trophoblast migration . Hence, here we evaluated the effect of IgGs purified from these pooled sera on trophoblast invasion and found that our results agree with previous reports using polyclonal IgG antibodies obtained from patients with APS, demonstrating aPL‐induced reduction in trophoblast cell invasion. The next step was to evaluate the effects of drugs currently used to prevent pregnancy complications associated with APS such as low‐molecular‐weight heparin (LMWH) and aspirin because several studies have suggested that they may exert direct effects on placental trophoblast cells, independently of their antithrombotic activity .…”

“…Therefore, our results indicate that other mechanisms may be involved. Recently, the role of toll‐like receptors (in particular TLR‐4) in aPL‐induced pro‐inflammatory responses in HTR‐8/SVneo cells via the TLR4/MyD88 pathway and in aPL‐induced decreased invasion was demonstrated …”

Antiphospholipid syndrome

“…Heparan sulfate, Toll-like receptors 2 and 4, apolipoprotein E receptor 2, and annexin II that are expressed by trophoblasts and decidual cells are the main candidate receptors for β2GPI identified by in vitro studies [62]. In particular, apolipoprotein E receptor 2 has been suggested to be the key molecule mediating trophoblast dysfunction in a mouse model [64], and Tolllike receptor 4 has been demonstrated to mediate the in vitro inhibition of trophoblast invasion induced by purified aPL IgG from patients with OAPS but not by aPL IgG from non-OAPS [65].…”

Obstetric Anti-phospholipid Syndrome: State of the Art

“…Even though the syndrome was initially described as a single disorder, the distinction between obstetric (ob-APS) and thrombotic APS has been well established during the last 10 years given the following observations: (1) patients can display vascular thrombosis with no pregnancy complications or, alternatively, obstetric manifestations alone [2]; (2) the coexistence of both thrombosis and miscarriages only affects about 2.5-5% of APS pregnancies [3]; (3) IgG fractions from pure ob-APS display different effects in vitro on monocyte and trophoblast cells [4].…”