Showing papers in "American Journal of Reproductive Immunology in 2017"

Oxidative stress, placental ageing-related pathologies and adverse pregnancy outcomes

Abstract: Oxidative stress (OS), an imbalance between free radical generation and antioxidant defence, is recognized as a key factor in the pathogenesis of adverse pregnancy outcomes. Although OS is a common future of normal pregnancy, persistent, overwhelming OS leads to consumption and decline of antioxidants, affecting placental antioxidant capacity and reducing systems. The accumulation of OS causes damage to lipids, proteins and DNA in the placental tissue that induces a form of accelerated ageing. Premature ageing of the placenta is associated with placental insufficiency that prevents the organ meeting the needs of the foetus, and as a consequence, the viability of the foetus is compromised. This review summarizes the literature regarding the role of OS and premature placental ageing in the pathophysiology of pregnancy complications.

Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure.

Abstract: Problem The aim of this prospective study was to investigate the prevalence of chronic endometritis (CE) in infertile women with a history of repeated implantation failure (RIF) and to determine whether oral antibiotic treatment improves their live birth rate in the following embryo transfer (ET) cycles. Method of study Endometrial biopsy samples obtained from infertile women with RIF were subjected to immunohistochemistrical/histopathologic diagnosis of CE. Following antibiotic administration to the RIF/CE group, their histopathologic cure rate, microbial detection rate, and reproductive outcome in the subsequent ET cycles were prospectively studied. Results 33.7% of infertile women with RIF were diagnosed with CE. Following the first-line doxycycline treatment, the histopathologic cure rate in the subsequent endometrial biopsy was 92.3%. Following the second-line metronidazole/ciprofloxacin treatment, the overall cure rate was 99.1%. The live birth rate in the first ET cycle (P=.031, RR 1.48, 95% CI 1.03-2.12) and cumulative three ET cycles (P=.037, RR 1.39, 95% CI 1.02-1.90) following antibiotic treatment in the cured RIF/CE group (32.8% and 38.8%, respectively) was significantly higher than in the RIF/non-CE group (22.1% and 27.9%, respectively). Conclusion Chronic endometritis was found in one-third of infertile women with RIF. The oral antibiotic treatment against CE might be a promising therapeutic option for infertile women with RIF.

Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition

Abstract: Problem The extravillous trophoblasts (EVT) express HLA-C and HLA-G, but HLA-E and HLA-F are the subject of conflicting reports. In this study, we define the HLA expression profile during active EVT placental implantation, pregnancy development, and parturition. Method of study Immunohistochemistry, q-PCR, and Western blot were used to investigate HLA-C, HLA-E, and HLA-F placental expression across gestation from the early first trimester, late first trimester, second trimester (n=10 in each), preterm gestation (n=6) to elective term cesarean section and term vaginal deliveries (n=12, 38-41 weeks). EVT explants and Swan71 cells were used to assess HLA-C and HLA-F during active EVT migration. Results HLA-G, HLA-C, and HLA-F were expressed by 1st-trimester EVT and became intracellular and weaker as gestation progressed. HLA-E was only expressed in 1st-trimester placenta. HLA-F and HLA-C mRNA and protein expression levels showed a significant increase in the fetal villous mesenchyme across gestation. HLA-C levels increased with labor. We detected a 100-kDa HLA-F band in early pregnancy suggesting dimer formation on the EVT surface. These results were confirmed in EVT outgrowths and Swan71 trophoblast which showed that HLA-F and HLA-G are increased on the cell surface of migrating EVT, while HLA-C was internalized. Conclusion Expression of HLA-F and HLA-G on the cell surface of actively migrating EVT supports their specific role in early EVT invasion and interactions with uterine natural killer cells. HLA-C's limited expression to the proliferative EVT suggests a protective role in the earliest events of implantation but not in active EVT invasion. We also show for the first time that HLA-C may be involved in parturition.

Zika virus infection of Hofbauer cells

Abstract: Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non-placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal-placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV. In this review, we describe congenital abnormalities associated with ZIKV infection, the role of HBCs in the placental response to infection, and evidence for the susceptibility of HBCs to ZIKV infection. We conclude that HBCs may contribute to the spread of ZIKV in placenta and promote vertical transmission of ZIKV, ultimately compromising fetal and neonatal development and function. Current evidence strongly suggests that further studies are warranted to dissect the specific molecular mechanism through which ZIKV infects HBCs and its potential impact on the development of CZS.

Mitochondrial dysfunction and ovarian aging.

Abstract: Mitochondria are double-membrane-bound organelles that are responsible for the generation of most of the cell's energy. Mitochondrial dysfunction has been implicated in cellular senescence in general and ovarian aging in particular. Recent studies exploited this association by studying mitochondrial DNA (mtDNA) copy number as a potential biomarker of embryo viability and the use of mitochondrial nutrients and autologous mitochondrial transfer as a potential treatment for poor ovarian function and response.

Abnormal peritoneal regulation of chemokine activation—The role of IL‐8 in pathogenesis of endometriosis

Abstract: Problem Endometriosis is a chronic inflammatory disease associated with an impairment in immune response. Disorders in the peritoneal fluid and ectopic endometrium macrophage populations and their secretory products create a specific microenvironment inducing the development of the disease. The important factors involved in inflammation associated with endometriosis are chemokines, especially interleukin (IL)-8. For this reason, the current study briefly reviews the role of IL-8 in the pathogenesis of endometriosis. Method of study A systematic review was done on all published studies that compared IL-8 expression and concentration in patients with and without endometriosis to evaluate their potential as biomarkers for the disease. Results IL-8 induces chemotaxis of neutrophils and other immune cells; also, it is a potent angiogenic agent. Most researchers pointed to the increased peritoneal and serum IL-8 levels and showed correlation with the severity of the disease, size and number of the active lesions. IL-8 takes part in all processes during the development of the disease: adhesion, invasion, and implantation of ectopic tissue. Additionally, the chemokine plays a role in growth and maintenance of ectopic endometrial tissue directly affecting endometrial cell proliferation. IL-8 might also protect ectopic cells against death by apoptosis. Conclusion It may act as an autocrine growth factor in the endometrium and promotes the vicious circle of endometrial cell attachment and, in consequence, may lead to a transformation from acute to chronic inflammation stage.

CXCL10 and IL‐6: Markers of two different forms of intra‐amniotic inflammation in preterm labor

Abstract: Problem To determine whether amniotic fluid (AF) CXCL10 concentration is associated with histologic chronic chorioamnionitis in patients with preterm labor (PTL) and preterm prelabor rupture of the membranes (PROM) Method of Study This study included 168 women who had an episode of PTL or preterm PROM AF interleukin (IL)-6 and CXCL10 concentrations were determined by immunoassay Results (i) Increased AF CXCL10 concentration was associated with chronic (OR: 48; 95% CI: 17-14), but not acute chorioamnionitis; (ii) increased AF IL-6 concentration was associated with acute (OR: 42; 95% CI: 13-137) but not chronic chorioamnionitis; and (iii) an increase in AF CXCL10 concentration was associated with placental lesions consistent with maternal anti-fetal rejection (OR: 37; 95% CI: 13-104) (iv) All patients with elevated AF CXCL10 and IL-6 delivered preterm Conclusion Increased AF CXCL10 concentration is associated with chronic chorioamnionitis or maternal anti-fetal rejection, whereas increased AF IL-6 concentration is associated with acute histologic chorioamnionitis

Amniotic fluid neutrophils can phagocytize bacteria: A mechanism for microbial killing in the amniotic cavity.

Abstract: Problem Neutrophils are capable of performing phagocytosis, a primary mechanism for microbial killing. Intra-amniotic infection is characterized by an influx of neutrophils into the amniotic cavity. Herein, we investigated whether amniotic fluid neutrophils could phagocytize bacteria found in the amniotic cavity of women with intra-amniotic infection. Methods Amniotic fluid neutrophils from women with intra-amniotic infection were visualized by transmission electron microscopy (n=6). The phagocytic activity of amniotic fluid neutrophils from women with intra-amniotic infection and/or inflammation (n=10) or peripheral neutrophils from healthy individuals (controls, n=3) was tested using ex vivo phagocytosis assays coupled with live imaging. Phagocytosis by amniotic fluid neutrophils was also visualized by confocal microscopy (n=10) as well as scanning and transmission electron microscopy (n=5). Results (i) Intra-amniotic infection-related bacteria including cocci (eg Streptococcus agalactiae), bacilli (eg Bacteriodes fragilis and Prevotella spp.), and small bacteria without a cell wall (eg Ureaplasma urealyticum) were found inside of amniotic fluid neutrophils; (ii) peripheral neutrophils (controls) rapidly phagocytized S. agalactiae, U. urealyticum, Gardnerella vaginalis, and Escherichia coli; (iii) amniotic fluid neutrophils rapidly phagocytized S. agalactiae and G. vaginalis; and (iv) amniotic fluid neutrophils slowly phagocytized U. urealyticum and E. coli; yet, the process of phagocytosis of the genital mycoplasma was lengthier. Conclusion Amniotic fluid neutrophils can phagocytize bacteria found in the amniotic cavity of women with intra-amniotic infection, namely S. agalactiae, U. urealyticum, G. vaginalis, and E. coli. Yet, differences in the rapidity of phagocytosis were observed among the studied microorganisms. These findings provide a host defense mechanism whereby amniotic fluid neutrophils can kill microbes invading the amniotic cavity.

Physiological and pathological angiogenesis in endometrium at the time of embryo implantation.

Abstract: Embryo establishes contact with the endometrium during implantation. Proper endometrial vascular development and maintenance at the time of embryo implantation is crucial for successful pregnancy. Vascular development at the maternal-embryo interface can be regulated by various cell types, of which uterine natural killer (uNK) cells play an important role. Abnormal angiogenesis and uNK cell number/function may lead to reproductive failure, particularly in women with recurrent miscarriage (RM) and women with recurrent implantation failure (RIF) after IVF-ET treatment, which are the important clinical hurdles in reproductive medicine to overcome. In this review, we aim to discuss the current knowledge of physiological angiogenic processes and the pathological angiogenesis at the time of implantation, as well as the possible mechanism and potential treatment.

Mapping out p38MAPK.

Abstract: To generate new hypotheses, sometimes a "systems" approach is needed. In this review, I focus on the mitogen-activated kinase p38 because it has been recently shown to play an important role in the developmental programing and senescence of normal and stressed reproductive tissues. What follows is an overview of (i) pathways of p38 activation and their involvement in basic biological processes, (ii) evidence that p38 is involved in the homeostasis of reproductive tissues, (iii) how focus on p38 can be incorporated into investigation of normal and stressed pregnancies. Existence of excellent reviews will be mentioned as well as relevant animal models.

Efficacy of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) for Infertile women with thin endometrium: A systematic review and meta-analysis.

Abstract: This meta-analysis aimed to explore the efficiency of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) on infertile women with thin endometrium. Following PRISMA protocol, we conducted a comprehensive search of academic literatures on various databases including PubMed, EMbase, and Cochrane Library. Studies published in English before July 1, 2016 were included for primary screening. Data on the thickness of endometrium, cycle cancelation rate,clinical pregnancy rate, and embryo implantation rate were extracted and analyzed, respectively. Eleven eligible studies involving 683 patients were included in this meta-analysis. Compared with control group, G-CSF perfusion could significantly improve endometrial thickness (mean difference [MD]=1.79, 95% confidence interval (CI): 0.92-2.67), clinical pregnancy rate (risk ratio [RR]=2.52, 95% CI: 1.39-4.55), and embryo implantation rate (RR=2.35, 95% CI: 1.20-4.60), while it could decrease cycle cancelation rate (RR=0.38, 95% CI: 0.25-0.58). Funnel plots revealed that there was no evidence of publication bias. The current data indicate that intrauterine perfusion of G-CSF can improve endometrial thickness, clinical pregnancy rate, and embryo implantation rate, but decrease the cycle cancelation rate in women with thin endometrium.

Endometrial immune markers are potential predictors of normal fertility and pregnancy after in vitro fertilization

Abstract: Problem Elucidating immune mechanisms in the endometrium, which lead to the success of implantation and pregnancy, is important in reproductive medicine. Studies of immune cell abundance have shown conflicting results, and the expression and importance of HLA class Ib proteins in pre-implantation endometrium have not yet been investigated. Method of study The study population consisted of four subgroups: a hydrosalpinx, a salpingectomy, an unexplained infertility, and a fertile control group. Endometrial samples were collected during the implantation window. Immune markers (CD56+ and CD16+ cells, FoxP3+ Tregs, HLA-G, HLA-F) were quantified in the samples. The outcome of the subsequent IVF treatment was recorded. Results Increased CD56+ uNK cells and high HLA-G expression served as predictor for successful pregnancy outcome. HLA-F expression was positively correlated with uNK cells, being indirectly predictive for achieving pregnancy. Conclusion Endometrial uNK cell abundance in the pre-implantation endometrium seems to be important for normal fertility and pregnancy success, and they may be used as clinical markers to predict implantation success in IVF.

Maternal obesity and inflammatory mediators: A controversial association

Abstract: The link between maternal obesity and inflammatory mediators is still unclear. Our aim was to summarize the main findings of recently published studies on this topic. We performed a search in Medline for studies published in the last years on obesity, human pregnancy, and inflammatory mediators. We report the findings of 30 studies. The characteristics and number of participants, study design, gestational age at sample collection, and type of sample varied widely. Approximately two-thirds of them investigated more than one mediator, and 50% included participants in only one trimester of pregnancy. The most frequently investigated mediators were leptin, tumour necrosis factor-alpha (TNF-α), and interleukin (IL)-6. Almost all studies reported an association between maternal obesity, leptin, and C-reactive protein (CRP) serum levels but not with IL-1β and IL-10. The association of IL-6, TNF-α, monocyte chemo-attractant protein-1 (MCP-1), adiponectin, and resistin with maternal obesity is still controversial. To clarify the physiopathological link between maternal obesity and inflammation, more high-quality studies are needed.

The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery.

Abstract: Problem To characterize the amniotic fluid (AF) inflammatory-related protein (IRP) network in patients with a sonographic short cervix (SCx) and to determine its relation to early preterm delivery (ePTD). Method of study A retrospective cohort study included women with a SCx (≤25 mm; n=223) who had amniocentesis and were classified according to gestational age (GA) at diagnosis and delivery (ePTD <32 weeks of gestation). Results (i) In women with a SCx ≤ 22 1/7 weeks, the concentration of most IRPs increased as the cervix shortened; those with ePTD had a higher rate of increase in MIP-1α, MCP-1, and IL-6 concentrations than those delivering later; and (ii) the concentration of most IRPs and the correlation between several IRP pairs were higher in the ePTD group than for those delivering later. Conclusion Women with a SCx at 16-22 1/7 weeks have a unique AF cytokine network that correlates with cervical length at diagnosis and GA at delivery. This network may aid in predicting ePTD.

Uterine natural killer cells in patients with idiopathic recurrent miscarriage.

Abstract: Problem Uterine natural killer (uNK) cells are major players during implantation and early pregnancy. The aim of our study was to analyze uNK cell concentration in the endometrium of idiopathic recurrent miscarriage (iRM) patients and fertile controls. Method of study Out of n=130 couples with ≥3 consecutive, clinical RM screened according to a standardized diagnostic protocol, n=58 patients with iRM were identified. Endometrial biopsies were investigated in patients and n=17 fertile women (controls) via immunohistochemistry. Results Compared to controls, the concentration of uNK cells was significantly higher in iRM patients (257±212 vs. 148±73 uNK cells/mm², P=.04). IRM patients showed a higher prevalence of >300 uNK cells/mm² than controls (34.5% vs. 5.9%, P=.02). In 88% of controls and 62% of iRM patients, uNK cells were detected within the range of 40-300/mm². Conclusion Idiopathic recurrent miscarriage patients showed higher uNK cell levels than controls supporting the possible impact of uNK cells in the pathophysiology of miscarriage. Our cutoff levels might help to select RM patients which may benefit from immunomodulatory treatment.

Lnc-DC mediates the over-maturation of decidual dendritic cells and induces the increase in Th1 cells in preeclampsia

Abstract: Problem Preeclampsia is a severe pregnancy-related disease that involves an imbalance of the immune reaction, which is dominated by T helper1 (Th1) cells; however, the mechanism is unclear. Method of study We used flow cytometry, RT-PCR and western blotting to detect Th1 cells in the blood and mature dendritic cells, lnc-DC (a long non-coding RNA that is specifically expressed in DCs and can mediate dendritic cell maturation by phosphorylating STAT3) and p-STAT3 (phosphorylated transducer and activator of transcription 3) in the deciduas of normal pregnancies and preeclampsia patients. Results We found that the expression of lnc-DC and p-STAT3 was increased in the deciduas of preeclampsia patients. The proportion of Th1 cells and mature dendritic cells was significantly higher in the preeclampsia patients. Conclusion These results suggested the hypothesis that the overexpression of lnc-DCs induces the over-maturation of decidual dendritic cells in preeclampsia patients and leads to an increase in Th1 cells.

Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association

Abstract: Undifferentiated connective tissue diseases (UCTDs) are a heterogeneous group of disorders characterized by symptoms and signs suggestive of systemic autoimmune rheumatic disease (ARD), but which do not fulfill all the established criteria for definite diagnosis of a condition. Although a third of UCTDs can progress to a definite ARD within months or years, most UCTDs can remain stable for years with minimal disease activity. The annual incidence of UCTD in the general population ranges from 14 to 140 per 100 000 people. UCTDs are associated with the persistence of several circulating autoantibodies including antinuclear, antiphospholipid or antithyroid antibodies. Immunological evaluation of subjects with UCTDs suggests a proinflammatory state and dysregulation of the Th1/Th2 balance. Autoantibodies have well-known deleterious effects on placentation and have been associated with an increased risk of prematurity, fetal growth restriction (FGR), preeclampsia, and congenital atrioventricular heart block. Although epidemiological and biological data suggest a potential negative impact on reproductive outcomes, the relationship between UCTD and pregnancy outcomes has not been adequately studied. While awaiting definitive data from large studies, obstetricians should be aware that rheumatic disorders in their early, incomplete, or undifferentiated phases can adversely affect pregnancy outcomes, increasing the likelihood of pregnancy loss, FGR, preeclampsia, and prematurity.

Neutrophil extracellular traps in acute chorioamnionitis: A mechanism of host defense.

Abstract: Problem Neutrophil extracellular traps (NETs) were recently described as a mechanism for microbial killing in the amniotic cavity of women with intra-amniotic infection. Such a clinical condition can result in acute chorioamnionitis, a placental lesion characterized by the infiltration of maternal neutrophils in the chorioamniotic membranes. Herein, we investigated whether these infiltrating neutrophils form NETs in the chorioamniotic membranes from women who underwent spontaneous term or preterm labor with acute chorioamnionitis. Method of study Chorioamniotic membrane samples were collected from women who underwent spontaneous term or preterm labor with acute chorioamnionitis (n=10 each). Controls included chorioamniotic membrane samples from women who delivered at term or preterm with or without labor in the absence of acute chorioamnionitis (n=10 each). NETs were visualized and semiquantified in the chorioamniotic membranes by using antibodies against neutrophil elastase and histone H3 in combination with DAPI staining. Results Neutrophil extracellular traps were abundant in the chorioamniotic membranes from women who underwent spontaneous term or preterm labor with acute chorioamnionitis. NETs were rarely found, or not visualized at all, in the chorioamniotic membranes from women who delivered at term or preterm with or without labor in the absence of acute chorioamnionitis. Conclusion Neutrophil extracellular traps are abundant in the chorioamniotic membranes from women who underwent spontaneous term or preterm labor with acute chorioamnionitis. These findings suggest that chorioamniotic neutrophils can form NETs as a mechanism of host defense against infection or danger signals.

Lipopolysaccharide promotes the development of murine endometriosis‐like lesions via the nuclear factor‐kappa B pathway

Abstract: Problem Is lipopolysaccharide (LPS) involved in the development of endometriosis? Method of Study BALB/c mice (n=69) were used for the murine endometriosis model. Mice with surgically induced endometriosis were injected with LPS intraperitoneally. After 4 weeks of LPS injections with or without the nuclear factor-kappa B (NF-κB) inhibitor, the extent of endometriosis-like lesions was evaluated. Expression of inflammatory factors in the implants was evaluated using real-time RT-PCR. Cell proliferation, angiogenic activity, inflammation, and NF-κB phosphorylation were assessed by immunohistochemical staining. Results Lipopolysaccharide increased total number, size, and mRNA expression of Ptgs-2, Vegf, Ccl-2, and Il-6 in endometriosis-like lesions. LPS also increased the percentage of Ki67-positive cells and enhanced the intensity and rate of positive cells of CD3, F4/80, and PECAM. Intense expression of phospho-NF-κB p65 after LPS administration was observed. Treatment with the NF-kB inhibitor negated these LPS-induced effects. Conclusions LPS-induced pelvic inflammation status enhanced the development of murine endometriosis-like lesions via NF-κB pathway.

Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells.

Abstract: Problem Human chorionic gonadotropin (hCG) and regulatory T cells (Tregs) have been suggested to play important roles during the initial stage of pregnancy. However, the clinical relevance and mechanism of the effects of hCG on Treg functions in women with recurrent implantation failure (RIF) remain to be elucidated. Method of study Thirty-four RIF and twenty-three control women were included in the study. Endometrial and peripheral Tregs were analyzed by immunohistochemistry and flow cytometry, respectively. Tregs were generated from naive CD4+ T cells by stimulation with anti-CD3/CD28 in the presence or absence of hCG, and the subsets were analyzed by flow cytometry, Western blotting, and qPCR. Results The percentages of endometrial FOXP3+ Tregs and peripheral CCR4+FOXP3+ Tregs were significantly lower in the women with RIF than in the healthy controls. In addition, the percentages of CCR4+FOXP3+ Tregs and TGF-β-expressing FOXP3+ Tregs were increased following the stimulation of naive CD4+ T cells with anti-CD3/CD28, and these increases were concomitant with AKT and ERK dephosphorylation. Conclusions The results of this study provide novel evidence supporting a role of hCG in regulating the differentiation of peripheral FOXP3+ Tregs. The alterations of circulating Tregs may positively affect the pregnancy outcomes of patients with a history of RIF.

Zika virus: A new threat to human reproduction

Abstract: Zika virus (ZIKV) was first isolated in 1947 in a rhesus monkey from the Zika forest of Uganda. Until 2007, only 14 human cases were reported. The first large human outbreak occurred in 2007 (Yap Island, Federated States of Micronesia, Pacific) followed by French Polynesia in 2013 and Brazil in 2015. The virus is mainly transmitted through Aedes mosquito bites, but sexual and post-transfusion transmissions have been reported. Symptoms include low-grade fever, maculopapular rash, conjunctivitis, myalgia, arthralgia, and asthenia. During the recent outbreaks in French Polynesia and Brazil, ZIKV infection has been associated with two major complications: microcephaly and Guillain-Barre syndrome. Since fetal infection includes other birth defects, congenital Zika syndrome has been used to define in utero infection. The majority of sexual transmission occurred from a symptomatic male to a female, but female-to-male and male-to-male transmission have been reported. Asymptomatic male-to-female transmission has also been described. Importantly, ZIKV RNA can persist at least 6 months in semen. The male urogenital tract may therefore act as a reservoir for the virus. ZIKV RNA was detected in a cervical swab of a patient 3 days after presenting the classic symptoms suggesting a potential tropism for the female genital tract. Long-lasting presence of ZIKV RNA might not indicate that the individual is infectious but makes recommendation for couples potentially exposed to the virus and willing to conceive difficult. It will also be important to determine whether genital ZIKV infection might have a deleterious effect on male and female fertility.

Immunosuppressive treatment using tacrolimus promotes pregnancy outcome in infertile women with repeated implantation failures.

Abstract: PROBLEM We aim to investigate whether the peripheral blood T helper (Th) 1 cell level could predict pregnancy outcome in patients who have experienced repeated implantation failure (RIF, three or more) after ART cycles. METHOD OF STUDY This is a prospective cohort study of total 124 women with RIF who showed elevated Th1/Th2 (CD4+ IFN-γ+ /CD4+ IL-4+ ) cell ratios (≥10.3) and received tacrolimus at Sugiyama Clinic between November 2011 and July 2016. Patients were divided into three groups as per Th1 cell levels: Th1 level of <22.8 as Low; 22.8 to <28.8 as Middle, and 28.8 or greater as High group. The study patients received daily dose of tacrolimus 1-3 mg based on initial Th1/Th2 cell ratio. RESULTS The clinical pregnancy rates of Low, Middle, and High groups were 48.8%, 43.9%, and 33.3%, respectively (P=NS), with tacrolimus treatment. The ongoing pregnancy/delivery rate of Low group (46.3%) was significantly higher than that of High group (21.4%, P<.05). Middle group (34.3%) had higher success rate than High group, albeit without statistical significant. CONCLUSION We confirm our previous report that Th1/Th2 ratio can predict ART outcomes in patients with RIF and immunosuppressant treatment with tacrolimus, and peripheral blood Th1 cell levels were negatively correlated with pregnancy outcome.

Inflammasome assembly in the chorioamniotic membranes during spontaneous labor at term

Abstract: Problem Inflammasome activation requires two steps: priming and assembly of the multimeric complex. The second step includes assembly of the sensor molecule and adaptor protein ASC (an apoptosis-associated speck-like protein containing a CARD), which results in ASC speck formation and the recruitment of caspase (CASP)-1. Herein, we investigated whether there is inflammasome assembly in the chorioamniotic membranes and choriodecidual leukocytes from women who underwent spontaneous labor at term. Method of Study Using in situ proximity ligation assays, ASC/CASP-1 complexes were determined in the chorioamniotic membranes from women who delivered at term without labor or underwent spontaneous labor at term with or without acute histologic chorioamnionitis (n=10-11 each). Also, ASC speck formation was determined by flow cytometry in the choriodecidual leukocytes isolated from women who delivered at term with or without spontaneous labor (n=9-12 each). Results (i) ASC/CASP-1 complexes were detected in the chorioamniotic membranes; (ii) ASC/CASP-1 complexes were greater in the chorioamniotic membranes from women who underwent spontaneous labor at term than in those without labor; (iii) ASC/CASP-1 complexes were even more abundant in the chorioamniotic membranes from women who underwent spontaneous labor at term with acute histologic chorioamnionitis than in those without this placental lesion; (iv) ASC speck formation was detected in the choriodecidual leukocytes; and (v) ASC speck formation was greater in the choriodecidual leukocytes isolated from women who underwent spontaneous labor at term than in those without labor. Conclusion There is inflammasome assembly in the chorioamniotic membranes and choriodecidual leukocytes during spontaneous labor at term.

Current concepts in maternal-fetal immunology: Recognition and response to microbial pathogens by decidual stromal cells.

Abstract: Chorioamnionitis is an acute inflammation of the gestational (extraplacental) membranes, most commonly caused by ascending microbial infection. It is associated with adverse neonatal outcomes including preterm birth, neonatal sepsis, and cerebral palsy. The decidua is the outermost layer of the gestational membranes and is likely an important initial site of contact with microbes during ascending infection. However, little is known about how decidual stromal cells (DSCs) respond to microbial threat. Defining the contributions of individual cell types to the complex medley of inflammatory signals during chorioamnionitis could lead to improved interventions aimed at halting this disease. We review available published data supporting the role for DSCs in responding to microbial infection, with a special focus on their expression of pattern recognition receptors and evidence of their responsiveness to pathogen sensing. While DSCs likely play an important role in sensing and responding to infection during the pathogenesis of chorioamnionitis, important knowledge gaps and areas for future research are highlighted.

Immunological function of vitamin D during human pregnancy.

Abstract: The well-established classic role of vitamin D is implicated in the regulation of the balance between calcium and phosphorus. Furthermore, vitamin D is also involved in many non-classic physiological processes, mainly including the regulation of cell proliferation, differentiation, apoptosis and immune function, participation in the inflammatory response and maintenance of genome stability function. During pregnancy, vitamin D receptor and its metabolic enzymes are expressed at the placenta and decidua, indicating the potential role in the mechanism of immunomodulation at the maternal-fetal interface. The insufficiency or deficiency of vitamin D may affect the mother directly and is related to specific pregnancy outcomes, such as preeclampsia, gestational diabetes, and recurrent miscarriage. This article reviews the effects of vitamin D on immune regulation during pregnancy.

Downregulation of genes related to immune and inflammatory response in IVF implantation failure cases under controlled ovarian stimulation.

Abstract: Problem Implantation failure (IF) even after the good-quality embryo transfer (ET) is main obstacle in in vitro fertilization (IVF). We aim to study the genomics of endometrial receptivity in IF patients under controlled ovarian stimulation (COS) during which ET is generally practised in IVF. Method of study Endometrial gene expression profiling in IF patients (n=10) and oocyte donors (n=8) were compared during window of implantation under COS by microarray. Enrichment analysis of microarray data was performed to determine dysregulated pathways. Microarray results were validated by real-time PCR. Localization of genes related to immune response (progestagen-associated endometrial protein (PAEP), leukaemia inhibitory factor (LIF), interleukin-6 signal transducer (IL6ST) was detected by immunohistochemistry. Results The gene ontology, pathway analysis and enrichment mapping revealed significant downregulation in activation and regulation of immune and inflammation response in IF patients under COS. The lower expression of PAEP, LIF and IL6ST in cases compared to controls by real time and immunohistochemistry suggests the functional importance of these genes. Conclusion Importance of immune and inflammatory response in endometrial receptivity adds on to the current knowledge of gene expression profile in IF under COS. The panel of genes involved in these pathways would be useful in determining further line of treatment for IF during IVF.

Telomere length and fetal programming: A review of recent scientific advances.

Abstract: We sought to synthesize a comprehensive literature review comprising recent research linking fetal programming to fetal telomere length. We also explored the potential effects fetal telomere length shortening has on fetal phenotypes. Utilizing the PubMed database as our primary search engine, we retrieved and reviewed 165 articles of published research. The inclusion criteria limited the articles to those that appeared within the last ten years, were pertinent to humans, and without restriction to language of publication. Our results showed that socio-demographic factors like age, sex, genetic inheritance, and acquired disease impact telomere length. Further, we found several maternal characteristics to be associated with fetal telomere length shortening, and these include maternal chemical exposure (eg, tobacco smoke), maternal stress during pregnancy, maternal nutritional and sleeping disorders during pregnancy as well as maternal disease status. Due to paucity of data, our review could not synthesize evidence directly linking fetal phenotypes to telomere length shortening. Although the research summarized in this review shows some association between determinants of intrauterine programming and fetal telomere length, there is still significant work that needs to be done to delineate the direct relationship of telomere attrition with specific fetal phenotypes.

Distribution of invariant natural killer T cells and dendritic cells in late pre-term birth without acute chorioamnionitis.

Abstract: Problem Acute chorioamnionitis (aCAM) is an important cause of pre-term birth. However, little is known about the pathogenesis of late pre-term birth without aCAM that was the most common category of pre-term birth. Here we analyze the kinetics of immune cells obtained from the decidua of women with late pre-term births with and without aCAM. Method of study Deciduas were obtained from women who underwent labor with late pre-term birth without aCAM (PB-n/aCAM) or with aCAM (PB-w/aCAM). The population of DEC-205+ dendritic cells (DCs), macrophages, invariant natural killer T (iNKT) cells, NK cells, CD8+ T cells, and CD4+ T cells were analyzed by flow cytometry. Results The number of iNKT cells was higher in the decidua obtained from women with PB-n/aCAM than PB-w/aCAM. DEC-205+ DCs obtained from women with PB-n/aCAM preferentially induced iNKT cell proliferation. Conclusion iNKT cell accumulation with DEC-205+ DCs in PB-n/aCAM suggests that iNKT cells contribute to the onset of PB-n/aCAM.

Successful treatment with intrauterine delivery of dexamethasone for repeated implantation failure.

Abstract: Problem Effective therapy for endometrial receptivity of patients with repeated embryo implantation failure (RIF) is far undeveloped. Whether intrauterine perfusion of dexamethasone (DXM), local administration of drugs with less systematic side-effects, benefit for embryo implantation by suppressing uterine NK (uNK) cells to improve endometrial receptivity remains unknown. Method of study Women with RIF were analyzed for the correlation between the percentage of uNK cells during implantation window and following clinical pregnancy rate to determine the appropriate range of uNK for embryo implantation. Women with RIF and extremely increased uNK cells were treated with transvaginal intrauterine perfusion of DXM. Quantification of uNK cells before and after this treatment was analyzed by immunohistochemistry staining for understanding potential underlying mechanism. Pregnancy outcome was evaluated for the efficiency and safety of this novel therapy. Results The clinical pregnancy rate was decreased if the percentage of uNK cells was higher than the 75th percentile (18.06%), which was considered as the cutoff value for increased uNK cells. All eight patients with increased uNK cells responded to DXM-induced decrease on uNK cells number, and seven got clinical pregnancy. Three delivered with a healthy baby at term without any pregnancy complication and three achieved an ongoing pregnancy, but one suffered from early miscarriage. Conclusion We report for the first time the beneficial effect of intrauterine perfusion of DXM for patients with RIF characterized by high number of uNK cells. The potential mechanism is downregulation of the proportion of uNK cells, which may improve endometrial receptivity and enhance embryo implantation.

Use of D-dimer measurement to guide anticoagulant treatment in recurrent pregnancy loss associated with antiphospholipid syndrome.

Abstract: Problem To examine whether the level of plasma D-dimer can guide anticoagulant treatment in recurrent pregnancy loss (RPL) associated with antiphospholipid syndrome (APS). Methods A total of 1096 RPL women with APS between 2012 and 2015 in a single-center hospital were randomly divided into two groups (group A, 75 mg of low-dose aspirin [LDA] daily; group B, 75 mg of LDA plus 4100 U of low molecular weight heparin [LMWH] subcutaneously daily); 1015 of the total successfully completed the trial. Plasma D-dimer level and live birth rates were estimated. Results For APS women with an elevated D-dimer level at baseline, higher live birth rates were reached in LDA plus LMWH group compared to LDA alone group (92.71% vs 61.68%, P < .0001); however, no significant differences were found between the two groups of women with a normal D-dimer level (87.08% vs 83.76%, P = .48). Women with a normal D-dimer level at all blood draw points had the highest live birth rates (92.88%), as compared with those with persistently abnormal D-dimer at all blood draw points or increased D-dimer level after treatment (P < .001). Conclusion The combination therapy with LDA and LMWH is not essential for all APS women, but has proven to be beneficial for women with an elevated D-dimer level.