Purified IgG from patients with obstetric but not IgG from non-obstetric antiphospholipid syndrome inhibit trophoblast invasion.

Katie Poulton,Charis Pericleous,Yiannis Ioannou,Vera M Ripoll,Pier Luigi Meroni,Maria Gerosa,Anisur Rahman,Ian P Giles

doi:10.1111/aji.12341

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.

Highlights

Patients with the antiphospholipid syndrome (APS) have circulating antiphospholipid antibodies which cause vascular thrombosis (VT) and/or pregnancy morbidity (PM)
Similar effects were seen in healthy volunteers’ monocytes exposed to pooled IgG from patients with thrombotic APS. Supporting this observation, we have shown that IgG isolated from individual patients with thrombotic APS caused activation of p38 mitogen-activated protein kinase (MAPK) and NFjB signalling pathways and up-regulation of tissue factor (TF) activity in human monocytes compared with IgG from patients with non-thrombotic APS, which lacked these effects.[11]
We report a comparison of the effects of IgG from patients with VT+/PMÀ, patients with VTÀ/PM+ and healthy control (HC) subjects on invasion of human trophoblast cells and their intracellular effects on the TLR4 pathway

Summary

Introduction

Patients with the antiphospholipid syndrome (APS) have circulating antiphospholipid antibodies (aPL) which cause vascular thrombosis (VT) and/or pregnancy morbidity (PM). Mulla et al.[12] showed that two murine monoclonal anti-b2 glycoprotein I (b2GPI) antibodies ID2 and IIC5 induced a TLR4/myeloid differentiation primary-response gene 88 (MyD88)-mediated proinflammatory response in the human first-trimester trophoblast line HTR-8, leading to reduced cell viability and up-regulation of interleukin (IL)-8, monocyte chemo-attractant protein (MCP)-1, growth-related oncogene (GRO)-a and IL-1b They demonstrated that IgG purified from patients with APS and PM stimulated trophoblast production of IL-8 and GRO-a12 significantly more than IgG from patients with APS but no PM (thrombosis only). Their expression has been shown to be increased when HTR-8 cells are exposed to human or murine aPL.[12,13]

Materials and methods

Results

Discussion

Rai RS