An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development.

Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.

TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation.

Sumoylation regulates many cellular processes, but its role in signaling via the T cell antigen receptor (TCR) remains unknown. We found that the kinase PKC-θ was sumoylated upon costimulation with antigen or via the TCR plus the coreceptor CD28, with Lys325 and Lys506 being the main sumoylation sites. We identified the SUMO E3 ligase PIASxß as a ligase for PKC-θ. Analysis of primary mouse and human T cells revealed that sumoylation of PKC-θ was essential for T cell activation. Desumoylation did not affect the catalytic activity of PKC-θ but inhibited the association of CD28 with PKC-θ and filamin A and impaired the assembly of a mature immunological synapse and central co-accumulation of PKC-θ and CD28. Our findings demonstrate that sumoylation controls TCR-proximal signaling and that sumoylation of PKC-θ is essential for the formation of a mature immunological synapse and T cell activation.

Trophoblast-derived miR-410-5p induces M2 macrophage polarization and mediates immunotolerance at the fetal-maternal interface by targeting the STAT1 signaling pathway.

BACKGROUND: Macrophages phenotypic deviation and immune imbalance play vital roles in pregnancy-associated diseases such as spontaneous miscarriage. Trophoblasts regulate phenotypic changes in macrophages, however, their underlying mechanism during pregnancy remains unclear. Therefore, this study aimed to elucidate the potential function of trophoblast-derived miRNAs (miR-410-5p) in macrophage polarization during pregnancy. METHODS: Patient decidual macrophage tissue samples in spontaneous abortion group and normal pregnancy group (those who had induced abortion for non-medical reasons) were collected at the Reproductive Medicine Center of Renmin Hospital of Wuhan University from April to December 2021. Furthermore, placental villi and decidua tissue samples were collected from patients who had experienced a spontaneous miscarriage and normal pregnant women for validation and subsequent experiments at the Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), from March 2021 to September 2022. As an animal model, 36 female mice were randomly divided into six groups as follows: naive-control, lipopolysaccharide-model, agomir-negative control prevention, agomir-410-5p prevention, agomir-negative control treatment, and agomir-410-5p treatment groups. We analyzed the miR-410-5p expression in abortion tissue and plasma samples; and supplemented miR-410-5p to evaluate embryonic absorption in vivo. The main source of miR-410-5p at the maternal-fetal interface was analyzed, and the possible target gene, signal transducer and activator of transcription (STAT) 1, of miR-410-5p was predicted. The effect of miR-410-5p and STAT1 regulation on macrophage phenotype, oxidative metabolism, and mitochondrial membrane potential was analyzed in vitro. RESULTS: MiR-410-5p levels were lower in the spontaneous abortion group compared with the normal pregnancy group, and plasma miR-410-5p levels could predict pregnancy and spontaneous abortion. Prophylactic supplementation of miR-410-5p in pregnant mice reduced lipopolysaccharide-mediated embryonic absorption and downregulated the decidual macrophage pro-inflammatory phenotype. MiR-410-5p were mainly distributed in villi, and trophoblasts secreted exosomes-miR-410-5p at the maternal-fetal interface. After macrophages captured exosomes, the cells shifted to the tolerance phenotype. STAT1 was a potential target gene of miR-410-5p. MiR-410-5p bound to STAT1 mRNA, and inhibited the expression of STAT1 protein. STAT1 can drive macrophages to mature to a pro-inflammatory phenotype. MiR-410-5p competitive silencing of STAT1 can avoid macrophage immune disorders. CONCLUSION: MiR-410-5p promotes M2 macrophage polarization by inhibiting STAT1, thus ensuring a healthy pregnancy. These findings are of great significance for diagnosing and preventing spontaneous miscarriage, providing a new perspective for further research in this field.

Connecting the dots: the role of fatigue in female infertility.

Fatigue, an increasingly acknowledged symptom in various chronic diseases, has garnered heightened attention, during the medical era of bio-psycho-social model. Its persistence not only significantly compromises an individual's quality of life but also correlates with chronic organ damage. Surprisingly, the intricate relationship between fatigue and female reproductive health, specifically infertility, remains largely unexplored. Our exploration into the existing body of evidence establishes a compelling link between fatigue with uterine and ovarian diseases, as well as conditions associated with infertility, such as rheumatism. This observation suggests a potentially pivotal role of fatigue in influencing overall female fertility. Furthermore, we propose a hypothetical mechanism elucidating the impact of fatigue on infertility from multiple perspectives, postulating that neuroendocrine, neurotransmitter, inflammatory immune, and mitochondrial dysfunction resulting from fatigue and its co-factors may further contribute to endocrine disorders, menstrual irregularities, and sexual dysfunction, ultimately leading to infertility. In addition to providing this comprehensive theoretical framework, we summarize anti-fatigue strategies and accentuate current knowledge gaps. By doing so, our aim is to offer novel insights, stimulate further research, and advance our understanding of the crucial interplay between fatigue and female reproductive health.

Comparing the peri-implantation endometrial T-bet/GATA3 ratio between control fertile women and patients with recurrent miscarriage: establishment and application of a reference range.

STUDY QUESTION: Is the ratio of endometrial T-box expressed in T cell (T-bet) and GATA-binding protein 3 (GATA3) changed in patients with recurrent miscarriage (RM) compared to fertile controls? SUMMARY ANSWER: Our study showed a significantly higher T-bet/GATA3 ratio in patients with RM compared with fertile controls. WHAT IS KNOWN ALREADY: The endometrial T-bet (Th1 lineage-committed transcription factor)/GATA3 (Th2 lineage-committed transcription factor) ratio could represent the Th1/Th2 balance, which is particularly important for healthy pregnancy. However, a reliable reference range for the T-bet/GATA3 ratio during the peri-implantation period has not yet been established for use in clinical practice. STUDY DESIGN, SIZE, DURATION: This was a retrospective study carried out in a private fertility center. The control group included 120 women in couples undergoing IVF treatment for male infertility, who had experienced a live-birth baby following the first IVF cycle. The study group included 93 women diagnosed with RM that experienced at least two consecutive clinically spontaneous miscarriages before gestational week 12. The ratio of T-bet/GATA3 was calculated in the control group and RM group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrium samples were collected at mid-luteal phase of the menstrual cycle prior to IVF treatment or pregnancy. The percentage of T-bet+ and GATA3+ cells in total endometrial cells was analyzed using immunohistochemical staining and quantitative analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Using the 95th percentile to define the upper limits of the endometrial T-bet/GATA3 ratio during the mid-luteal phase, the reference range of control fertile women was ≤0.22. Compared with the control group, the RM group exhibited a significantly higher T-bet/GATA3 ratio (P = 0.02), and 19.4% (18/93) women with RM exhibited a T-bet/GATA3 ratio above the reference range in the mid-luteal phase. LIMITATIONS, REASONS FOR CAUTION: All patients were recruited from a single center. The stability and clinical value of the endometrial T-bet/GATA3 ratio require further investigation. WIDER IMPLICATIONS OF THE FINDINGS: The present study suggests that an abnormal endometrial T-bet/GATA3 ratio may be one of the risk factors of RM. Further studies are needed to follow up the pregnancy outcomes in patients with RM with normal and abnormal endometrial T-bet/GATA3 ratio according to the reference range. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Shenzhen Fundamental Research Program (JCYJ20180228164631121, JCYJ20190813161203606, JCYJ20220530172817039). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Association of antimüllerian hormone with polycystic ovarian syndrome phenotypes and pregnancy outcomes of in vitro fertilization cycles with fresh embryo transfer.

OBJECTIVE: The current study was undertaken to investigate the relationship between antimüllerian hormone (AMH) and polycystic ovarian syndrome (PCOS) phenotypes and to determine whether AMH is associated with pregnancy outcomes in infertile women undergoing their first in vitro fertilization (IVF) treatment. METHODS: We performed a retrospective cohort study of 2973 infertile women, including 418 women with PCOS undergoing their first IVF treatment at a private fertility center from January 2014 to March 2018. Women were stratified into three groups using cutoffs defined by the 25th and 75th percentiles of the serum AMH level: 746 women had AMH ≤ 2.25 ng/mL; 1486 women had AMH between 2.25 to 5.71 ng/mL; and 741 women had AMH > 5.71 ng/mL. Endocrine characteristics, PCOS phenotypes, stimulation outcomes, pregnancy outcomes were compared among these groups. When there were any statistical differences (P < 0.05) among the three groups, Bonferroni test was performed as post-hoc tests to determine where the statistical differences existed. To assess the relationships between AMH and pregnancy outcomes in total patients and PCOS patients, logistic regression analysis, adjusted for potential confounding covariates, were performed. RESULTS: Women with high AMH had greater prevalence of hyperandrogenism (HA), polycystic ovarian morphology (PCOM) and amenorrhea than women with low or average AMH. The clinical pregnancy rate were significantly higher in the high-AMH group compared with low- and average-AMH groups (69.9% vs. 58.8% and 64.7% respectively; P < 0.001). The live birth rate was significantly lower in women with AMH ≤ 2.25 ng/mL compared with average- and high-AMH groups (47.6% vs. 55.2 and 59.5% respectively; P < 0.001). However, after controlling for maternal age, oocyte yield, as well as other confounders, AMH was no longer associated with a higher live birth rate (aOR 1.037, 95% CI 0.853-1.261, P = 0.717; aOR 1.099, 95% CI 0.858-1.408, P = 0.455, respectively) and clinical pregnancy rate (aOR 1.064, 95% CI 0.834-1.359, P = 0.617; aOR 1.181, 95% CI 0.875-1.595, P = 0.276, respectively). Moreover, pregnancy outcomes did not differ in PCOS women according to AMH quartiles. CONCLUSION: Increased AMH levels associated with PCOS severity and greater ovarian stimulation. However, AMH was not associated with clinical pregnancy rate and live birth rate after controlling for other confounders in women undergoing IVF. Thus, AMH should not be used to alter clinical decisions and exclude patients based on a low or even undetectable AMH value.

Multi-omics reveals a relationship between endometrial amino acid metabolism and autophagy in women with recurrent miscarriage†.

Deterioration of the endometrial environment is an essential cause of recurrent miscarriage (RM). However, current studies in terms of endometrial amino acid metabolic characterization and autophagy are still inadequate. We tried to (1) identify the alternation in metabolite profiles in the RM endometrium; (2) investigate the expression of autophagy-related proteins in RM; and (3) elucidate the association between amino acid metabolism and autophagy in RM. Our results showed that glutamine metabolites were up-regulated in the endometrium of RM women. The levels of autophagy-associated proteins, LC3B, ATG12, and Beclin-1, were significantly higher in RM. Hemostasis, autophagy and IFNα signaling were the top three differentially activated signaling pathways between women with RM and normal pregnancy. Interestingly the expression of AMPK and GCN2 was significantly up-regulated in the endometrium of women with RM, and the same expression trend was also observed in the human endometrial stromal cells cultured in glutamine deprivation medium. Furthermore, inhibition of AMPK decreased the level of GCN2, indicating a positive correlation between GCN2 and AMPK. The expression of GCN2 was consistent with the expression of ATG12 and beclin-1; however, it was opposite to that of p62. Exposure to glutamine deprivation increased the level of LC3B, GCN2, ATG12, and beclin-1. Altogether, these findings suggested significant crosstalk between amino acid metabolism and autophagy. In summary, our data suggested that aberrant crosstalk between amino acid metabolism and autophagy may contribute to the impaired endometrial microenvironment of RM. Our study may provide new insight into the diagnosis of RM due to endometrial factors.

Characterization of dendritic cell (DC)-10 in recurrent miscarriage and recurrent implantation failure.

During pregnancy, the maternal immune system must tolerate the persistence of semi-allogeneic fetus in the maternal tissue. Inadequate recognition of fetal antigens may lead to pregnancy complications, such as recurrent miscarriage (RM) and recurrent implantation failure (RIF). Dendritic cells (DCs) are key regulators of protective immune responses and the development and maintenance of tolerance. Regarding that DCs are important in the establishment of immune tolerance in human pregnancy, it would be important to study the microenvironment in which DCs reside or are activated may affect their functions toward tolerance rather than active immune response. IL-10 plays a critical role in the maintenance of normal pregnancy, and the increased production of IL-10 is associated with successful pregnancy. In this study, we provide an in-depth comparison of the phenotype and cytokine production by DC-10 and other DC subsets, such as iDC and mDC. CD14+ monocyte-derived DCs were differentiated in the presence of IL-10 (DC-10) in vitro from ten normal fertile controls, six RM women and seven RIF women, and characterized for relevant markers. DC-10 was characterized by relatively low expression of costimulatory molecule CD86, as well as MHC class II molecule HLA-DR, high expression of tolerance molecules HLA-G, ILT2, ILT4 and immunosuppressive cytokine IL-10, but produced little or no proinflammatory cytokines, such as TNF-α, IL-6 and IL-12p70. Our study provides a better understanding of the phenotypical properties of DC-10, which may participate in the complex orchestration that leads to maternal immune tolerance and homeostatic environment in human pregnancy.

The pro-inflammatory and anti-inflammatory cytokine profile in peripheral blood of women with recurrent implantation failure.

Limited information is available on the balance state of pro- and anti-inflammatory cytokines in patients with recurrent implantation failure (RIF). This study assessed the pro- and anti-inflammatory cytokines in plasma of 34 patients with RIF, compared with those of 25 women with a successful pregnancy in the first IVF/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycle. The IFN-γ, IL-1ß, IL-6 and IL-4 concentrations were higher, whereas the TGF-ß1 concentration was lower in the RIF group compared with the control group. Furthermore, the ratios of pro-inflammatory and anti-inflammatory cytokines IFN-γ/IL-4, IFN-γ/IL-10, IFN-γ/TGF-ß1, IL-6/IL-10, IL-6/TGF-ß1, IL-1ß/TGF-ß1 and TNF-α/TGF-ß1 were higher in the RIF group (all P < 0.01). The results suggested a shift toward a pro-inflammatory state in peripheral blood of the patients with RIF.

TNFR-associated factor 6 regulates TCR signaling via interaction with and modification of LAT adapter.

TNFR-associated factor (TRAF)6 is an essential ubiquitin E3 ligase in immune responses, but its function in adaptive immunity is not well understood. In this study, we show that TRAF6 is recruited to the peripheral ring of the T cell immunological synapse in Jurkat T cells or human primary CD4(+) T cells conjugated with staphylococcal enterotoxin E-pulsed B cells. This recruitment depends on TRAF6 interacting with linker for activation of T cells (LAT) via its TRAF domain. Although LAT was indispensable for TCR/CD28-induced TRAF6 ubiquitination and its ligase activity, RNA interference-induced TRAF6 knockdown in T cells decreased TCR/CD28-induced LAT ubiquitination, tyrosine phosphorylation, and association with tyrosine kinase ZAP70. Overexpression of TRAF6 or its catalytically inactive form C70A promoted and decreased, respectively, LAT tyrosine phosphorylation upon stimulation. Moreover, LAT was ubiquitinated at Lys(88) by TRAF6 via K63-linked chain. In addition, TRAF6 was required for and synergized with LAT to promote the TCR/CD28-induced activation of NFAT. These results reveal a novel function and mechanism of TRAF6 action in the TCR-LAT signaling pathway distinct from its role in TCR-induced NF-κB activation, indicating that LAT also plays an adapter role in TCR/CD28-induced activation of TRAF6.

Laser-assisted hatching improves clinical outcomes of vitrified-warmed blastocysts developed from low-grade cleavage-stage embryos: a prospective randomized study.

The aim of this study was to evaluate the effects of quarter zona-pellucida (ZP) opening by laser-assisted hatching (QLAH) on the clinical outcomes following transfer of vitrified-warmed blastocysts developed from low-grade cleavage-stage embryos in patients with all high-grade and fair-grade cleavage-stage embryos transferred without achieving pregnancy. Patients were randomized into two groups: QLAH (n=101) and control (n=102). The implantation and clinical pregnancy rates were significantly higher in the QLAH group compared with the control group (P=0.021 and P=0.034, respectively). The live birth rate of the QLAH group was also higher, although not significantly. When the clinical outcomes according to the day of blastocyst vitrification were compared between the groups, the implantation, clinical pregnancy and live birth rates of the QLAH group were significantly higher (P<0.05) than those of the control group for day 6 blastocysts, but not for day 5 or day 5/day 6 blastocysts. These results suggest that QLAH improves the clinical outcomes of vitrified-warmed blastocysts, especially of day 6 vitrified blastocysts, developed from low-grade cleavage-stage embryos.

The role of extracellular vesicles from placenta and endometrium in pregnancy: Insights from tumor biology.

Extracellular vesicles (EVs) are small membrane-bound particles secreted by various cell types that play a critical role in intercellular communication by packaging and delivering biomolecules. In recent years, EVs have emerged as essential messengers in mediating physiological and pathological processes in tumor biology. The tumor microenvironment (TME) plays a pivotal role in tumor generation, progression, and metastasis. In this review, we provide an overview of the impact of tumor-derived EVs on both tumor cells and the TME. Moreover, we draw parallels between tumor biology and pregnancy, as successful embryo implantation also requires intricate intercellular communication between the placental trophecepiblast and the endometrial epithelium. Additionally, we discuss the involvement of EVs in targeting immune responses, trophoblast invasion, migration, and angiogenesis, which are shared biological processes between tumors and pregnancy. Specifically, we highlight the effects of placenta-derived EVs on the fetal-maternal interface, placenta, endometrium, and maternal system, as well as the role of endometrium-derived EVs in embryo-endometrial communication. However, challenges still exist in EVs research, including the standardization of EVs isolation methods for diagnostic testing, which also apply to reproductive systems where EVs-mediated communication is proposed to take place. Through this review, we aim to deepen the understanding of EVs, particularly in the context of reproductive biology, and encourage further investigation in this field.

Hyperandrogenic environment regulates the function of ovarian granulosa cells by modulating macrophage polarization in PCOS.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder characterized by oligo-anovulation, hyperandrogenism, and polycystic ovaries, with hyperandrogenism being the most prominent feature of PCOS patients. However, whether excessive androgens also exist in the ovarian microenvironment of patients with PCOS, and their modulatory role on ovarian immune homeostasis and ovarian function, is not clear. METHODS: Follicular fluid samples from patients participating in their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment were collected. Androgen concentration of follicular fluid was assayed by chemiluminescence, and the macrophage M1:M2 ratio was detected by flow cytometry. In an in vitro model, we examined the regulatory effects of different concentrations of androgen on macrophage differentiation and glucose metabolism levels using qRT-PCR, Simple Western and multi-factor flow cytometry assay. In a co-culture model, we assessed the effect of a hyperandrogenic environment in the presence or absence of macrophages on the function of granulosa cells using qRT-PCR, Simple Western, EdU assay, cell cycle assay, and multi-factor flow cytometry assay. RESULTS: The results showed that a significantly higher androgen level and M1:M2 ratio in the follicular fluid of PCOS patients with hyperandrogenism. The hyperandrogenic environment promoted the expression of pro-inflammatory and glycolysis-related molecules and inhibited the expression of anti-inflammatory and oxidative phosphorylation-related molecules in macrophages. In the presence of macrophages, a hyperandrogenic environment significantly downregulated the function of granulosa cells. CONCLUSION: There is a hyperandrogenic microenvironment in the ovary of PCOS patients with hyperandrogenism. Hyperandrogenic microenvironment can promote the activation of ovarian macrophages to M1, which may be associated with the reprogramming of macrophage glucose metabolism. The increased secretion of pro-inflammatory cytokines by macrophages in the hyperandrogenic microenvironment would impair the normal function of granulosa cells and interfere with normal ovarian follicle growth and development.

CD317+ MSCs expanded with chemically defined media have enhanced immunological anti-inflammatory activities.

BACKGROUND: Although both preclinical and clinical studies have shown the great application potential of MSCs (mesenchymal stem/stromal cells) in treating many kinds of diseases, therapeutic inconsistency resulting from cell heterogeneity is the major stumbling block to their clinical applications. Cell population diversity and batch variation in the cell expansion medium are two major inducers of MSC heterogeneity. METHODS: Cell population diversity was investigated through single-cell RNA sequencing analysis of human MSCs derived from the umbilical cord and expanded with fully chemically defined medium in the current study. Then, the MSC subpopulation with enhanced anti-inflammatory effects was studied in vitro and in vivo. RESULTS: Our data showed that MSCs contain different populations with different functions, including subpopulations with enhanced functions of exosome secretion, extracellular matrix modification and responses to stimuli (regeneration and immune response). Among them, CD317+ MSCs have improved differentiation capabilities and enhanced immune suppression activities. Underlying mechanism studies showed that higher levels of TSG6 confer enhanced anti-inflammatory functions of CD317+ MSCs. CONCLUSIONS: Thus, CD317+ MSCs might be a promising candidate for treating immunological disorder-related diseases.

Lupus and recurrent pregnancy loss: the role of female sex hormones and B cells.

Systemic lupus erythematosus is a debilitating autoimmune disease characterized by uncontrolled activation of adaptive immunity, particularly B cells, which predominantly affects women in a 9 to 1 ratio compared to men. This stark sex disparity strongly suggests a role for female sex hormones in the disease's onset and progression. Indeed, it is widely recognized that estradiol not only enhances the survival of autoreactive B cells but also stimulates the production of autoantibodies associated with systemic lupus erythematosus, such as anti-nuclear antibodies and anti-dsDNA antibodies. Clinical manifestations of systemic lupus erythematosus typically emerge after puberty and persist throughout reproductive life. Furthermore, symptoms often exacerbate during the premenstrual period and pregnancy, as increased levels of estradiol can contribute to disease flares. Despite being fertile, women with lupus face a heightened risk of pregnancy-related complications, including pregnancy loss and stillbirth, which significantly surpass the rates observed in the healthy population. Therefore, this review aims to summarize and discuss the existing literature on the influence of female sex hormones on B-cell activation in patients with systemic lupus erythematosus, with a particular emphasis on their impact on pregnancy loss.

The function of decidua natural killer cells in physiology and pathology of pregnancy.

The role of decidual natural killer (dNK) cells in maintaining immune tolerance at the maternal-fetal interface during pregnancy is a significant topic in reproductive health. Immune tolerance is essential for a successful pregnancy and involves a complex immune response involving various immune cells and molecules. DNK cells comprise the largest population of lymphocyte subsets found in the decidua and play important roles in maintaining immune tolerance. These cells exert multiple functions to maintain homeostasis of the decidual microenvironment, including modulation of trophoblast invasion, promotion of fetal development, regulation of endometrial decidualization and spiral artery remodeling. DNK cells can also be divided into different subsets based on their functions as NKtolerant , NKcytotoxic , and NKregulatory cells. However, the relationship between dNK cells function and pregnancy outcomes is complex and poorly understood. In this review, we will focus on the physiological role of dNK cells during pregnancy and highlight the potential role in pathological pregnancies and therapeutic approaches.

Association between immunity and different clinical symptoms in patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a disease with endocrine and metabolic disorders. The main symptoms are hyperandrogenemia (HA), insulin resistance (IR), and ovulation disorder. However, the pathogenesis and pathophysiological process of these major symptoms in PCOS are still not well defined. In recent studies, the chronic low-grade inflammatory state has become one of the factors affecting PCOS. Some alterable immune factors in PCOS, such as interleukin-15 and interleukin-1, have been identified to be related to androgen synthesis and insulin resistance in PCOS. In addition, a disturbed immune microenvironment in the ovary leads to impaired follicular growth and ovulation. Previous studies have roughly reviewed the relationship between immunity and PCOS. However, the link between the different clinical manifestations of PCOS and immunity has not been well explored and analyzed. The clinical presentation of each patient is diverse, and symptomatic treatment is mainly used. Therefore, this article reviews several representative immunological factors that affect these three symptoms to explore the underlying mechanism, which will be beneficial for developing new treatment strategies.

Characterization of progesterone-induced dendritic cells in metabolic and immunologic reprogramming.

The role of maternal-fetal immune tolerance in the establishment and maintenance of pregnancy has been well established. Dendritic cells (DCs) as a crucial part of the decidual microenvironment, have high plasticity in immunogenicity and tolerogenicity. The regulatory mechanisms of DCs phenotype or function at the maternal-fetal interface, however, have not been fully developed. Studies from the field of immunometabolism have highlighted that the metabolic pathways of DCs are closely associated with their immunity. Our previous study showed that progesterone (P4) up-regulated a series of enzymes involved in DCs mitochondrial oxidative phosphorylation and fatty acid metabolism. In this study, we confirmed that P4 induced significant alternations in DCs metabolic pathways, promoting their glycolysis, mitochondrial function, and the dependency and capacity of fatty acids as mitochondrial fuel. Moreover, P4 also increased the inhibitory molecule ILT4 expression on DCs and down-regulated the CD86, which may coordinate their immune tolerance function in pregnancy. Together, our study helps to understand the role of P4 in DCs metabolic and immunologic reprogramming and may provide novel insights into the hormonal immunometabolism regulation of DCs during normal pregnancy.

γδ-T cell with high toxic potential was associated with recurrent miscarriage.

PROBLEM: RM is a common clinical disease in reproduction, affecting approximately 1%-3% of women worldwide. Previous studies have shown the role of peripheral blood γδ-T cells during physiological pregnancy. However, the relationship between the immune status of peripheral blood γδ-T cells and RM is still not well defined. METHOD OF STUDY: In this study, mid-luteal peripheral blood from 51 RM patients and 40 healthy women was collected to determine the immune status of γδ-T cells. The percentage of peripheral blood γδ-T cells, and the molecules mediating their toxic potential, including cytotoxic granules (perforin, granzyme B, and granulysin) and receptors (NKG2D, CD158a, and CD158b), were detected by flow cytometry. RESULTS: Compared to healthy control, an increase in the proportion of total CD3+ T cells in lymphocytes and a decrease in the ratio of γδ-T cells to CD3+ T cells were observed in patients with RM. The percentages of granzyme B+ γδ-T cells and CD158a+ γδ-T cells in total γδ-T cells or lymphocytes were significantly increased in patients with RM, compared with healthy control. Conversely, CD158b+ γδ-T cells in total γδ-T cells or lymphocytes were significantly decreased in the RM group. CONCLUSION: Increased peripheral blood γδ-T cell with high toxic potential was associated with RM.

The effectiveness and safety of intrauterine infusion of autologous regulatory T cells (Tregs) in patients with recurrent pregnancy loss and low levels of endometrial FoxP3+ cells: A retrospective cohort study.

PROBLEM: Regulatory T cells (Tregs) are a specialized type of T cells that help maintain immune tolerance and homeostasis. The potential of Tregs cell-based therapies in treating diseases has been demonstrated in several clinical trials, which have shown promising outcomes and high safety in autoimmune diseases, transplant rejection, and graft-versus-host disease. However, their effectiveness and safety in improving endometrial receptivity and reducing pregnancy loss in human reproduction are unknown. METHOD OF STUDY: The study used a retrospective design and included patients with recurrent pregnancy loss (RPL) and lower levels of endometrial FoxP3+ Tregs. Patients in the Tregs group (n = 33) received intrauterine Tregs infusion three times during the follicular phase, while the control group (n = 28) did not receive any intrauterine infusion. RESULTS: The intrauterine infusion of autologous Tregs increased the levels of FoxP3+ Tregs and CD56+ NK cells. Patients in the Treg group had higher live birth rates and lower miscarriage rates, especially early miscarriage rates. However, the two groups had no differences in the implantation rate, clinical pregnancy rate, and percentage of preterm delivery. CONCLUSIONS: The findings suggest that intrauterine Tregs infusion may be a potential therapeutic approach for RPL. Further research in larger clinical trials is needed to confirm these findings.