bims-reprim 2021-10-17 papers

bims-reprim

Biomed News

on Reproductive immunology

Issue of 2021‒10‒17
seven papers selected by
Iva Filipovic
Karolinska Institutet

Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth.
TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells.
Expression of Sex Hormone Receptor and Immune Response Genes in Peripheral Blood Mononuclear Cells During the Menstrual Cycle.
The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes and preterm birth and neonatal mortality in mice†.
The identification of endometrial immune cell densities and clustering analysis in the mid-luteal phase as predictor for pregnancy outcomes after IVF-ET treatment.
Seroprevalence of SARS-CoV-2 immunoglobulins in pregnant women and neonatal cord blood from a highly impacted region.
Uterus transplantation: the importance of uterine natural killer cells.

Nat Commun. 2021 Oct 13. 12(1): 5967

Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth.

Pamela Pruski, Gonçalo D S Correia, Holly V Lewis, Katia Capuccini, Paolo Inglese, Denise Chan, Richard G Brown, Lindsay Kindinger, Yun S Lee, Ann Smith, Julian Marchesi, Julie A K McDonald, Simon Cameron, Kate Alexander-Hardiman, Anna L David, Sarah J Stock, Jane E Norman, Vasso Terzidou, T G Teoh, Lynne Sykes, Phillip R Bennett, Zoltan Takats, David A MacIntyre.

The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n = 160; 455 swabs; VMET II, n = 205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics.

DOI: https://doi.org/10.1038/s41467-021-26215-w
Cancers (Basel). 2021 Oct 01. pii: 4955. [Epub ahead of print]13(19):

TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells.

Adriana Albini, Matteo Gallazzi, Maria Teresa Palano, Valentina Carlini, Riccardo Ricotta, Antonino Bruno, William G Stetler-Stevenson, Douglas M Noonan.

  Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56bright, CD16-, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP's new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic-therapeutic roles.

Keywords:  Natural Killer cells; TGFβ; TIMP-1; TIMP-2; angiogenesis; cancer; decidual-NK cells; inflammation; innate immunity; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13194955
Front Endocrinol (Lausanne). 2021 ;12 721813

Expression of Sex Hormone Receptor and Immune Response Genes in Peripheral Blood Mononuclear Cells During the Menstrual Cycle.

Peik M A Brundin, Britt-Marie Landgren, Peter Fjällström, Mohamed M Shamekh, Jan-Åke Gustafsson, Anders F Johansson, Ivan Nalvarte.

  Sex hormones are known to interact with the immune system on multiple levels but information on the types of sex hormone receptors (SHR) and their expression levels in immune cells is scarce. Estrogen, testosterone and progesterone are all considered to interact with the immune system through their respective cell receptors (ERα and ERβ including the splice variant ERβ2, AR and PGR). In this study expression levels of SHR genes in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4+ and CD8+ T-cells, CD56+ NK-cells, CD14+ monocytes and CD19+ B-cells) were analyzed using standard manual qPCR or a qPCR array (TLDA). Nine healthy individuals including men (n = 2), premenopausal (Pre-MP, n = 5) and postmenopausal (post-MP, n = 2) women were sampled for PBMCs which were separated to cell subsets using FACS. Ten Pre-MP women were longitudinally sampled for total PBMCs at different phases of the menstrual cycle. We found that ERα was most abundant and, unexpectedly, that ERβ2 was the dominant ERβ variant in several FACS sorted cell subsets. In total PBMCs, SHR (ERα, ERβ1, ERβ2, and AR) expression did not fluctuate according to the phase of the menstrual cycle and PGR was not expressed. However, several immune response genes (GATA3, IFNG, IL1B, LTA, NFKB1, PDCD1, STAT3, STAT5A, TBX21, TGFB1, TNFA) were more expressed during the ovulatory and mid-luteal phases. Sex hormone levels did not correlate significantly with gene expression of SHR or immune response genes, but sex hormone-binding globulin (SHBG), a steroid hormone transporting protein, was positively correlated to expression of ERβ1 gene. This study provides new insights in the distribution of ERs in immune cells. Furthermore, expression patterns of several immune response genes differ significantly between phases of the menstrual cycle, supporting a role for sex hormones in the immune response.

Keywords:  estrogen; estrogen receptor; immune response; menstrual cycle; progesterone; sex hormone

DOI:  https://doi.org/10.3389/fendo.2021.721813
Biol Reprod. 2021 Oct 11. pii: ioab188. [Epub ahead of print]

The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes and preterm birth and neonatal mortality in mice†.

Kenichiro Motomura, Roberto Romero, Olesya Plazyo, Valeria Garcia-Flores, Meyer Gershater, Jose Galaz, Derek Miller, Nardhy Gomez-Lopez.

  Sterile inflammation is triggered by danger signals or alarmins released upon cellular stress or necrosis. Sterile inflammation occurring in the amniotic cavity (i.e. sterile intra-amniotic inflammation) is frequently observed in women with spontaneous preterm labor resulting in preterm birth, the leading cause of neonatal morbidity and mortality worldwide, and is associated with increased amniotic fluid concentrations of alarmins. However, the mechanisms whereby alarmins induce sterile intra-amniotic inflammation are still under investigation. Herein, we investigated the mechanisms whereby the alarmin S100A12 induces inflammation of the human chorioamniotic membranes in vitro and used a mouse model to establish a causal link between this alarmin and adverse perinatal outcomes. We report that S100A12 initiates sterile inflammation in the chorioamniotic membranes by upregulating the expression of inflammatory mediators such as pro-inflammatory cytokines and pattern recognition receptors. Importantly, S100A12 induced the priming and activation of inflammasomes, resulting in the activation of caspase-1 and the subsequent release of mature IL-1β by the chorioamniotic membranes. This alarmin also caused the activation of the chorioamniotic membranes by promoting MMP-2 activity and collagen degradation. Lastly, the ultrasound-guided intra-amniotic injection of S100A12 at specific concentrations observed in the majority of women with sterile intra-amniotic inflammation induced preterm birth (rates: 17% at 200 ng/sac; 25% at 300 ng/sac; 25% at 400 ng/sac) and neonatal mortality (rates: 22% at 200 ng/sac; 44% at 300 ng/sac; 31% at 400 ng/sac), demonstrating a causal link between this alarmin and adverse perinatal outcomes. Collectively, our findings shed light on the inflammatory responses driven by alarmins in the chorioamniotic membranes, providing insight into the immune mechanisms leading to preterm birth in women with sterile intra-amniotic inflammation.

Keywords:  Amniotic cavity; NLRP3; calgranulin C; caspase-1; chorioamnionitis; decidua; fetal membranes; funisitis; inflammasome; interleukin-1β; matrix metalloproteinase-2; pregnancy

DOI:  https://doi.org/10.1093/biolre/ioab188
J Reprod Immunol. 2021 Oct 05. pii: S0165-0378(21)00161-3. [Epub ahead of print]148 103431

The identification of endometrial immune cell densities and clustering analysis in the mid-luteal phase as predictor for pregnancy outcomes after IVF-ET treatment.

Yiwei Zhao, Gene Chi Wai Man, Ji Wang, Yingyu Liu, Joseph Kwong, Tao Zhang, Jacqueline Pui Wah Chung, Chi Chiu Wang, Xiaoyan Chen, Tin-Chiu Li.

  Changes in endometrial immune cell density has been reported to be associated with reproductive failure. The prognostic value of endometrial immune cell density measurement remains uncertain. We aimed to investigate the prognostic value of endometrial immune cells measurement on pregnancy outcome after IVF in women. In this prospective study, one hundred twenty-eight women underwent endometrial sampling in a natural cycle preceding single frozen-thawed embryo transfer (ET). Endometrial biopsy was obtained precisely 7 days after luteinizing hormone surge (LH + 7). Multiplex immunohistochemical method was employed to simultaneously stain the endometrium samples with a panel of human antibodies against CD56 for uterine natural killer (uNK) cells, CD3 and CD8 for T cell, CD3 for pan T cells and CD68 for macrophages. The density of the various immune cells and the clustering levels between them were measured. ET was performed at the blastocyst stage. Women who did not conceive had a significantly higher density of uNK cells and higher clustering level between uNK cells-and-macrophages than women who did conceive. In accordance, the prognostic value of uNK measurement on pregnancy outcome was significantly improved when combined with uNK-to-macrophage clustering analysis simultaneously. Taken together, our results suggested that uNK cells density and clustering level between uNK cells-and macrophages may be a promising predictor for successful implantation after IVF-ET.

Keywords:  Endometrium; Immune cells clustering level; Multiplex immunohistochemical staining; Prognostic value

DOI:  https://doi.org/10.1016/j.jri.2021.103431
Placenta. 2021 Oct 06. pii: S0143-4004(21)00610-X. [Epub ahead of print]115 146-150

Seroprevalence of SARS-CoV-2 immunoglobulins in pregnant women and neonatal cord blood from a highly impacted region.

Hector Zambrano, Ketty Anchundia, Dalila Aviles, Ruffo Andaluz, Nathaly Calderon, Estefanie Torres, Nicolas Gonzalez-Granda, Anthony Maxwell, Kang Chen, Bernard Gonik, Gil Mor.

  There is inadequate screening for SARS-COV-2 during pregnancy. We aimed to determine the impact of maternal and neonatal cord blood SARS-COV-2 antibodies and placental transfer ratios in a region with a low screening plan. We performed a blind study in one of the SARS-CoV-2 epicenters in South America. 32% of pregnant women were serological positive. Importantly, there is an efficient passive immunization of the fetus to SARS-CoV-2. We report high incidence of SARS-CoV-2 infection during pregnancy, which is higher than officially reported. Therefore the need of active immunization to enhance maternal protection and fetal passive immunization.

Keywords:  IgG; IgM; Placenta; Pregnancy; SARS-COV-2

DOI:  https://doi.org/10.1016/j.placenta.2021.10.001
Curr Opin Organ Transplant. 2021 Oct 13.

Uterus transplantation: the importance of uterine natural killer cells.

Aaron C K Lucander, Paige M Porrett.

PURPOSE OF REVIEW: Murine studies have established that uterine natural killer (uNK) cells are critical regulators of normal placentation and fetal development in mammals. However, the biology of uNK cells in humans remains poorly understood. This ignorance represents a costly knowledge gap, as disordered placentation is thought to underpin a variety of pregnancy complications that impact maternal and neonatal health. In the context of uterus transplantation (UTx), uNK cells are anticipated to play a critical role within the allograft. Here, we review the current understanding of uNK cells in pregnancy biology and explore how this critically important cell population may contribute to pregnancy and graft outcomes in uterus transplant recipients.RECENT FINDINGS: Recent studies have characterized differences in NK cell populations between anatomic compartments in humans. In the endometrium, at least five phenotypically and functionally distinct subpopulations of uNK cells have been identified, with research into mechanisms regulating their differentiation and function currently underway.
SUMMARY: Further elucidating uNK cell biology has the potential to influence the outcomes of pregnancy and UTx and benefit human health. UTx is a unique opportunity to study uNK cell biology and may shed light on mechanisms by which immunological tolerance is established at the maternal-fetal interface.

DOI: https://doi.org/10.1097/MOT.0000000000000928