The role of selenium in human conception and pregnancy

Selenium (Se) is a trace element essential for the appropriate course of vital processes in the human body. It is also a constituent of the active center of glutathione peroxidase that protects cellular membranes against the adverse effects of H₂O₂ lipid peroxides. Epidemiological surveys have demonstrated that selenium deficiency in the body may contribute to an increased risk for certain neoplasmic diseases (including colonic carcinoma, gastric carcinoma, pulmonary carcinoma and prostate carcinoma), as well as diseases of the cardiovascular, osseous and nervous systems. Apart from its cancer prevention and antioxidative activities, selenium protects the body against detrimental effects of heavy metals and determines the proper functioning of the immunological system.Furthermore, selenium plays a significant role in the undisturbed functioning of the reproductive system. Many studies have addressed correlations between its intake and fertility as well as disorders of procreation processes. Selenium deficiencies may lead to gestational complications, miscarriages and the damaging of the nervous and immune systems of the fetus. A low concentration of selenium in blood serum in the early stage of pregnancy has been proved to be a predictor of low birth weight of a newborn. A deficiency of this element may also cause infertility in men by causing a deterioration in the quality of semen and in sperm motility. For this reason, supplementation in the case of selenium deficiencies in the procreation period of both women and men is of utmost significance.     

The emerging role of soluble HLA-G in the control of chemotaxis

HLA-G is an immunosuppressive molecule, that impairs the function of different immune cell populations, both in physiological and pathological conditions.Here, we have analyzed data obtained by our group and others regarding sHLA-G concentration in plasma from patients with different diseases. Next, we have summarized novel data regarding the impairment of chemotaxis of different immune effector cells mediated by sHLA-G. Finally, we have discussed the impact of this function on the immune response during cancer, viral infection, autoimmunity, and on B cell differentiation in secondary lymphoid organs. In conclusion, we have delineated a role of sHLA-G in the control of chemotaxis of immune effector cells, that may be relevant to modulate immune responses in different settings.     

HLA-G in murine peripheral blood after interruption of pregnancy

HLA-G antigens are highly expressed in maternal peripheral blood during early pregnancy in transgenic mice. In this study, we determined the levels of HLA-G in white blood cells during early pregnancy and after interruption of pregnancy in triple transgenic mice (H-2K(b)/HLA-G, hbeta2m, and hCD2/hCD8-TRI). The pregnancies were interrupted on day 7 using the anti-progesterone agent mifepristone (RU486). Blood samples of 20 pregnant TRI mice were taken and the HLA-G levels were determined on days 2, 4 and 6 of pregnancy and on days 9, 11 and 13 after fertilization. The monoclonal antibody W6/32, specific for monomorphic determinant HLA class I molecules, was used in combination with an immunolocalization method using a photonic microscope. The HLA-G levels increased gradually on days 2, 4 and 6 of pregnancy, and the interruption of pregnancy on day 7 was followed by a decrease of HLA-G levels. The data indicate that pregnancy is characterized by the early presence of HLA-G in maternal peripheral blood in TRI transgenic mice and suggest that HLA-G may serve as a useful indicator for pregnancy maintenance and well-being.     

Role of HLA-G and other immune mechanisms in pregnancy

Pregnancy loss (abortion) and pre-eclampsia represent the most common disorders in pregnant women. Besides infection, there are anatomical, endocrinological, genetic and immunological factors that can induce pregnancy disorders. Because the exact mechanisms of physiological pregnancy maintenance are still not clearly understood, the search for genes and proteins fulfilling this role is still in progress. One of the immune molecules that plays a beneficial role in pregnancy is the nonclassical HLA-G molecule. The molecule is mainly expressed on trophoblast cells in the foetal placenta and induces the immune tolerance of the foetus via its interaction with inhibitory receptors on maternal NK cells and CD8⁺ T lymphocytes. In relation to pregnancy disorders, associations between HLA-G polymorphism, HLA-G level and HLA-G function were described. Thus, the HLA-G molecule can be used as a new diagnostic marker and, potentially, for the future therapy of pregnancy disorders.     

A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape

HLA-G is a nonclassical MHC molecule with highly limited tissue distribution that has been attributed chiefly immune regulatory functions. Glioblastoma is paradigmatic for the capability of human cancers to paralyze the immune system. To delineate the potential role of HLA-G in glioblastoma immunobiology, expression patterns and functional relevance of this MHC class Ib molecule were investigated in glioma cells and brain tissues. HLA-G mRNA expression was detected in six of 12 glioma cell lines in the absence of IFN-gamma and in 10 of 12 cell lines in the presence of IFN-gamma. HLA-G protein was detected in four of 12 cell lines in the absence of IFN-gamma and in eight of 12 cell lines in the presence of IFN-gamma. Immunohistochemical analysis of human brain tumors revealed expression of HLA-G in four of five tissue samples. Functional studies on the role of HLA-G in glioma cells were conducted with alloreactive PBMCs, NK cells, and T cell subpopulations. Expression of membrane-bound HLA-G1 and soluble HLA-G5 inhibited alloreactive and Ag-specific immune responses. Gene transfer of HLA-G1 or HLA-G5 into HLA-G-negative glioma cells (U87MG) rendered cells highly resistant to direct alloreactive lysis, inhibited the alloproliferative response, and prevented efficient priming of cytotoxic T cells. The inhibitory effects of HLA-G were directed against CD8 and CD4 T cells, but appeared to be NK cell independent. Interestingly, few HLA-G-positive cells within a population of HLA-G-negative tumor cells exerted significant immune inhibitory effects. We conclude that the aberrant expression of HLA-G may contribute to immune escape in human glioblastoma.     

Adrenomedullin 2/intermedin regulates HLA-G in human trophoblasts

Adrenomedullin 2 (ADM2), also referred to as intermedin (IMD), is expressed in trophoblast cells in human placenta and enhances the invasion and migration of first-trimester HTR-8SV/neo cells. Further infusion of ADM2 antagonist in pregnant rat causes fetoplacental growth restriction, suggesting a role for ADM2 in maintaining a successful pregnancy. This study was undertaken to assess whether ADM2 protein is present in decidual tissue and colocalized with HLA-G-positive cytotrophoblast cells and natural killer cells; to assess whether ADM2 regulates expression of HLA-G in trophoblast cells; and to identify whether mitogen-activated protein kinase (MAPK) signaling pathway is involved in ADM2-induced trophoblast cell invasion and migration. Using immunohistochemical methods and RT-PCR, this study shows that ADM2 protein is colocalized with HLA-G-expressing cytotrophoblast cells as well as with NCAM1 (CD56) immunoreactivity in human first-trimester decidual tissue, and that ADM2 mRNA is expressed in peripheral blood natural killer cells. Further, ADM2 dose dependently increases the expression of HLA-G antigen in HTR-8SV/neo cells as well as in term placental villi explants, suggesting involvement of ADM2 in the regulation of HLA-G in trophoblast cells. In addition, interference with the activity of RAF and MAPK3/1 by their inhibitors, manumycin and U0126, respectively, reduces ADM2-induced HTR-8SV/neo cell invasion and migration. In summary, this study suggests a potential involvement for ADM2 in regulating HLA-G antigen at the maternal-fetal interface in human pregnancy and facilitating trophoblast invasion and migration via MAPK3/1 phosphorylation.     

The role of ultrasound in multiple pregnancy.

The advances in reproductive technologies have changed the demographics of multifetal pregnancies. In the first trimester, ultrasound allows to diagnose the number of multiples, chorionicity and amnionicity, the presence or absence of nuchal translucency, early growth discordance, severe malformations and the origin of activities and contacts between multiples. In the second and third trimester, the opportunity to examine the cervix by transvaginal ultrasound should not be missed to detect the risk of premature delivery. Ultrasound is essential for the early grading and treatment of twin-to-twin transfusion syndrome (TTTS), the diagnosis of malformations and growth disturbances. Doppler velocimetry has proven to be able to reduce perinatal mortality in twin pregnancies. Finally, ultrasound is used for the detection of the position of multiples and the decision of the optimal route of delivery. This is of main importance in delayed interval delivery and expectant management of multifetal pregnancies and early cervical dilatation.     

The role of oxytocin in mating and pregnancy

The hormone oxytocin (OT) is released both centrally and peripherally during and after mating. Although research in humans suggests a central role in sexuality, the most reliable findings to date involve peripheral activation. This review will discuss these results and will particularly focus on understanding the most recent findings from fMRI data and the effects of exogenous peripheral OT administration. We will then consider hypotheses of the roles played by central and systemic OT release as well as their control and modulation in the female, summarizing recent findings from animal research. Finally, we will discuss the contribution of OT to the initiation of pregnancy in rodents. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

HLA-G expression in human embryonic stem cells and preimplantation embryos

Human leukocyte Ag-G, a tolerogenic molecule that acts on cells of both innate and adaptive immunity, plays an important role in tumor progression, transplantation, placentation, as well as the protection of the allogeneic fetus from the maternal immune system. We investigated HLA-G mRNA and protein expression in human embryonic stem cells (hESC) derived from the inner cell mass (ICM) of blastocysts. hESC self-renew indefinitely in culture while maintaining pluripotency, providing an unlimited source of cells for therapy. HLA-G mRNA was present in early and late passage hESC, as assessed by real time RT-PCR. Protein expression was demonstrated by flow cytometry, immunocytochemistry, and ELISA on an hESC extract. Binding of HLA-G with its ILT2 receptor demonstrated the functional active status. To verify this finding in a physiologically relevant setting, HLA-G protein expression was investigated during preimplantation development. We demonstrated HLA-G protein expression in oocytes, cleavage stage embryos, and blastocysts, where we find it in trophectoderms but also in ICM cells. During blastocyst development, a downregulation of HLA-G in the ICM cells was present. This data might be important for cell therapy and transplantation because undifferentiated hESC can contaminate the transplant of differentiated stem cells and develop into malignant cancer cells.     

HLA-G in the human placenta: expression and potential functions

HLA-G is a non-classical class I molecule specifically expressed in the placenta, suggesting that it might have a physiological function at the materno-foetal interface. The structural characteristics of HLA-G, the placental pattern of expression and the functional properties of this class Ib glycoprotein in vitro are described and evaluated in the context of pregnancy. The possible anti-viral function of HLA-G, its modulatory role of natural killer cell activity and its likely non-immunological functions are discussed.     

Modulation of HLA-G expression in human neural cells after neurotropic viral infections

HLA-G is a nonclassical human major histocompatibility complex class I molecule. It may promote tolerance, leading to acceptance of the semiallogeneic fetus and tumor immune escape. We show here that two viruses-herpes simplex virus type 1 (HSV-1), a neuronotropic virus inducing acute infection and neuron latency; and rabies virus (RABV), a neuronotropic virus triggering acute neuron infection-upregulate the neuronal expression of several HLA-G isoforms, including HLA-G1 and HLA-G5, the two main biologically active isoforms. RABV induces mostly HLA-G1, and HSV-1 induces mostly HLA-G3 and HLA-G5. HLA-G expression is upregulated in infected cells and neighboring uninfected cells. Soluble mediators, such as beta interferon (IFN-beta) and IFN-gamma, upregulate HLA-G expression in uninfected cells. The membrane-bound HLA-G1 isoform was detected on the surface of cultured RABV-infected neurons but not on the surface of HSV-1-infected cells. Thus, neuronotropic viruses that escape the host immune response totally (RABV) or partially (HSV-1) regulate HLA-G expression on human neuronal cells differentially. HLA-G may therefore be involved in the escape of certain viruses from the immune response in the nervous system.     

Soluble HLA-G inhibits cell cycle progression in human alloreactive T lymphocytes

HLA-G is involved in regulating T cell responses. Various mechanisms have been proposed to explain the inhibition of T cell proliferation. In this context, the possible role of HLA-G in cell cycle regulation remains to be explored. Using stably transfected M8 cells expressing the secreted isoform (HLA-G5) of HLA-G, we investigated the role of HLA-G in inducing apoptosis and in controlling the cell cycle of activated T cells. Soluble HLA-G (HLA-G5) inhibited both CD4 and CD8 T cell proliferation. However, HLA-G5 did not induce T cell apoptosis, as determined by 3,3'-diethyloxacarbocyanine and propidium iodine labeling. It induced accumulation of the retinoblastoma protein, but not its phosphorylated and active form. Treatment of activated T cells with HLA-G5 also reduced the amounts of cyclin D2, E, A, and B by >80%. In contrast, it induced an accumulation of p27kip, but not p21cip, in activated T cells. HLA-G does not induce apoptosis of alloreactive T cells, but induces p27kip1 and inhibits cell cycle progression.     

The role of Plasmodium falciparum var genes in malaria in pregnancy

Sequestration of Plasmodium falciparum-infected erythrocytes in the placenta is responsible for many of the harmful effects of malaria during pregnancy. Sequestration occurs as a result of parasite adhesion molecules expressed on the surface of infected erythrocytes binding to host receptors in the placenta such as chondroitin sulphate A (CSA). Identification of the parasite ligand(s) responsible for placental adhesion could lead to the development of a vaccine to induce antibodies to prevent placental sequestration. Such a vaccine would reduce the maternal anaemia and infant deaths that are associated with malaria in pregnancy. Current research indicates that the parasite ligands mediating placental adhesion may be members of the P. falciparum variant surface antigen family PfEMP1, encoded by var genes. Two relatively well-conserved subfamilies of var genes have been implicated in placental adhesion, however, their role remains controversial. This review examines the evidence for and against the involvement of var genes in placental adhesion, and considers whether the most appropriate vaccine candidates have yet been identified.     

The role of CFU-GEMM in human hemopoiesis

The assay for CFU-GEMM has provided a measurement for pluripotent hemopoietic precursors in normal and abnormal hemopoiesis. While these cells are able to express the functional repertoire that includes not only myelopoiesis but also lymphopoiesis attempts to determine their self-renewal have shown little or no self-renewal capability. It is currently not known whether this observation reflects culture conditions favouring differentiation processes and suppressing self-renewal, or whether the observation made in culture truly reflects the potential of cells in vivo. Recent advances in molecular biology have lead to the identification of the genomic sequences of at least one of the hemopoietic growth factors thus confirming their importance as regulators.     

制作工具在人类演化中的地位与作用

制作工具曾经被视作人类独有的行为能力,"人类"曾经据此而定义。但目前学术界将直立行走作为人类区别于其他灵长类最重要的体质与行为特征。少量其他动物种类,尤其是非人高等灵长类,也能使用工具乃至简单制作工具。如何认识制作工具在人类演化中的作用?人类制作工具的能力与其他动物有何区别?考古学是否有能力分辨人类的工具和其他灵长类的产品?本文通过对现代巴西猴群敲砸石头的行为及其产品、4300年前黑猩猩的"石制品"和早期人类石制品的比较研究,指出人类的工具与其他动物制作和使用的工具存在根本的区别;工具制作和使用对确定人类的演化方向,增强人类的适应生存能力,塑造人类的大脑与心智及行为方式,提升语言和交流能力,形成现代人类的身心和社会,至关重要,不可或缺。考古工作者一方面需要谨慎分辨、研究人类工具制作初期的产品,不使其与自然的产物和其他动作的作品相混淆,另一方面应该认识到人类工具制作在计划性、目的性、预见性、规范性和精美度上具有唯一性,有内在的智能控制、思维逻辑和规律可循。学科发展的积累和现代科技的支撑使考古学者具有多方面的利器,能够把人类工具制作的历史挖掘、复原出来,能够破译特定的石器技术和功能,进而将人类演化的历史画卷描绘得更加精细,更加完整。