RESUMEN
PROBLEM: The decidualization process conditions monocytes to the immunosuppressive and tolerogenic dendritic cell (DC)-10 profile, a DC subset with high IL-10 production. Since the implantation process implies an embryo-endometrium-immune crosstalk, here we focused on the ability of embryonic soluble factors to modify decidual DC conditioning accordingly with its quality. METHOD OF STUDY: Human endometrial stromal cell line (HESC) decidualized with medroxyprogesterone and dibutyryl-cAMP (Dec) was stimulated with human embryo-conditioned media (ECM), classified as normal (ND) or impaired developed (ID) for 48 h (n = 18/group). Monocytes isolated from six healthy women were differentiated to DCs with rhGM-CSF+rhIL-4 in the presence/absence of conditioned media (CM) from decidualized cells stimulated with ECM or nontreated. RESULTS: We found that decidualized cells stimulated with ECM sustain a myeloid regulatory cell profile on monocyte-derived culture with increased frequency of CD1a-CD14+ and CD83+CD86low cells. ND-Dec sustained the higher expression of the DC-10 markers, HLA-G and IL-10 whereas ID-Dec diminished IL-10 production (ID-Dec: 135 ± 37.4 vs. Dec: 223.3 ± 49.9 pg/mL, p < 0.05). The treatment with ECM-Dec sustained a higher IL-10 production and prevented the increase of CD83/CD86 after LPS challenge regardless of embryo quality. Notably, TNF-α production increased in ID-Dec cultures (ID-Dec: 475.1 ± 134.7 vs. Dec: 347.5 ± 98 pg/mL, p < 0.05). CONCLUSIONS: Although remaining in a tolerogenic profile compatible with DC-10, DCs can differentially respond to decidual secreted factors based on embryo quality, changing their secretome. These results suggest that in the presence of arrested embryo, DCs could differentially shape the immunological microenvironment, contributing to arrested embryo clearance during the menstrual phase.
Asunto(s)
Decidua , Células Dendríticas , Implantación del Embrión , Tolerancia Inmunológica , Humanos , Femenino , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Implantación del Embrión/inmunología , Decidua/inmunología , Decidua/citología , Diferenciación Celular , Medios de Cultivo Condicionados , Interleucina-10/metabolismo , Adulto , Células del Estroma/inmunología , Células del Estroma/metabolismo , Células Cultivadas , Embrión de Mamíferos , Endometrio/inmunología , Endometrio/citología , Línea Celular , Monocitos/inmunología , EmbarazoRESUMEN
Infertility affects 15â¯% of couples in the US, and many turn to assisted reproductive technologies, including in vitro fertilization and subsequent frozen embryo transfer (FET) to become pregnant. This study aimed to perform a broad assessment of the maternal immune system to determine if there are systemic differences on the day of FET in cycles that result in a live birth compared to those that do not. Women undergoing FET of euploid embryos were recruited and blood was collected on the day of FET as well as at early timepoints in pregnancy. Sixty immune and angiogenic proteins were measured in plasma, and gene expression of 92 immune-response related genes were evaluated in peripheral blood mononuclear cells (PBMCs). We found plasma concentrations of interleukin-13 (IL-13) and macrophage derived chemokine (MDC) were significantly lower on the day of FET in cycles that resulted in a live birth. We also found genes encoding C-C chemokine receptor type 5 (CCR5), CD8 subunit alpha (CD8A) and SMAD family member 3 (SMAD3) were upregulated in PBMCs on the day of FET in cycles that resulted in live birth. Measurements of immune mediators from maternal blood could serve as prognostic markers during FET to guide clinical decision making and further our understanding of implantation failure.
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Criopreservación , Transferencia de Embrión , Fertilización In Vitro , Humanos , Femenino , Embarazo , Transferencia de Embrión/métodos , Adulto , Fertilización In Vitro/métodos , Receptores CCR5/genética , Receptores CCR5/metabolismo , Interleucina-13/metabolismo , Interleucina-13/sangre , Proteína smad3/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Implantación del Embrión/inmunología , Nacimiento VivoRESUMEN
Recurrent implantation failure (RIF) is a condition where a woman fails to obtain pregnancy after multiple embryo transfer cycles, even with superior-quality blastocysts. There are various factors that can contribute to RIF, including immunologic disturbances. The immune system is extremely important during pregnancy. Immune cells such as T cells, B cells, natural killer (NK) cells, and macrophages (MQ) are present in the female reproductive tract and are accountable for regulating the immune response to invading pathogens and maintaining tissue homeostasis. Dysregulation of these immune cells can lead to inflammation, which can impair fertility. One of the most common immunological disturbances observed in RIF is an altered Th1/Th2 ratio, along with changes in NK cell and macrophage numbers. In addition, the presence of some antibodies, such as anti-ovarian antibodies, can also contribute to RIF. Interleukins have been implicated in the development of an inflammatory response that can interfere with successful embryo implantation. As a result, a comprehensive understanding of immunological compartments in RIF women could assist us in determining the immunological origins of this disease. We will discuss immunological factors that might contribute to RIF etiology, including cellular and molecular components.
Asunto(s)
Inmunidad Adaptativa , Implantación del Embrión , Inmunidad Innata , Humanos , Femenino , Implantación del Embrión/inmunología , Embarazo , Infertilidad Femenina/inmunología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Transferencia de EmbriónRESUMEN
The transition from oviparity to viviparity and the establishment of feto-maternal communications introduced the placenta as the major anatomical site to provide nutrients, gases, and hormones to the developing fetus. The placenta has endocrine functions, orchestrates maternal adaptations to pregnancy at different periods of pregnancy, and acts as a selective barrier to minimize exposure of developing fetus to xenobiotics, pathogens, and parasites. Despite the fact that this ancient organ is central for establishment of a normal pregnancy in eutherians, the placenta remains one of the least studied organs. The first step of pregnancy, embryo implantation, is finely regulated by the trophoectoderm, the precursor of all trophoblast cells. There is a bidirectional communication between placenta and endometrium leading to decidualization, a critical step for maintenance of pregnancy. There are three-direction interactions between the placenta, maternal immune cells, and the endometrium for adaptation of endometrial immune system to the allogeneic fetus. While 65% of all systemically expressed human proteins have been found in the placenta tissues, it expresses numerous placenta-specific proteins, whose expression are dramatically changed in gestational diseases and could serve as biomarkers for early detection of gestational diseases. Surprisingly, placentation and carcinogenesis exhibit numerous shared features in metabolism and cell behavior, proteins and molecular signatures, signaling pathways, and tissue microenvironment, which proposes the concept of "cancer as ectopic trophoblastic cells". By extensive researches in this novel field, a handful of cancer biomarkers has been discovered. This review paper, which has been inspired in part by our extensive experiences during the past couple of years, highlights new aspects of placental functions with emphasis on its immunomodulatory role in establishment of a successful pregnancy and on a potential link between placentation and carcinogenesis.
Asunto(s)
Placenta , Humanos , Embarazo , Femenino , Placenta/inmunología , Placenta/metabolismo , Animales , Placentación , Endometrio/inmunología , Endometrio/metabolismo , Neoplasias/inmunología , Neoplasias/etiología , Implantación del Embrión/inmunologíaRESUMEN
PROBLEM: Although endometrial receptivity is a key factor in influencing implantation in both naturally conceived and assisted reproductive technology (ART) cycles, very little is known about the endometrium milieu around the time of implantation. Previous studies have demonstrated the presence of several cytokines in the endometrium that affect implantation. However, there is lacking data about the presence of immune cell subtypes within the endometrium and in the uterine cavity at the time of implantation. METHOD OF STUDY: This study was approved by the Institutional Review Board (# 225589). The study was designed as a prospective observational cohort study between May 2021 and December 2022 at a single academic-based fertility center. All patients underwent at least one In Vitro Fertilization (IVF) cycle and have frozen embryos. Twenty-four participants were recruited for this study which was conducted during the frozen embryo transfer (FET) cycle regardless of the outcome of previous cycles. Two samples were acquired from each subject, denoted as lower and upper. A trial transfer catheter was introduced under ultrasound guidance into the lower uterine segment. Upon removal, the tip was rinsed in IMDM medium containing 10% FBS (lower uterus). A transfer catheter was then loaded with the embryo that was placed in the upper uterus under ultrasound guidance. The tip of the transfer catheter was rinsed in separate aliquot of the above media (upper uterus). After centrifugation, pelleted cells were stained for the following surface markers: CD45, CD3, CD19, CD4, CD8, gamma delta TCR, CD25, CD127, CD66b, CD14, CD16, CD56 and acquired on Sony SP6800 Spectral Analyzer. RESULTS: Upon staining the pelleted cells, we were able to identify viable leukocytes from samples obtained from both, upper and lower uterus (0.125 × 106 cells ± SD 0.32), (0.123 × 106 cells ± SD 0.12), respectively. Among total viable cells, there was no significant difference in both percent and number of CD45+ cells between the upper and lower uterus (9.88% ± 6.98 SD, 13.67% ± 9.79 SD, p = .198) respectively. However, there was significantly higher expression of CD3+ (p = .006), CD19+ (p = .032) and CD14+ (p = .019) cells in samples collected from upper compared to lower uterus. Within all CD3+ cells, we found that gamma delta T cells (GDT) were the major population of T cells in both upper and lower uterus. In contrast, CD8+ T cells were significantly higher in the lower uterus when compared to the upper uterus (p = .009). There was no statistically significant difference in the expression of CD4+ T cells, T regulatory cells (CD4+CD25+CD127-), NK cells (CD56+), neutrophils (CD66b+) and FcγRIII+ cells (CD16+) between upper and lower uterus. CONCLUSIONS: We believe the immune milieu at the time of embryo transfer will affect implantation. Understanding the composition of immune cells will guide further research in identifying optimal immune milieus that favor implantation. Comprehensive analysis of endometrium is expected to lead to new diagnostic and therapeutic approaches to improve IVF outcomes.
Asunto(s)
Transferencia de Embrión , Endometrio , Útero , Humanos , Femenino , Adulto , Transferencia de Embrión/métodos , Útero/inmunología , Endometrio/inmunología , Endometrio/citología , Estudios Prospectivos , Implantación del Embrión/inmunología , Fertilización In Vitro , Embarazo , Líquidos Corporales/inmunologíaRESUMEN
Autophagy is a process that occurs in almost all eukaryotic cells and this process is controlled by several molecular processes. Its biological roles include the provision of energy, the maintenance of cell homeostasis, and the promotion of aberrant cell death. The importance of autophagy in pregnancy is gradually becoming recognized. In literature, it has been indicated that autophagy has three different effects on the onset and maintenance of pregnancy: embryo (embryonic development), feto-maternal immune crosstalk, and maternal (decidualization). In humans, proper decidualization is a major predictor of pregnancy accomplishment and it can be influenced by different factors. This review highlights the genes, pathways, regulation, and function of autophagy in endometrial decidualization and other involved factors in this process.
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Autofagia , Decidua , Endometrio , Complicaciones del Embarazo , Transducción de Señal , Humanos , Femenino , Embarazo , Autofagia/inmunología , Transducción de Señal/inmunología , Complicaciones del Embarazo/inmunología , Decidua/inmunología , Decidua/metabolismo , Endometrio/inmunología , Endometrio/metabolismo , Animales , Desarrollo Embrionario/inmunología , Desarrollo Embrionario/genética , Implantación del Embrión/inmunologíaRESUMEN
Sperm must pass a complex route in the female reproductive tract (FRT) to reach the fertilization site and join the oocyte. Thus, it should employ several mechanisms to survive against the female immune system, fertilize the oocyte, and successfully transmit paternal genes to the next generation. In addition to self-protection, sperm may be involved in the immune tolerance to the developing embryo and regulating the FRT for embryo implantation and subsequent pregnancy. Hence, this review intends to summarize the mechanisms that protect sperm in the FRT: including immunomodulatory factors that are carried by seminal plasma, cell-to-cell and molecular interaction of sperm with epithelial and immune cells of the FRT, high regulated secretions of inflammatory factors such as cytokines, chemokines, and growth factors, inducing immune tolerance to paternal antigens, and specialized expression of cell receptors and binding proteins. In most of these events sperm induces the FRT to protect itself by modulating immune responses for its own benefit. However, not all sperm in the semen are able to trigger the survival mechanisms and only high-quality sperm will overcome this challenge. A clear understanding of the molecular mechanisms that maintain sperm viability and function in the FRT can lead to new knowledge about infertility etiology and a new approach in assisted reproductive technologies for the preparation and selection of the best sperm based on the criteria that physiologically happen in-vivo.
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Tolerancia Inmunológica , Espermatozoides , Humanos , Femenino , Espermatozoides/inmunología , Espermatozoides/metabolismo , Masculino , Animales , Embarazo , Genitales Femeninos/inmunología , Genitales Femeninos/metabolismo , Semen/inmunología , Semen/metabolismo , Implantación del Embrión/inmunologíaRESUMEN
Interferon-τ (IFN-τ) participates in the establishment of endometrial receptivity in ruminants. However, the precise mechanisms by which IFN-τ establishes bovine endometrial receptivity remain largely unknown. Interferon regulatory factor 1 (IRF1) is a classical interferon-stimulated gene (ISG) induced by type I interferon, including IFN-τ. Leukemia inhibitory factor receptor (LIFR) is a transmembrane receptor for leukemia inhibitory factor (LIF), which is a key factor in regulating embryo implantation in mammals. This study aimed to investigate the roles of IRF1 and LIFR in the regulation of bovine endometrial receptivity by IFN-τ. In vivo, we found IRF1 and LIFR were upregulated in the bovine endometrial luminal epithelium on Day 18 of pregnancy compared to Day 18 of the estrous cycle. In vitro, IFN-τ could upregulate IRF1, LIFR, and endometrial receptivity markers (LIF, HOXA10, ITGAV, and ITGB3) expression, downregulate E-cadherin expression and reduce the quantity of microvilli of bovine endometrial epithelial cells (bEECs). Overexpression of IRF1 had similar effects to IFN-τ on endometrial receptivity, and interference of LIFR could block these effects, suggesting the positive effects of IRF1 on endometrial receptivity were mediated by LIFR. Dual luciferase reporter assay verified that IRF1 could transactivate LIFR transcription by binding to its promoter. In conclusion, IFN-τ can induce IRF1 expression in bovine endometrial epithelial cells, and IRF1 upregulates LIFR expression by binding to LIFR promoter, contributing to the enhancement of bovine endometrial receptivity.
Asunto(s)
Implantación del Embrión , Endometrio , Factor 1 Regulador del Interferón , Interferón Tipo I , Animales , Femenino , Bovinos , Endometrio/metabolismo , Endometrio/inmunología , Factor 1 Regulador del Interferón/metabolismo , Factor 1 Regulador del Interferón/genética , Implantación del Embrión/inmunología , Interferón Tipo I/metabolismo , Embarazo , Receptores OSM-LIF/metabolismo , Proteínas Gestacionales/metabolismo , Proteínas Gestacionales/genética , Activación Transcripcional , Células Cultivadas , Células Epiteliales/metabolismo , Células Epiteliales/inmunologíaRESUMEN
The maternal-fetal interaction has been hypothesized to involve the human leucocyte antigen (HLA). It has been suggested that excessive HLA antigen sharing between spouses is a mechanism causing maternal hyporesponsiveness to paternal antigens encountered during pregnancy and thus leading to a miscarriage. Participants in this retrospective study are RIF and RPL couples who visited Gunasheela Surgical and Maternity Hospital, Bangalore, India from November 2019 to September 2022. A total of 40 couples with RIF and 195 couples with RPL are included in the study. We observed that the DQB1*02:01:01 allele is associated with an increase in risk of both RIF and RPL, while the C*12:02:01 allele increases risk of only RPL. On the contrary, DQB1*02:02:01 and DQB1*06:03 alleles appear to be protective against both RPL and RIF. In addition, the C*07:02:01 allele was observed to be protective against RPL. In conclusion, C*12:02:01 and DQB1*02:01:01 could play a major role in RPL which is consistent with other studies, while DQB1*02:01:01 is the risk allele in our RIF group. The protective alleles C*07:02:01 in the RPL group, DQB1*02:02:01, and DQB1*06:03 in both RIF and RPL, were discovered for the first time. Allele frequencies will vary in population-based studies depending on the ethnicities of the cohort. Meta-analysis and antibody testing will provide additional insights on whether and how this data can be adopted into clinical practices.
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Aborto Habitual , Frecuencia de los Genes , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Femenino , Estudios Retrospectivos , Aborto Habitual/genética , Aborto Habitual/inmunología , India , Embarazo , Masculino , Adulto , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Predisposición Genética a la Enfermedad , Alelos , Antígenos HLA-C/genética , Antígenos HLA-C/inmunología , Antígenos HLA-B/genética , Antígenos HLA-A/genética , Implantación del Embrión/inmunología , Implantación del Embrión/genéticaRESUMEN
Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system. Progesterone, a critical hormone during pregnancy, is known to promote immune tolerance and prevent preterm labor. However, the mechanism by which progesterone mediates these effects remains unclear. In this study, we investigated the role of the non-classical progesterone receptor membrane component 1 (PGRMC1) in progesterone signaling at the maternal-fetal interface. Using JEG3 cells, a trophoblast model cell line, we observed that progesterone stimulation increased the expression of human leukocyte antigen-C (HLA-C) and HLA-G, key molecules involved in immune tolerance. We also found that progesterone upregulated the expression of the transcription factor ELF3, which is known to regulate trophoblast-specific HLA-C expression. Interestingly, JEG3 cells lacked expression of classical progesterone receptors (PRs) but exhibited high expression of PGRMC1, a finding we confirmed in primary trophoblasts by mining sc-RNA seq data from human placenta. To investigate the role of PGRMC1 in progesterone signaling, we used CRISPR/Cas9 technology to knockout PGRMC1 in JEG3 cells. PGRMC1-deficient cells showed a diminished response to progesterone stimulation. Furthermore, we found that the progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner, suggesting that RU486 acts as a progesterone antagonist by competing for receptor binding. Additionally, we found that RU486 inhibited cell invasion, an important process for successful pregnancy, and this inhibitory effect was dependent on PGRMC1. Our findings highlight the crucial role of PGRMC1 in mediating the immunoregulatory effects of progesterone at the maternal-fetal interface.
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Proteínas de la Membrana , Progesterona , Receptores de Progesterona , Trofoblastos , Humanos , Receptores de Progesterona/metabolismo , Femenino , Embarazo , Progesterona/metabolismo , Progesterona/farmacología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Trofoblastos/metabolismo , Trofoblastos/inmunología , Placenta/inmunología , Placenta/metabolismo , Transducción de Señal/inmunología , Intercambio Materno-Fetal/inmunología , Implantación del Embrión/inmunologíaRESUMEN
This study aimed to evaluate the effectiveness of the endometrial receptivity array (ERA), endometrial immune profiling, and a combination of both in improving the pregnancy outcomes for multiple implantation failure patients. According to patients' willingness, 1429 women who incurred at least two or more consecutive implantation failures in IVF/ICSI treatment opted for frozen embryo transfer and were divided into four groups: 'No test', 'Immune Profiling', 'ERA' and 'ERA+ Immune Profiling'. Women in three test groups underwent timed endometrial biopsy for ERA, immune profiling, a combination of both. We observed the overall incidence rates of the displaced window of implantation (WOI) and endometrial immune dysregulation were 75.14% and 79.29%, respectively. After 1:1 propensity score matching (PSM), our data revealed that the 'ERA' and 'ERA + Immune Profiling' groups demonstrated significantly higher rates of biochemical, clinical, ongoing pregnancy, and implantation compared to the 'No test' group (p < 0.01). The 'Immune Profiling' group showed a higher implantation rate compared to 'No test' group (p < 0.05). Furthermore, when comparing three test groups, the 'ERA + Immune Profiling' group exhibited notably higher rates of clinical and ongoing pregnancy compared to the 'Immune Profiling' group (p < 0.017). However, there was no association between endometrial immune profiling and ERA phases, and their results did not differ between embryo implantation and non-implantation in these patients. Our findings underline the increased implantation rates by use of ERA and endometrial immune profiling in patients with multiple implantation failure, either individually or corporately. Moreover, a combination of both could improve their pregnancy outcomes significantly.
Asunto(s)
Implantación del Embrión , Transferencia de Embrión , Endometrio , Fertilización In Vitro , Puntaje de Propensión , Humanos , Femenino , Endometrio/inmunología , Endometrio/patología , Embarazo , Implantación del Embrión/inmunología , Adulto , Estudios Retrospectivos , Transferencia de Embrión/métodos , Fertilización In Vitro/métodos , Resultado del Embarazo , Índice de EmbarazoRESUMEN
PURPOSE: Using a comprehensive flow cytometric panel, simultaneously obtained mid-luteal immunophenotypes from peripheral blood and endometrium were compared and values correlated. Is a peripheral blood evaluation of reproductive immunophenotype status meritorious relative to local endometrial evaluation to directly assess the peri-implantation environment? METHODS: Fifty-five patients had a mid-luteal biopsy to assess the local endometrial immunophenotype, while simultaneously providing a peripheral blood sample for analysis. Both samples were immediately assessed using a comprehensive multi-parameter panel, and lymphocyte subpopulations were described and compared. RESULTS: Distinct lymphocyte proportions and percentage differences were noted across the two compartments, confirming the hypothesis that they are distinct environments. The ratio of CD4 + to CD8 + T cells were reversed between the two compartments, as were Th1 and Th2-type CD4 + T cell ratios. Despite these differences, some direct relationships were noted. Positive Pearson correlations were found between the levels of CD57 + expressing natural killer cells, CD3 + NK-T cells and CD4 + Th1 cells in both compartments. CONCLUSIONS: Flow cytometric evaluation provides a rapid and objective analysis of lymphocyte subpopulations. Endometrial biopsies have become the gold standard technique to assess the uterine immunophenotype in adverse reproductive outcome, but there may still a place for peripheral blood evaluation in this context. The findings demonstrate significant variations in cellular proportions across the two regions, but some positive correlations are present. Immunological assessment of these specific peripheral blood lymphocyte subtypes may provide insight into patients with potential alterations of the uterine immune environment, without the risks and inconveniences associated with an invasive procedure.
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Endometrio , Citometría de Flujo , Inmunofenotipificación , Femenino , Humanos , Endometrio/inmunología , Citometría de Flujo/métodos , Inmunofenotipificación/métodos , Células Asesinas Naturales , Reproducción , Útero , Implantación del Embrión/inmunología , Técnicas Reproductivas AsistidasRESUMEN
Obesity and being overweight are growing worldwide health problems that also affect women of reproductive age. They impair women's fertility and are associated with lower IVF success rates. The mechanism by which increased body weight disrupts fertility has not yet been established. One possibility is that it affects the process of embryo implantation on the endometrial level. The purpose of our study was to determine the differences in enriched biological pathways in the endometrium of overweight and obese women undergoing IVF procedures. For this purpose, 14 patients (5 pregnant, 9 non-pregnant) were included in the study. Endometrial samples were obtained during the window of implantation and RNA sequencing was performed. There were no differences in general patient's and IVF cycle characteristics between pregnant and non-pregnant women. In the endometrial samples of women who did not conceive, pathways related to the immune response, inflammation, and reactive oxygen species production were over-expressed. Our findings show that the reason for implantation failure in overweight and obese women could lie in the excessive immune and inflammatory response at the endometrial level.
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Implantación del Embrión/inmunología , Endometrio/inmunología , Fertilización In Vitro , Infertilidad Femenina/inmunología , Obesidad/inmunología , RNA-Seq , Transcriptoma/inmunología , Femenino , Humanos , Inflamación/inmunología , Adulto JovenRESUMEN
Proper communication between natural killer cells and the human leukocyte antigens of the embryonic trophoblast at the maternal-fetal interface during pregnancy is essential for successful reproduction. However, specific combinations of embryonic human leukocyte antigen-C with killer immunoglobulin-like receptors on decidual natural killer cells (the immunological code of pregnancy) can be associated with obstetric morbidity and pregnancy loss. This article presents an updated review of the mechanisms underlying the interaction between embryonic human leukocyte antigen-C and maternal killer immunoglobulin-like receptors and their relevance to the physiology and pathophysiology of human reproduction.
Una adecuada comunicación entre las células asesinas naturales en la interfase materno-fetal con las moléculas de los antígenos de histocompatibilidad del trofoblasto embrionario es clave en el éxito de la reproducción. Sin embargo, combinaciones de determinados antígenos leucocitarios humanos tipo C embrionarios con los receptores tipo inmunoglobulina presentes en las células asesinas naturales deciduales (el código inmunológico del embarazo), pueden asociarse con morbilidad obstétrica y pérdidas gestacionales. En este artículo se presenta una revisión actualizada de los mecanismos subyacentes a la interacción entre el antígeno de histocompatibilidad tipo C embrionario y los receptores tipo inmunoglobulina maternos, y su relevancia tanto en la fisiología como en la fisiopatología de la reproducción humana.
Asunto(s)
Aborto Habitual/inmunología , Antígenos HLA-C/inmunología , Células Asesinas Naturales/inmunología , Placentación/fisiología , Receptores KIR/inmunología , Medicina Reproductiva , Útero/inmunología , Aborto Espontáneo/inmunología , Implantación del Embrión/inmunología , Femenino , Antígenos HLA , Antígenos HLA-C/fisiología , Humanos , Células Asesinas Naturales/fisiología , Embarazo , Receptores KIR/fisiologíaRESUMEN
The latest vaccination campaign has actualized the potential impact of antigenic stimuli on reproductive functions. To address this, we mimicked vaccination's effects by administering keyhole limpet hemocyanin (KLH ) to CD1 male mice and used their sperm for in vitro fertilization (IVF). Two-cell embryos after IVF with spermatozoa from control (C) or KLH-treated (Im) male mice were transferred to surrogate mothers mated with vasectomized control (C) or KLH-treated (Im) male mice, resulting in four experimental groups: C-C, Im-C, C-Im, and Im-Im. The pre-implantation losses were significantly lower in the Im-C group than in the C-Im group. At the same time, the resorption rates reduced markedly in the C-Im compared to the Im-C group. Embryo and placenta weights were significantly higher in the Im-Im group. Although the GM-CSF levels were lower in the amniotic fluid of the gestating surrogate mothers in the Im-Im group, they were strongly correlated with embryo mass. The number-size trade-off was only significant in the Im-Im group. This suggests a positive, cooperative effect of spermatozoa and seminal fluid from immune-primed males on embryo growth and the optimal distribution of surrogate mother maternal resources despite the negative impact of males' antigenic challenge on the IVF success rate.
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Adyuvantes Inmunológicos/administración & dosificación , Transferencia de Embrión/métodos , Desarrollo Embrionario/inmunología , Fertilización In Vitro/métodos , Hemocianinas/administración & dosificación , Semen/inmunología , Espermatozoides/inmunología , Vacunación/métodos , Animales , Anticuerpos/sangre , Blastocisto/inmunología , Blastocisto/metabolismo , División Celular/inmunología , Implantación del Embrión/inmunología , Femenino , Hemocianinas/inmunología , Inmunoglobulina G/sangre , Masculino , Ratones , Embarazo , Vasectomía/métodosRESUMEN
Seminal plasma (SP), particularly SP exosomes (sExos), alters with age and can affect female mouse uterine immune microenvironment. However, the relationship between fertility decline in reproductively older males, and SP and sExos age-related changes, which may compromise the uterine immune microenvironment, remains unclear. The present study demonstrated that the implantation rate of female mice treated with SP from reproductively older male mice (aged-SP group) was lower than that of those treated with SP from younger male mice (young-SP group). RNA-sequencing analysis revealed altered levels of dendritic cell (DC)-related cytokines and chemokines in the uteri of the former group compared with those of the latter group. In vivo and in vitro experiments demonstrated a weaker inhibitory effect of aged SP on DC maturation than of young SP upon stimulation. After isolating and characterizing sExos from young and advanced-age male mice, we discovered that insemination of a subset of the aged-SP group with sExos from young male mice partially recovered the implantation rate decline. Additional in vivo and in vitro experiments revealed that sExos extracted from age male mice exerted a similar effect on DC maturation as SP of aged mice, indicating an age-related sExos inhibitory effect. In conclusion, our study demonstrated that age-related alterations of sExos may be partially responsible for lower implantation rates in the aged-SP group compared with those in the young-SP group, which were mediated by uterine immunomodulation. These findings provide new insights for clinical seminal adjuvant therapy.
Asunto(s)
Implantación del Embrión/inmunología , Exosomas/fisiología , Inmunomodulación/inmunología , Semen/inmunología , Útero/inmunología , Envejecimiento , Animales , Citocinas/inmunología , Endometrio/citología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Semen/citología , Interacciones Espermatozoide-ÓvuloRESUMEN
Many factors impede embryonic implantation, and excluding obvious known factors such as chronic endometritis, the immune status of the endometrium may be related to pregnancy. Although an abundantly large number of immune cells infiltrate the endometrium during the secretory phase, whether these immune cells can be used as a predictor of prognosis in ART has not yet been clarified. In the present study we therefore retrospectively analyzed 97 CD138-negative women with a previous fresh-embryo-transfer failure. We assessed the expression of CD56+ uNK cells, CD16+ NK cells, CD57+ NK cells, CD68+ pan-macrophages, CD163+ M2 macrophages, CD4+T cells, CD8+T cells, FOXP3+ regulatory T cells, and CD19+ B cells in the endometrium by IHC to evaluate mid-luteal endometrial immune cells as prognostic indicators of pregnancy outcome in the next frozen-embryo-transfer cycle. CD19-positive cells and the intraglandular CD163-positivity rate increased significantly in the clinically non-pregnant group (0.47 % vs. 0.20 %, P = 0.021; 61 % vs. 30 %, P = 0.017). The ratios of CD4/CD8 were also higher in the non-pregnant group (1.96 vs. 1.45, P = 0.005).The area under the ROC curve of CD19 cell number alone, the intraglandular CD163-positivity alone, and CD19 number combined with the intraglandular CD163-positivity were 0.692 (95 % CI, 0.55-0.834), 0.661 (95 % CI, 0.514-0.809), and 0.748 (95 % CI, 0.614-0.882), respectively. The optimal cut-off value of CD19 was 0.464 %, and the clinical pregnancy rate and live-birth rate diminished significantly when the CD19 level was above this cut-off value. Our study suggests that CD19-positive cells and intraglandular CD163-positivity can be used as prognostic indicators of pregnancy outcome in CD138-negative patients who experienced first-fresh-embryo transfer failure.
Asunto(s)
Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Implantación del Embrión/inmunología , Transferencia de Embrión/métodos , Endometrio/inmunología , Infertilidad Femenina/terapia , Receptores de Superficie Celular/análisis , Adulto , Antígenos CD/metabolismo , Antígenos CD19/análisis , Antígenos CD19/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Transferencia de Embrión/estadística & datos numéricos , Endometrio/metabolismo , Femenino , Humanos , Infertilidad Femenina/inmunología , Embarazo , Resultado del Embarazo , Pronóstico , Receptores de Superficie Celular/metabolismo , Valores de Referencia , Estudios Retrospectivos , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
Extracellular vesicles (EVs) in utero play a role in cellular interactions between endometrium-conceptuses (embryo plus extraembryonic membranes) during peri-implantation periods. However, how intrauterine EVs function on endometrium have not been well characterized. In our previous study, bta-miR-98 found in intrauterine EVs from uterine flushing fluids (UFs) on pregnant day 20 (a half day after initial conceptus attachment, P20) could regulate the maternal immune system and collaborate with other miRNAs and/or components of EVs for conceptus implantation. We, therefore, hypothesized that in addition to bta-miR-98, other miRNAs present in bovine intrauterine EVs may regulate the maternal immune system in the endometrial epithelium. A global analysis of differentially expressed proteins between EVs from P17 and P20 UFs revealed that components of intrauterine P20 EVs had the effect on the down-regulation of "neutrophil activation involved in immune response" and "neutrophil mediated immunity". In silico analyses predicted bta-miR-26b as one of potential miRNA to regulate maternal immune system. In our cell culture experiments, bta-miR-26b negatively regulated several immune system-related genes PSMC6, CD40, and IER3 in bovine endometrial epithelial cells. Our findings revealed that intrauterine EV-derived bta-miR-26b contributes to the down-regulation of the maternal immune system, allowing conceptus implantation to the uterine endometrium. Furthermore, our results suggest that intrauterine EVs extracted from P20 UFs could regulate neutrophils, the first line of immunological defense, to modulate endometrial immune and inflammatory responses for implanting conceptuses.
Asunto(s)
Implantación del Embrión/inmunología , Vesículas Extracelulares/inmunología , Sistema Inmunológico/inmunología , MicroARNs/inmunología , Animales , Bovinos , Células Cultivadas , MicroARNs/genéticaRESUMEN
Due to the high rate of spontaneous abortion (SAB) in porcine pregnancy, there is a major interest and concern on commercial pig farming worldwide. Whereas the perturbed immune response at the maternal-fetal interface is an important mechanism associated with the spontaneous embryo loss in the early stages of implantation in porcine, data on the specific regulatory mechanism of the SAB at the end stage of the implantation remains scant. Therefore, we used high-throughput sequencing and bioinformatics tools to analyze the healthy and arresting endometrium on day 28 of pregnancy. We identified 639 differentially expressed lncRNAs (DELs) and 2357 differentially expressed genes (DEGs) at the end stage of implantation, and qRT-PCR was used to verify the sequencing data. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immunohistochemistry analysis demonstrated weaker immune response activities in the arresting endometrium compared to the healthy one. Using the lasso regression analysis, we screened the DELs and constructed an immunological competitive endogenous RNA (ceRNA) network related to SAB, including 4 lncRNAs, 11 miRNAs, and 13 genes. In addition, Blast analysis showed the applicability of the constructed ceRNA network in different species, and subsequently determined HOXA-AS2 in pigs. Our study, for the first time, demonstrated that the SAB events at the end stages of implantation is associated with the regulation of immunobiological processes, and a specific molecular regulatory network was obtained. These novel findings may provide new insight into the possibility of increasing the litter size of sows, making pig breeding better and thus improving the efficiency of animal husbandry production.
Asunto(s)
Aborto Espontáneo/etiología , ARN Largo no Codificante/metabolismo , Porcinos/fisiología , Animales , Implantación del Embrión/inmunología , Femenino , Perfilación de la Expresión Génica , Genoma , Embarazo , ARN Mensajero/metabolismoRESUMEN
OBJECTIVES: Trophoblastic invasion at the maternal-fetal interface can affect pregnancy outcomes. To describe an intuitive theme trends and knowledge structure of trophoblastic invasion-related literature from a bibliometric perspective, and provide researchers with new research hotspots. STUDY DESIGN: The literature form PubMed database related to trophoblastic invasion from January 1, 2012 to April 30, 2021 were extracted, and then biclustering analysis, co-word analysis, strategy diagram and social network analysis were performed to provide immature, or newly emerging research hotspots for researchers. RESULTS: A total of 96 high-frequency medical subjects heading terms were extracted and classified into 6 clusters. Themes in the first and second quadrant of strategy diagram, including trophoblasts metabolism, placenta metabolism, pre-eclampsia, etc., as the mature parts of the research on trophoblastic invasion have been well developed. On the other hand, themes in the third and fourth quadrants of strategy diagram, such as embryo implantation and trophoblasts immunology, pregnancy complication, matrix metalloproteinase and trophoblasts metabolism, habitual abortion and trophoblasts metabolism, etc., are immature themes. Social network analysis suggests that themes at the edge, such as habitual abortion / metabolism, placenta / immunology, natural killer cells / physiology, natural killer cells / immunology, embryo implantation / immunology, are considered new research hotspots and have considerable research space. CONCLUSION: By analyzing the research hotspots related to trophoblastic invasion, immature themes and emerging hotspots deserve more attention and can be considered as hints when launching new research projects.