Poulton, KS; (2013) Understanding mechanisms of cellular injury in the antiphospholipid syndrome. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Patients with the Antiphospholipid Syndrome (APS) have circulating antiphospholipid antibodies (aPL) which cause vascular thrombosis (VT) and/or pregnancy morbidity (PM). Previously we have shown that IgG isolated from patients with APS and VT alone (APS-VT) caused activation of p38 MAPK and NFκB signalling pathways and up-regulation of tissue factor (TF) activity in monocytes. These effects were not seen with IgG from patients with APS and PM alone (APS-PM) or healthy controls. TF up-regulation caused by the APS-VT samples was reduced by p38 MAPK, NFκB, and TLR4 inhibitors, thus implicating a TLR4-MyD88 dependent signalling mechanism. Therefore, my PhD aimed to examine whether IgG isolated from patients with different manifestations of the APS have differential effects upon activation of a pregnancy related cell type; trophoblast cells and a thrombotic related cell type; endothelial cells (EC). IgG was purified from the serum of APS-VT patients, APS-PM patients and two control groups. Using a human first trimester trophoblast cell line, HTR-8 cells, I identified that APS-PM but not APS-VT increased TLR4 and TRIF mRNA expression. HTR-8 cell migration was significantly inhibited in cells treated with APS-PM but not APS-VT and this inhibited migration was restored after pre-treatment with a TLR4 inhibitor. I also identified that both APS-VT and APS-PM increased protease-activated receptor (PAR)-1 and PAR-2 mRNA expression in HTR-8 cells, which was not seen in control IgG treated cells. Work carried out in HUVEC identified that only APS-VT phosphorylated p38 MAPK and not APS-PM or healthy controls. When investigating p38 MAPK phosphorylation in HTR-8 cells however, neither APS-PM nor APS-VT phosphorylated p38 MAPK in this pregnancy related cell type. The results obtained in this thesis identify that IgG purified from patients with different clinical manifestations of the APS have differential effects on a pregnancy related cell type than they do on a thrombotic related cell type.

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