**3. Preeclampsia: state of knowledge**

Preeclampsia (PE) is the most common placental disorder affecting pregnancy [77]. PE is associated with vascular dysfunction and deregulated inflammation, oxidative stress, and endothelial dysfunctions [78–80]. This chronic inflammation begins early in pregnancy as a result of stimulation of maternal immune response by trophoblasts and trophoblasts derived-products. It is associated with leukocyte activation, vascular activation and dysfunction and high serum levels of cytokines such as Tumor Necrosis Factor-α (TNF-α) [81–83]. Changes in the levels of immune factors (e.g., cytokines, chemokines) are followed by changes in blood coagulation factors, and apoptotic markers [78, 84–87]. Leukocyte activation is driven by TNFα, and monocyte-derived cytotoxic protein, that also induces vascular endothelial adhesion molecules. Indeed, increased TNF-α levels in early pregnancy can increase the expression of intercellular adhesion molecule-1 (ICAM-1) on vascular endothelial cells (ECs) and trophoblasts, thereby activating them. Consequently, coagulation cascade, vascular tone, and permeability are disturbed. Moreover, chronic inflammation also activates lymphocyte function-associated antigen-1 (LFA-1) on leukocytes, resulting in the above consequences [84, 85, 88, 89]. This chronic inflammation is also associated with oxidative stress [90] which increases the adhesion of leukocytes to the vascular endothelium and the release of cytokines and anti-angiogenic molecules. Adhesion molecules (e.g., soluble E-selectin and soluble ICAM-1) and reactive oxygen species level are increased in blood collected early in pregnancy from women who develop later PE [83, 91]. During PE, abnormal levels of anti-vascular growth factors

*Perspective Chapter: Role of Cytotrophoblast Cells and Placenta-Derived Exosomes… DOI: http://dx.doi.org/10.5772/intechopen.108335*

(e.g., sFlt-1 and sEng)) lead to maternal vascular inflammatory syndrome characteristics [58]. These antiangiogenic factors induce the decrease of angiogenic placental growth factor (PlGF), poorly affecting angiogenesis during placentation [92]. Defective placenta secreted PlGF into the maternal circulation as a result of impaired endovascular invasion by trophoblast cells and is underlying by cellular oxidative or endoplasmic reticulum stress [93]. Therefore, the level of these factors in the maternal peripheral blood might enable an early diagnosis of PE. Nevertheless, these methods are questioned and did not allow an early prediction (i.e., during the first trimester) of the occurrence of PE [94, 95].

Commonly, PE results in multi-organ failure (e.g., renal insufficiency, liver dysfunction, neurological or hematological complications, uteroplacental dysfunction) in the mother and poor perinatal outcome. Thereby, PE results in significant maternal and perinatal morbidity and mortality [77]. PE affects 2 to 8% of pregnancies and low and middle-income countries (LMIC) are mostly affected [1–3]. PE is defined as new onset hypertension arising after 20 weeks' gestation, but can also occur at a later stage, i.e., 4–12 weeks postpartum [96, 97].

PE is a consequence of failure of paternal antigen-specific tolerance. Moreover, first pregnancy, first pregnancy after partner change, and long interval between pregnancies increase PE risk [98, 99]. The reduced opportunities for exposure to seminal plasma, and pregnancy by sperm or oocyte donation or pregnancies with donated greatly increase PE risk [100–103].

### **4. Immune regulation and immune tolerance during pregnancy**

Contrary to what would be expected, the maternal immune system does not reject the semi-allogeneic fetus allowing the maintenance of the pregnancy [104], but still reacting with infectious agents. This is the result of interplay between maternal and fetal cells creating a tolerogenic microenvironment at the feto-maternal interface [105]. During PE, immunotolerance to fetal antigens, (e.g. trophoblast) is impaired, resulting in disrupted remodeling of the spiral artery and thereby poor placentation. Regulatory T (Tregs) cells play a crucial role in this tolerogenic microenvironment [106, 107] and the maintenance of pregnancy depends on the balance between Tregs and cytotoxic T cells. The ability of fetal cells to escape destruction by maternal immune cells is based on the expression of human leukocyte antigen (HLA)-C molecules by EVTs alone. Therefore, maternal T-cell reactivity to fetal cells is reduced [18]. The T cells immunosuppression during pregnancy is also mediated by HLA-G, E, F and programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) expression by EVTs [18–20, 108–110]. EVTs also induce T cell suppression by expressing cytokines including IL-10, TGF-β, and IL-35 [12, 13]. At the beginning of pregnancy, CD56brightCD16− decidual natural killer (NK) cells (dNK cells) represent more than 60% of decidual immune cell and express high level of immunosuppressive receptors [111, 112]. Immunotolerance is maintained at the feto-maternal interface by interaction between HLA-G expressed on EVTs and dNK cells and dNK derivedcytokines [57, 113, 114]. To maintain immunotolerance at the feto-maternal interface, between dendritic cells (DCs) and Tregs [115], the cross-presentation of paternal antigens to maternal cytotoxicity T CTLs and CD4+ T cells [115, 116] is altered by fetal antigen-specific Tregs at the feto-maternal interface [117–121]. Seminal plasma components such as TGF-β, prostaglandins, MHCs, and minor antigens also functionally affect maternal antigen-presenting cells (APC). These functional changes

were maintained by EVTs [103, 122]. In mice, these functional changes favor fetalantigen-specific Tregs cell expansion in the uterus and uterine drainage lymph nodes [123–125]. Moreover, in mice, PD-L2-expressing dendritic cells (DCs) increase during implantation in allogeneic pregnancy in mice [126]. These cells limit inflammation whereas, the decrease of M2 macrophages, which inhibit inflammation and promote tissue repair, results in implantation failure in mice [127]. Furthermore, *in vitro*, the close interaction between decidual macrophages and EVTs results in an increased number of Tregs after co-culture with peripheral blood-derived CD4<sup>+</sup> T cells [128, 129]. These results show clearly that EVTs oriented the differentiation of CD4<sup>+</sup> conventional T cells into antigen-specific peripheral Tregs [121].

Miscarriages, PE, and implantation failure are some characteristics of pregnancy complications. The dysfunction of Tregs is clearly involved [121, 130]. Indeed, in recurrent pregnancy loss and during PE, low level of Tregs in the peripheral blood and uterus has been reported [121]. A recent study has shown that during PE, clonally expanded effector Tregs were significantly decreased in the decidua compared with normal pregnancy, suggesting an insufficient Tregs antigen-specific tolerance [131].

In addition to this induced-immunosuppression, decidual CTLs were also suppressed by EVTs and other immune cells; to allow a good course of pregnancy, without suppression of CTLs functions against virus [117]. During late gestation, le level of PD-L1 on clonally expanded CTLs increases significantly compared to the beginning of pregnancy, showing that strong suppressive signals are necessary to inhibit the allo-reaction by CTLs in the late gestational period [119]. Moreover, during late onset of PE, the level of PD-L1 on clonal CTLs decreased compared with that in normal pregnancy [119], suggesting insufficient suppression of antigen-specific CTLs in PE.

Overall, during normal pregnancy although Tregs and CTLs recognize fetal antigens at the feto-maternal interface, antigen-specific Tregs induce tolerance, while the cytotoxic function of CTLs is suppressed. Therefore, the imbalance of suppressive role of Tregs and activation of CTLs is likely associated with PE.

In PE, type-1 T helper (Th1) cells numbers are also increased [73] and secrete pro-inflammatory cytokines, such as TNF-α, interferon-γ (IFN-γ), and interleukin (IL)-6. Increased Th17 cells secreting the pro-inflammatory cytokine IL-17 are also found during PE [83, 132].
