Role of purinergic signalling in the pathophysiology of antiphospholipid antibody induced miscarriages
AffiliationMedicine (St Vincent's)
Document TypePhD thesis
Access StatusOpen Access
© 2017 Dr. Anushka Samudra
Antiphospholipid syndrome (APS) is an autoimmune disorder in antibodies are generated against cell membrane and self-antigens (aPL-ab) hence the name Antiphospholipid disorder. This autoimmune disorder characterised by the presence of antibodies against β2Glycoprotein-1 and cardiolipin. Pathophysiology includes thrombosis ('blood clotting') and devastating pregnancy complications such as recurrent morbidity (miscarriage), low birth weight and preeclmapsia. Antiphospholipid antibodies bind to endothelial cells and platelets causing vascular complications including thrombosis ultimately leading to clot formation at the site of the injury. The key components implicated in the parthenogenesis of APS are complement cascade, Tissue factor expression, inflammation and coagulation. Increasing evidence shows extensive cross talk between inflammation and coagulation, wherein inflammation leads to activation of coagulation and coagulation considerably enhances inflammatory activity. Purinergic signalling involving catabolism of ATP “danger signal” to adenosine by orchestrated action of cell surface enzymes CD39 and CD73 has been shown to have anti-inflammatory and anti-thrombotic effects. In this project, we aimed to ascertain whether activities of CD39 and CD73are important in developing aPL-ab induced miscarraiges. We utilised mouse model of misccaraiges by passive transfusion of purified human aPL-ab to pregnant wildtype and mice that are modified for CD39 and CD73 activity. We were able to show that aPL-ab infusion in pregnant CD39 and CD73 knock out mice trigger an increase in the rate of miscarriages associated wth increased expression of tissue factor, complement deposition and elevated oxidative stress. There is also an increase in the pro-inflammatory TNF-α and IL-10 expression within the placental vasculature. In contrast to these observations, we also observed that mice over expressing CD39 were protected against aPL-ab induced miscarriages. These mice had reduced TF expression in the decidua, along with reduction in the complement C3D component deposition. Diminished lipid peroxidation and reduction in the proinflammatory TNF-αexpression was also observed in these mice. Taken together, our results provide a rationale for both perturbations in the purinergic pathway to explain disease associated with aPL-ab and for the development of endothelial cell targeted soluble CD39 as a novel therapeutic for management of APS.
Keywordspurinergic signalling; antiphospholipid antibodies; miscarriages
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