Pathogenesis of complications of Oocytes Donation (od)

Ng Pui Yee; Wong Chew Ling Irene

Электронное научное издание Альманах Пространство и Время Т. 15. Вып. 1 • 2017

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UDC 618.177-089.888.11

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Ng Pui Yee ,

Irene Wong Chew Ling

**

Ng Pui Yee

Irene Wong Chew Ling

Pathogenesis of Complications of Oocytes Donation (OD)

Supervised by Professor E.A. Kogan, M.D., Head of Academician A.I. Strukov Chair of Pathological Anatomy, I.M. Sechenov First Moscow State Medical University.

Ng Pui Yee, 6th year student at Medical Department of I.M. Sechenov Moscow State Medical University, ORCID ID https://orcid.org/0000-0002-3687-0708 E-mail: [email protected]; [email protected]

**Irene Wong Chew Ling, 6th year student at Medical Department of I.M. Sechenov Moscow State Medical University ORCID ID https://orcid.org/0000-0002-4803-2824

E-mail: [email protected]; [email protected]

Oocyte donation (OD) is the process by which donated eggs are used to conceived in another woman with donor sperm or own husband's sperm. OD makes it possible for subfertile women to conceive. OD is a specific method of artificial reproductive technology that is accompanied by higher risk of preeclampsia during pregnancy. Pregnancies achieved using OD with unrelated donors are unique, since the entire fetal genome is allogeneic to the mother. The more antigenic dissimilarity, the more risk of maternal morbidity due to disturbance of immune tolerance which intervenes in modulating pregnancy related pathologies. Besides that, dysregulation of the local immune response at the fetal-maternal interface lead to higher incidence of placental pathological lesions, such as chronic villitis of unknown etiology, chronic deciduitis and massive chronic intervillositis in OD.

This paper is maternofetal immunological tolerance phenomenon studies review, and to characterize it and relate this phenomenon during pregnancies with a semiallogeneic fetus, and those with an allogeneic fetus in OD pregnancies we used source, phenomenological, problem and system analysis, classification and descriptive methods. Using these approaches we also addressed whether an inadequate maternal immunological response to the allogenic fetus could lead to a higher prevalence of preeclampsia in OD pregnancies.

We conclude that OD provides a valuable addition to the list of treatment options for women who require artificial reproductive technology. The benefits of having a take-home baby are counter-balanced by the higher risk of maternal morbidity. The increased rate of complications may be related to the allogeneic nature of the fetus. Understanding the role of the immune system in successful OD pregnancies also has broader biomedical significance in that it may also give insight into immune mechanisms leading to immunologic tolerance for HLA mismatched solid organ transplants.

Keywords: oocyte donation; preeclampsia; chronic villitis of unknown etiology; chronic deciduitis and massive chronic intervillositis; immunological tolerance.

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Ng Pui Yee, Irene Wong Chew Ling. Pathogenesis of Complications of Oocytes Donation (OD)

Introduction

Oocyte donation (OD) is the process by which donated eggs are used to conceived in another woman with donor sperm or own husband's sperm. OD is used by women with three types of reproductive problems: women who lack functioning ovaries, women who cannot achieve pregnancy for some reason through IVF, and women who use donated eggs for genetic reasons.OD is a specific method of artificial reproductive technology (ART) that is accompanied by higher risk of preeclampsia during pregnancy. It is important to evaluate that as a result of the allogeneic nature of the fetus in OD pregnancies, it is possible that the immunological modulation against the fetus is inadequate, resulting in the development of specific hypertensive complications during these pregnancies.

Fig. 1. Hannah, mother of the prophet Samuel, prays to God in the temple of Shiloh for giving her a son, miniature from the 13th-century Bible

Fig. 2. Royal couple in prayer for bestowing them a Fig. 3. Reverends Cyril and Maria of Radonezh heir, 14th-century England book miniature pray for bestowing them a child, 17th-century

Russian book miniature

OD pregnancies are associated with complications as a higher risk of pregnancy-induced hypertension, Caeserean section deliveries and bleeding complications during pregnancy and postpartum [Soderstrom-Anttila et al. 1998] compared with spontaneous and in vitro fertilisation (IVF) pregnancies, even after correction of maternal age and multiple gestation. OD pregnancies are characterized by an unnaturally high number of HLA mismatches [Van der Hoorn et al. 2013]. Besides that, dysregulation of the local immune response at the fetal-maternal interface [Perni et al. 2005] lead to higher incidence of placental pathological lesions, such as chronic villitis of unknown etiology, chronic deciduitis and massive chronic intervillositis in OD.

Hypertension during pregnancy is defined as systolic blood pressure (SBP) > 140 mmHg and/or a diastolic blood pressure (DBP) > 90 mmHg and is classified into four categories: preeclampsia, chronic hypertension, chronic hypertension with superimposed preeclampsia, and gestational hypertension.

Preeclampsia was usually defined as new-onset hypertension (i.e. SBP > 140 mmHg and/or DBP> 90 mmHg) and proteinuria (> 0.3 g/day) arising after 20 weeks of gestation in a previously normotensive woman [Lambert, Brichant 2014]. Preeclampsia complicates 5 to 8% of all pregnancies. This represents 8.5 million cases a year worldwide. This pathology remains one of the three leading causes of maternal death. The majority of these maternal deaths are related to cerebral hemorrhage that is secondary to poorly controlled hypertension (SBP > 160 mmHg). Renal failure, pulmonary edema, liver failure or rupture, seizures (eclampsia), disseminated intravascular coagulation (DIC), retinal detachment, cortical blindness, abruption placentae, and hemorrhage represent other complications of preeclampsia. All contribute to preeclampsia-associated maternal morbidity and mortality.

The aim of this review is to characterize and relate the maternofetal immunological tolerance phenomenon during pregnancies with a semiallogeneic fetus, and those with an allogeneic fetus in OD pregnancies. Moreover, whether an inadequate maternal immunological response to the allogenic fetus could lead to a higher prevalence of preeclampsia in OD pregnancies has been addressed.

In fact, abnormal placentation is thought to be immunologically mediated [Heikkila et al. 2005]. As prevention and prediction of preeclampsia are still not possible, symptomatic clinical management should focus on preventing maternal morbidity (eg., generalized seizures of preeclampsia) and mortality.

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Pathophysiology of Preeclampsia in OD Pregnancies

1. Mechanisms of Intolerance of Maternofetal Immunology for Preeclampsia in OD Pregnancies

In normal pregnancies, after conception, expression of fetal HLA-C on extravillous trophoblast cause recognition of decidual natural killer (NK) cell and regulatory T cells which interact with indoleamine 2,3-dioxygenase act as the immunoregulation to semi-allogenenic fetus. This and other immunoregulatory mechanisms attempt to prevent fetal cells from being innately rejected upon their implantation [Van Nieuwenhoven et al. 2003].

1.1. Defect in Implantation and Trophoblast Invasion Regulation Due to Inadequate Maternal Immunological Response on the Maternofetal Surface

In order to successfully complete implantation, the maternal decidua undergoes immunological changes which already begin in the secretory phase of the menstruation cycle. Then, they adapt to the immune response from a preconceptional stage. The cells that involved in adequate immune regulation are uterine NK (uNK) cells that act as immuneregulator and proangiogenic and antigen-presenter cells such as macrophages and dendritic cells (DCs). During human placentation, three main changes take place in the pregnant uterus. First, the formation of decidua as the endometrium is differentiated into the dense cell matrix. Second, fetal trophoblast cells invade the decidua and the underlying myometrium. Third, extravillous cytotrophoblast (EVT), penetrates maternal vessels, which alters and replaces the endothelium and part of the muscle layer. In this way, the maternal uterine arteries are transformed into wide low resistence vessels due to the destruction of their muscular layers [Red-Horse et al. 2004]. This is important as it can lead to increased maternal flow to the placenta during normal pregnancies.

In OD pregnancies, placental pathology is the outcome of poor placentation in early pregnancy (weeks 8-18). It comprises failure to remodel spiral arteries supplying the uteroplacental circulation. Failure of uteroplacental circulation is caused by the immunologically- initiated impaired trophoblast invasion of spiral arteries between 8 to 10 gestation weeks. Placental ischemia ensues, with oxidative stress, inflammation, apoptosis, and structural damage [Lam et al. 2005].

2. Implantation and Maternal Immunological Response on the Maternofetal Surface

2.1. Uterine Natural Killer (uNK) Cells 2.1.1. Angiogenic Imbalance as a Consequence of Placental Ischemia

NK cells are characterized by the expression of surface markers CD56 and CD16 and are subdivided into two populations based on the density of marker CD56 (bright-strong or dim-medium). Of the NK cells circulating in peripheral blood, 90-95% of them are highly cytotoxic and belong to the CD56 dim CD16+ phenotype. The rest of them possess CD56 bright CD16- and are highly efficient at secreting cytokines. In the decidua, the majority of NK cells possess a CD56 bright CD16- phenotype. Thus, uNK cells differ phenotypically from NK cells in peripheral blood and are characterized by poor toxicity and a good capacity to secrete cytokines and angiogenic mediators.

Serum levels of granulysin, a cytotoxic granule protein of NK cells and cytotoxic T lymphocytes, are significantly high in preeclamptic patients as compared with women with normal pregnancies [Sakai et al. 2004, Qiu et al. 2006]. Indeed, the proportion of granulysin-producing cytotoxic T-cells notably increases in the peripheral blood of preeclamptic patients in comparison to healthy pregnant women [Molvarec et al. 2011].

uNK cells regulate trophoblast invasion through the secretion of angiogenic growth factors, cytokines, and chemokines. Cytokines produced by uNK cells at the human fetal-maternal interface include interleukin (IL) 8, interferon-inducible-protein-10 (IP-10) and the regulated upon activation normal T-cells expressed and secreted (RANTES) which triggers the migration of invasive trophoblast. Angiogenic factors released by uNK cells include vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). uNK cells participate in uterine spiral artery remodelling by promoting angiogenesis at embryonic implantation sites by means of a gradient of cytokines and vasoactive mediators [Leonard et al. 2006].

2.1.2. Defect in Trophoblast Invasion Regulation

Specific trophoblast recognition is carried by uNK cells. These cells possess activator or inhibitor receptors which belong to three main families: the type-C lectin family (CD94/NKG), the killer immunoglobulin-like receptor (KIR), and immunoglobulin like transcripts (ILT or the leukocyte immunoglobulin-like receptor) [Guleria, Sayegh 2007]. The effector functions of NK cells depend on fine tuning between these inhibitor and activator receptors, and they are considered activated when KIR receptors are constitutively expressed. It has been demonstrated that extravillous trophoblast cells express maternal and paternal HLA-C. The HLA-C ligands for maternal KIR receptors are divided into two groups,C1 and C2. The interaction between the trophoblast HLA

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molecules and the KIR receptors of the uNK cells of the maternal endometrium inhibits cytotoxic activity and modulates cytokine production and growth factors by uNK cells to favor trophoblast growth, endometrium invasion, and vascular remodeling [Hiby et al. 2004]. In normal pregnancies, recognition of fetal HLA-C by receptor KIR-BB of uNK triggers the release of cytokines by uNK cells. These include transforming growth factor beta (TGF-^), whose participation in immunoregulation and angiogenesis has been well-established, and angiogenic factors placenta growth factor (PIGF), and vascular endothelial growth factor (VEGF).

The KIR receptors family recognizes the HLA molecules of the trophoblast .The maternal KIR genotype can be AA (inhibitor), AB, or BB. The combination of the maternal KIR AA genotype with a fetal HLAC2 (HLAClys80) increases the risk of preeclampsia [Laresgoiti-Servitje et al. 2010]. This interaction causes strong inhibitor signal to uNK cells, predispose to preeclampsia. uNK cells would be unable to participate in uterine arterial remodeling because they are inhibited. During pregnancy, the frequency of the maternal KIR AA genotype increases with pathologies related to defective placentation (preeclampsia, intrauterine growth restriction, and recurrent spontaneous abortions), but only when the fetus possesses more C2 genes than the mother or when the only C2 that the fetus possesses is of paternal origin.

Conversely in preeclampsia, when KIR-AA of maternal uNK cells recognize the HLA-C of the extravillous trophoblast, uNK cells display a poorer expression of these mediators, as well as an overexpression of antiangiogenic factors like soluble endoglin (sENG) and soluble fms-like tyrosine (sFLT1) kinase-1 factor. sENG inhibits TGF-^1 from binding to the surface of its receptors and diminishes nitric oxide-mediated endothelial signaling. sFLT1 binds to angiogenic proteins VEGF and PIGF and blocks their actions [Saito et al. 2007]. Interestingly, significantly lower PIGF levels, but with higher sFLT1 and sENG concentrations, have been demonstrated before gestation week 30 in the serum or plasma of pregnant women who have developed preeclampsia if compared with pregnant women who have not develop this disease. Therefore, they can be used as predictor markers of preeclampsia [Kleinrouweler et al. 2012].

2.2. Antigen Presenter Cells: Dendritic cells (DC) and Macrophages

DCs, which are the most powerful APC, are required to initiate and modulate immune responses and to induce immunological tolerance. In humans, the density of endometrial immature DCs (CD1a+) is significantly greater than that of mature DCs (CD83+) throughout the menstrual cycle. Indeed, uterine DCs play a key role in embryo implantation, when they show an immature phenotype [Plaks et al. 2008].

Macrophages. DCs and macrophages, present in the human endometrium, play a role in decidualization and implantation. Macrophages also contribute to local immune tolerance. Macrophages congregate around spiral arteries, while the placenta develops and supports vascular remodeling by releasing proangiogenic factors, such as VEGF and MMPs and by removing apoptotic cells [Nagamatsu, Schust 2010]. Functional macrophage maturation leads to a macrophage effector phenotype, either M1 or M2. M1-type macrophages, or classically activated monocytes, participate in the progression of inflammation by segregating tumor necrosis factor a (TNFa) and IL-12, and they play a role in tissue destruction [Devaraj, Jialal 2011].

M2 macrophages, or alternatively activated monocytes, generate an enhanced production of anti-inflammatory cytokines, IL-1 receptor antagonist, IL-10, and transforming growth factor (TGF-) beta. Thus, M2 macrophages repair tissues and inhibit inflammation .M2 polarization is in fact characterized by an increased expression of innate immunity receptors. The polarization of decidual macrophages toward M2, found in normal pregnancies, indicates that their immunosuppressive activities are critical for maintaining immunological homeostasis during pregnancy.

The decidual differentiation of macrophages and DCs is regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) .GM-CSF is a growth factor for the trophoblast [Huang et al. 2010]. GM-CSF could play a role in the preeclampsia pathogenesis. GM-CSF levels in decidual cells are higher in patients with preeclampsia if compared with gestational age matched controls. Besides, the cytokines involved in preeclampsia TNFa and IL-1^ upregulate GM-CSF mRNA in cultured firsttrimester human decidual cells. In line with this, GM-CSF levels in blood and GM-CSF/total protein levels in the placenta are significantly higher in gestations with preeclampsia than in normal pregnancies [Hayashi et al. 2004]. Therefore, it is feasible to hypothesize that increased GM-CSF in patients with preeclampsia might contribute to DC maturity and the decidual macrophage polarization to M1.

2.3. Complement System 2.3.1. Defect and Excessive Activation of Complement System in OD Pregnancies

The complement system is an essential component of innate humoral immunity composed of proteins. These mediate the clearance of pathogens, apoptotic cells, and immune complexes by forming a membrane attack complex (MAC), which leads to cell lysis. C3a and C5a exert these proinflammatory effects by binding to their respective receptors, C3a receptor (C3aR), and the two receptors for C5, C5a receptor (C5aR; CD88) and C5a receptor-like 2 receptor(C5L2). Syncytiotrophoblasts, villous

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cytotrophoblasts, and EVT express the three regulatory proteins of the complement, these being decay-accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 which avoids the formation of the MAC and subsequent cell lysis .Thus, excessive complement activation is prevented in successful human pregnancies thanks to the presence of these three regulatory proteins in trophoblast membranes.

The component of complement C1q plays a very important role in trophoblast migration, spiral arteries remodeling, and normal placentation [Singh et al. 2011]. In line with this, C1q-deficient pregnant [C1q (-/-)] rats present the main findings of human preeclampsia: hypertension, albuminuria, endotheliosis, diminished placental VEGF, and elevated levels of soluble VEGF receptor 1 (sFlt-1), with high fetal mortality. Their placentas also display increased oxidative stress and reduced blood flow. Mannose-binding lectin (MBL) activates the lectin pathway of the complement. Patients with preeclampsia show higher median plasma MBL concentrations when compared to women with uncomplicated pregnancies [Than et al. 2008].

The serum obtained from preeclamptic women has been found to prevent the interaction between EVT and DECs, which avoids the endovascular invasion of trophoblastic cells. Increased serum MBL in women with preeclampsia inhibits the interaction of EVT with C1q, which interferes with the process of EVT adhesion to and migration through DECs. Beside this, the lectin pathway of complement is also activated by ficolins, which mediate a primitive opsonophagocytosis. They are soluble molecules of the innate immune system that recognize carbohydrate molecules on microbial pathogens, apoptotic, and necrotic cells. Plasma ficolin-2 levels are low in preeclamptic patients if compared with healthy pregnant women. These reduced plasma ficolin-2 concentrations in preeclampsia might contribute to the development of the maternal syndrome of the disease by the impaired removal of the trophoblast-derived material released into the maternal circulation by the hypoxic and oxidatively stressed preeclamptic placenta [Halmos et al. 2012].

Although the complement components are normally high during pregnancy, excessive complement activation, particularly enhanced C5a synthesis, is associated with pregnancy complications such as recurrent abortion, preterm birth, and preeclampsia. C5 can be harmful because it induces antiangiogenic sFlt-1; sFlt-1 sequesters VEGF and PIGF, which are crucial growth factors for normal placental development and for successful pregnancy. Therefore, it has been postulated that C5a can harm angiogenesis by contributing to abnormal placentation, which allows fetal loss in early pregnancy stages or preeclampsia in later stages. Preeclamptic patients have significantly higher C4d, C3a, and C5b9 levels and substantially lower C3 concentrations than healthy pregnant women [Derzsy et al. 2010]. Women with preeclampsia present significantly higher plasma levels of C5a than women with uncomplicated pregnancy. Before gestation week 20, women who later developed any hypertensive disease related to pregnancy or gestational hypertension showed higher plasma levels of C3a when compared with those who did not develop these diseases. In the placentas of human severe early-onset preeclampsia, a low C3aR expression has been found as compared to women with preterm non-preeclamptic pregnancies.

2.3.2. Activation of Complement C3aR through Autoantibodies to

Angiotensin II Type 1 Receptor

The activation of complement C3aR through autoantibodies has been revealed to contribute to preeclampsia pathogenesis. The human maternal angiotensin II type 1 receptor agonistic autoantibody stimulates the deposition of complement C3 in placentas and kidneys of pregnant mice through the activation of angiotensin II type 1 receptor. Interference with C3a signaling through a complement C3aR-specific antagonist significantly decreases hypertension and proteinuria in angiotensin II type 1 receptor agonistic autoantibody-injected pregnantmice. Complement C3aR antagonist significantly not only inhibits autoantibody induced circulating sFlt-1, a well-known antiangiogenic protein related to preeclampsia, but also reduces small placental size with damaged angiogenesis and intrauterine growth restriction. In humans, it has been demonstrated that the placentas of preeclamptic patients present a significantly higher C3 deposition than normotensive controls. In cultured human villous explants, its complement C3aR activation has been seen as an important mechanism that underlies autoantibody-induced sFlt-1 secretion and decreased angiogenesis [Wang et al. 2012]. The C3aR antagonist may contribute to preeclampsia treatment. Nevertheless, the low C3aR expression in the placentas of women with preeclampsia indicates that further studies are required to evaluate the usefulness of the postulated therapy.

2.4. The Roles of Toll-like Receptor (TLR)

Cells of the innate immune system respond to infectious microorganisms by pattern recognition receptors, such as TLRs. The innate immune response of macrophages is regulated by signalling mediated by pattern recognition receptors, that is, toll-like receptors (TLRs). Recognition of microbes by TLRs on macrophages is the primary host defense mechanism in the deciduas. The human decidual cell expresses functional TLR 1, 2, 4, and 6. At the end of pregnancy, macrophages with an inflammatory phenotype participate in cervical ripening and in onset of labor. It is known that human first-trimester

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trophoblasts constitutively secrete chemokines like growth-related oncogene, growth-related oncogene a, IL-8, and monocyte chemotactic protein-1 (MCP-1). These chemokines recruit monocytes, NK cells, and neutrophils.

A significant increase in the TLR-4 protein expression is observed in placental trophoblasts of preeclamptic patients as compared to normotensive pregnant women [Abrahams et al. 2005, Bernardi et al. 2012].

Surprisingly, the expression of TLR-2 and TLR-4 in maternal neutrophils has been found to diminish in preeclampsia when compared with normal pregnant controls of similar gestational ages [Nitsche et al. 2011]. Further studies are required to explain the discordant TLR-4 expression between placental trophoblasts and maternal neutrophils in preeclamptic patients.

3. Antigens and Trophoblast Activity 3.1. The Trophoblast HLA Expression Pattern

The vast majority of the trophoblast that comes into contact with maternal tissue does not possess the antigenic determinants required for maternal T-cell activation; indeed it prevents the potential maternal antifetal rejection. The syncytiotrophoblast that is the main trophoblast to come into contact with the maternal immune system lacks classic class I and II HLA antigens. EVT has an invasive phenotype and forms columns of cells that invade the maternal decidua and replace the endothelium of spiral arteries. This EVT expresses a single class I HLA expression pattern with nonpolymorphic molecules, which include HLA-E, -F, -G, and -C.

HLA-G is crucial in maternal tolerance to the semiallogeneic or allogeneic fetus in ED pregnancies. The HLA-G expression in EVT has been found throughout pregnancy [Moffett, Loke 2006]. With Fas-L, soluble HLA-G induces CD8+ T cell apoptosis [Guleria, Sayegh 2007] .HLA-G expressed in EVT inhibits not only cytotoxic T lymphocyte responses, but also NK cell functions. A leader peptide of HLA-G forms a complex with HLA-E on the trophoblast cell surface and binds to the CD94/NKG2 receptor in NK cells. NK cell activity is subsequently inhibited. Of all the HLA class I molecules expressed by EVT, only HLA-C displays the variability required to constitute a fetal alloantigen, and it is recognized

by maternal uNK cells through their KIR receptors.

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The HLA-DR phenotype of the responder plays a determinative role in the immunogenicity of mismatched HLA antigens , as T helper cells are triggered based on indirect recognition of allopeptides presented by self-HLA class II molecules. To develop a successful and uncomplicated fully HLA-DR mismatched pregnancy, possibly a stronger peripheral immune regulation is necessary. Van der Hoorn with colleagues [Van der Hoorn et al. 2013] showed a lower proliferation of maternal peripheral blood mononuclear cells after OD pregnancies in a mixed lymphocyte reaction. HLA-A, HLA-DR, and HLA-DQ mismatches correlated significantly with an increased percentage of CD4+CD25dim in peripheral OD blood.

OD pregnancies are characterised by an unnaturally high number of HLA mismatches. It is shown, that a higher degree of peripheral immunoregulation in OD and IVF pregnancies compared with natural conceived pregnancies. Moreover, they found a higher number of CD4+CD25dim activated T cells with more HLA-DR mismatches in OD pregnancies while the ratio CD4+CD25dim:CD4+CD25bright was not affected, indicating also higher numbers of regulatory T cells with higher number of mismatching. A higher number of HLA mismatches in successful OD pregnancies leads to increased percentages of activated T cells in peripheral blood, but not to a higher alloreactivity to the fetus. Chernyshov et al. demonstrated hyperactivation of T helper (Th) 2 and T helper 1 cells in maternal blood of OD pregnancies and suggested an additional Th2 mechanism in successful allogeneic pregnancies.As Th2 cells synthesize cytokines that induce humoral immunity ,we also suggest that to sustain an uncomplicated pregnancy, allogeneic fetal cells should induce an additional activation of Th2, rather than a Th1 type of immune response. The more genetically distinct the fetus is, the greater the immunological tolerance becomes during pregnancy. This occurs during pregnancies by oocyte donation (OD), when the fetus is allogenic.It is probable that multiple genetic and immune factors, resulting in fetal allograft intolerance, may limit placentation

3.2. B7 Costimulation and Intracellular Indoleamine-2,3-Dioxygenase Expression in

Peripheral Blood of Pre-Eclamptic Women

In order to provoke efficient T-cell activation, a positive costimulatory signal is required, which is mediated by the interaction between CD28, which is constitutively expressed in most mature T-cells, and molecules B7-1 and B7-2 exposed by APC [Salimi et al. 2014]. Interestingly, blockade of B7-1 and B7-2 at the time of murine implantation has been reported to induce the inhibition of maternal fetus rejection in abortion-prone CBA/JxDBA/2 matings [Jin et al. 2005]. Lower expression of B7-1 and B7-2 proteins on peripheral monocytes in PE might indicate a secondary regulatory mechanism in response to the ongoing systemic maternal inflammation. IDO plays an important role in the pregnancy-specific immune tolerance, and might be a contributing factor in the pathogenesis of PE.

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4. Systemic Maternal Immunological Response during Pregnancy 4.1 Characteristic Cytokine Profile of T Helper 2 Cells

Th lymphocytes can be classified as Th1 or Th2. Initially, it was suggested that the human fetus is not rejected by the maternal immune system due to the prevalent cytokine production of Th2 cells [Wegmann et al. 1993]. The characteristic cytokines ofTh2 cells are IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. Although these cells participate in the development of humoral immunity against extracellular pathogens, they also repress the functions of phagocytic cells. Th1 cells not only synthesize interferon-g (IFN-g), IL-2, and tumor necrosis factor-a (TNF-a), but also trigger cell mediated immunity and phagocyte-dependent inflammation [Kwak-Kim et al. 2005]. A tendency for immuneTh1 responses has been found in human pregnancy-related complications, such as recurrent spontaneous abortions [Raghupathy et al. 1999].

Th2 preponderance in normal pregnancy shifts to Th1 predominance in preeclampsia. It is known that in peripheral blood in preeclampsia, the percentage of Th1 cells and the Th1/Th2 ratio are significantly higher, while the percentage of Th2 cells is significantly lower than in the third trimester of healthy pregnancy [Szarka et al. 2010]. A change to Th1-type immunity is expressed in the serum of preeclamptic patients by an increase in the IL2/IL4 and IFNg/IL4 ratios. In addition, preeclampsia is associated with a proinflammatory systemic environment due to the elevated circulating levels of proinflammatory cytokines IL-6 and TNF-alpha, chemokines IL-8, IP-10, andMCP-1, and adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-1) as compared to normal pregnancy. Surprisingly, the increased IP-10, MCP-1, ICAM-1, and VCAM-1 concentrations in preeclamptic patients correlate significantly with blood pressure values and liver and renal function parameters. In line with this, the peripheral blood mononuclear cell production of IL-12, which induces Th1 responses, diminishes in normal pregnant women but increases in preeclamptic patients [Sakai et al. 2002].

4.2. Immunosuppressor Activity of T Regulatory Cells

In the maternal immune response against the fetus, which may be considered a semiallograft or an allograft in pregnancies by ED, the role of CD4+CD25+Foxp3+ Treg cells is particularly relevant. The transcriptional regulatory protein forkhead box P3 (FOXP3) is a transcriptional repressor required for the development and function of Treg cells. Whereas decidual CD4+CD25bright Treg cells are involved in the regulation of immune responses in humans, decidual CD4+CD25dim Tcells display an activated phenotype by expressing raised levels of CD69 and low levels of FOXP3 and cytotoxic T lymphocyte antigen (CTLA)-4 [Tilburgs et al. 2009b].

Thus not only women with unexplained recurrent spontaneous abortions, but also patients with preeclampsia display low levels of Tregs in both maternal blood and placenta. In fact, in preeclamptic patients, the percentage of CD25bright cells in the CD4+ T cell population in peripheral blood mononuclear cells is considerably lower than in women with normal pregnancies and non-pregnant healthy controls. Moreover, placental samples from preeclamptic patients show a low percentage of FoxP3+ cells in CD3+ T-cells as compared to those reported in normal pregnancy subjects. It has been suggested that cytotoxic T-cells increase at the decidua basalis in preeclampsia since the CD8+ T/CD3+ T-cells ratio in placental preeclamptic samples was much higher than in the samples taken from healthy pregnancies [Sasaki et al. 2007]. The frequency of conventional CD4+ CD25high FoxP3+ Tregs and that of nonconventional CD4+ CD25- FoxP3+ Tregs diminish in peripheral blood in preeclamptic patients as compared to healthy pregnant women [Toldi et al. 2012]. In addition, the prevalence of Th17 cells and the Th17/Treg ratio increases in peripheral blood in preeclampsia as compared with normal pregnancy [Toldi et al. 2011].

Since the complete fetal genome is allogeneic to the mother in ED pregnancies, maternofetal immune tolerance is particularly essential for pregnancy success. The substantially large number of T CD4+ and NK cells in the basal plaque of placentas from OD pregnancies, if compared with those from non-donor IVF pregnancies, may reveal that maternal immune tolerance against the fetal allograft is enhanced.

4.3. B Lymphocytes and Maternal Antibodies against Fetal HLA

In human pregnancies, fetal antigens induce an adaptive maternal humoral immune system response. Accordingly, maternal antibodies against fetal HLA can be generated, which are especially prone to increase when the HLA mismatches between the mother and fetus are high. Since OD pregnancies may be associated with a larger number of HLA mismatches than spontaneously conceived pregnancies, women with OD pregnancies might produce higher levels of antibodies. In preeclamptic patients, the autoantibody against angiotensin II type I receptor (AT1-AA) has been found. It binds to the AT1 receptor, which is highly expressed in the placenta and triggers the activation of an intracellular cascade, which results in the production of antiangiogenic factors sFlt1 and endoglin.

B2 and B1b cells produce adaptative antibodies upon antigen stimulation, while B1a cells synthesize natural antibodies in the absence of antigenic stimuli. It is known that AAT1-AA autoantibodies are produced by the CD19+CD5+B1a cells, but not by

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CD19+CD5-B2 cells, obtained from peripheral blood of non-pregnant women and stimulated in vitro with serum from preeclamptic women [Jensen et al., 2012]. In pregnant women with uncomplicated pregnancies, CD19+CD5+ levels are significantly lower toward the third trimester, while CD19+CD5+ levels remain high in preeclamptic patients.

Morphology of Placenta. Placental Pathology

At the fetal-maternal interface significant histological and immunohistochemical differences are present when comparing OD and non-donor IVF pregnancies. Characteristic pathologic findings in OD cases include a higher incidence of villitis of unknown etiology, chronic deciduitis, massive chronic intervillositis, maternal floor infarction and ischemic changes, as seen with preeclampsia [Styer et al. 2003, Perni et al. 2005, Gundogan et al. 2009]. The chronic deciduitis observed in OD placentas is characterized by its severity and the presence of a dense, fibrinoid deposition in the basal plate. Furthermore, an increased infiltration of CD4+ T-helper cells and CD56+ natural killer (NK) cells is present in the basal plate of OD placentas. It is in the basal plate where extravillous trophoblast (of fetal origin) interfaces with and invades the maternal tissue. The extravillous trophoblast cells do not express classical HLA-A and HLA-B molecules, thereby preventing interaction with cytotoxic T cells. However, they do express a unique combination of HLA antigens (HLA-C and the non-classical HLA-E and HLA-G) that interact with KIR receptors on uterine NK cells, although HLA-C can also serve as a target molecule for CD8+ T-cells [Tilburgs et al. 2009.a, b]. The striking findings of a dense fibroid deposition and mononuclear cell infiltration in the basal plate suggest that the placental abnormalities are related to an immune-mediated response that is more pronounced in OD pregnancies. The placental damage may be the consequence of a type of graft-versus-host disease and/or organ rejection type of reaction.

Conclusions

OD provides a valuable addition to the list of treatment options for women who require ART. The benefits of having a take-home baby are counter-balanced by the higher risk of maternal morbidity. The increased rate of complications may be related to the allogeneic nature of the fetus. To understand the underlying mechanism(s) of acceptance of the allogeneic fetus, more research regarding the unique immunologic aspects of OD pregnancies is warranted. Understanding the role of the immune system in successful OD pregnancies also has broader biomedical significance in that it may also give insight into immune mechanisms leading to immunologic tolerance for HLA mismatched solid organ transplants. Therefore, suitable knowledge of the maternal immune response during pregnancy will enable us to understand the etiopathogeny to elucidate prevention and to improve the treatment of these pathologies.

Fig. 4. Ancient Roman marble relief from Fig. 5. Birth scene, miniature from Book of Fig. 6. Chinese greeting cheap popular print "Lotus Ostia Antica with omage of a woman giving Hours, MS Douce 112, Oxford, gives birth to precious seeds" (this is goodwill that can

birth, now in Blythe House, London Bodleian Library, early 16th c. be read as "Let noble sons be born all the time")

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Achievements in Human Sciences

Elektronische wissenschaftliche Auflage Almanach 'Raum und Zeit Bd. 15., Ausgb. 1 'STUDIA STUDIOSORUM: Fortschritte der Nachwuchsforscher'

Fortschritte in der Humanwissenschaften

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Cite MLA 7:

Ng, P. Y., and I. Wong Chew Ling. "Pathogenesis of Complications of Oocytes Donation (OD)." Electronic Scientific Edition Almanac Space and Time 15.1 (Studia Studiosorum: Achievements of Young Researchers) (2017). Web. <2227-9490e-aprovr_e-ast15-1.2017.26>.

ПАТОГЕНЕЗ ОСЛОЖНЕНИЙ ДОНАЦИИ ООЦИТОВ (ДО)

Нг Пуи Йее, студентка 6 курса лечебного факультета Первого Московского государственного медицинского университета им. И.М. Сеченова

ORCID ID https://orcid.org/0000-0002-3687-0708

E-mail: [email protected]; [email protected]

Ирене Вонг Чеу Линг, студентка 6 курса лечебного факультета Первого Московского государственного медицинского университета им. И.М. Сеченова

ORCID ID https://orcid.org/0000-0002-4803-2824

E-mail: [email protected]; [email protected]

Донация ооцитов (ДО) — это процесс, с помощью которого женщине подсаживают бластоцисты, образованные из яйцеклетки другой женщины и донорской спермы или спермы собственного мужа. ДО предоставляет бесплодным женщинам возможность забеременеть. Это особый метод искусственных репродуктивных технологий, который имеет повышенный риск преэклампсии во время беременности. Беременность, достигнутая с использованием ДО с несвязанными донорами, уникальна, поскольку весь геном плода является аллогенным для матери. Чем больше антигенного несходства, тем больше риск развития осложненеий беременности из-за нарушения иммуннологической толерантности. Кроме того, дисрегуляция локального иммунного ответа может приводить и к плацентарной патологии, такой как хронический вил-лит, хронический децидиутик и массивный хронический интервиллозит. Цель этого обзора — охарактеризовать механизмы развития осложнений беременности при ДО.

Ключевые слова: донация ооцитов; преэклампсия; хронический виллит; хронический децидиутик; массивный хронический интервиллозит; иммуннологическая толерантность.

Литература:

1. Abrahams V.M., Visintin I., Aldo P.B., Guller S., Romero R., Mor G. "A Role for TLRs in the Regulation of Immune Cell Migration by First Trimester Trophoblast Cells." Journal of Immunology 175.12 (2005): 8096—8104.

Ng Pui Yee, Irene Wong Chew Ling. Pathogenesis of Complications of Oocytes Donation (OD)

Electronic Scientific Edition Almanac Space and Time volume 15, issue 1

'STUDIA STUDIOSORUM: Achievements of Young Researchers'

Achievements in Human Sciences

Elektronische wissenschaftliche Auflage Almanach 'Raum und Zeit Bd. 15., Ausgb. 1. 'STUPIA STUPIOSORUM: Fortschritte der Nachwuchsforscher'

Fortschritte in der Humanwissenschaften

Ng Pui Yee, Irene Wong Chew Ling. Pathogenesis of Complications of Oocytes Donation (OD)

2. Bernardi F.C.B., Felisberto F., Vuolo F., Petronilho F., Souza D.R., Luciano T.F., de Souza C.T., Ritter C., Dal-Pizzol F.

"Oxidative Damage, Inflammation, and Toll-like Receptor 4 Pathway Are Increased in Preeclamptic Patients: A Case-control Study." Oxidative Medicine and Cellular Longevity 2012 (2012): ID 636419. 6 p.

3. Derzsy Z., Prohászka Z., J. Rigó J. Jr., Füst G., Molvarec A. "Activation of the Complement System in Normal

Pregnancy and Preeclampsia." Molecular Immunology 47.7—8 (2010): 1500 — 1506.

4. Devaraj S., Jialal I. "C-reactive Protein Polarizes Human Macrophages to an M1 Phenotype and Inhibits Transfor-