Search

The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development., (© 2024. The Author(s).)

Study Question: What are the similarities and differences in endometrial B cells in the normal human endometrium and benign reproductive pathologies?, Summary Answer: Endometrial B cells typically constitute <5% of total endometrial CD45 + lymphocytes, and no more than 2% of total cells in the normal endometrium, and while their relative abundance and phenotypes vary in benign gynaecological conditions, current evidence is inconsistent., What Is Known Already: B cells are vitally important in the mucosal immune environment and have been extensively characterized in secondary lymphoid organs and tertiary lymphoid structures (TLSs), with the associated microenvironment germinal centre. However, in the endometrium, B cells are largely overlooked, despite the crucial link between autoimmunity and reproductive pathologies and the fact that B cells are present in normal endometrium and benign female reproductive pathologies, scattered or in the form of lymphoid aggregates (LAs). A comprehensive summary of current data investigating B cells will facilitate our understanding of endometrial B cells in the endometrial mucosal immune environment., Study Design Size Duration: This systematic review retrieved relevant studies from four databases (MEDLINE, EMBASE, Web of Science Core Collection and CINAHL) from database inception until November 2021., Participants/materials Setting Methods: The search strategy combined the use of subject headings and relevant text words related to 'endometrium', 'B cells' and B-cell derivatives, such as 'antibody' and 'immunoglobulin'. Non-benign diseases were excluded using cancer-related free-text terms, and searches were limited to the English language and human subjects. Only peer-reviewed research papers were included. Each paper was graded as 'Good', 'Fair' or 'Poor' quality based on the NEWCASTLE-OTTAWA quality assessment scale. Only 'Good' quality papers were included., Main Results and the Role of Chance: Twenty-seven studies met the selection criteria and were included in this review: 10 cross-sectional studies investigated B cells in the normal endometrium; and 17 case-control studies compared the characteristics of endometrial B cells in control and benign female reproductive pathologies including endometritis, endometriosis, infertility, abnormal uterine bleeding, endometrial polyps and uterine fibroids. In all studies, B cells were present in the endometrium, scattered or in the form of LAs. CD20 + B cells were more abundant in patients with endometritis, but the data were inconsistent as to whether B-cell numbers were increased in endometriosis and patients with reproductive pathologies., Limitations Reasons for Caution: Although only 'good' quality papers were included in this systematic review, there were variations in patients' age, diagnostic criteria for different diseases and sample collection time among included studies. Additionally, a large number of the included studies only used immunohistochemistry as the identification method for endometrial B cells, which may fail to provide an accurate representation of the numbers of endometrial B cells., Wider Implications of the Findings: Histological studies found that endometrial B cells are either scattered or surrounded by T cells in LAs: the latter structure seems to be under hormonal control throughout the menstrual cycle and resembles TLSs that have been observed in other tissues. Further characterization of endometrial B cells and LAs could offer insights to endometrial B-cell function, particularly in the context of autoimmune-associated pathologies, such as endometriosis. Additionally, clinicians should be aware of the limited value of diagnosing plasma cell infiltration using only CD138., Study Funding/competing Interests: This study was funded by Finox Biotech. The authors have no conflicts of interest to declare., Prospero Registration Number: This systematic review was registered in PROSPERO in January 2020 (PROSPERO ID: CRD42020152915)., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10 -8 , odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10 -8 , OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10 -9 , OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10 -8 , OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Extracellular vesicles (EVs) are membrane-bound complexes secreted from cells under both physiological and pathological conditions. They contain proteins, nucleic acids and lipids and act as messengers for cell-cell communication and signalling, particularly between immune cells. EV research is a rapidly evolving and expanding field, and it appears that all biological fluids contain very large numbers of EVs; they are produced from all cells that have been studied to date, and are known to have roles in several reproductive processes. This review analyses the evidence for the role of EVs throughout human reproduction, starting with the paternal and maternal gametes, followed by the establishment and continuation of successful pregnancies, with specific focus, where possible, on the interaction of EVs with the maternal immune system. Importantly, variations within the EV populations are identified in various reproductive disorders, such as pre-term labour and pre-eclampsia.

A variety of 'debris' is shed from the syncytial surface of the human placenta ranging from large deported multinuclear fragments to sub-cellular components. It is increasingly clear that at least some of this material has signalling functions. Many categories of circulating debris are increased in pre-eclampsia, and exhibit proteins that are pro-inflammatory and could contribute to the systemic inflammatory response in normal pregnancy, which is exaggerated in pre-eclampsia. It is now evident that there is a large 'hidden' population of microvesicles and nanovesicles (including exosomes) which are hard to investigate because of their size. We have used a new technology, nanoparticle tracking analysis, to measure the size and concentration of syncytiotrophoblast vesicles prepared by placental perfusion. The vesicles range in size from 50 nm to 1 μm with the majority being <500 nm (which includes both exosomes and microvesicles). We speculate whether changes not only in the numbers, but also in the size (beneficial syncytiotrophoblast exosomes and harmful microvesicles) might be important in the maternal syndrome of pre-eclampsia., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Immune adaptation is a critical component of successful pregnancy. Of primary importance is the modification of cytokine production upon immune activation. With the discovery that normal pregnancy itself is a pro-inflammatory state, it was recognised that the classical Th1/Th2 cytokine paradigm, with a shift towards 'type 2' cytokine production (important for antibody production), and away from 'type 1' immunity (associated with cell mediated immunity and graft rejection), is too simplistic. It is now generally agreed that both arms of cytokine immunity are activated, but with a bias towards 'type 2' immunity. Many factors are released from the placenta that can influence the maternal cytokine balance. Here we focus on syncytiotrophoblast microvesicles (STBM) which are shed from the placenta into the maternal circulation. We show that STBM can bind to monocytes and B cells and induce cytokine release (TNFα, MIP-1α, IL-1α, IL-1β, IL-6, IL-8). Other cytokines are down-modulated, such as IP-10 which is associated with 'type 1' immunity. Therefore STBM may aid the 'type 2' skewed nature of normal pregnancy. We also observed that PBMC from third trimester normal pregnant women produce more TNFα and IL-6 in response to STBM than PBMC from non-pregnant women, confirming that maternal immune cells are primed by pregnancy, possibly through their interaction with STBM.

Invariant natural killer T (iNKT) cells are implicated in the pathogenesis of several diseases. They influence both innate and adaptive immune responses through their capacity to rapidly produce large quantities of cytokines upon activation. During pregnancy maternal immunity is biased towards type 2 cytokine production to regulate type 1 cytokines that could be harmful for the developing fetus. This shift to type 2 cytokines does not occur in preeclamptic women and there is an exaggerated maternal inflammatory response which is dangerous for both mother and baby. We have therefore investigated the numbers, phenotype and functional activity of iNKT cells throughout pregnancy and in women diagnosed with preeclampsia. We demonstrate that the numbers of iNKT cells in the peripheral blood do not change between the first, second and third trimesters of pregnancy, but the cells become activated and less able to produce the type 1 cytokine IFNγ. However, iNKT cells are unchanged in preeclamptic women, when compared to normal pregnancy, suggesting that these cells are not primary players in the pathogenesis of the disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)