Functions of interferon tau as an immunological regulator for establishment of pregnancy

The establishment of a successful pregnancy requires a “fine quality embryo”, “maternal recognition of pregnancy”, and a “receptive uterus” during the period of conceptus implantation to the uterine endometrium. In ruminants, a conceptus cytokine, interferon tau (IFNT), a major cytokine produced by the peri‐implantation trophectoderm, is known as a key factor for maternal recognition of pregnancy. IFNT can be considered one of the main factors in conceptus–uterus cross‐talk, resulting in the rescue of ovarian corpus luteum (CL), induction of endometrial gene expressions, activation of residual immune cells, and recruitment of immune cells. Much research on IFNT has focused on the CL life‐span (pregnancy recognition) and uterine gene expression through IFNT and related genes; however, immunological acceptance of the conceptus by the mother has not been well characterized. In this review, we will discuss the progress in IFNT and implantation research made by us and others for over 10 years, and relate this progress to pregnancy in mammalian species other than ruminants.     

Effect of the maternal-fetal interface immunoregulation on the occurrence of intrahepatic cholestasis of pregnancy

Maternal immune tolerance of the fetus is indispensable for a healthy pregnancy. Currently, the study of the immune microenvironment of the maternal-fetal interface has been a heated topic in reproductive immunology research. More and more studies show that the immune imbalance in the maternal-fetal interface plays a very important role in the incidence of intrahepatic cholestasis of pregnancy(ICP). However, the precise etiology and mechanism of immune imbalance in the occurrence of ICP is still unknown. In order to clarify the potential immunologic mechanisms of ICP, this review summarizes the recent studies of the decidual immunology microenvironment and the potential immunologic mechanisms related to the development of ICP.     

Transfusion-associated graft versus host disease (TAGVHD) – with reference to neonatal period

Transfusion-associated graft versus host disease [TAGVHD] results from the engraftment of transfused immuno-competent cells in blood transfusion recipients, whose immune system is unable to reject them. All blood products containing viable, immuno-competent T cells have been implicated in TAGVHD. Presence of a “one-way HLA match between donor and recipient” is associated with a significantly increased risk of TAGVHD. Though sharing of haplotype is the most probable explanation, it is far from adequate. Since TAGVHD is not seen in patients with AIDS, and an acute GVHD-like syndrome has been noted in some identical twins and autologous (self) transplants, some other processes, possibly of an “autoimmune” nature are responsible for TAGVHD. Most of the cases have been reported from Japan. This clustering in space and time is rather intriguing. We offer here alternative hypothesis. Foetal and then neonatal lymphocytes exhibit tolerance towards donor cytotoxic T lymphocytes; and consequently very few cases of TAGVHD have been reported in neonates than expected. This tolerance is a part of altered immunology of pregnancy. We feel that it is possible to use maternal blood for transfusion to her newborn baby by following certain protocol and procedure and TAGVHD is no barrier.     

反复胚胎植入失败和流产与子宫内膜免疫因素

胚胎着床及发育是一个母-胎相互识别、相互适应的复杂过程。在此过程中,滋养细胞表达胚胎抗原并分泌细胞因子,逃避母体免疫系统的攻击,母体蜕膜特征性免疫细胞的富集形成母-胎界面独特的免疫微环境,从而有利于胚胎着床及发育。虽然近年来体外受精-胚胎移植（IVF-ET）的成功率已有很大提高,反复种植失败（RIF）仍是困扰辅助生殖技术发展的难题。胚胎作为同种异体移植物不被母体免疫系统排斥是妊娠建立和维持的关键,母-胎免疫调节异常可致复发性流产（RSA）,给患者夫妇身心及经济均带来极大负担。随着生殖免疫学的发展,子宫内膜免疫因素在RIF和RSA发病中的作用日益受到关注,针对性的免疫治疗也在RIF和RSA的治疗方案中扮演着越来越重要的角色。文章就RIF和RSA子宫内膜免疫因素的分子病理机制及其免疫治疗的当今认识进行阐述,以期为未来的科学研究及临床治疗提供参考。     

反复胚胎植入失败和流产与子宫内膜免疫因素

胚胎着床及发育是一个母-胎相互识别、相互适应的复杂过程。在此过程中，滋养细胞表达胚胎抗原并分泌细胞因子，逃避母体免疫系统的攻击，母体蜕膜特征性免疫细胞的富集形成母-胎界面独特的免疫微环境，从而有利于胚胎着床及发育。虽然近年来体外受精-胚胎移植（IVF-ET）的成功率已有很大提高，反复种植失败（RIF）仍是困扰辅助生殖技术发展的难题。胚胎作为同种异体移植物不被母体免疫系统排斥是妊娠建立和维持的关键，母-胎免疫调节异常可致复发性流产（RSA），给患者夫妇身心及经济均带来极大负担。随着生殖免疫学的发展，子宫内膜免疫因素在RIF和RSA发病中的作用日益受到关注，针对性的免疫治疗也在RIF和RSA的治疗方案中扮演着越来越重要的角色。文章就RIF和RSA子宫内膜免疫因素的分子病理机制及其免疫治疗的当今认识进行阐述，以期为未来的科学研究及临床治疗提供参考。     

A successful pregnancy in a Turner syndrome with oocyte donation

Advances in reproductive medicine using oocyte donation have made it possible for women with Turner syndrome (TS) to achieve successful pregnancies. These pregnancies carry substantial fetal and maternal risks, with hypertensive disorders or pregnancy and fetal growth restriction common, and an increased risk of aortic dissection, sometimes fatal, for the woman. Careful prepregnancy assessment and fetal and maternal vigilance during pregnancy is a necessary prerequisite for a successful outcome. We present a case of a woman with Turner syndrome achieving a successful pregnancy from donor oocyte and review the relevant literature.     

Connective tissue and dermatological conditions in pregnancy

Connective tissue disorders are common in women of reproductive age, and hence are seen frequently in maternal medicine clinics. The disorders, and their treatments, may have significant adverse effects on fertility, the developing fetus, and on pregnancy outcomes. In turn pregnancy may affect the natural course of the illness. Pre-pregnancy planning and multidisciplinary management are vital to optimise maternal and fetal outcomes. This review will cover a general approach and specific management points of common autoimmune and genetic conditions.Alterations in the maternal immune system affect the disease course of pre-existing skin conditions during pregnancy, and pharmacotherapy may be limited due to effects on the fetus. Some dermatological conditions arise de novo during pregnancy. Women may present to maternity services directly; therefore obstetricians must be able to diagnose, investigate and initiate management of pregnancy dermatoses, with input from dermatologists where available.     

子宫内膜容受性的无创性评价

子宫内膜容受性是胚胎着床、成功妊娠的必要条件。对子宫内膜容受性进行评估是辅助生育技术中重要的一环。其评价指标有很多,目前应用较为广泛的包括内膜活检、超声检查、内分泌检查和内膜分泌物分析等。内膜活检法因其创伤性使临床应用受到限制;超声虽能简便有效地预测内膜容受性,但存在很大的争议;激素及分子生物学指标从分子生物学方面阐明了影响内膜容受性的重要因素,具有其独特的临床应用价值;内膜分泌物分析在评价子宫内膜容受性方面,具有无创性、信息量大等优势,近年来正在成为生殖领域研究的热点。     

Current knowledge on natural killer cells, pregnancy and pre-eclampsia. Introduction

The introduction to this review discusses briefly why immunology, perceived as difficult by assisted reproduction technology clinicians, need nevertheless be envisaged as a central actor in the reproduction process, and how the maternal immune system, initially perceived as a threat to the fetoplacental unit, is in fact utterly necessary for successful pregnancy. The key cells in such a process are uterine natural killer cells, which can act as friend or foe to the fetus, but are now known to play a key role in local vasculogenesis. As an ultimate consequence in cases of dysfunction/dysregulation, these factors result in implantation failure, abortion or pre-eclampsia.     

Comparison of Immune Cell Recruitment and Function in Endometrium During Development of Epitheliochorial (Pig) and Hemochorial (Mouse and Human) Placentas

The role of maternal immune cells in early implantation sites has received special attention from reproductive biologists because immune cells participate in tissue transplant rejection. During normal pregnancy, endometrial immune cells differ from those in blood by subset distribution and appear to be activated but non-destructive of conceptuses. The immune system evolved well before placental mammals. By comparing the regulation and functions of endometrial immune cells between species in two phylogenetic clades that model differently evolved placental types (pig (Sus scrofa) versus mouse (Mus musculus) and human (Homo sapiens)), we seek to understand how “non-self” trophoblast cells thrive in most pregnancies. Our studies suggest recruitment of specific immune cells to conceptus-associated endometrium and immune cell-promoted endometrial angiogenesis are of key importance for mammalian conceptus well-being.     

Decidual immune cells: Guardians of human pregnancies

During human pregnancy, trophoblast cells, the main cellular component of the placenta, invade deeply into uterine blood vessels and the modified endometrium (decidua). Hence, the maternal immune system must adapt to it. A successful pregnancy requires the tolerance of genetically different (allogenic) cells while the mother's immune competence is maintained. This tolerance is ensured through multiple overlapping and occasionally redundant innate and adaptive immune mechanisms. The present article aims to provide a broad overview on uterine immune cell components and the phenotypical and functional changes that they experience during pregnancy. Particularly, we seek to highlight very recent findings in functional adaptations to pregnancy in immune cell populations encountered in the decidua. These adaptations not only ensure tolerance to allogenic trophoblast cells but also promote optimal placental and fetal growth, simultaneously endeavoring to maintain immune surveillance to provide defense against infections.     

PIBF - Progesterone-Induced Blocking Factor

Pregnancy is a unique immunological situation in which 2 allogeneic organisms live in intimate symbiosis without developing rejection reactions. At different locations, interfaces exist between mother and foetus with direct contact between both individuals: 1) maternal blood surrounds foetal villi, which are covered with syncitiotrophoblast cells; 2) cytotrophoblast cells invade the decidua, in which they touch tissue lymphocytes; 3) trophoblast cells, which substitute endothelium of maternal arterioles filled with maternal blood; and 4) trophoblast particles, which are expressed from syncytiotrophoblast and circulate within the maternal blood until they settle in the lung capillaries, where they become degraded by alveolar macrophages. Several factors are known which support the specific immunotolerance of the mother to her foetus and are focussed by current research in reproductive immunology. One of these factors is progesterone-induced blocking factor (PIBF). Originally, it was discovered as a 34?kDa protein, which is released from lymphocytes of healthy pregnant women under the influence of progesterone. PIBF has immunomodulatory functions in vivo and in vitro, which are important for the establishment of immunotolerance between mother and foetus and, thereby, for the regular course of pregnancy. Finally, during the last years, several tumours have been identified to produce PIBF, which supports their immune escape and which may have the potential to become a novel tumour biomarker and which may lead to the development of new therapeutic strategies.     

Evidence-based Prevention of Preterm Birth and Rupture of Membranes: Infection and Inflammation

Prevention of preterm birth and subsequent newborn immaturity is a primary goal of health care in Canada and throughout North America. Much accumulated evidence shows that (I) as many as 30 to 50 percent of preterm births are caused by common genital tract infections and subsequent maternal/fetal inflammatory responses; (2) microbial and maternal host factors (phospholipases, proteases) play roles in preterm labour and preterm premature rupture of membranes (pPROM); (3) identification and systemic treatment of common genitourinary infections, most importantly bacterial vaginosis (BV), reduces risks of preterm delivery and PROM; and, (4) antimicrobial treatment with erythromycin, clindamycin or other antibiotics can significantly delay delivery and reduce the risks of maternal and neonatal morbidity as well as reduce the risk of early onset group B streptococcal sepsis in women with pPROM or preterm labour prior to 34 completed weeks gestation.Diagnosis of EV can be made inexpensively and accurately by using Amsel’s clinical criteria: homogeneous discharge, pH ≥4.5, positive amine test, and “clue” cell identification (3 of 4). Optimal treatment for BV during pregnancy is either prompt administration of oral metronidazole or clindamycin followed by a “test of cure” evaluation and retreatment as necessary. Screening and treatment for BV and other prevalent reproductive tract infections and bacteriuria are most easily and effectively performed during the initial antepartum visit. Screening and treatment can be repeated at 20 or 28 weeks gestation in patients judged at risk for repeated infection. Partners of women with sexually transmitted diseases should be treated; both patients and partners should have “tests of cure.” Both asymptomatic and symptomatic infections should be treated. Potentially powerful interactions of reproductive tract infection and inflammation with other obstetric factors, including a prior history of preterm birth, first trimester bleeding, and possibly, short cervix and multiple gestation can be mitigated by effective treatment of reproductive tract infections. Medical care providers now have the opportunity and the obligation to reduce infection-mediated preterm birth by expeditiously identifying and treating prevalent reproductive tract infections in their pregnant patients.     

母胎免疫中巨噬细胞作用机制的研究进展

胚泡植入是妊娠过程中的关键步骤，包括胚泡在子宫内膜的定位、黏附和侵入。对于母体子宫来说，胚泡是一种半同种异型移植物，植入成功与否依赖于母体子宫免疫细胞对胚泡的识别，以及随后对其建立和维持的免疫耐受。巨噬细胞是母胎交流中的第二大类免疫细胞，在母胎界面免疫耐受的建立、维持，组织重建以及螺旋动脉重塑过程中发挥关键作用。近年来，许多研究发现巨噬细胞分化和功能异常与病理性妊娠有关，而研究蜕膜巨噬细胞的种类和功能对妊娠异常性疾病的诊断与治疗均有重要的意义。综述母胎界面中巨噬细胞的来源、分类及其在胚泡植入和病理性妊娠过程中作用。     

Spontaneous abortions with increased CD5 positive cells in the placental tissue during the first trimester of gestation

Most spontaneous abortions occur before 12 weeks' gestation, and most are due to chromosomal errors in the conceptus. Relatively few truly spontaneous abortions take place between 12 and 20 weeks' gestation. Thereafter, between 20 and 30 weeks another type of premature spontaneous termination due to ascending infection becomes prevalent. The number of cells expressing the various lymphocytic markers changes throughout pregnancy. In the present study, we investigated the immunohistochemical expression of mononuclear infiltrations in paraffin-embedded placentas, from fetuses after spontaneous abortion (8th, 10th, and 12th week of gestational age), and those after therapeutic abortion at the same time, using a panel of monoclonal antibodies for the identification of leukocytes (CD45/LCA), B-lymphocytes (CD20/L-26), T-lymphocytes (CD45RO/UCHL1) and CD5 cells. Immunologic factors in human reproductive failure are plausible mechanisms of infertility and spontaneous abortion. Approximately 25% of cases of premature ovarian failure appear to result from an autoimmune etiology. Unfortunately, current therapeutic options for these women are limited to exogenous hormone or gamete substitution. Local inflammation at the sites of endometriosis implants are postulated to mediate the pain and reduce fecundability associated with this clinical syndrome. The recruitment of immune cells, particularly monocytes and T cells, neovascularization around foci of invading peritoneal lesions, and the possible development of antiendometrial autoantibodies support an immunologic basis of this disorder. To date, treatment of pain and infertility associated with endometriosis is primarily surgical, although immune-based adjuvants are theoretical possibilities for the future. Finally, although hypotheses supporting immunologic mechanisms of recurrent pregnancy loss have been popular over the past decade, most clinical investigations in this area do not provide compelling evidence for this position. Reputable specialists in reproductive medicine use experimental immunotherapies judiciously in selected cases of repetitive abortion. For example, the use of anticoagulation therapy can be beneficial in cases with documented antiphospholipid antibodies. At present, however, efficacious immunotherapy protocols for general application have not been established. Despite these caveats, continued strides in our understanding of human reproductive immunology, should yield considerable future progress in this field. We conclude that, 1) maternal cells, probably CD45RO/UCHL1 positive cells, cross the maternofetal barrier and participate in spontaneous (involuntary) abortions, 2) a small proportion of maternal cells (approximately 30%), probably CD5 positive cells, also cross the maternal fetal barrier and cause growth delay and recurrent reproductive failure. The results were statistically significant (p < 0.0001, Student's t-test).     

Immune modulation of i.v. immunoglobulin in women with reproductive failure

Background

The mechanism of maternal immune tolerance of the semi‐allogenic fetus has been explored extensively. The immune reaction to defend from invasion by pathogenic microorganisms should be maintained during pregnancy. An imbalance between the immune tolerance to the fetus and immune activation to the pathogenic organisms is associated with poor pregnancy outcomes. This emphasizes that the immune mechanism of successful reproduction is not just immune suppression, but adequate immune modulation.

Methods

In this review, the action of i.v. immunoglobulin G (IVIg) on the immune system and its efficacy in reproductive failure (RF) was summarized. Also suggested is the indication of IVIg therapy for women with RF.

Main findings (Results)

Based on the mechanism of the immune regulation of IVIg and following confirmation of the immune modulation effects of it in various aberrant immune parameters in patients with RF, it is obvious that IVIg is effective in recurrent pregnancy losses and repeated implantation failures with immunologic disturbances.

Conclusion

The authors recommend IVIg therapy in patients with RF with aberrant cellular immunologic parameters, including a high natural killer cell proportion and its cytotoxicity or elevated T helper 1 to T helper 2 ratio, based on each clinic's cut‐off values. Further clinical studies about the safety of IVIg in the fetus and its efficacy in other immunologic abnormalities of RF are needed.     

Maternal Posture for Cephalic Version of Breech Presentation: A Review of the Evidence

Abstract: Background : Maternal posture is commonly recommended to promote cephalic version of breech presentation during pregnancy, but the few studies conducted to examine the efficacy of this obstetric practice are inconclusive. The purpose of this systematic review was to evaluate the research evidence base for postural management of breech presentation. Methods : This review critically examined the research on maternal posture for breech presentation using guidelines from the third United States Preventive Services Task Force. Database searches were conducted of Ovid Medline, Cumulative Index of Nursing and Allied Health Literature, PubMed, and Cochrane Database of Systematic Reviews, using the keywords “pregnancy,”“maternal posture,”“maternal position,”“postural management,”“breech,”“presentation.” Hand searches were conducted on reference citations from databases, and all research articles, commentaries, and reports of clinical cases were included. Results : Conceptual and methodological issues in the individual studies posed threats to internal validity in each study. Interpretation of the nonsignificant results in the research reports is debatable because the randomized controlled trials were underpowered, and flaws in each study challenged validity of the results. Meta‐analysis of previous findings may be inappropriate. Conclusions : Further research based on explicit theory and improved methods, including sufficient sample size, is needed to determine whether maternal posture promotes cephalic version for pregnant women with breech presentation. (BIRTH 32:2 June 2005)     

Baby born too soon: an overview and the impact beyond the infection

Spontaneous preterm delivery, prematurity, and low birth weight due to prematurity account for a great part of neonatal morbidity and mortality. Inflammation may cause preterm labor, with the involvement of different mediators that produce diverse aspects of the inflammatory response. Although bacteria are considered to be the main trigger for intrauterine infection/inflammation, immunological factors also appear to be involved. Recently, molecular genetic studies have helped us better understand the underlying pathophysiologic processes. During mammalian pregnancy, maternal–fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. This review focuses on the specific immune parameters that become altered during human pregnancy, the identity and function of some immune modulators that have been best characterized to date, as well as a comprehensive evaluation of the pregnancy-associated mechanisms that downregulate proinflammatory immunity to a level sufficient to prevent the triggering of premature common pathway of labor and damage to developing organs.     

胚胎植入的研究进展:从基础到临床

胚胎植入是生殖医学领域的一个重要研究方向。胚胎植入的成功与否决定了妊娠结局甚至子代健康。文章总结了以小鼠为模式动物获得的研究成果及相关的临床研究进展,以期为提高临床辅助生殖技术妊娠率及降低孕早期流产率提供参考和指导。