bims-reprim Biomed News
on Reproductive immunology
Issue of 2020‒10‒11
twelve papers selected by
Iva Filipovic
Karolinska Institutet


  1. Front Immunol. 2020 ;11 2070
    Hoo R, Nakimuli A, Vento-Tormo R.
      During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations.
    Keywords:  decidua; innate immunity; trophoblast; uterine-placental interface; vertical transmission
    DOI:  https://doi.org/10.3389/fimmu.2020.02070
  2. Front Immunol. 2020 ;11 1864
    Aneman I, Pienaar D, Suvakov S, Simic TP, Garovic VD, McClements L.
      Preeclampsia is a complex cardiovascular disorder of pregnancy with underlying multifactorial pathogeneses; however, its etiology is not fully understood. It is characterized by the new onset of maternal hypertension after 20 weeks of gestation, accompanied by proteinuria, maternal organ damage, and/or uteroplacental dysfunction. Preeclampsia can be subdivided into early- and late-onset phenotypes (EOPE and LOPE), diagnosed before 34 weeks or from 34 weeks of gestation, respectively. Impaired placental development in early pregnancy and subsequent growth restriction is often associated with EOPE, while LOPE is associated with maternal endothelial dysfunction. The innate immune system plays an essential role in normal progression of physiological pregnancy and fetal development. However, inappropriate or excessive activation of this system can lead to placental dysfunction or poor maternal vascular adaptation and contribute to the development of preeclampsia. This review aims to comprehensively outline the mechanisms of key innate immune cells including macrophages, neutrophils, natural killer (NK) cells, and innate B1 cells, in normal physiological pregnancy, EOPE and LOPE. The roles of the complement system, syncytiotrophoblast extracellular vesicles and mesenchymal stem cells (MSCs) are also discussed in the context of innate immune system regulation and preeclampsia. The outlined molecular mechanisms, which represent potential therapeutic targets, and associated emerging treatments, are evaluated as treatments for preeclampsia. Therefore, by addressing the current understanding of innate immunity in the pathogenesis of EOPE and LOPE, this review will contribute to the body of research that could lead to the development of better diagnosis, prevention, and treatment strategies. Importantly, it will delineate the differences in the mechanisms of the innate immune system in two different types of preeclampsia, which is necessary for a more personalized approach to the monitoring and treatment of affected women.
    Keywords:  early-onset preeclampsia; immune cells; inflammation; innate immunity; late-onset preeclampsia; preeclampsia; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2020.01864
  3. Front Cell Dev Biol. 2020 ;8 633
    Lin F, Yang C, Feng T, Yang S, Zhou R, Li H.
      Small for gestational age (SGA) refers to a birth weight that is less than the 10th percentile of the mean weight of infants at the same gestational age. This condition is associated with a variety of complications, and a high risk of cardiovascular and cerebrovascular diseases in adulthood. Decidual natural killer (dNK) cells at the maternal-fetal interface have received significant research attention in terms of normal pregnancy or miscarriage; however, data relating to SGA are limited. In this study, we aimed to investigate the characteristics and regulatory role of dNK cells at the maternal-fetal interface in SGA. Using immunofluorescence assays, we found that dNK cells maintained close contact with extra-villous trophoblasts, and the proportion of dNK cells in SGA decreased more than in appropriate for gestational age (AGA). Flow cytometry also showed that there was a significantly lower percentage of dNK cells in SGA (25.01 ± 2.43%) than in AGA (34.25 ± 2.30%) (p = 0.0103). The expression of the inhibitory receptor NKG2A on dNK cells and the secretion levels of both perforin and TGF-β1 from dNK cells were significantly higher in SGA than in AGA, while the cytotoxicity of dNK cells in SGA against K562 cells was attenuated. Compared to AGA, the functional ability of dNK cells in SGA showed significant functional impairment in promoting proliferation, migration, invasion, and tube formation in trophoblast cells or vascular endothelial cells. The abnormal function of dNK cells may affect fetal growth and development, and could therefore participate in the pathogenesis of SGA.
    Keywords:  decidua; innate immunity; maternal-fetal interface; natural killer cells; small for gestational age
    DOI:  https://doi.org/10.3389/fcell.2020.00633
  4. Clin Exp Immunol. 2020 Oct 05.
    Liang Q, Tong L, Xiang L, Shen S, Pan C, Liu C, Zhang H.
      Semi-allogeneic embryos are not rejected by the maternal immune system due to maternal-fetal immune tolerance. Progesterone (P) receptor (PR)-expressing γδ T cells are present in healthy pregnant women. In the presence of P, these cells secrete an immunomodulatory protein called progesterone-induced blocking factor (PIBF), which can facilitate immune escape and is important in preventing embryonic rejection. This work investigated the correlations of the expression of γδ T cells and their costimulatory molecules TIGIT, PD-1, ICOS, and BTLA with PR and PIBF in peripheral blood and decidual tissue in women with unexplained recurrent spontaneous abortion (URSA) and normal pregnant (NP) women. We confirmed that γδ T cell proportions and PIBF expression in the peripheral blood and decidua of URSA women decreased significantly, while PR expression in decidua decreased. However, TIGIT, PD-1, ICOS, and BTLA expression in γδ T cells in peripheral blood did not change, while TIGIT and PD-1 expression in γδ T cells in decidua increased significantly. Under the action of PHA-P (10 µg/ml), co-blocking of TIGIT (15 µg/ml) and PD-1 (10 µg/ml) antibodies further induced γδ T cell proliferation, but PIBF levels in the culture medium supernatant did not change. At 10-10 M P, γδ T cells proliferated significantly, and PIBF concentrations in the culture medium supernatant increased. γδ T cells co-cultured with P, TIGIT and PD-1 blocking antibodies showed the most significant proliferation, and PIBF concentrations in the culture medium supernatant were the highest. These results confirm that P is necessary for PIBF production. The TIGIT and PD-1 pathways participate in γδ T cell proliferation and activation and PIBF expression and play important roles in maintaining pregnancy.
    Keywords:  PIBF; PR; Spontaneous abortion; costimulatory molecule; γδ T cells
    DOI:  https://doi.org/10.1111/cei.13534
  5. Front Immunol. 2020 ;11 557720
    Yasuda I, Shima T, Moriya T, Ikebuchi R, Kusumoto Y, Ushijima A, Nakashima A, Tomura M, Saito S.
      Dendritic cells (DCs) are essential for successful embryo implantation. However, the properties of uterine DCs (uDCs) during the implantation period are not well characterized. In this study, we investigated the dynamic changes in the uDC phenotypes during the period between coitus and implantation. In virgin mice, we evaluated the expressions of CD103 and XCR1, this is the first report to demonstrate uDCs expressing CD103 in XCR1+cDC1s and XCR1+cDC2s. On day 0.5 post coitus (pc), the number of uterine CD11c+CD103-MHC classIIhighCD86high-mature DCs rapidly increased and then decreased to non-pregnancy levels on days 1.5 and 2.5 pc. On day 3.5 pc just before implantation, the number of CD11c+CD103+MHC class IIdimCD86dim-immature DCs increased in the uterus. The increase in mature uDCs on day 1.5 pc was observed in both allogeneic- and syngeneic mating, suggesting that sexual intercourse, or semen, play a role in this process. Meanwhile, the increase in immature uDCs on day 3.5 pc was only observed in allogeneic mating, suggesting that allo-antigens in the semen contribute to this process. Next, to understand the turnover and migration of uDCs, we monitored DC movement in the uterus and uterine draining lymph nodes (dLNs) using photoconvertible protein Kikume Green Red (KikGR) mice. On day 0.5 pc, uDCs were composed of equal numbers of remaining DCs and migratory DCs. However, on day 3.5 pc, uDCs were primarily composed of migratory DCs, suggesting that most of the uDCs migrate from the periphery just before implantation. Finally, we studied the expression of PD-L2-which induces immunoregulation-on DCs. On day 3.5 pc, PD-L2 was expressed on CD103+-mature and CD103--mature DCs in the uterus. However, PD-L2 expression on CD103--immature DCs and CD103+-immature DCs was very low. Furthermore, both remaining and migratory DCs in the uterus and uterus-derived-DCs in the dLNs on day 3.5 pc highly expressed PD-L2 on their surface. Therefore, our study findings provide a better understanding of the dynamic changes occurring in uterine DCs and dLNs in preparation for implantation following allogeneic- and syngeneic mating.
    Keywords:  Kikume Green Red (KikGR); PD-L2; feto-maternal tolerance; photoconvertible protein; tolerogenic dendritic cells; uterus
    DOI:  https://doi.org/10.3389/fimmu.2020.557720
  6. J Reprod Immunol. 2020 Sep 26. pii: S0165-0378(20)30133-9. [Epub ahead of print]142 103212
    Campuzano M, Bueno-Sánchez J, Agudelo-Jaramillo B, Quintana-Castillo JC, Chaouat GC, Maldonado-Estrada JG.
      New evidence suggests that glycan expression in placental cells of women with invasive disorders of pregnancy differs from that in normal pregnant women. Hypothesizing that modifications of glycan expression could account for the course of preeclampsia, we established placental villous histocultures and compared glycan expression in women with preeclampsia with that in normal pregnant women and also in syncytialized BeWo cells, and we tested the effect of glycan expression on the functional phenotypes of circulating natural killer (NK) cells. Histocultures of third-trimester placentae from women with preeclampsia and full-term placentae from healthy pregnant women and BeWo choriocarcinoma cells were assessed for the expression of terminal glycans by lectin-binding assays. Circulating NK cells from nonpregnant healthy donors were tested in vitro for their cytotoxic activity and intracellular cytokine content. Histocultures from women with preeclampsia expressed significantly more mannose than did those from healthy pregnant women. Both histocultures and BeWo cells expressed terminal fucose, mannose, sialic acid, and N -acetylgalactosamine, although mean fluorescence intensity (MFI) expression was lower in choriocarcinoma cells than in cells from histocultures. Cocultures of circulating NK cells with K562 target cells resulted in a dose-dependent cytotoxicity effect, but the use of BeWo cells as target reduced cytotoxic activity; this reduction was not affected by syncytialization. Histocultures of placental villous tissue of women with preeclampsia expressed high levels of terminal mannose. We proposethat placental glycans may modulate the functional activity of circulating NK cells in the context of systemic inflammatory response in preeclampsia.
    Keywords:  Chorionic villii; Cytotoxicity NK cells; Polysaccharides; Preeclampsia (MESH-verified)
    DOI:  https://doi.org/10.1016/j.jri.2020.103212
  7. Autophagy. 2020 Oct 08.
    Lu H, Yang HL, Zhou WJ, Lai ZZ, Qiu XM, Fu Q, Zhao JY, Wang J, Li DJ, Li MQ.
      Deficiency in decidualization has been widely regarded as an important cause of spontaneous abortion. Generalized decidualization also includes massive infiltration and enrichment of NK cells. However, the underlying mechanism of decidual NK (dNK) cell residence remains largely unknown. Here, we observe that the increased macroautophagy/autophagy of decidual stromal cells (DSCs) during decidualization, facilitates the adhesion and retention of dNK cells during normal pregnancy. Mechanistically, this process is mediated through activation of the MITF-TNFRSF14/HVEM signaling, and further upregulation of multiple adhesion adhesions (e.g, Selectins and ICAMs) in a MMP9-dependent manner. Patients with unexplained spontaneous abortion display insufficient DSC autophagy and dNK cell residence. In addition, poor vascular remodeling of placenta, low implantation number and high ratio of embryo loss are observed in NK cell depletion mice. In therapeutic studies, low doses of rapamycin, a known autophagy inducer that significantly promotes endometrium autophagy and NK cell residence, and improves embryo absorption in spontaneous abortion mice models, which should be dependent on the activation of MITF-TNFRSF14/HVEM-MMP9-adhension molecules axis. This observation reveals novel molecular mechanisms underlying DSCs autophagy-driven dNK cell residence, and provides a potential therapeutic strategy to prevent spontaneous abortion.
    Keywords:  MITF; MMP9; NK cells; TNFRSF14/HVEM; abortion; autophagy; decidual stromal cells; early pregnancy; residence
    DOI:  https://doi.org/10.1080/15548627.2020.1833515
  8. Front Immunol. 2020 ;11 1920
    Clements T, Rice TF, Vamvakas G, Barnett S, Barnes M, Donaldson B, Jones CE, Kampmann B, Holder B.
      Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccination had no impact on neonatal levels of the subclasses, nor transfer. However, within Tdap vaccinated pregnancies, later gestation at Tdap vaccination was associated with higher transplacental transfer. Our study provides information regarding levels and transfer of IgG subclasses in healthy term pregnancies and demonstrates the importance of recording detailed clinical information in studies of antibody transfer, including parity, ethnicity, and timing of maternal vaccine delivery.
    Keywords:  IgG; antibody; immunology; infection; maternal vaccination; neonatal; placenta; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2020.01920
  9. Placenta. 2020 Oct 01. pii: S0143-4004(20)30377-5. [Epub ahead of print]101 230-233
    Bulmer JN, Innes BA, Robson SC, Lash GE.
      Spiral artery (SpA) remodelling is essential for a successful pregnancy and is best described by its morphological features; vascular smooth muscle cell separation and loss, vessel dilatation, and invasion by extravillous trophoblast cells (EVT). Current opinion holds that EVT fully replace the endothelial cells (EC) of the SpA and take on EC-like characteristics. Placental bed biopsies (6-20 weeks gestation) were immunostained for EC and EVT, showing transient loss of EC. In vessels containing an endovascular EVT plug (n = 28) 77.6 ± 19.3% of the lumen was covered by EC while in vessels without endovascular EVT (n = 100) it was 100 ± 0%.
    Keywords:  Endothelial cells; Extravillous trophoblast cells; Spiral artery remodelling
    DOI:  https://doi.org/10.1016/j.placenta.2020.10.003
  10. J Perinat Med. 2020 Oct 09. pii: /j/jpme.ahead-of-print/jpm-2020-0025/jpm-2020-0025.xml. [Epub ahead of print]
    Denney JM, Nelson E, Wadhwa P, Waters T, Mathew L, Goldenberg RL, Culhane JF.
      Objectives To assess deviations in longitudinally measured cytokines with preterm birth (PTB). Methods Prospective longitudinal study targeting 80 subjects. Phlebotomy specimens for broad panel of cytokine analysis were obtained at three time (T) intervals: first trimester (T1: 8-14 weeks' gestation), second trimester (T2: 18-22 weeks' gestation), and third trimester (T3: 28-32 weeks' gestation). Important demographics and outcomes were tracked. Data were stratified and the target groups were analyzed as follows: "Uncomplicated" (delivered ≥37 weeks) or "Preterm Birth" (<37 weeks). Generalized Linear Modeling determined rate of change T1-T3 by outcome. Results Complete data replete with phlebotomy at all three visits were obtained on 80 women. Birth outcomes were as follows: 11 Uncomplicated Term Birth (UTB), 28 PTB, 4 low birth weight (LBW), 16 OB complications (OBC), 11 current infections (IFN), and 10 mixed complications (MC=2 or more of the above). 28 PTB were compared to 11 uncomplicated term deliveries. In both groups, T helper type 1 (TH1) cytokine (IL-1β), pleiotrophic pro-inflammatory cytokine (IL-6), and counter-regulatory cytokine (IL-10) responses decreased over gestation, but rates of change in IL-1β, IL-6, and IL-10 were significantly different. Stratification of women by smoking status additionally demonstrated significant variance in immune status over the course of pregnancy Conclusions Women delivering PTB demonstrated significant differences in cytokine trajectory over pregnancy; these data further validate key role played by immune regulation in directing pregnancy outcome. Likewise, smoking impacts longitudinal trajectory of cytokines over pregnancy.
    Keywords:  cytokines; immune profiling; inflammation; preterm birth
    DOI:  https://doi.org/10.1515/jpm-2020-0025
  11. Cytokine. 2020 Oct 05. pii: S1043-4666(20)30332-X. [Epub ahead of print]137 155316
    Florova V, Romero R, Tarca AL, Galaz J, Motomura K, Ahmad MM, Hsu CD, Hsu R, Tong A, Ravel J, Theis KR, Gomez-Lopez N.
      BACKGROUND: Recent studies suggest that alterations in the vaginal microbiome allow for the assessment of the risk for spontaneous preterm birth (PTB), the leading cause of neonatal morbidity and mortality worldwide. However, the associations between the local immune response and the vaginal microbiome are still poorly understood. Herein, we characterize the vaginal host immune-microbiome interactions in women who ultimately underwent PTB and in those who delivered at term.METHODS: Vaginal fluid samples from 52 pregnant women (of whom 18 underwent PTB and 34 delivered at term) were collected between 10 and 32 weeks of gestation in a case-control study. Concentrations of 33 immune mediators were determined using sensitive and specific immunoassays. The previously published 16S rRNA gene sequence and bacterial phylotype data of these subjects were utilized in this study. Linear mixed effects models were utilized to test associations between vaginal immune mediator concentrations and bacterial phylotype relative abundances.
    RESULTS: 1) In the overall study population, vaginal concentrations of CXCL10, CCL2, CCL3, SLP1 and VEGF negatively correlated with non-Lactobacillus, Community State Type IV (CST IV) members of the vaginal microbiome; 2) CXCL10, in particular, negatively correlated with 15 bacterial phylotypes, most of which are typical members of CST IV, such as Gardnerella vaginalis, Megasphaera spp., and Atopobium vaginae; 3) Gemella spp., also members of CST IV, negatively correlated with vaginal concentrations of VEGF, CCL2, CCL3, SLPI, and CXCL10; 4) when comparing PTB cases to term controls, five soluble immune mediators (CCL26, CCL22, CCL2, CXCL10, and IL-16), especially CCL26, were negatively correlated with five typical members of CST IV: Sneathia sanguinegens, Parvimonas micra, Veillonellaceae, BVAB2, and Gemella spp.; and 5) Sneathia sanguinegens had stronger negative associations with all five soluble immune mediators (CCL26, CCL22, CCL2, CXCL10, and IL-16) in PTB cases than in term controls.
    CONCLUSIONS: The assessment of vaginal host immune-microbiome interactions revealed that specific soluble immune mediators, mainly CXCL10, negatively correlated with typical members of CST IV of the vaginal microbiome. Sneathia sanguinegens, in particular, had stronger negative associations with different immune mediators, including CXCL10 and CCL26, in women who ultimately underwent PTB compared to those who delivered at term. These findings provide insight into the vaginal host immune-microbiome interactions in normal and complicated pregnancies.
    Keywords:  16S rRNA gene; CCL26; CXCL10; Chemokines; Cytokines; Pregnancy; Sneathia; Vaginal microbiota; β-defensins
    DOI:  https://doi.org/10.1016/j.cyto.2020.155316
  12. BJOG. 2020 Oct 05.
    Schwartz A, Yogev Y, Zilberman A, Alpern S, Many A, Yousovich R, Gamzu R.
      OBJECTIVE: To determine whether SARS-CoV-2 is present in the vaginal secretions of both reproductive-aged and postmenopausal women during acute SARS-CoV-2 infection.DESIGN: Prospective study.
    SETTING: a single tertiary, university-affiliated medical center in Israel. Time period, June 1, 2020 through July 31, 2020.
    POPULATION: Women that were hospitalized in a single tertiary medical center, who were diagnosed with acute SARS-CoV-2 infection by a nasopharyngeal RT-PCR test.
    METHODS: A prospective study of women who were diagnosed with acute SARS-CoV-2 infection by a nasopharyngeal RT-PCR test. Vaginal RT-PCR swabs were obtained from all study participants after a proper cleansing of the perineum.
    MAIN OUTCOME MEASURES: Detection of SARS-CoV-2 in vaginal RT-PCR swabs.
    RESULTS: Vaginal and nasopharyngeal swabs were obtained from 35 women, aged 21-93 years. Twenty-one patients (60%) were in their reproductive years, of them, 5 patients were in their third trimester of pregnancy. Most of the participants (57%) were healthy without any underlying medical conditions. Of the 35 patients sampled, 2 (5.7%) had a positive vaginal RT-PCR for SARS-CoV-2, one was pre-menopausal and the other was a post-menopausal woman. Both women had mild disease.
    CONCLUSION: Our findings contradict most previous reports, which did not detect the presence of viral colonization in the vagina. Although passage through the birth canal exposes neonates to the vaginal polymicrobial flora, an acquisition of pathogens does not necessarily mandate neonatal infection or clinical disease. Nevertheless, when delivering a woman with acute SARS-CoV-2 infection, a clinician should consider the possibility of vaginal colonization, even if it is uncommon.
    Keywords:  SARS-CoV-2; Vaginal secretion
    DOI:  https://doi.org/10.1111/1471-0528.16556