bims-reprim 2020-11-01 papers

bims-reprim

Biomed News

on Reproductive immunology

Issue of 2020–11–01
eightteen papers selected by
Iva Filipovic, Karolinska Institutet

Innate Immune Responses to Acute Viral Infection During Pregnancy.
Viral-Immune Cell Interactions at the Maternal-Fetal Interface in Human Pregnancy.
Newly characterized decidual Tim-3+ Treg cells are abundant during early pregnancy and driven by IL-27 coordinately with Gal-9 from trophoblasts.
Increased Peripheral NKG2A-NKG2D+CD3-CD16+CD56dim NK Cell Subset Was Positively Correlated with Antiphospholipid Antibodies in Patients of Obstetric Antiphospholipid Syndrome.
Single-cell expression profiles of ACE2 and TMPRSS2 reveals potential vertical transmission and fetus infection of SARS-CoV-2.
Single Cell Transcriptome Research in Human Placenta.
Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies.
Pregnancy Alters Innate and Adaptive Immune Responses to Zika Virus Infection in the Reproductive Tract.
Intrauterine Growth Restriction Is Associated with Unique Features of the Reproductive Microbiome.
Characterizing the endometrial fluid cytokine profile in women with endometriosis.
The presence and role of hypoxia in the endometrium.
Prospective association of maternal immune proinflammatory responsivity and regulation in pregnancy with length of gestation.
Placental macrophages: Origin, heterogeneity, function and role in pregnancy-associated infections.
Sex Specific Expression of Interleukin 7, 8 and 15 in Placentas of Women with Gestational Diabetes.
Circulating CD56+ NKG2D+ NK cells and postoperative fertility in ovarian endometrioma.
Vaginal Microbiome in Preterm Rupture of Membranes.
Role of inflammation in virus pathogenesis during pregnancy.
Modeling ascending infection with a feto-maternal interface organ-on-chip.

Front Immunol. 2020 ;11 572567

Innate Immune Responses to Acute Viral Infection During Pregnancy.

Emily F Cornish, Iva Filipovic, Fredrika Åsenius, David J Williams, Thomas McDonnell.

  Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.

Keywords:  Ebola virus; Lassa virus; dengue virus; emerging coronavirus; hepatitis E; influenza virus; innate antiviral immunity; pregnancy

DOI:  https://doi.org/10.3389/fimmu.2020.572567
Front Immunol. 2020 ;11 522047

Viral-Immune Cell Interactions at the Maternal-Fetal Interface in Human Pregnancy.

Elaine L Parker, Rachel B Silverstein, Sonam Verma, Indira U Mysorekar.

  The human decidua and placenta form a distinct environment distinguished for its promotion of immunotolerance to infiltrating semiallogeneic trophoblast cells to enable successful pregnancy. The maternal-fetal interface also successfully precludes transmission of most pathogens. This barrier function occurs in conjunction with a diverse influx of decidual immune cells including natural killer cells, macrophages and T cells. However, several viruses, among other microorganisms, manage to escape destruction by the host adaptive and innate immune system, leading to congenital infection and adverse pregnancy outcomes. In this review, we describe mechanisms of pathogenicity of two such viral pathogens, Human cytomegalovirus (HCMV) and Zika virus (ZIKV) at the maternal-fetal interface. Host decidual immune cell responses to these specific pathogens will be considered, along with their interactions with other cell types and the ways in which these immune cells may both facilitate and limit infection at different stages of pregnancy. Neither HCMV nor ZIKV naturally infect commonly used animal models [e.g., mice] which makes it challenging to understand disease pathogenesis. Here, we will highlight new approaches using placenta-on-a-chip and organoids models that are providing functional and physiologically relevant ways to study viral-host interaction at the maternal-fetal interface.

Keywords:  Hofbauer cell; NK cells; T cells; decidua; human cytomegalovirus; macrophages; placenta; pregnancy

DOI:  https://doi.org/10.3389/fimmu.2020.522047
Hum Reprod. 2020 Oct 24. pii: deaa223. [Epub ahead of print]

Newly characterized decidual Tim-3+ Treg cells are abundant during early pregnancy and driven by IL-27 coordinately with Gal-9 from trophoblasts.

Xiaohui Hu, Qian Zhu, Yan Wang, Liling Wang, Zhihui Li, Gil Mor, Aihua Liao.

   STUDY QUESTION: What is the mechanism of Tim-3+ regulatory T (Treg)-cell accumulation in the decidua during early pregnancy and is its disruption associated with recurrent pregnancy loss (RPL)?
SUMMARY ANSWER: IL-27 and Gal-9 secreted by trophoblasts activate the Tim-3 signaling pathway in CD4+ T cells and Treg cells and so promote accumulation of Tim-3+ Treg cells, the abnormal expression of IL-27 and Gal-9 is associated with impaired immunologic tolerance in RPL patients.
WHAT IS KNOWN ALREADY: Tim-3+ Treg cells are better suppressors of Teff cell proliferation, and display higher proliferative activity than Tim-3- Treg cells. Tim-3+ Treg cells are tissue-specific promoters of T-cell dysfunction in many tumors. These cells express a unique factor that influences and shapes the tumor microenvironment.
STUDY DESIGN, SIZE, DURATION: The animal study included 80 normal pregnant mice. In human study, decidua tissues in the first trimester for flow cytometry analysis were collected from 32 normal pregnant women and 23 RPL patients. Placenta tissues for immunohistochemistry analysis were collected from 15 normal pregnant women. Placenta tissues for western blot analysis were collected from 5 normal pregnant women, 5 RPL patients and 5 women who have experienced one miscarriage. Blood samples for in vitro experiments were collected from 30 normal pregnant women. This study was performed between January 2017 and March 2019.
PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we investigated the kinetics of Tim-3+ CD4+ T-cell accumulation, and the proportions of Tim-3+ Treg cells throughout murine pregnancies using flow cytometry. We compared Tim-3 expression on decidual CD4+ T cells and Treg cells during normal pregnancies with expression on the same cell populations in women suffering from RPL. IL-27 and Gal-9 transcription and protein expression in the placenta were determined by RT-PCR and western blot, respectively. An in vitro co-culture model consisting of peripheral CD4+ T cells and primary trophoblasts from early pregnancy was used to mimic the maternal-fetal environment.
MAIN RESULTS AND THE ROLE OF CHANCE: The percentage of Tim-3+ Treg cells present in mouse uteri fluctuates as gestation proceeds but does not change in the spleen. Levels of Tim3+ Treg cells in uteri peaked at pregnancy Day 6.5 (E 6.5), then progressively diminished, and fell to non-pregnant levels by E18.5. In pregnant mice, Tim-3+ Treg cells constituted 40-70% of Treg cells in uteri but were present at much lower abundance in spleens. About 60% of decidual Treg cells were Tim-3 positive at E6.5. Of these decidual Tim3+ Treg cells, nearly 90% were PD-1 positive. However, only about 16% of Tim3- Treg cells expressed PD-1. Blocking the Tim-3 signaling pathway decreased the proportion of Treg cells and led to embryo resorption. Moreover, much lower Tim-3 expression was observed on CD4+ T cells and Treg cells in women who had suffered from RPL at 6-9 gestational weeks compared with those who had normal pregnancies at matched gestations. In a normal pregnancy, Tim-3 expression on decidual CD4+ T cells is induced initially by IL-27. Then Gal-9-Tim-3 interaction promotes differentiation of decidual Tim-3+ CD4+ T cells into Treg cells. IL-27 and Gal-9 cooperatively induced Tim-3+ Treg cells in vitro.
LARGE SCALE DATA: N/A.
LIMITATIONS, REASONS FOR CAUTION: We did not investigate the kinetics of human decidual Tim-3+ CD4+ T and Tim-3+ Treg cell populations throughout pregnancy due to limited availability of second and third trimester decidua. In addition, functional suppressive data on the decidual Tim-3+ Treg cells are lacking due to limited and low quantities of these cells in decidua.
WIDER IMPLICATIONS OF THE FINDINGS: These findings might have therapeutic clinical implications in RPL.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the National Natural Science Foundation of China (No. 81871186) and National Key Research & Developmental Program of China (2018YFC1003900, 2018YFC1003904). The authors declare no conflict of interest.

Keywords:  PD-1; Tim-3; Treg cells; decidua; early pregnancy; galectin-9; interleukin 27; maternal–fetal interface; recurrent pregnancy loss; trophoblasts

DOI:  https://doi.org/10.1093/humrep/deaa223
Immunol Invest. 2020 Oct 26. 1-14

Increased Peripheral NKG2A-NKG2D+CD3-CD16+CD56dim NK Cell Subset Was Positively Correlated with Antiphospholipid Antibodies in Patients of Obstetric Antiphospholipid Syndrome.

Yinmei Zhang, Yang Zhao, Wenzhe Si, Boxin Yang, Mingmei Lin, Jiajia Zheng, Liyan Cui.

  Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder with severe life-threatening complications shown during pregnancy. It has been reported that the increase in CD16+CD56dim natural killer (NK) cells in peripheral blood are risk factors for recurrent miscarriages, but this expression of CD16+CD56dim NK cells in OAPS patients has not been reported, and the mechanism is not clearly illustrated. In this study, we compared the distributional profiles of different NK cell subsets and the expressions of NK cell-activating receptors in peripheral blood of patients with OAPS and healthy women. Our results showed significantly increased NKG2A-NKG2D+ subset and decreased NKG2A+NKG2D- subset in CD3- CD16+CD56dim NK cells, CD3-CD16-CD56bright NK cells and CD56+T cells in OAPS patients compared with those in healthy control women. The CD27-CD11b+ subset significantly increased in CD3-CD16+CD56dim NK cells in OAPS patients compared with those in healthy control women. In addition, the NKG2A-NKG2D+ subset in CD3-CD16 + CD56dim NK subset in triple positivity was higher than single positivity OAPS patients. At the optimal diagnostic threshold established by ROC analysis, using the cut-off of NKG2A-NKG2D+ and CD27-CD11b+ subset in CD3-CD16+CD56dim NK cells is 10.10% and 92.75%, the sensitivity of NKG2A-NKG2D+ and CD27-CD11b+ to detect patients with OAPS compared with healthy control results was 94.1% and 60.8%, and specificity was 84.2% and 89.5%, respectively, with an area under the curve (AUC) of 0.903 and 0.829, respectively. The NKG2A-NKG2D+ subset in CD3-CD16+CD56dim NK cells was positively correlated with the antiphospholipid antibodies lg anti-aCL IgG, lg anti-aCL IgM, lg anti-aCL IgA, lg anti-β2GP1 IgM and Complement 4(C4), while the CD27+CD11b+ subset in CD3-CD16 + CD56dim NK cells was correlated with lg anti-β2GP1 IgG and lg anti-β2GP1 IgA. These results suggested that the NK cytotoxic function enhanced in OAPS patients and unbalanced of NK activating receptors and inhibiting receptors may contribute to the immune pathogenesis of OAPS.

Keywords:  CD11b; CD27; CD3−CD16+CD56dim NK cells; NKG2A; NKG2D; Obstetric antiphospholipid syndrome

DOI:  https://doi.org/10.1080/08820139.2020.1835949
Aging (Albany NY). 2020 Oct 26. 12

Single-cell expression profiles of ACE2 and TMPRSS2 reveals potential vertical transmission and fetus infection of SARS-CoV-2.

Mengdie Lü, Li Qiu, Guangshuai Jia, Rongqun Guo, Qibin Leng.

  Morbidity and mortality of coronavirus disease 2019 (COVID-19) is age-dependent. It remains unclear whether vertical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs during pregnancy and how such infection will affect fetal development. Here, we performed single-cell transcriptomic analysis of placenta and other tissues from fetuses in comparison with those from adults using public-available datasets. Our analysis revealed that a very small proportion of trophoblast cells expressed the Angiotensin I Converting Enzyme 2 (ACE2) gene, suggesting a low possibility of vertical transmission of SARS-CoV-2 from mother to fetus during pregnancy. We found that the fetal adrenal gland, heart, kidney and stomach were susceptible to SARS-CoV-2 infection, because these organs contained cell clusters that expressed high levels of the ACE2 gene. In particular, a higher proportion of ACE2-expressing cell clusters in the adrenal gland and kidney also expressed the Transmembrane Serine Protease 2 (TMPRSS2) gene compared with other organs. Surprisingly, ACE2-expressing type II alveolar (AT2) equivalent cells were absent in fetal lungs. This is in sharp contrast to adult lungs. As ACE2 expression is regulated by various conditions, including oxygen concentration, inflammation and smoking, caution is warranted to avoid triggering potential ACE2 expression in fetal and placental tissue.

Keywords:  COVID-19; SARS-CoV-2; fetus; pathogenesis; placenta

DOI:  https://doi.org/10.18632/aging.104015
Reproduction. 2020 Sep 01. pii: REP-20-0231.R2. [Epub ahead of print]

Single Cell Transcriptome Research in Human Placenta.

Hui Li, Qianhui Huang, Yu Liu, Lana X Garmire.

Human placenta is a complex and heterogeneous organ interfacing between the mother and the fetus that supports fetal development. Alterations to placental structural components are associated with various pregnancy complications. To reveal the heterogeneity among various placenta cell types in normal and diseased placentas, as well as elucidate molecular interactions within a population of placental cells, a new genomics technology called single cell RNA-Seq (or scRNA-seq) has been employed in the last couple of years. Here we review the principles of scRNA-seq technology, and summarize the recent human placenta studies at scRNA-seq level across gestational ages as well as in pregnancy complications such as preterm birth and preeclampsia. We list the computational analysis platforms and resources available for the public use. Lastly, we discuss the future areas of interest for placenta single cell studies, as well as the data analytics needed to accomplish them.

DOI: https://doi.org/10.1530/REP-20-0231
Front Immunol. 2020 ;11 564712

Cholesterol Crystals and NLRP3 Mediated Inflammation in the Uterine Wall Decidua in Normal and Preeclamptic Pregnancies.

Gabriela Brettas Silva, Lobke Marijn Gierman, Johanne Johnsen Rakner, Guro Sannerud Stødle, Siv Boon Mundal, Astrid Josefin Thaning, Bjørnar Sporsheim, Mattijs Elschot, Karin Collett, Line Bjørge, Marie Hjelmseth Aune, Liv Cecilie Vestrheim Thomsen, Ann-Charlotte Iversen.

  Preeclampsia is a hypertensive and inflammatory pregnancy disorder associated with cholesterol accumulation and inflammation at the maternal-fetal interface. Preeclampsia can be complicated with fetal growth restriction (FGR) and shares risk factors and pathophysiological mechanisms with cardiovascular disease. Cholesterol crystal mediated NLRP3 inflammasome activation is central to cardiovascular disease and the pathway has been implicated in placental inflammation in preeclampsia. Direct maternal-fetal interaction occurs both in the uterine wall decidua and at the placental surface and these aligned sites constitute the maternal-fetal interface. This study aimed to investigate cholesterol crystal accumulation and NLRP3 inflammasome expression by maternal and fetal cells in the uterine wall decidua of normal and preeclamptic pregnancies. Pregnant women with normal (n = 43) and preeclamptic pregnancies with (n = 28) and without (n = 19) FGR were included at delivery. Cholesterol crystals were imaged in decidual tissue by both second harmonic generation microscopy and polarization filter reflected light microscopy. Quantitative expression analysis of NLRP3, IL-1β and cell markers was performed by immunohistochemistry and automated image processing. Functional NLRP3 activation was assessed in cultured decidual explants. Cholesterol crystals were identified in decidual tissue, both in the tissue stroma and near uterine vessels. The cholesterol crystals in decidua varied between pregnancies in distribution and cluster size. Decidual expression of the inflammasome components NLRP3 and IL-1β was located to fetal trophoblasts and maternal leukocytes and was strongest in areas of proximity between these cell types. Pathway functionality was confirmed by cholesterol crystal activation of IL-1β in cultured decidual explants. Preeclampsia without FGR was associated with increased trophoblast dependent NLRP3 and IL-1β expression, particularly in the decidual areas of trophoblast and leukocyte proximity. Our findings suggest that decidual accumulation of cholesterol crystals may activate the NLRP3 inflammasome and contribute to decidual inflammation and that this pathway is strengthened in areas with close maternal-fetal interaction in preeclampsia without FGR.

Keywords:  IL-1β; NLRP3 inflammasome; cholesterol crystals; decidua; fetal growth restriction; inflammation; placenta; preeclampsia

DOI:  https://doi.org/10.3389/fimmu.2020.564712
J Immunol. 2020 Oct 30. pii: ji2000882. [Epub ahead of print]

Pregnancy Alters Innate and Adaptive Immune Responses to Zika Virus Infection in the Reproductive Tract.

Kelsey E Lesteberg, Dana S Fader, J David Beckham.

Recent outbreaks of Zika virus (ZIKV) have been associated with birth defects, including microcephaly and neurologic impairment. However, the mechanisms that confer potential susceptibility to ZIKV during pregnancy remain unclear. We hypothesized that poor outcomes from ZIKV infection during pregnancy are due in part to pregnancy-induced alteration of innate immune cell frequencies and cytokine expression. To examine the impact of pregnancy on innate immune responses, we inoculated immunocompetent pregnant and nonpregnant female C57BL/6 mice with 5 × 105 focus-forming units of ZIKV intravaginally. Innate immune cell frequencies and cytokine expression were measured by flow cytometry at day 3 postinfection. Compared with nonpregnant mice, pregnant mice exhibited higher frequencies of uterine macrophages (CD68+) and CD11c+ CD103+ and CD11c+ CD11b+ dendritic cells. Additionally, ZIKV-infected pregnant mice had lower frequencies of CD45+ IL-12+ and CD11b+ IL-12+ cells in the uterus and spleen. Next, we measured the frequencies of Ag-experienced CD4 (CD4+ CD11a+ CD49d+) and CD8 (CD8lo CD11ahi) T cells at day 10 postinfection to determine the impact of pregnancy-associated changes in innate cellular IL-12 responses on the adaptive immune response. We found that pregnant mice had lower frequencies of uterine Ag-experienced CD4 T cells and ZIKV-infected pregnant mice had lower frequencies of uterine Ag-experienced CD8 T cells compared with ZIKV-infected nonpregnant mice. These data show that pregnancy results in altered innate and adaptive immune responses to ZIKV infection in the reproductive tract of mice and that pregnancy-associated immune modulation may play an important role in the severity of acute ZIKV infection.

DOI: https://doi.org/10.4049/jimmunol.2000882
Reprod Sci. 2020 Oct 26.

Intrauterine Growth Restriction Is Associated with Unique Features of the Reproductive Microbiome.

Jianzhong Hu, Paula Benny, Michelle Wang, Yula Ma, Luca Lambertini, Inga Peter, Yajuan Xu, Men-Jean Lee.

  Intrauterine growth restriction (IUGR) is an obstetrical complication with an increased risk of perinatal mortality and morbidity. The uterus, once considered to be a sterile environment, has now been described in recent microbiome studies to harbor diverse commensal placenta microbiota, as well as potentially pathogenic flora known to cause infection. Therefore, in this pilot study, we tested whether IUGR was associated with changes to the reproductive microbiome. The reproductive microbiome was surveyed using 16S sequencing (20 IUGR, 20 controls). Alpha and beta diversity were compared, and differential taxa features associated with IUGR were identified. Microbial screening of the placenta demonstrated a diverse range of flora predominantly including Proteobacteria, Fusobacteria, Firmicutes, and Bacteroidetes. Neither alpha- nor beta-diversity was significantly different by IUGR status. However, at the taxa level, IUGR patients had significantly higher prevalence of Neisseriaceae, mucosal β-hemolytic bacteria known to uptake iron-bound host proteins including hemoglobin. Moreover, the increase in anaerobic bacteria such as Desulfovibrio reflects the emergence of a hypoxic environment in the IUGR placenta. Further analysis of the reproductive microbiome of IUGR samples showed lower levels of H202-producing Bifidobacterium and Lactobacillus that switch from respiration to fermentation, a less energetic metabolic process, when oxygen levels decrease. Source tracking analysis showed that the placental microbial contents were predominantly contributed from an oral source, as compared to a gut or vaginal source. Our results suggest that the reproductive microbiome profiles may, in the future, constitute potential biomarkers for fetal health during pregnancy, while Neisseriaceae may constitute promising therapeutic targets for IUGR treatment.

Keywords:  16S; Intrauterine growth restriction; Microbiome; Placenta; Pregnancy

DOI:  https://doi.org/10.1007/s43032-020-00374-5
J Assist Reprod Genet. 2020 Oct 30.

Characterizing the endometrial fluid cytokine profile in women with endometriosis.

Natalia C Llarena, Elliott G Richards, Anju Priyadarshini, David Fletcher, Tracey Bonfield, Rebecca L Flyckt.

   PURPOSE: To compare growth factor and cytokine profiles in the endometrial secretions of patients with and without endometriosis to determine whether a particular protein profile is predictive of the disease.
METHODS: Patients undergoing laparoscopic gynecologic surgery for benign indications were recruited for this prospective cohort study. Prior to surgery, endometrial fluid was aspirated and multiplex immunoassay was used to quantify 7 cytokines and growth factors. During surgery, each patient was staged according to the ASRM staging system for endometriosis. Cytokines and growth factors were evaluated using the Mann-Whitney and Kruskal-Wallis tests. Combinations of cytokines were evaluated using logistic regression analysis, and ROC curves were generated to evaluate the predictive capacity of the assay.
RESULTS: Endometrial secretions were analyzed from 60 patients. Nineteen had stage 3-4 endometriosis, 19 had stage 1-2 disease, and 22 had no endometriosis. There were no significant differences between controls and stage 1-2 endometriosis; however, levels of IL-1α and IL-6 were significantly increased in women with moderate-to-severe disease. A combination of IL-1α, IL-1β, and IL-6 in endometrial secretions predicts stage 3-4 endometriosis with an AUC of 0.78. A threshold value of 118 pg/mL yields a sensitivity of 75% and specificity of 70%.
CONCLUSION: Aspiration of endometrial fluid is a safe and effective approach for evaluating the endometrial profile of women with endometriosis. Women with moderate-to-severe endometriosis demonstrate a distinct cytokine profile compared to controls. A combination of IL-1α, IL-1β, and IL-6 in the endometrial secretions is predictive of stage 3-4 endometriosis, but is not predictive of minimal-to-mild disease.

Keywords:  Cytokines; Endometrial fluid profiling; Endometriosis; Endometrium

DOI:  https://doi.org/10.1007/s10815-020-01989-y
Reproduction. 2020 Aug 01. pii: REP-20-0268.R1. [Epub ahead of print]

The presence and role of hypoxia in the endometrium.

Rocío Martínez-Aguilar, Lucy E Kershaw, Jane J Reavey, Hilary O D Critchley, Jacqueline A Maybin.

The endometrium is a multicellular tissue that is exquisitely responsive to the ovarian hormones. The local mechanisms of endometrial regulation to ensure optimal function are less well characterised. Transient physiological hypoxia has been proposed as a critical regulator of endometrial function. Herein, we review the literature on hypoxia in the non-pregnant endometrium. We discuss the pros and cons of animal models, human laboratory studies and novel in vivo imaging for the study of endometrial hypoxia. These research tools provide mounting evidence of a transient hypoxic episode in the menstrual endometrium and suggest that endometrial hypoxia may be present at the time of implantation. This local hypoxia may modify the inflammatory environment, influence vascular remodelling and modulate endometrial proliferation to optimise endometrial function. Finally, we review current knowledge of the impact of this hypoxia on endometrial pathologies, with a focus on abnormal uterine bleeding. Throughout the manuscript areas for future research are highlighted with the aim of concentrating research efforts to maximise future benefits for women and society.

DOI: https://doi.org/10.1530/REP-20-0268
Am J Reprod Immunol. 2020 Oct 25. e13366

Prospective association of maternal immune proinflammatory responsivity and regulation in pregnancy with length of gestation.

Lauren E Gyllenhammer, Sonja Entringer, Claudia Buss, Hyagriv N Simhan, William A Grobman, Emma K Adam, Lauren Keenan-Devlin, Ann E Borders, Pathik D Wadhwa.

   PROBLEM: The immune system represents a leading pathway of interest in the pathophysiology of preterm birth. The majority of human clinical studies interrogating this pathway have utilized circulating immune biomarkers; however, these concentrations typically reflect only basal production but not key functional properties of the immune system, particularly variation in the pro-inflammatory response to antigen challenge and the regulation of this response. Thus, in this study, we utilized an ex vivo stimulation protocol that quantifies these processes, and we examined their prospective association with the gestation length and risk of preterm birth.
METHOD OF STUDY: Immune responsiveness and regulation were assessed in 128 pregnant women in mid gestation using an ex vivo stimulation protocol. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the proinflammatory cytokines IL-6, TNF-α, and IL-1β in response to antigen stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of stimulated cytokine response upon co-incubation with increasing dexamethasone concentrations (i.e., glucocorticoid receptor resistance; GRR).
RESULTS: Higher maternal GRR, indicating impaired regulation of the proinflammatory response, was significantly and independently associated with shorter gestational length (β= -0.42, p=0.0091) and a 3.0-fold increase in risk for preterm birth (OR= 3.01, 95%CI= 1.17-7.70, p=0.0218). Basal circulating IL-6 and TNF-α were not associated with either outcome.
CONCLUSIONS: The association of maternal GRR with length of gestation and preterm birth risk suggests that the processes represented by this measure -- maternal pro-inflammatory propensity and immune regulation -- may provide further mechanistic insight into the pathophysiology of preterm birth.

Keywords:  cortisol; glucocorticoid resistance; inflammation; interleukin-1 beta; interleukin-6; length of gestation; preterm birth; tumor necrosis factor

DOI:  https://doi.org/10.1111/aji.13366
Placenta. 2020 Oct 17. pii: S0143-4004(20)30414-8. [Epub ahead of print]103 94-103

Placental macrophages: Origin, heterogeneity, function and role in pregnancy-associated infections.

Soraya Mezouar, Maria Katsogiannou, Amira Ben Amara, Florence Bretelle, Jean-Louis Mege.

  Placental macrophages are a heterogenous population of immune cells present throughout pregnancy. They are essential for maintenance of the homeostatic placenta environment and host defense against infections. The characterization of placental macrophages as well as their activation have been limited for a long time by the lack of convenient tools. The emergence of unbiased methods makes it possible to reappraise the study of placental macrophages. In this review, we discuss the diversity and the functions of placental macrophages to better understand their dysfunctions during placental infections.

Keywords:  Infectious pregnancy; M1/M2 polarization; Macrophages; Placenta

DOI:  https://doi.org/10.1016/j.placenta.2020.10.017
Int J Mol Sci. 2020 Oct 28. pii: E8026. [Epub ahead of print]21(21):

Sex Specific Expression of Interleukin 7, 8 and 15 in Placentas of Women with Gestational Diabetes.

Simon Keckstein, Sophia Pritz, Niklas Amann, Sarah Meister, Susanne Beyer, Magdalena Jegen, Christina Kuhn, Stefan Hutter, Julia Knabl, Sven Mahner, Thomas Kolben, Udo Jeschke, Theresa M Kolben.

  Gestational diabetes mellitus (GDM) is known to increase the risk for feto-maternal complications during pregnancy. A state of low-grade inflammation, with elevated levels of proinflammatory molecules, similar to patients with obesity or diabetes mellitus type 2 has also been partly described in GDM. The placenta, as unique interface between mother and fetus, is not only passively affected by changes in one of these organisms, but also acts as a modulator by expressing hormones and cytokines. This study aimed to investigate the expression of the proinflammatory cytokines Interleukin (IL) 7, 8 and 15 in GDM in placental tissue. A total number of 80 placentas were included (40 GDM/40 control group). The expression of IL-7, 8 and 15 was investigated in extravillous trophoblast (EVT) and syncytiotrophoblast (SCT) by immunohistochemistry and immunofluorescence double staining. The immunohistochemical staining was evaluated with the semiquanitfied immunoreactive score (IRS). While the expression IL-15 was significantly upregulated in EVTs of women with GDM. The expression of IL-8 was significantly decreased in EVT of the GDM group. Furthermore, significant fetal sex specific differences were detectable in all three cytokines. Our findings suggest an involvement of the investigated cytokines in the maintenance of a state of chronic low-grade inflammation on placental level in patients suffering from GDM.

Keywords:  cytokines; decidua; gestational diabetes; placenta; trophoblast

DOI:  https://doi.org/10.3390/ijms21218026
Sci Rep. 2020 Oct 29. 10(1): 18598

Circulating CD56+ NKG2D+ NK cells and postoperative fertility in ovarian endometrioma.

Zhi-Qin Liu, Mei-Yin Lu, Bin Liu.

The current biomarkers for postoperative fertility assessment caused by ovarian endometrioma (OE) are insufficient. The present study hypothesized that the peripheral lymphocyte subpopulation can be used as a candidate biomarker of postoperative infertility in OE. The association of the number of circulating CD4/CD8 T, NK, and γδ T cells with postoperative fertility was assessed in 33 OE patients aged 20 ~ 40 years between June 2018 and January 2019. Concomitantly, 68 healthy female subjects were recruited. The changes in the baseline immune characteristics between the two groups were compared. The data demonstrated significant differences in the ratio of CD4/CD8 T cells and the number of CD56+ NKG2D+ NK cells and γδ T cells between OE patients and control subjects. The patients were followed-up till December 2019 and the number of CD56+ NKG2D+ NK cells in the cases was a significant predictor for postoperative fertility as determined by different COX regression models (crude HR = 0.220, 95% CI = 0.059-0.822; adjusted HR = 0.127, 95% CI = 0.024-0.675). A significant delay to successful pregnancy was noted in OE patients (median time, 173 vs. 99 days, log-rank P = 0.013). The present findings suggested that CD56+ NKG2D+ NK cells are a candidate biomarker of postoperative fertility in OE patients. Larger population studies are warranted.

DOI: https://doi.org/10.1038/s41598-020-75570-z
Obstet Gynecol Clin North Am. 2020 Dec;pii: S0889-8545(20)30066-8. [Epub ahead of print]47(4): 503-521

Vaginal Microbiome in Preterm Rupture of Membranes.

Phillip Robert Bennett, Richard Gailon Brown, David Alan MacIntyre.

  There is an association between vaginal microbiota dysbiosis and preterm premature rupture of membranes (PPROM). In PPROM, reduced Lactobacillus spp abundance is linked to the emergence of high-risk vaginal microbiota, close to the time of membrane rupture. Although PPROM itself can change vaginal microbial composition, antibiotic therapy profoundly effects community structure. Erythromycin may have a beneficial effect in women deplete in Lactobacillus spp but damages a healthy microbiome by targeting Lactobacillus spp. Increased rates of chorioamnionitis and early-onset neonatal sepsis are associated with vaginal microbiota dysbiosis close to the time of delivery.

Keywords:  Inflammation; Membranes; PPROM; Preterm birth; Vaginal microbiome

DOI:  https://doi.org/10.1016/j.ogc.2020.08.001
J Virol. 2020 Oct 28. pii: JVI.01381-19. [Epub ahead of print]

Role of inflammation in virus pathogenesis during pregnancy.

Anna Chudnovets, Jin Liu, Harish Narasimhan, Yang Liu, Irina Burd.

Viral infections during pregnancy lead to a spectrum of maternal and fetal outcomes, ranging from asymptomatic disease to more critical conditions presenting with severe maternal morbidity, stillbirth, preterm birth, intrauterine growth restriction, and fetal congenital anomalies, either apparent at birth or later in life. In this manuscript, we review the pathogenesis of several viral infections, particularly relevant in the context of pregnancy and intrauterine inflammation. Understanding the diverse mechanisms employed by viral pathogens as well as the repertoire of immune responses induced in the mother may help to establish novel therapeutic options to attenuate changes in the maternal-fetal interface and prevent adverse pregnancy outcomes.

DOI: https://doi.org/10.1128/JVI.01381-19
Lab Chip. 2020 Oct 28.

Modeling ascending infection with a feto-maternal interface organ-on-chip.

Lauren S Richardson, Sungjin Kim, Arum Han, Ramkumar Menon.

Maternal infection (i.e., ascending infection) and the resulting host inflammatory response are risk factors associated with spontaneous preterm birth (PTB), a major pregnancy complication. However, the path of infection and its propagation from the maternal side to the fetal side have been difficult to study due to the lack of appropriate in vitro models and limitations of animal models. A better understanding of the propagation kinetics of infectious agents and development of the host inflammatory response at the feto-maternal (amniochorion-decidua, respectively) interface (FMi) is critical in curtailing host inflammatory responses that can lead to PTB. To model ascending infection and determine inflammatory responses at the FMi, we developed a microfluidic organ-on-chip (OOC) device containing primary cells from the FMi (decidua, chorion, and amnion [mesenchyme and epithelium]) and collagen matrix harvested from primary tissue. The FMi-OOC is composed of four concentric circular cell/collagen chambers designed to mimic the thickness and cell density of the FMi in vivo. Each layer is connected by arrays of microchannels filled with type IV collagen to recreate the basement membrane of the amniochorion. Cellular characteristics (viability, morphology, production of nascent collagen, cellular transitions, and migration) in the OOC were similar to those seen in utero, validating the physiological relevance and utility of the developed FMi-OOC. The ascending infection model of the FMi-OOC, triggered by exposing the maternal (decidua) side of the OOC to lipopolysaccharide (LPS, 100 ng mL-1), shows that LPS propagated through the chorion, amnion mesenchyme, and reached the fetal amnion within 72 h. LPS induced time-dependent and cell-type-specific pro-inflammatory cytokine production (24 h decidua: IL-6, 48 h chorion: GM-CSF and IL-6, and 72 h amnion mesenchyme and epithelium: GM-CSF and IL-6). Collectively, this OOC model and study successfully modeled ascending infection, its propagation, and distinct inflammatory response at the FMi indicative of pathologic pathways of PTB. This OOC model provides a novel platform to study physiological and pathological cell status at the FMi, and is expected to have broad utility in the field of obstetrics.

DOI: https://doi.org/10.1039/d0lc00875c