bims-reprim 2021-09-05 papers

bims-reprim

Biomed News

on Reproductive immunology

Issue of 2021–09–05
seven papers selected by
Iva Filipovic, Karolinska Institutet

NK cells that differ in expression of NKp46 might play different roles in endometrium.
Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection.
Mixtures of persistent organic pollutants are found in vital organs of late gestation human fetuses.
Using principle component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes.
Is there an inflammatory stimulus to human term labour?
High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment.
Oral microbiome shifts during pregnancy and adverse pregnancy outcomes: Hormonal and Immunologic changes at play.

J Reprod Immunol. 2021 Aug 24. pii: S0165-0378(21)00097-8. [Epub ahead of print]147 103367

NK cells that differ in expression of NKp46 might play different roles in endometrium.

Chuxian Mai, Atsushi Fukui, Ryu Takeyama, Mayu Yamamoto, Shinichiro Saeki, Ayano Yamaya, Toru Kato, Yuji Ukita, Yu Wakimoto, Hiroaki Shibahara.

  NKp46 is a natural cytotoxicity receptor expressed by NK cells and its expression is decreased in reproductive failure patients. NKp46 can be subdivided into NKp46dim and NKp46bright according to different fluorescence staining intensities. We investigated the role of the NKp46 receptor in determining the reproductive outcomes. Uterine endometrium was collected from 34 women with reproductive failure and divided into the pregnant and failed groups based on the results of a pregnancy reaction test during a 1-year follow-up period. NKp46 receptor and other activating or inhibitory receptors expressed on NK cells as well as intracellular cytokine production by NK cells were analyzed by multicolor flow cytometry. In the failed group, the percentage of NKp46dim NK cells (P < 0.05) was significantly higher and percentages of NKp46bright NK cells (P < 0.01) and CD16-/CD56bright NK cells (P < 0.05) were significantly lower than those in the pregnant group. NKp46dim NK cells were significantly and positively correlated with CD16+/NKp46dim NK cells; NKp46bright NK cells were significantly and positively correlated with CD16-/NKp46bright NK cells. CD16+/NKp46dim NK cells were significantly and positively correlated with IFN-γ- and/or TNF-α-producing NK cells; CD16-/NKp46bright NK cells were significantly and positively correlated with TGF-β1-producing NK cells. We suggest that the NKp46 receptor plays different roles in reproduction based on the different fluorescence intensities associated with NK cells, i.e. NKp46dim NK cells are involved in killing cells, whereas NKp46bright NK cells are involved in cytokine production, indicating that NKp46 could be a predictive marker to see a tolerate condition for embryos.

Keywords:  IFN-γ; NK cell; NKp46; Recurrent pregnancy loss; Repeated implantation failure

DOI:  https://doi.org/10.1016/j.jri.2021.103367
bioRxiv. 2021 Aug 23. pii: 2021.08.23.457408. [Epub ahead of print]

Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection.

Suhas Sureshchandra, Michael Z Zulu, Brianna Doratt, Allen Jankeel, Delia Tifrea, Robert Edwards, Monica Rincon, Nicole E Marshall, Ilhem Messaoudi.

Pregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.

DOI: https://doi.org/10.1101/2021.08.23.457408
Chemosphere. 2021 Jun 08. pii: S0045-6535(21)01597-6. [Epub ahead of print]283 131125

Mixtures of persistent organic pollutants are found in vital organs of late gestation human fetuses.

Richelle D Björvang, Marie-Therese Vinnars, Nikos Papadogiannakis, Sebastian Gidlöf, Linn Salto Mamsen, Daniel Mucs, Hannu Kiviranta, Panu Rantakokko, Päivi Ruokojärvi, Christian H Lindh, Claus Yding Andersen, Pauliina Damdimopoulou.

  Persistent organic pollutants (POPs) are industrial chemicals with long half-lives. Early life exposure to POPs has been associated with adverse effects. Fetal exposure is typically estimated based on concentrations in maternal serum or placenta and little is known on the actual fetal exposure. We measured the concentrations of nine organochlorine pesticides (OCPs), ten polychlorinated biphenyl (PCB) congeners, and polybrominated diphenyl ether (PBDE) congeners by gas chromatography - tandem mass spectrometry in maternal serum, placenta, and fetal tissues (adipose tissue, liver, heart, lung and brain) in 20 pregnancies that ended in stillbirth (gestational weeks 36-41). The data were combined with our earlier data on perfluoroalkyl substances (PFASs) in the same cohort (Mamsen et al. 2019). HCB, p,p'-DDE, PCB 138 and PCB 153 were quantified in all samples of maternal serum, placenta and fetal tissues. All 22 POPs were detected in all fetal adipose tissue samples, even in cases where they could not be detected in maternal serum or placenta. Tissue:serum ratios were significantly higher in later gestations, male fetuses, and pregnancies with normal placental function. OCPs showed the highest tissue:serum ratios and PFAS the lowest. The highest chemical burden was found in adipose tissue and lowest in the brain. Overall, all studied human fetuses were intrinsically exposed to mixtures of POPs. Tissue:serum ratios were significantly modified by gestational age, fetal sex and placental function. Importantly, more chemicals were detected in fetal tissues compared to maternal serum and placenta, implying that these proxy samples may provide a misleading picture of actual fetal exposures.

Keywords:  Human fetal exposure; Organochlorine pesticides; Perfluoroalkyl substances; Persistent organic pollutants; Polybrominated diphenyl ether; Polychlorinated biphenyls

DOI:  https://doi.org/10.1016/j.chemosphere.2021.131125
Am J Reprod Immunol. 2021 Sep 03.

Using principle component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes.

Lauren S Keenan-Devlin, Madeleine Caplan, Alexa Freedman, Kristine Kuchta, William Grobman, Claudia Buss, Emma K Adam, Sonja Entringer, Gregory E Miller, Ann E B Borders.

   OBJECTIVE: Inflammation as a risk factor for preterm birth is well-established. The primary objective of this analysis was to examine whether individual cytokines versus a composite indicator of mid-pregnancy inflammation are significantly associated with risk for adverse birth outcomes.
STUDY DESIGN: A multi-site prospective study was conducted in a socio-demographically diverse cohort of 610 pregnant participants. At a study visit between 12 and 20 6/7 weeks' gestation, low-grade inflammation was measured via log-transformed serum concentrations of the biomarkers IFN-γ, IL-10, IL-13, IL-6, IL-8, TNF-α, and CRP. Principal component analysis (PCA) was used to identify underlying dimensions of inflammatory activity from the seven biomarkers measured. Gestational age and birth weight at delivery were obtained from medical chart review. The associations between inflammatory profiles and birth outcomes were assessed via linear and logistic regression models. Results were compared with those from individual inflammatory biomarkers, and model fit was assessed using Akaike's Information Criterion (AIC).
RESULTS: PCA analysis yielded a two-factor solution, with the first factor (IF1) composed of IL-8, IL-10, IL-13, IFN-ɣ, and TNF-α, and the second factor (IF2) containing IL-6 and CRP. When adjusted for race, education, BMI, smoking status, gestational age at time of blood draw, and study site, a one standard deviation (SD) increase in IF1 remained significantly associated with a decrease in standardized gestational age (β = -0.13, 95% CI: -0.21, -0.05) and an increase in odds of preterm delivery (OR = 1.46, 95% CI: 1.13, 1.88) (Table 3). A one SD increase in IF2 was similarly associated with a decrease in standardized gestational age at delivery (β = -0.13, 95% CI: -0.23, -0.04) and an increase in odds of preterm delivery (OR: 1.46, 95% CI: 1.04, 2.05). Neither IF1 nor IF2 was associated with measures of fetal growth. AIC identified that IL-6 was a slightly better fit for length of gestation compared to either composite measure, though all performed similarly.
CONCLUSION: Independent of known sociodemographic risk factors, an elevated mid-pregnancy inflammatory profile was associated with a nearly 50% increase in odds of preterm delivery. The composite performed similarly to IL-6. These results suggest that maternal low-grade inflammation is a risk factor for preterm delivery, and that mid-pregnancy inflammatory biomarkers may be useful in predicting risk for preterm delivery. This article is protected by copyright. All rights reserved.

Keywords:  inflammation; inflammatory factors; preterm birth; small for gestational age

DOI:  https://doi.org/10.1111/aji.13497
PLoS One. 2021 ;16(8): e0256545

Is there an inflammatory stimulus to human term labour?

Natasha Singh, Bronwen Herbert, Garvin Sooranna, Nishel M Shah, Ananya Das, Suren R Sooranna, Mark R Johnson.

Inflammation is thought to play a pivotal role in the onset of term and some forms of preterm labour. Although, we recently found that myometrial inflammation is a consequence rather than a cause of term labour, there are several other reproductive tissues, including amnion, choriodecidua parietalis and decidua basalis, where the inflammatory stimulus to labour may occur. To investigate this, we have obtained amnion, choriodecidual parietalis and decidua basalis samples from women at various stages of pregnancy and spontaneous labour. The inflammatory cytokine profile in each tissue was determine by Bio-Plex Pro® cytokine multiplex assays and quantitative RT-PCR. Active motif assay was used to study transcription activation in the choriodecidua parietalis. Quantitative RT-PCR was use to study the pro-labour genes (PGHS-2, PGDH, OTR and CX43) in all of the tissues at the onset of labour and oxytocin (OT) mRNA expression in the choriodecidual parietalis and decidua basalis. Statistical significance was ascribed to a P value <0.05. In the amnion and choriodecidua parietalis, the mRNA levels of various cytokines decreased from preterm no labour to term no labour samples, but the protein levels were unchanged. The choriodecidua parietalis showed increase in the protein levels of IL-1β and IL-6 in the term early labour samples. In the amnion and decidua basalis, the protein levels of several cytokines rose in term established labour. The multiples of the median derived from the 19-plex cytokine assay were greater in term early labour and term established labour samples from the choriodecidua parietalis, but only in term established labour for myometrium. These data suggest that the inflammatory stimulus to labour may begin in the choriodecidua parietalis, but the absence of any change in prolabour factor mRNA levels suggests that the cytokines may act on the myometrium where we observed changes in transcription factor activation and increases in prolabour gene expression in earlier studies.

DOI: https://doi.org/10.1371/journal.pone.0256545
Cell Rep. 2021 Aug 31. pii: S2211-1247(21)01075-5. [Epub ahead of print]36(9): 109632

High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment.

Veronica D Gonzalez, Ying-Wen Huang, Antonio Delgado-Gonzalez, Shih-Yu Chen, Kenyi Donoso, Karen Sachs, Andrew J Gentles, Grace M Allard, Kevin S Kolahi, Brooke E Howitt, Ermelinda Porpiglia, Wendy J Fantl.

  Tubo-ovarian high-grade serous carcinoma (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we apply mass cytometry and uncover decidual-like natural killer (dl-NK) cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in newly diagnosed HGSC samples that correlate with both tumor and transitioning epithelial-mesenchymal cell abundance. We show different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within three HGSC tumor compartments: epithelial (E), transitioning epithelial-mesenchymal (EV), and mesenchymal (vimentin expressing [V]), with a more inhibitory ligand phenotype in V cells. In cocultures, NK-92 natural killer cells acquire CD9 from HGSC tumor cells by trogocytosis, resulting in reduced anti-tumor cytokine production and cytotoxicity. Cytotoxicity in these cocultures is restored with a CD9-blocking antibody or CD9 CRISPR knockout, thereby identifying mechanisms of immune suppression in HGSC. CD9 is widely expressed in HGSC tumors and so represents an important new therapeutic target with immediate relevance for NK immunotherapy.

Keywords:  CD9; HGSC; NK cells; NK immunotherapy; T cells; cytokine production; cytotoxicity; decidual-like; epithelial tumor; epithelial-mesenchymal; high-grade serous carcinoma; immune infiltrate; immune tolerance; trogocytosis; tubo-ovarian tumor

DOI:  https://doi.org/10.1016/j.celrep.2021.109632
Periodontol 2000. 2021 Oct;87(1): 276-281

Oral microbiome shifts during pregnancy and adverse pregnancy outcomes: Hormonal and Immunologic changes at play.

Changchang Ye, Yvonne Kapila.

  Because of hormonal and immunologic changes, there are significant changes in the oral microbiome that emerge during pregnancy. Recent evidence further suggests that there is an association between the presence of periodontal disease and a pregnancy-associated oral dysbiosis. Although this oral dysbiosis and pathogenic periodontal bacteria are considered to be associated with adverse pregnancy outcomes, it is still not clear how an oral dysbiosis during pregnancy can modulate oral diseases and birth outcomes. To develop preventive or therapeutic interventions, it is critical to understand the oral microbiome changes that emerge during pregnancy and their association with adverse pregnancy outcomes. In the present review, we summarize the current literature on normal changes in the oral microbiome that occur during pregnancy; the pathogenic changes in the oral microbiome believed to occur in association with adverse pregnancy outcomes; and the association between the placental microbiome and the oral microbiome.

Keywords:  adverse pregnancy outcomes; oral microbiome; periodontal pathogens; placental microbiome

DOI:  https://doi.org/10.1111/prd.12386