mproving pregnancy outcomes in Systemic Lupus Erythematosus (SLE): The role of vascular and immune dysfunction.

Abstract

Systemic Lupus Erythematosus (SLE) is a multi-system autoimmune disorder associated with increased pregnancy complications. It is associated with marked immune dysfunction .T regulatory cells (T reg cells) are immunosuppressive whilst T helper17 cells (Th17 cells) are proinflammatory. Both require transforming growth factor beta 1(TGFβ1), a cell regulatory protein for differentiation. A disruption in the balance of T reg cells and Th-17 cells may play an important role in the pathogenesis of SLE and affect fetal tolerance in pregnancy. Chronic inflammation favours endothelial dysfunction in SLE, which can worsen in the procoagulant state of pregnancy. The evaluation of endothelial dysfunction, through arterial stiffness indices and microparticles, has been used in previous studies. Microparticles (MPs) are cell membrane elements that are released on activation or apoptosis of various cells and are increasingly evident in procoagulant diseases. These particles may influence both immune and endothelial vascular function. They may therefore contribute to the inherent immune and endothelial dysfunction associated with SLE, that persists in pregnancy and influence pregnancy outcomes.Objective: To study T cells (T reg cells, Th17 cells), TGFβ1 activation index (TGFβ1 AI) and arterial stiffness and microparticles as surrogate markers of endothelial dysfunction, between healthy women and women with SLE during and outside pregnancy.Methods: Blood samples were obtained from pregnant and non-pregnant women with SLE and compared to their healthy counterparts. T cells and MPs were isolated and studied by flowcytometry. TGF-β1AI was measured with an in-house ELISA. Arterial stiffness index (SI) was assessed by digital pulse trace (Pulse trace PCA 2).Results: Women with SLE had significantly reduced Treg cells and a lower ability to activate TGFβ1 compared to healthy women, both pregnant and non-pregnant. Non-pregnant women with SLE had a non-significant increase in arterial SI compared to healthy individuals. In pregnancy, there was no significant difference between arterial stiffness between both groups. Platelet and endothelial MPs were significantly elevated in the women with SLE outside of pregnancy compared to their healthy counterparts.Conclusion: There is an impairment of T reg cells and TGF-β1activation in women with SLE which persists through pregnancy. Elevated circulating microparticle levels during pregnancy in these women are indicative of increased endothelial injury inspite of gestational vascular adaptations. Women with SLE have underlying immune and endothelial dysfunction and suboptimal regulation of these dysfunctions may ultimately predispose these women to adverse pregnancy complications.

Date of Award	1 Aug 2014
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Clare Tower (Supervisor) & Ian Crocker (Supervisor)