Maternal Immunological Adaptation During Normal Pregnancy

The article is devoted to the problem of the lexicographic description of the so-called verbative synlexes – the steady nominative units issued separately, which are functional analogs of the verbs. The principles of the organization of entries for the explanatory dictionary of the verbative synlexes are considered and examples of such entries are given.

In the last decade, the microbiota, i.e., combined populations of microorganisms living inside and on the surface of the human body, has increasingly attracted attention of researchers in the medical field. Indeed, since the completion of the Human Microbiome Project, insight and interest in the role of microbiota in health and disease, also through study of its combined genomes, the microbiome, has been steadily expanding. One less explored field of microbiome research has been the female reproductive tract. Research mainly from the past decade suggests that microbial communities residing in the reproductive tract represent a large proportion of the female microbial network and appear to be involved in reproductive failure and pregnancy complications. Microbiome research is facing technological and methodological challenges, as detection techniques and analysis methods are far from being standardized. A further hurdle is understanding the complex host-microbiota interaction and the confounding effect of a multitude of constitutional and environmental factors. A key regulator of this interaction is the maternal immune system that, during the peri-conceptional stage and even more so during pregnancy, undergoes considerable modulation. This review aims to summarize the current literature on reproductive tract microbiota describing the composition of microbiota in different anatomical locations (vagina, cervix, endometrium, and placenta). We also discuss putative mechanisms of interaction between such microbial communities and various aspects of the immune system, with a focus on the characteristic immunological changes during normal pregnancy. Furthermore, we discuss how abnormal microbiota composition, “dysbiosis,” is linked to a spectrum of clinical disorders related to the female reproductive system and how the maternal immune system is involved. Finally, based on the data presented in this review, the future perspectives in diagnostic approaches, research directions and therapeutic opportunities are explored.

Dendritic cells (DC) are critically involved in decisions related to the acceptance or rejection of the foreign fetal antigens by the maternal immune system. However, particularly for human peripheral blood DCs (PBDC), available literature is rather inconsistent and the factors regulating these cells are ill-defined. Here, we investigated the phenotype and functionality of different human PBDC subsets during normal and pathologic pregnancies and studied an involvement of human chorionic gonadotropin (hCG) in PBDC regulation. Peripheral blood samples were obtained from normal pregnant women in all three trimesters, from first trimester miscarriage patients and from healthy non-pregnant women. Samples were analyzed for plasma hCG levels, for regulatory T (Treg) cell numbers, for frequencies of total and mature plasmacytoid (PDC) and myeloid (MDC1 and MDC2) PBDC subsets and for their cytokine secretion. In vitro assays, culturing PDC, MDC1 or MDC2 in the presence of two trophoblast cell lines, placenta explant supernatants or two hCG preparations were performed. The Treg-inducing capability of hCG- or non-hCG-treated stimulated MDC1 was assessed. Total and mature MDC1 and MDC2 frequencies increased during the first and second trimester of normal pregnancy, respectively. Miscarriage was associated with a reduced MDC1 and an increased MDC2 activation profile. PDC were not altered neither during normal pregnancy progression nor during miscarriage. In vitro, the culture of isolated PBDC subsets in the presence of placenta-derived factors impaired the maturation of MDC1 and differentially affected PDC maturation. An inhibitory effect on MDC1 and PDC maturation was also proven for the urine-derived hCG preparation. Finally, we observed a Treg cell elevation during early normal pregnancy that was not present in miscarriages. Stimulated MDC1 induced Treg cells in vitro, however, hCG was not involved in this process. Our findings suggest that during normal pregnancy PBDC subsets are differentially regulated dependent on gestational age. Miscarriage seems to be associated with dysregulations in the myeloid PBDC subsets and with disturbances in Treg cell frequencies. Moreover, our results propose an interdependency between MDC1 and Treg cells during early pregnancy. hCG, although shown to impair MDC1 maturation, does not seem to be a key regulator of PBDC alterations during pregnancy.

Circulatory neutrophils exhibit an increased basal activation state in human pregnancy, which is overt in preeclampsia, a severe pregnancy specific disorder. Neutrophils play a defining role in combating infection either by phagocytosis or by degranulation; moreover, there have recently been shown to form neutrophil extracellular traps (NETs), containing extruded DNA, histones and granular proteins. The main activity of the NETs is the entrapment of bacteria, viruses and eukaryotic microorganisms, but more interestingly they seem to play a central role in the regulation of the overall inflammatory response. Pregnancy presents an extraordinary immunological challenge to the maternal immune system. Successful gestation to term, birth and postpartum survival require tolerance to the semi-allogeneic fetus while maintaining the potential to mount a vigorous response against infection. During normal pregnancy insulin sensitivity also declines with advancing gestation, while a compensatory increase in insulin maintains the normal glucose homeostasis. Gestational diabetes mellitus (GDM) is a condition of glucose intolerance first recognized during pregnancy resulting in hyperglycemia of variable severity. GDM develops when the pancreatic beta cells are unable to regulate the increased insulin demand. During pregnancy there is increased degranulation and phagocytic activity of circulating neutrophils indicates that these immune cells play a key role in pregnancy adaptations. The mechanisms remain unknown, though sex hormones provide likely candidates. We therefore investigated and characterized the neutrophil activity during normal pregnancies and in pregnancies affected with gestational diabetes. For this purpose, first we explored neutrophil activity during each trimester of normal pregnancy and in addition we studied the neutrophil response in pregnancies during and after the diagnosis of GDM. Neutrophils were isolated from EDTA blood, while products of NETosis were examined in serum and plasma. Cell-free circulating nucleosomes, myeloperoxidase (MPO), neutrophil elastase (NE), granulocyte-colony circulating factor (G- CSF) and tumor necrosis factor α (TNFα) were determined by ELISA. NET formation was detected by Sytox Green, a fluorescent non-permeable DNA dye and verified by immunofluorescence staining and morphometric analysis. The activated state of neutrophils was also evaluated by monitoring the reactive oxygen species generation. NET associated protein levels were analyzed by Western blots. Our primary results during normal pregnancy show that neutrophil numbers in the periphery increase during gestation, in parallel with circulatory G-CSF. G-CSF induced NET formation and primed neutrophils toward an intense pro-NETotic response at concentrations prevalent in pregnancy. Moreover, detailed investigation of signaling related to the neutrophil activation revealed that the propensity to form NETs was advanced by both chorionic gonadotropin and estrogen/estriol. In contrast, progesterone acted by retaining cells in a primed pro-NETotic state, but inhibited their progress to formation of NETs. This coincided with the prevention of neutrophil elastase translocation from the cytoplasm to the nucleus, an indispensible step for NET release. Neutrophils isolated from pregnant women with GDM were determined to be highly reactive and formed NETs more vigorously when compared to neutrophils isolated from healthy pregnant women, as observed by fluorimetry, immunocytochemistry and morphometric analysis. Moreover, high glucose and TNFα, which are increased in gestational diabetic individuals, primed neutrophils towards NET formation. The infiltration to the placenta of these primed neutrophils led to excessive NE release and the degradation of insulin receptor substrate 1 (IRS1). Our data provide evidence that the increased neutrophil priming and NET formation observed during normal pregnancy is well modulated by the sex steroid hormones and G-CSF. Moreover we propose that neutrophils participate to the pathobiology of GDM. Our data demonstrate that the TNFα driven inflammation, resulting from high glucose levels in the circulation, enhances neutrophil priming and NET formation. The released NE can locally modify glucose tolerance and metabolism in the placenta, which probably results to the anatomical, physiological and functional changes observed in placenta of pregnant women suffering from GDM.

Background: The immune system of the mother’s body undergoes several modifications throughout pregnancy to protect the baby from harm and prevent the mother’s immune system from attacking it. In addition, physiological and immunological changes that occur during pregnancy increase the risk and severity of some infections. Aim of the study: Provide comprehensive documentation of immune system adaptation in pregnant mothers and variables associated with the immune system. Methods: In this study, 40 pregnant women between the ages of 15 and 43 participated. The Abu Alkhaseeb General Hospital in Basra City filed data from March 2023 to August 2023. The data gathered included age, the number of abortions, the impact of WBC levels during pregnancy, and frequent diseases during pregnancy. Results and Discussion: Urinary tract infection was found to be the most frequent referral among pregnant women, constituting about 62% of the data, and comparisons of proportions were performed. A p-value below 0.05 was considered statistically significant. The results indicated that the number of white blood cells in the first, second, and third trimesters does not differ significantly. The highest white blood cell count was recorded in the third trimester (10.34), while the percentages for the first and second trimesters were close at 9.935 and 9.510, respectively. Conclusion: There are no significant associations with maternal white blood cell count during the first, second, and third trimester. Urinary tract infection was indicated to be the most frequent among pregnant women. 86% of pregnant women did not miscarry.

Normal pregnancy is an immunotolerant state. Many factors, including environmental, socioeconomic, genetic, and immunologic changes by infection and/or other causes of inflammation, may contribute to inter-individual differences resulting in a normal or pathologic pregnancy. In particular, imbalances in the immune system can cause many pregnancy-related diseases, such as infertility, abortions, pre-eclampsia, and preterm labor, which result in maternal/fetal death, prematurity, or small-for-gestational age newborns. New findings imply that myeloid regulatory cells and regulatory T cells (Tregs) may mediate immunotolerance during normal pregnancy. Effector T cells (Teffs) have, in contrast, been implicated to cause adverse pregnancy outcomes. Furthermore, feto-maternal tolerance affects the developing fetus. It has been shown that the Treg/Teff balance affects litter size and adoptive transfer of pregnancy-induced Tregs can prevent fetal rejection in the mouse. Heme oxygenase-1 (HO-1) has a protective role in many conditions through its anti-inflammatory, anti-apoptotic, antioxidative, and anti-proliferative actions. HO-1 is highly expressed in the placenta and plays a role in angiogenesis and placental vascular development and in regulating vascular tone in pregnancy. In addition, HO-1 is a major regulator of immune homeostasis by mediating crosstalk between innate and adaptive immune systems. Moreover, HO-1 can inhibit inflammation-induced phenotypic maturation of immune effector cells and pro-inflammatory cytokine secretion and promote anti-inflammatory cytokine production. HO-1 may also be associated with T-cell activation and can limit immune-based tissue injury by promoting Treg suppression of effector responses. Thus, HO-1 and its byproducts may protect against pregnancy complications by its immunomodulatory effects, and the regulation of HO-1 or its downstream effects has the potential to prevent or treat pregnancy complications and prematurity.

Background: Various hematological and immunological changes can occur in pregnancy which could be beneficial for the growth of the fetus and the maintenance of the pregnancy although some of these changes could be hazardous to the fetus and can cause complications during pregnancy. Thus, this study was conducted to investigate the hematological and immunological changes in normal pregnancy and preeclampsia (PE). Materials and Methods: To this end, hematological and immunological changes were evaluated in 62 normal pregnant women and 56 pregnant women with PE. Moreover, 58 healthy non-pregnant women were studied as the control group. The study was done between December 1, 2018 to May 1, 2019 in Chwarbakh Private Clinic and Shorsh Teaching Hospital. The venous peripheral blood from the antecubital vein was used in this study. Results: The results revealed a significant increase in the number of granulocytes, monocytes, and mean platelet (PLT) volume in both normal pregnant women and PE patients in comparison to normal (non-pregnant) controls (P<0.01). In addition, there was a significant correlation between a reduction in their hematocrit (HCT), PLT, and lymphocytes (P<0.01). With regard to immunological changes, a significant increase was also observed in the serum interleukin-4 (IL-4) levels in both normal pregnancy and preeclamptic patients when compared to non-pregnant controls (P<0.01), but gamma interferon was not significantly different. Conversely, there were no significant associations between the serum level of antiphospholipid antibodies and anticardiolipin antibodies in the study groups except for antiphospholipid antibodies which were significantly lower in the third trimester of pregnancy in the preeclamptic patients (P<0.05). Conclusion: In general, significant changes in hematological and immunological parameters were observed in both normal pregnant and PE patients although further studies are required to include more immunological parameters.

If maternal atopy and environmental exposure affect prenatal Th cell development, the maternal and fetal immune systems should display common Th1/Th2 phenotypes. To test this hypothesis, we studied maternal and neonatal blood samples from mothers with total serum IgE <300 IU/mL. Basal levels of IFN-γ, IL-4, and eotaxin in paired maternal and fetal sera were tightly correlated. Polyclonal T cell activation in vitro by Staphylococcal exotoxin B induced co-ordinate IFN-γ production from paired maternal and fetal mononuclear cells, accompanied by co-ordinate increases in activated CD4+CD69+ cells that display the CCR4+Th2 and CXCR3+ Th1 phenotypes. Maternal and fetal CD4+CXCR3+ T cells were subsequently identified as the major producers of IFN-γ. The data established that a transplacental nexus exists during normal pregnancy and that fetal Th cell responses may be biased by the maternal immune system.

Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific

ABSTRACTProblemDuring pregnancy, the maternal immune system undergoes different adaptations to establish tolerance toward the fetus. Several factors are known to affect maternal immune adaptations, including fetal allo‐antigens. Although, the effects of fetal antigens have clearly been shown in early pregnancy, the influence of these antigens in mid‐ and late pregnancy are not fully known.Method of StudyIn this study, we investigated the impact of fetal allo‐antigens during pregnancy on maternal immune adaptations by comparing immunological changes in semi‐allogeneic and syngeneic pregnancies in mice. Pregnant mice were analyzed at gestation day 10 (GD10) and gestation day 18 (GD18), and immune responses were assessed in the spleen, uterus draining para‐aortic lymph nodes (PALN) and peripheral blood analyzing T cells, monocytes and their subsets. In addition, T cells were analyzed after stimulation using PMA or male antigens.ResultsAnalyses of memory T cells, Tregs and monocytes (and subsets) demonstrated that fetal semi‐allogeneity only had a minor influence on the maternal immune parameters in mid and late gestation. Immune stimulation experiments, using either PMA or syngeneic or allogeneic paternal antigens, revealed minor differences in cytokine production between general immune stimulation and paternal specific stimulation.ConclusionsOur results show that immune adaptations ad mid and late pregnancy are likely not mainly driven by fetal allo‐antigens. This study contributes to a deeper understanding of the maternal immune system during pregnancy (either syngeneic or semi‐allogeneic).

Immunological changes in normal pregnancy

To investigate trophoblast invasion and vascular changes in placental bed spiral arteries in normal and severe pre-eclamptic pregnancies. A histological and immunohistochemical study of placental bed biopsies containing spiral arteries. The University Hospital, Leuven, Belgium. Twenty-one placental bed biopsies from 21 normal pregnancies and 24 placental bed biopsies from 24 severe pre-eclamptic pregnancies, taken at caesarean section. Histological and immunohistochemical appearance of spiral arteries (stained with haematoxylin and eosin), periodic acid schiff, and a monoclonal antibody to low molecular weight cytokeratin. One hundred and twenty-seven spiral arteries were studied. In the 21 biopsies from clinically normal pregnancies at term, 100% of the decidual spiral arteries and 76% of the myometrial arteries showed trophoblast invasion. In the 24 biopsies from women with severe pre-eclampsia, trophoblast invasion was seen in 44% and 18% of the decidual and myometrial segments, respectively. Endovascular trophoblast invasion was complete, partial or isolated. A variety of morphological features was present not only in different spiral arteries from the same biopsy but also in different segments of the same artery. The vascular change most commonly associated with normal pregnancies was physiological change and subintimal thickening of both segments of the spiral arteries. In pre-eclampsia medial disorganisation and hyperplasia in the myometrial arteries and acute atherosis in decidual arteries were common. Endovascular trophoblast did not show an all or none invasive phenomenon in normal and pre-eclamptic pregnancies. More decidual than myometrial arteries were invaded in both groups of patients, and there was a gradient in the percentage of decidual and myometrial arteries invaded from normal pregnancy to pre-eclampsia. Morphological features in one spiral artery may not necessarily be representative of all of those in a placental bed.

Pregnancy is a special state in a woman’s life, which can definitely be considered an «immunological paradox», because the growth of a genetically «alien» fetus takes place in a woman’s body. Despite the direct contact between cells of fetal origin (syncytiotrophoblast) and cells of the maternal immune system, which are in excess in the decidual membrane of the uterus, rejection of the semi-allogeneic fetus does not occur. A state of permanent natural immunological tolerance, during which the body does not respond to certain antigens expressed by trophoblast cells, while maintaining the ability to respond immunologically to other immunogens is the opposite phenomenon of the immune response, it is acquired by the body during its development and is not genetically determined. Purpose - to analyze the phasing of immunological changes in the mother’s body, which are aimed at the development and preservation of pregnancy, to specify their role in the correct flow of placental waves, prevention of the development of placental dysfunction and obstetric complications associated with it. A review of modern medical literature on the processes of immunological changes during trophoblast invasion and placentation in early pregnancy is given. For a more detailed understanding, the influence of each link of the immune response in the process of developing immune tolerance was analyzed. It has been established that for the development of a normal pregnancy there is a genetically programmed immune mechanism that ensures a decrease in the local and systemic immune response to the semi-alien implanted blastocyst, embryo and fetus. This is achieved through the step-by-step course of three phases of immunological shifts: the unfolded immune conflict; suppression of the immune response and intense immune conflict. The physiological course of gestation and the development of the placenta, in which the balance between the processes of neoangiogenesis and apoptosis is maintained, is ensured by adequate expression of HLA-G locus molecules by trophoblast cells, inhibition of Th1-type cytotoxic reactions against placenta cells by the mother's body. Analyzed changes in the cytokine balance, which shifts towards immunosuppressive cytokines, which suppress cellular immune reactions and stimulate the production of blocking antibodies, the quantitative composition of which can be considered decisive when carrying a genetically foreign fetus. Consequently, a relative secondary cellular immunodeficiency is formed, which is mainly due to a deficiency of circulating T-helper/inducers, a decrease in the CD4/CD8 immunoregulatory index and suppression of the functional activity of the T-cell immune system. It has been proven that impaired immunological tolerance, trophoblast invasion and vascular remodelling processes controlled by the maternal immune system at the local and systemic levels lead to early reproductive losses, premature birth, placental dysfunction, and are associated with fetal growth retardation syndrome, pre-eclampsia and other complications. No conflict of interests was declared by the authors.

Pregnancy is associated various physiological changes in order to ensure care, support and protection of the developing embryo and also prepare mother for labour and delivery. These changes influence all physical, physiological, biochemical and immunological status of the mother. Normal physiological changes that are observed include missed period, nausea, fatigue, motion sickness, mood swings, bloating, and tenderness in breast while biochemical and immunological changes include change in levels of blood levels of certain parameters like urea, creatinine, human chorionic gonadotropin, localisation of immune-modulators in uterus etc. This review highlights the important changes taking place during normal pregnancy so that it may aid in educating the expectant mothers regarding such changes facilitate them to cope up with proper health care. Keywords: Pregnancy, Trimester, Foetus, Biochemical, Physiological, Physical, Immunity.

The intimate association between maternal and placental tissues elicits an interesting immunological paradox. Placental tissue contains paternal antigens, but under normal circumstances the semi-allogeneic fetus and placenta are not attacked by the maternal immune system. Interestingly, this tolerance to fetal antigens occurs in the presence of a large number of maternal leukocytes, almost all of which are members of the innate immune system. Macrophages are one of the most abundant leukocytes in the decidua and their numbers remain constant throughout gestation. They are recruited to the decidua by both stromal cells and trophoblast cells, where they adopt a specialized phenotype that may assist in various aspects of decidual homeostasis, placental development, and tolerance to the semi-allogeneic trophoblast. Aberrant behavior of these macrophages can affect trophoblast function and placental development, potentially leading to a spectrum of adverse pregnancy outcomes ranging from pre-eclampsia to fetal growth restriction or demise. This review will focus on the phenotype and putative functions of decidual macrophages in normal pregnancy, and how abnormal activation of these cells can affect various aspects of placental development.