All authors have read and agreed to the published version of the manuscript. (IL-6) and a higher prevalence of the polymorphism in the plasminogen activator inhibitor type-1 (gene, suggesting an expression of an overall enhanced immune response. The concomitant changes in plasma thermograms confirm the potential of the DSC approach for distinguishing changes in the pathological state of the blood plasma proteome. gene, tumor necrosis factor , interleukin-6 1. Introduction Early pregnancy loss (EPL) or fetal loss is a relatively common pathology [1]. Some of the causes of fetal loss include chromosomal abnormalities [2,3], genetic syndromes, thrombophilia [4,5], infections [6], antiphospholipid syndrome, and maternal diseases such as diabetes and hypertension, and inflammation [7]. Nevertheless, more than 50% of EPLs remain idiopathic [8]. Despite a wide range of investigations, no specific biomarkers with a high predictive value of threatening pregnancy losses have been recognized. Normal pregnancy Gastrofensin AN 5 free base is a complex and dynamic process during which the immune system balances the mothers physiological changes and the growing needs of the fetus. During pregnancy, the function of the maternal immune system is to protect the mother and the fetus from pathogens, as well as prevent the rejection of the allogeneic transplant of the fetalCplacental unit [9]. On the surface of trophoblast cells MHC class, I antigens are offered by antigen-presenting cells (APCs) to maternal helper T cells [10]. Thus, activated lymphocytes start to secrete pro- and anti-inflammatory cytokines. Th1 secretion includes interferon-gamma (INF-), interleukin Il-1 (Il-1), Il-2, Il-12, Il-15, and tumor necrosis factor (TNF-) [11], whereas Th2 cells produce mainly Il-10, as well as Il-4, Il-5, Il-6, Il-9, Il-13, tumor growth factor (TGF-1). Th1 cytokines participate in the late hypersensitivity reaction and direct the cellular response, while Th2 cytokines activate B cells, Gastrofensin AN 5 free base thereby enhancing the humoral response [12]. Circulating cytokine levels in the mothers bloodstream reflect her immune status [13]. IL-6 and TNF- are widely expressed in the female reproductive tract and gestational tissues and exert regulatory functions in embryo implantation and placental development [14,15]. IL-6 and TNF- play a significant role in many pregnancy complications, including early miscarriage suggesting their pathogenesis in such conditions [16,17]. Embryo implantation and trophoblast invasion involve a local inflammatory environment that supports blastocyst adhesion, a consequent invasion of the blastocyst and the trophoblast, and tissue reorganization in the uterine wall [18]. The embryo, therefore, develops in a low-oxygen environment, thus protecting differentiating cells from damaging reactive oxygen species (ROS). An over-expressed inflammatory reaction and ROS production can lead to pregnancy complications or early miscarriage [19]. The invasion of the trophoblast could be severely impaired due to the high levels of oxidative stress in the periphery [20]. Hence, considerable syncytiotrophoblastic oxidative damage is likely one of the major factors of EPL. The discovery of new biomarkers in biological fluids is one of the still unresolved difficulties that experts are facing due to the high molecular components complexity, as well as their wide and dynamic concentration range in the bloodstream. The dramatic changes that occur in the mothers body also exert an effect on the blood plasma proteome from the beginning of pregnancy to birth [21]. For example, it is known that plasma proteins, such Gastrofensin AN 5 free base as free protein Rabbit Polyclonal to PIAS4 S and protein C, responsible for the reduction of fibrinolytic activity, take on lower levels during pregnancy [22]. Polymorphisms associated with these proteins can cause severe complications during pregnancy such Gastrofensin AN 5 free base as first trimester miscarriages. In line with this, Trauscht-Van Horn et al. found a relationship between protein C deficiency, miscarriage, and thrombosis [23,24]. Fibrinolytic activity is also reduced in normal pregnancy due to the increased levels of plasminogen activator inhibitor type 1 (in the blood is.