bims-reprim Biomed News
on Reproductive immunology
Issue of 2022‒05‒15
ten papers selected by
Iva Filipovic
Karolinska Institutet
  1. Uterine NK cell functions at maternal-fetal interface.
  2. Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome.
  3. Immunologically active cells and infertility - Quantification of uterine Natural Killer cells in endometrial samples from patients with recurrent implantation failure.
  4. The Immunobiology of Preterm Labor and Birth: Intra-Amniotic Inflammation or Breakdown of Maternal-Fetal Homeostasis.
  5. Tim-3+ decidual Mφs induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132.
  6. Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure.
  7. Thymic and extrathymic Aire-expressing cells in maternal-fetal tolerance.
  8. Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy.
  9. PD-1 Mediates Decidual γδ T Cells Cytotoxicity During Recurrent Pregnancy Loss.
  10. The vaginal microbiome and the risk of preterm birth: a systematic review and network meta-analysis.
  1. Biol Reprod. 2022 May 11. pii: ioac094. [Epub ahead of print]
    Uterine NK cell functions at maternal-fetal interface.
    Xiuxiu Xu, Yonggang Zhou, Binqing Fu, Haiming Wei.
      During pregnancy, maternal decidual tissue interacts with fetal trophoblasts. They constitute the maternal-fetal interface responsible for supplying nutrition to the fetus. Uterine natural killer (uNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy and play critical roles throughout pregnancy. This review provides current knowledge about the functions of uNK cells. uNK cells have been shown to facilitate remodeling of the spiral artery, control the invasion of extravillous trophoblast (EVT) cells, contribute to the induction and maintenance of immune tolerance, protect against pathogen infection, and promote fetal development. Pregnancy-trained memory of uNK cells improves subsequent pregnancy outcomes. In addition, this review describes the distinct functions of three uNK cell subsets: CD27-CD11b-, CD27+ and CD27-CD11b+ uNK cells.
    Keywords:  Natural killer cells1pregnancydeciduaEVTspiral arteryinfection
    DOI:  https://doi.org/10.1093/biolre/ioac094
  2. Front Immunol. 2022 ;13 825075
    Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome.
    Emily F Cornish, Thomas McDonnell, David J Williams.
      Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes.
    Keywords:  CD8+ T lymphocytes; allograft rejection; chronic histiocytic intervillositis; chronic placental inflammation; fetal growth restriction; massive perivillous fibrin deposition; stillbirth; villitis of unknown etiology
    DOI:  https://doi.org/10.3389/fimmu.2022.825075
  3. FASEB J. 2022 May;36 Suppl 1
    Immunologically active cells and infertility - Quantification of uterine Natural Killer cells in endometrial samples from patients with recurrent implantation failure.
    Ivan Varga, Lenka Lapides, Martin Klein, Pavel Babal.
      BACKGROUND: Despite enormous advancements of reproductive medicine, recurrent implantation failure and habitual abortion remain an ongoing issue. One of the most important aspects of successful implantation is the intricate immune regulation necessary for the acceptance of the hemiallogenic embryo. The most numerous immune cells in the decidua are uterine Natural Killer (uNK) cells. Studies suggest that changes in the uNK cells count and physiology may be responsible for the aforementioned conditions. Thus, the uNK cells testing may provide valuable insights into their pathogenesis.METHODS: We compared Pipelle endometrial sampling with conventional curettage to find out whether the less invasive Pipelle method is a viable alternative of tissue collection.
    RESULTS: We examined tissue samples from 9 patients obtained by both methods. The average size of tissue samples obtained with pipelle was 10,27 mm2, samples obtained with curettage had on average 18,74 mm2. Using immunohistochemical visualization of CD56 (NK cells) and granzyme B antigens (serine protease-expressing activation state of NK cells), we found out that the average total count of CD56 / mm2 was for pipelle 90,13 and 84,04 for curettage. We also proved a correlation between granzyme B positivity and identification of NK cells clusters. The results showed that Pipelle endometrial sampling is a suitable method of tissue harvesting for the purpose of uNK cells examination.
    DISCUSSION: Pipelle endometrial sampling is safe, cost-effective and can be performed on an outpatient basis without the need of anaesthesia or analgesia. Several issues remain to be solved: how to standardize the subsequent uNK cells testing, how to interpret the results and finally yet importantly, how to use this knowledge in personalized treatment protocols.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R4421
  4. Reproduction. 2022 May 01. pii: REP-22-0046. [Epub ahead of print]
    The Immunobiology of Preterm Labor and Birth: Intra-Amniotic Inflammation or Breakdown of Maternal-Fetal Homeostasis.
    Nardhy Gomez-Lopez, Jose Galaz, Derek Miller, Marcelo Farias-Jofre, Zhenjie Liu, Marcia Arenas-Hernandez, Valeria Garcia-Flores, Zachary Shaffer, Jonathan Greenberg, Kevin R Theis, Roberto Romero.
      Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, results from preterm labor, a syndrome that includes multiple etiologies. In this review, we have summarized the immune mechanisms implicated in intra-amniotic inflammation, the best-characterized cause of preterm labor and birth. While the intra-amniotic inflammatory responses driven by microbes (infection) or alarmins (sterile) have some overlap in the participating cellular and molecular processes, the distinct natures of these two conditions necessitate the implementation of specific approaches to prevent adverse pregnancy and neonatal outcomes. Intra-amniotic infection can be treated using the correct antibiotics, whereas sterile intra-amniotic inflammation could potentially be treated using a combination of anti-inflammatory drugs (e.g., betamethasone, inflammasome inhibitors, etc.). Recent evidence also supports a role for fetal T-cell activation as a newly described trigger for preterm labor and birth in a subset of cases. Moreover, here we also provide evidence of two potential immune mechanisms responsible for a subset of preterm births formerly considered to be idiopathic. First, the impairment of maternal Tregs can lead to preterm birth, likely due to the loss of immunosuppressive activity resulting in unleashed effector T-cell responses. Second, homeostatic macrophages were shown to be essential for maintaining pregnancy and promoting fetal development, and the adoptive transfer of homeostatic M2-polarized macrophages shows great promise for preventing inflammation-induced preterm birth. Collectively, in this review, we discuss established and novel immune mechanisms responsible for preterm birth and highlight potential targets for novel strategies aimed at preventing the multi-etiological syndrome of preterm labor.
    DOI:  https://doi.org/10.1530/REP-22-0046
  5. Cell Death Dis. 2022 May 12. 13(5): 454
    Tim-3+ decidual Mφs induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132.
    Mengdie Li, Fengrun Sun, Yuanyuan Xu, Lanting Chen, Chunqin Chen, Liyuan Cui, Jinfeng Qian, Dajin Li, Songcun Wang, Meirong Du.
      T-cell immunoglobulin mucin-3 (Tim-3) plays roles in the functional regulation of both adaptive and innate immune cells and is greatly involved in many diseases. However, the precise roles of Tim-3 on macrophages (Mφs) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3+ decidual Mφs (dMφs) in response to trophoblasts. The reduced abundance of Tim-3 on Mφs was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3+Mφs, but not Tim-3-Mφs, relieved murine embryo absorption induced by Mφ depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3+ and Tim-3-dMφs were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) Mφs. However, with higher CD132 expression, Tim-3+dMφs subset induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dMφ function and maintaining normal pregnancy, and suggested that Tim-3 on Mφs is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3-Mφs could rescue the fetal resorption induced by Mφ depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.
    DOI:  https://doi.org/10.1038/s41419-022-04899-2
  6. J Reprod Immunol. 2022 May 09. pii: S0165-0378(22)00163-2. [Epub ahead of print]151 103634
    Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure.
    Kilian Vomstein, Simon Reider, Bettina Böttcher, Christina Watschinger, Christiana Kyvelidou, Herbert Tilg, Alexander R Moschen, Bettina Toth.
      In contrast to the former notion of a sterile womb, sequencing techniques have proven a bacterial colonization of the uterus. However, timing of microbiota analysis regarding possible intra-cycle variations as well as specific alterations in patients with recurrent miscarriage (RM) or recurrent implantation failure (RIF) remain unknown. In total, n = 20 RM-, n = 20 RIF-patients and n = 10 healthy controls were included in this prospective study. In every subject, uterine flushing was performed during follicular, ovulatory and luteal phase. Bacterial DNA was isolated and 16S amplicon sequencing analysis of the V3-V4 region was carried out. Diversity measures were compared between samples from the disease groups and the control group separately for each timepoint of the menstrual cycle and over time. In the control group a significant decrease of species richness and evenness was shown around ovulation which remained at this lower level during the luteal phase (Shannon index), indicating a more uniform distribution of microbiota (p < 0.05). This loss of diversity during the menstrual cycle was not apparent in RIF and RM patients. A higher similarity was seen in taxonomic distribution between RM and RIF patients compared to the control group. Longitudinal dynamics included increases in Firmicutes (controls and RM only) and a concomitant loss of Proteobacteria in controls that was not present in RIF and RM. We demonstrate longitudinal intra-cycle-dependent changes in the endometrial microbiota of healthy controls. An increased diversity in both patient groups could be the cause or consequence of a micro-environment that is more prone to pregnancy failures.
    Keywords:  Microbiota; Recurrent implantation failure; Recurrent miscarriage; Uterine flushing
    DOI:  https://doi.org/10.1016/j.jri.2022.103634
  7. Immunol Rev. 2022 May 10.
    Thymic and extrathymic Aire-expressing cells in maternal-fetal tolerance.
    Im-Hong Sun, Eva Gillis-Buck, Tippi C Mackenzie, James M Gardner.
      Healthy pregnancy requires maternal immune tolerance to both fetal and placental tissues which contain a range of self- and non-self-antigens. While many of the components and mechanisms of maternal-fetal tolerance have been investigated in detail and previously and thoroughly reviewed (Erlebacher A. Annu Rev Immunol. 2013;31:387-411), the role of autoimmune regulator (Aire), a critical regulator of central tolerance expressed by medullary thymic epithelial cells (mTECs), has been less explored. Aire is known to facilitate the expression of a range of otherwise tissue-specific antigens (TSAs) in mTECs, and here we highlight recent work showing a role for mTEC-mediated thymic selection in maintaining maternal-fetal tolerance. Recently, however, our group and others have identified additional populations of extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. These hematopoietic antigen-presenting cells possess the ability to induce functional inactivation and/or deletion of cognate T cells, and deletion of maternal eTACs during pregnancy increases T-cell activation in the lymph nodes and lymphocytic infiltration of the uterus, leading to pregnancy complications including intrauterine growth restriction (IUGR) and fetal resorption. In this review, we briefly summarize findings related to essential Aire biology, discuss the known roles of Aire-deficiency related to pregnancy complications and infertility, review the newly discovered role for eTACs in the maintenance of maternal-fetal tolerance-as well as recent work defining eTACs at the single-cell level-and postulate potential mechanisms by which eTACs may regulate this process.
    Keywords:  Aire; eTAC; extrathymic; tolerance
    DOI:  https://doi.org/10.1111/imr.13082
  8. Nat Commun. 2022 May 10. 13(1): 2414
    Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy.
    Smriti Prasad, Erkan Kalafat, Helena Blakeway, Rosemary Townsend, Pat O'Brien, Edward Morris, Tim Draycott, Shakila Thangaratinam, Kirsty Le Doare, Shamez Ladhani, Peter von Dadelszen, Laura A Magee, Paul Heath, Asma Khalil.
      Safety and effectiveness of COVID-19 vaccines during pregnancy is a particular concern affecting vaccination uptake by this vulnerable group. Here we evaluated evidence from 23 studies including 117,552 COVID-19 vaccinated pregnant people, almost exclusively with mRNA vaccines. We show that the effectiveness of mRNA vaccination against RT-PCR confirmed SARS-CoV-2 infection 7 days after second dose was 89·5% (95% CI 69·0-96·4%, 18,828 vaccinated pregnant people, I2 = 73·9%). The risk of stillbirth was significantly lower in the vaccinated cohort by 15% (pooled OR 0·85; 95% CI 0·73-0·99, 66,067 vaccinated vs. 424,624 unvaccinated, I2 = 93·9%). There was no evidence of a higher risk of adverse outcomes including miscarriage, earlier gestation at birth, placental abruption, pulmonary embolism, postpartum haemorrhage, maternal death, intensive care unit admission, lower birthweight Z-score, or neonatal intensive care unit admission (p > 0.05 for all). COVID-19 mRNA vaccination in pregnancy appears to be safe and is associated with a reduction in stillbirth.
    DOI:  https://doi.org/10.1038/s41467-022-30052-w
  9. Am J Reprod Immunol. 2022 May 14.
    PD-1 Mediates Decidual γδ T Cells Cytotoxicity During Recurrent Pregnancy Loss.
    Rong Guo, Silin Jiang, Jianliang Zhang, Quanli Yang, Liang Gao, Wei Xia, Lingxia Tong, Peiran Feng, Yan Xu, Tao Zhang, Hao Cheng, CuiPing Liu, Xueguang Zhang, Zhinan Yin, Hong Zhang.
      PROBLEM: Recurrent pregnancy loss (RPL) is one of the big challenges of normal pregnancy. Immune dysregulation has been proposed for the key underline mechanisms of RPL. However, the essential roles of T cells, especially γδ T cells, have not been defined.METHOD OF STUDY: Decidua were obtained from normal pregnancy women or recurrent pregnancy loss patients and the surface molecules of γδ T cells in decidua were evaluated via flow cytometric analysis. The expression of PD-1 in clinical samples was analyzed by immunohistochemistry assay. The intracellular cytokines of decidual PD-1+ and PD-1- γδ T cells were evaluated by flow cytometric analysis. The cytotoxicity of PD-1- γδ T cells were confirmed via an in vitro co-culture experiment. The specific inhibitors for Erk, p38 and JNK against the MAPK pathway were added to the co-culture media to evaluate the functions of the Erk, p38 and JNK.
    RESULTS: We demonstrated that PD-1 was significantly decreased on decidual tissue γδ T cells of patients with RPL, resulting in the enhanced cytotoxicity of γδ T cells against trophoblasts. We further elucidated an Erk-dependent TNF-α production mediates the γδ T cell cytotoxicity against the trophoblast cells. Finally, the reduced expression of PD-L1 in the villi tissues of patients with RPL might be the cause of the reduction of PD-1 on the tissue γδ T cells.
    CONCLUSION: Our study uncovers an important role of PD-1 expression on decidual γδ T cells in maintaining the normal pregnancy, and may provide a new strategy for immune therapy against RPL. This article is protected by copyright. All rights reserved.
    Keywords:  Dedidua; PD-1; Recurrent Pregnancy Loss (RPL); TNF-α; Trophoblast; γδ T cells
    DOI:  https://doi.org/10.1111/aji.13562
  10. Sci Rep. 2022 May 13. 12(1): 7926
    The vaginal microbiome and the risk of preterm birth: a systematic review and network meta-analysis.
    Unnur Gudnadottir, Justine W Debelius, Juan Du, Luisa W Hugerth, Hanna Danielsson, Ina Schuppe-Koistinen, Emma Fransson, Nele Brusselaers.
      Preterm birth is a major cause of neonatal morbidity and mortality worldwide. Increasing evidence links the vaginal microbiome to the risk of spontaneous preterm labour that leads to preterm birth. The aim of this systematic review and network meta-analysis was to investigate the association between the vaginal microbiome, defined as community state types (CSTs, i.e. dominance of specific lactobacilli spp, or not (low-lactobacilli)), and the risk of preterm birth. Systematic review using PubMed, Web of Science, Embase and Cochrane library was performed. Longitudinal studies using culture-independent methods categorizing the vaginal microbiome in at least three different CSTs to assess the risk of preterm birth were included. A (network) meta-analysis was conducted, presenting pooled odds ratios (OR) and 95% confidence intervals (CI); and weighted proportions and 95% CI. All 17 studies were published between 2014 and 2021 and included 38-539 pregnancies and 8-107 preterm births. Women presenting with "low-lactobacilli" vaginal microbiome were at increased risk (OR 1.69, 95% CI 1.15-2.49) for delivering preterm compared to Lactobacillus crispatus dominant women. Our network meta-analysis supports the microbiome being predictive of preterm birth, where low abundance of lactobacilli is associated with the highest risk, and L. crispatus dominance the lowest.
    DOI:  https://doi.org/10.1038/s41598-022-12007-9
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