bims-reprim Biomed News
on Reproductive immunology
Issue of 2020‒11‒22
eleven papers selected by
Iva Filipovic
Karolinska Institutet


  1. JCI Insight. 2020 Nov 19. pii: 135775. [Epub ahead of print]5(22):
    Hadas R, Gershon E, Cohen A, Atrakchi O, Lazar S, Golani O, Dassa B, Elbaz M, Cohen G, Eilam R, Dekel N, Neeman M.
      Successful implantation is associated with a unique spatial pattern of vascular remodeling, characterized by profound peripheral neovascularization surrounding a periembryo avascular niche. We hypothesized that hyaluronan controls the formation of this distinctive vascular pattern encompassing the embryo. This hypothesis was evaluated by genetic modification of hyaluronan metabolism, specifically targeted to embryonic trophoblast cells. The outcome of altered hyaluronan deposition on uterine vascular remodeling and postimplantation development were analyzed by MRI, detailed histological examinations, and RNA sequencing of uterine NK cells. Our experiments revealed that disruption of hyaluronan synthesis, as well as its increased cleavage at the embryonic niche, impaired implantation by induction of decidual vascular permeability, defective vascular sinus folds formation, breach of the maternal-embryo barrier, elevated MMP-9 expression, and interrupted uterine NK cell recruitment and function. Conversely, enhanced deposition of hyaluronan resulted in the expansion of the maternal-embryo barrier and increased diffusion distance, leading to compromised implantation. The deposition of hyaluronan at the embryonic niche is regulated by progesterone-progesterone receptor signaling. These results demonstrate a pivotal role for hyaluronan in successful pregnancy by fine-tuning the periembryo avascular niche and maternal vascular morphogenesis.
    Keywords:  Angiogenesis; Embryonic development; Mouse models; Reproductive Biology
    DOI:  https://doi.org/10.1172/jci.insight.135775
  2. Front Immunol. 2020 ;11 571300
    van der Zwan A, van Unen V, Beyrend G, Laban S, van der Keur C, Kapsenberg HJM, Höllt T, Chuva de Sousa Lopes SM, van der Hoorn MP, Koning F, Claas FHJ, Eikmans M, Heidt S.
      During healthy pregnancy, a balanced microenvironment at the maternal-fetal interface with coordinated interaction between various immune cells is necessary to maintain immunological tolerance. While specific decidual immune cell subsets have been investigated, a system-wide unbiased approach is lacking. Here, mass cytometry was applied for data-driven, in-depth immune profiling of the total leukocyte population isolated from first, second, and third trimester decidua, as well as maternal peripheral blood at time of delivery. The maternal-fetal interface showed a unique composition of immune cells, different from peripheral blood, with significant differences between early and term pregnancy samples. Profiling revealed substantial heterogeneity in the decidual lymphoid and myeloid cell lineages that shape gestational-specific immune networks and putative differentiation trajectories over time during gestation. Uncovering the overall complexity at the maternal-fetal interface throughout pregnancy resulted in a human atlas that may serve as a foundation upon which comprehension of the immune microenvironment and alterations thereof in pregnancy complications can be built.
    Keywords:  decidua; human atlas; immune profiling; peripheral blood; placenta; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2020.571300
  3. Gynecol Oncol. 2020 Nov 16. pii: S0090-8258(20)34113-5. [Epub ahead of print]
    Hoeijmakers YM, Gorris MAJ, Sweep FCGJ, Bulten J, Eysbouts YK, Massuger LFAG, Ottevanger PB, de Vries JIJM.
      OBJECTIVE: In 15% of patients with complete hydatidiform mole (CHM), disease progresses to post-molar gestational trophoblastic neoplasia (GTN) after curettage. Tumor infiltrating lymphocytes (TILs) are essential in overcoming disease in many tumors. Infiltrating lymphocyte composition and density may influence trophoblast regression and development of post-molar GTN. We analyzed immune cell composition and density in curettaged endometrium of patients with CHM which spontaneously regressed, and of patients with CHM which progressed to post-molar GTN.METHODS: Sixteen patients with CHM and spontaneous regression, and 16 patients with CHM which progressed to post-molar GTN were selected. Immune cell composition and density of natural killer (NK) cells, natural killer T (NKT)-like cells, Cytotoxic T cells, T-Regulatory and T-Helper cells, were determined by multiplex immunohistochemistry (mIHC).
    RESULTS: Curettaged endometrium of patients with CHM and spontaneous regression contained a slightly higher number of immune cells compared to patients with CHM which progressed to post-molar GTN. NKT-like cell density was significantly higher in patients with spontaneous regression compared to patients with CHM which progressed to post-molar GTN (483 ± 296 vs.295 ± 143 (mean ± SD), p = 0.03) respectively. NKT-like cell density in the spontaneous regression group was split in 'high' and 'low' (i.e. above and below the median number of NKT-like cells). In patients with high NKT-like cell density, hCG normalized earlier than in patients with low NKT-like cell density (9.5 weeks, (range 3.7-14) vs. 12.9 weeks, (range 8.6-17.9), p = 0.05).
    CONCLUSION: A high number of NKT-like cells in the endometrium of CHMs may contribute to spontaneous regression of molar trophoblast cells.
    Keywords:  Complete hydatidiform mole; Multiplex immunohistochemistry; Natural killer t-like cells; Tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.ygyno.2020.11.005
  4. Placenta. 2020 Dec;pii: S0143-4004(20)30049-7. [Epub ahead of print]102 21-26
    Burton GJ, Cindrova-Davies T, Turco MY.
      Development of the placenta must always be in advance of that of the embryo. Evidence from domestic species demonstrates that the placenta is capable of stimulating its own development through a signalling dialogue with the endometrial glands. Placental lactogens produced by the trophoblast lead to increased expression and release of uterine secretions and mitogenic growth factors, including epidermal growth factor, that have a close temporal and spatial relationship with trophoblast proliferation. Here, we review evidence that an equivalent mechanism operates in the human. The same repertoire of receptors is present on the endometrial gland cells, and the epithelial cells have long been known to adopt a hypersecretory phenotype following an implantation. Furthermore, early pregnancy hormones stimulate the secretion of glycodelin-A and osteopontin, two 'uterine milk proteins' that have multiple potential effects at the maternal-placental interface, from organoid cultures derived from endometrial glands. Prolactin appears to be an important stimulant, but unlike in domestic species the human trophoblast does not secrete this hormone. Instead, it is a major product of decidual cells. Hence, complications of pregnancy that have their pathophysiological roots in deficient trophoblast proliferation may be due primarily to problems of decidualisation. Ensuring the endometrium is in an optimal state pre-conceptionally should therefore be a priority for women's health. Trophoblast stemness and proliferative capacity show a sharp decline at the switch from histotrophic to haemotrophic nutrition. This may reflect the increase in oxygen concentration or loss of growth factor support. Either way, there are implications for adaptive growth of the organ.
    Keywords:  Endometrium; First trimester; Histotroph
    DOI:  https://doi.org/10.1016/j.placenta.2020.02.008
  5. Placenta. 2020 Dec;pii: S0143-4004(19)30721-0. [Epub ahead of print]102 17-20
    Tong M, Abrahams VM.
      Preterm birth is a serious global health problem that affects 5-18% of pregnancies worldwide. In addition to being the major cause of neonatal mortality and morbidity, preterm birth is associated with short term and long term complications in the offspring. Despite this, the causes and pathogenesis of preterm birth remain unclear. Neutrophils are innate immune cells that infiltrate the maternal-fetal interface during normal parturition and their accumulation is dramatically increased during preterm birth, especially in the presence of an infection. Indeed, a defining feature of chorioamnionitis (inflammation of the chorioamnionic fetal membranes) that is associated with more than 40% of preterm births, is neutrophil accumulation. While these cells may play an important role during normal term parturition as well as preterm birth, their functions at the maternal-fetal interface are unclear. This review will provide a broad overview of the relevant studies to enable a better understanding of the roles of neutrophils during normal parturition and preterm birth.
    Keywords:  Extracellular trap; Fetal membranes; Infection; Inflammation; Preterm labor; Rupture
    DOI:  https://doi.org/10.1016/j.placenta.2019.12.010
  6. Sci Rep. 2020 Nov 20. 10(1): 20288
    Antonson AM, Evans MV, Galley JD, Chen HJ, Rajasekera TA, Lammers SM, Hale VL, Bailey MT, Gur TL.
      Maternal stress during pregnancy is widespread and is associated with poor offspring outcomes, including long-term mental health issues. Prenatal stress-induced fetal neuroinflammation is thought to underlie aberrant neurodevelopment and to derive from a disruption in intrauterine immune homeostasis, though the exact origins are incompletely defined. We aimed to identify divergent immune and microbial metagenome profiles of stressed gestating mice that may trigger detrimental inflammatory signaling at the maternal-fetal interface. In response to stress, maternal glucocorticoid circuit activation corresponded with indicators of systemic immunosuppression. At the maternal-fetal interface, density of placental mononuclear leukocytes decreased with stress, yet maternal whole blood leukocyte analysis indicated monocytosis and classical M1 phenotypic shifts. Genome-resolved microbial metagenomic analyses revealed reductions in genes, microbial strains, and metabolic pathways in stressed dams that are primarily associated with pro-inflammatory function. In particular, disrupted Parasutterella excrementihominis appears to be integral to inflammatory and metabolic dysregulation during prenatal stress. Overall, these perturbations in maternal immunological and microbial regulation during pregnancy may displace immune equilibrium at the maternal-fetal interface. Notably, the absence of and reduction in overt maternal inflammation during stress indicates that the signaling patterns driving fetal outcomes in this context are more nuanced and complex than originally anticipated.
    DOI:  https://doi.org/10.1038/s41598-020-77265-x
  7. Front Immunol. 2020 ;11 528202
    Di Simone N, Santamaria Ortiz A, Specchia M, Tersigni C, Villa P, Gasbarrini A, Scambia G, D'Ippolito S.
      Hormonal changes during and after pregnancy are linked with modifications in the maternal microbiota. We describe the importance of the maternal microbiota in pregnancy and examine whether changes in maternal microbiotic composition at different body sites (gut, vagina, endometrium) are associated with pregnancy complications. We analyze the likely interactions between microbiota and the immune system. During pregnancy, the gastrointestinal (gut) microbiota undergoes profound changes that lead to an increase in lactic acid-producing bacteria and a reduction in butyrate-producing bacteria. The meaning of such changes needs clarification. Additionally, several studies have indicated a possible involvement of the maternal gut microbiota in autoimmune and lifelong diseases. The human vagina has its own microbiota, and changes in vaginal microbiota are related to several pregnancy-related complications. Recent studies show reduced lactobacilli, increased bacterial diversity, and low vaginal levels of beta-defensin 2 in women with preterm births. In contrast, early and healthy pregnancies are characterized by low diversity and low numbers of bacterial communities dominated by Lactobacillus. These observations suggest that early vaginal cultures that show an absence of Lactobacillus and polymicrobial vaginal colonization are risk factors for preterm birth. The endometrium is not a sterile site. Resident endometrial microbiota has only been defined recently. However, questions remain regarding the main components of the endometrial microbiota and their impact on the reproductive tract concerning both fertility and pregnancy outcomes. A classification based on endometrial bacterial patterns could help develop a microbiota-based diagnosis as well as personalized therapies for the prevention of obstetric complications and personalized treatments through nutritional, microbiotic, or pharmaceutical interventions.
    Keywords:  endometrium; gut; immunity; inflammasome; microbiota; pregnancy; vagina
    DOI:  https://doi.org/10.3389/fimmu.2020.528202
  8. JCI Insight. 2020 Nov 19. pii: 138812. [Epub ahead of print]5(22):
    Cappelletti M, Doll JR, Stankiewicz TE, Lawson MJ, Sauer V, Wen B, Kalinichenko VV, Sun X, Tilburgs T, Divanovic S.
      Infection-driven inflammation in pregnancy is a major cause of spontaneous preterm birth (PTB). Both systemic infection and bacterial ascension through the vagina/cervix to the amniotic cavity are strongly associated with PTB. However, the contribution of maternal or fetal inflammatory responses in the context of systemic or localized models of infection-driven PTB is not well defined. Here, using intraperitoneal or intraamniotic LPS challenge, we examined the necessity and sufficiency of maternal and fetal Toll-like receptor (TLR) 4 signaling in induction of inflammatory vigor and PTB. Both systemic and local LPS challenge promoted induction of inflammatory pathways in uteroplacental tissues and induced PTB. Restriction of TLR4 expression to the maternal compartment was sufficient for induction of LPS-driven PTB in either systemic or intraamniotic challenge models. In contrast, restriction of TLR4 expression to the fetal compartment failed to induce LPS-driven PTB. Vav1-Cre-mediated genetic deletion of TLR4 suggested a critical role for maternal immune cells in inflammation-driven PTB. Further, passive transfer of WT in vitro-derived macrophages and dendritic cells to TLR4-null gravid females was sufficient to induce an inflammatory response and drive PTB. Cumulatively, these findings highlight the critical role for maternal regulation of inflammatory cues in induction of inflammation-driven parturition.
    Keywords:  Cellular immune response; Cytokines; Inflammation; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.138812
  9. Front Immunol. 2020 ;11 557184
    Ono Y, Yoshino O, Hiraoka T, Sato E, Fukui Y, Ushijima A, Nawaz A, Hirota Y, Wada S, Tobe K, Nakashima A, Osuga Y, Saito S.
      Macrophages (MΦs) play important roles in implantation. Depletion of CD11b+ pan-MΦs in CD11b-diphtheria-toxin-receptor (DTR) mice is reported to cause implantation failure due to decreased progesterone production in the corpus luteum. However, of the M1 and M2, the type of MΦs that is important for implantation is unknown. In this study, we investigated the role of M2 MΦ in implantation using CD206-DTR mice. To deplete M2-MΦ, female CD206-DTR C57/BL6 mice were injected with DT before implantation. These M2-MΦ depleted mice (M2(-)) were naturally mated with Balb/C mice. As the control group, female C57/BL6 wild type (WT) mice injected with DT were mated with male Balb/C mice. The number of implantation sites and plasma progesterone levels at implantation were examined. Implantation-related molecule expression was determined using quantitative-PCR and immunohistochemistry of uterine tissues. The mRNA expression in the endometrial tissues of 38 patients with implantation failure was examined during the implantation window. In WT mice, CD206+M2-like MΦs accumulated in the endometrium at the implantation period, on embryonic (E) 4.5. In M2(-), the implantation number was significantly lower than that in control (p < 0.001, 7.8 ± 0.8 vs. 0.2 ± 0.4), although the plasma progesterone levels were not changed. Leukemia inhibitory factor (LIF) and CD206 mRNA expression was significantly reduced (p < 0.01), whereas the levels of TNFα were increased on E4.5 (p < 0.05). In M2(-), the number of Ki-67+ epithelial cells was higher than that in control at the pre-implantation period. Accelerated epithelial cell proliferation was confirmed by significantly upregulated uterine fibroblast growth factor (FGF)18 mRNA (P < 0.05), and strong FGF18 protein expression in M2(-) endometrial epithelial cells. Further, M2(-) showed upregulated uterine Wnt/β-catenin signals at the mRNA and protein levels. In the non-pregnant group, the proportion of M2-like MΦ to pan MΦ, CD206/CD68, was significantly reduced (p < 0.05) and the TNFα mRNA expression was significantly increased (p < 0.05) in the endometrial tissues compared to those in the pregnant group. CD206+ M2-like MΦs may be essential for embryo implantation through the regulation of endometrial proliferation via Wnt/β-catenin signaling.
    Keywords:  CD206; M2 macrophage; Wnt/β-catenin signal; diphtheria-toxin receptor mouse; fibroblast growth factor; implantation
    DOI:  https://doi.org/10.3389/fimmu.2020.557184
  10. Front Immunol. 2020 ;11 592010
    Xu X, Zhou Y, Wei H.
      During pregnancy, the maternal uterus and fetus form a special microenvironment at the maternal-fetal interface to support fetal development. Extravillous trophoblasts (EVTs), differentiated from the fetus, invade into the decidua and interact with maternal cells. Human leukocyte antigen (HLA)-G is a non-classical MHC-I molecule that is expressed abundantly and specifically on EVTs in physiological conditions. Soluble HLA-G (sHLA-G) is also found in maternal blood, amniotic fluid, and cord blood. The abnormal expression and polymorphisms of HLA-G are related to adverse pregnancy outcomes such as preeclampsia (PE) and recurrent spontaneous abortion (RSA). Here we summarize current findings about three main roles of HLA-G during pregnancy, namely its promotion of spiral artery remodeling, immune tolerance, and fetal growth, all resulting from its interaction with immune cells. These findings are not only of great significance for the treatment of pregnancy-related diseases but also provide clues to tumor immunology research since HLA-G functions as a checkpoint in tumors.
    Keywords:  extravillous trophoblasts; fetal development; human leukocyte antigen G; immunology; natural killer cells; pregnancy; spiral artery remodeling
    DOI:  https://doi.org/10.3389/fimmu.2020.592010