1.2.2. The Immunology of Pregnancy

Human pregnancy is an immunological paradox [23]. Maintenance of pregnancy relies on finely tuned immune adaptations at the maternal-fetal interface where the two distinct genomes of the mother and the fetus commingle to maintain tolerance to the fetal allograft while preserving innate and adaptive immune mechanisms for protection against microbial challenges. Studies by Co et al. [23] have reported that trophoblast interaction with the decidual natural killer cells (dNK) is crucial for the maternal-fetal immune tolerance early in pregnancy. Combinations of signals and responses originating from the maternal and fetal-placental immune systems are critical for a successful placentation, as well as for pregnancy outcome [24]. The signals that originate from the placenta has the ability to sense the infectious and non-infectious triggers and generate innate, immune-like responses [25]. The placenta not only uses several mechanisms to regulate immune tolerance and adaptation, but it may also modulate the way the maternal immune system adapts in the presence of potential dangerous signals [25,26]. Immunologic miscommunications that have origins at the placenta or in the mother may contribute to disruption to the regulatory and protective mechanisms leading to pregnancy complications including PE.

#### 1.2.3. Inflammation in the Development of PE

A generalized systemic inflammatory response is common to all pregnancies, as highlighted by Redman et al. [27] which proposed that PE is intrinsically similar to normal pregnancy and is characterized by the extreme end of a continuous spectrum of inflammatory responses. In PE, a deviation in the physiological immunoregulatory adaption to pregnancy has been described for promoting inhibitory reactivity to the fetus. Furthermore, in PE-a ffected pregnancies, an increase in immune cells has been demonstrated in response to activation of the innate immune system and inflammation in the maternal circulation and uteroplacental unit [28]. These events in turn contribute to the shallow invasion of EVT in the uterine wall and insu fficient spiral arteriole remodeling leading to placental ischemia (Figure 1).

As a consequence of placental ischemia, oxidative stress is augmented with an excessive release of placental factors, such as STB knots/debris, soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF) into the maternal circulation, which collectively contribute to the development of hypertension [29,30]. These angiogenic factors are also critical inflammatory mediators which contribute to maternal inflammation associated with PE [31]. Villous cytotrophoblasts mediate inflammation via the secretion of inflammatory cytokines including interleukins (ILs)-1β, -2, -4, -6, -8, -10, -12, and -18, transforming growth factor (TGF)-β1, IFN-γ-inducible protein 10/IP-10, tumor necrosis factor (TNF)- α, interferon (IFN)-γ, monocyte chemotactic protein (MCP)1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 [6,28,32–34], which contribute to the development of PE. This role is particularly important for cytotrophoblasts, which fuses to form STB, and is the site for maternal–fetal interactions. Several cytokines including IL-1β and IL-18 have also been correlated with maternal endothelial dysfunction [34]. These inflammatory cytokines can activate several downstream pathways both directly or indirectly to contribute to the clinical manifestations and progression of PE. Several triggers including elevated maternal serum concentrations of cholesterol and uric acid in PE have been shown to contribute to a heightened inflammatory response through STB [35]. Depending on the stimulant or physiological change(s) that occur during pregnancy, placental cells may mount either a regulated protective response that maintains and promotes a healthy pregnancy, or alternatively, promotes a damaging response that adversely impacts the outcome of pregnancy, as observed in PE. One such molecular mechanism by which inflammatory responses are regulated in the human placenta is via the molecular inflammasome platform [36], which are known producers of IL-1β and IL-18. A greater

understanding of the precise molecular pathways governed by inflammasomes in the placental sensing mechanisms is therefore critical for drug discovery and therapeutic targeting.

As a consequence of placental ischemia, oxidative stress is augmented with an excessive release of placental factors, such as STB knots/debris, soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF) into the maternal circulation, which collectively contribute to the development of hypertension [29,30]. These angiogenic factors are also critical inflammatory mediators which contribute to maternal inflammation associated with PE [31]. Villous cytotrophoblasts mediate inflammation via the secretion of inflammatory cytokines including interleukins (ILs)-1β, -2, -4, -6, -8, -10, -12, and -18, transforming growth factor (TGF)-β1, IFN-γ-inducible protein 10/IP-10, tumor necrosis factor (TNF)- α, interferon (IFN)-γ, monocyte chemotactic protein (MCP)1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 [6,28,32–34], which contribute to the development of PE. This role is particularly important for cytotrophoblasts, which fuses to form STB, and is the site for maternal–fetal interactions. Several cytokines including IL-1β and IL-18 have also been correlated with maternal endothelial dysfunction [34]. These inflammatory cytokines can activate several downstream pathways both directly or indirectly to contribute to the clinical manifestations and progression of PE. Several triggers including elevated maternal serum concentrations of cholesterol and uric acid in PE have been shown to contribute to a heightened inflammatory response through STB [35]. Depending on the stimulant or physiological change(s) that occur during pregnancy, placental cells may mount either a regulated protective response that maintains and promotes a healthy pregnancy, or alternatively, promotes a damaging response that adversely impacts the outcome of pregnancy, as observed in PE. One such molecular mechanism by which inflammatory responses are regulated in the human placenta is via the molecular inflammasome platform [36], which are known producers of IL-1β and IL-18. A greater understanding of the precise molecular pathways governed by inflammasomes in the placental sensing mechanisms is therefore critical for drug discovery and therapeutic targeting.
