bims-reprim 2021-10-03 papers

Issue of 2021–10–03
four papers selected by
Iva Filipovic, Karolinska Institutet

Front Immunol. 2021 ;12 725989

A Peripheral Immune Signature of Labor Induction.

Kazuo Ando, Julien J Hédou, Dorien Feyaerts, Xiaoyuan Han, Edward A Ganio, Eileen S Tsai, Laura S Peterson, Franck Verdonk, Amy S Tsai, Ivana Marić, Ronald J Wong, Martin S Angst, Nima Aghaeepour, David K Stevenson, Yair J Blumenfeld, Pervez Sultan, Brendan Carvalho, Ina A Stelzer, Brice Gaudillière.

Approximately 1 in 4 pregnant women in the United States undergo labor induction. The onset and establishment of labor, particularly induced labor, is a complex and dynamic process influenced by multiple endocrine, inflammatory, and mechanical factors as well as obstetric and pharmacological interventions. The duration from labor induction to the onset of active labor remains unpredictable. Moreover, prolonged labor is associated with severe complications for the mother and her offspring, most importantly chorioamnionitis, uterine atony, and postpartum hemorrhage. While maternal immune system adaptations that are critical for the maintenance of a healthy pregnancy have been previously characterized, the role of the immune system during the establishment of labor is poorly understood. Understanding maternal immune adaptations during labor initiation can have important ramifications for predicting successful labor induction and labor complications in both induced and spontaneous types of labor. The aim of this study was to characterize labor-associated maternal immune system dynamics from labor induction to the start of active labor. Serial blood samples from fifteen participants were collected immediately prior to labor induction (baseline) and during the latent phase until the start of active labor. Using high-dimensional mass cytometry, a total of 1,059 single-cell immune features were extracted from each sample. A multivariate machine-learning method was employed to characterize the dynamic changes of the maternal immune system after labor induction until the establishment of active labor. A cross-validated linear sparse regression model (least absolute shrinkage and selection operator, LASSO) predicted the minutes since induction of labor with high accuracy (R = 0.86, p = 6.7e-15, RMSE = 277 min). Immune features most informative for the model included STAT5 signaling in central memory CD8+ T cells and pro-inflammatory STAT3 signaling responses across multiple adaptive and innate immune cell subsets. Our study reports a peripheral immune signature of labor induction, and provides important insights into biological mechanisms that may ultimately predict labor induction success as well as complications, thereby facilitating clinical decision-making to improve maternal and fetal well-being.

Keywords: induction of labor; labor; machine learning; mass cytometry (CyTOF); parturition; pregnancy; systems immunology

DOI: https://doi.org/10.3389/fimmu.2021.725989

Am J Reprod Immunol. 2021 Sep 30.

Reduced innate lymphoid cells in the endometrium of women with endometriosis.

Takuya Sugahara, Yukiko Tanaka, Masahide Hamaguchi, Maya Fujii, Koki Shimura, Kanae Ogawa, Taisuke Mori, Izumi Kusuki, Michiaki Fukui, Jo Kitawaki.

PROBLEM: Innate lymphoid cells (ILCs), a recently discovered family of innate immune cells, are responsible for the early immune response, and control both innate and adapted immune system via cytokine secretion. The role of ILCs in endometriosis has not been investigated; therefore, here, we aimed to investigate how the proportion of ILCs changes in endometriosis.
METHOD OF STUDY: The percentage of each ILC group in CD45+ cells was examined in the peripheral blood, peritoneal fluid, endometrium, and ovarian endometrioma obtained from women with and without endometriosis (ERB-C-1216) using flow cytometry.
RESULTS: Specimens were obtained from 19 women with endometriosis and 15 without endometriosis. In the endometrium, patients with endometriosis had lower proportion of ILC2 and 3 compared to control specimens (ILC2: 0.02±0.01% vs 0.07±0.03%; P<0.05, ILC3: 0.31±0.14% vs 1.10±0.93%; P<0.05). There was no significant change in the peripheral blood or the peritoneal fluid between the two groups. Additionally, ovarian endometrioma increased the proportion of ILCs (ILC1: 0.92±1.12%, ILC2: 0.08±0.08%, ILC3: 0.70±0.39%) compared to the endometrium samples of patients with endometriosis each with P<0.05. Immunohistochemistry of IL-1β and IL-23, which are ILC3 inducing factors, showed no significant change in the H-score of the epithelium of the two groups, but a significant increase was found in ovarian endometrioma.
CONCLUSION: The proportion of ILC2 and 3 was reduced in the endometrium of patients with endometriosis, and ILCs were increased in ovarian endometrioma. Our findings may indicate a new immunological approach to understand the pathophysiology of endometriosis. This article is protected by copyright. All rights reserved.

Keywords: endometriosis; flow cytometry; inflammation; innate lymphoid cell; interleukins

DOI: https://doi.org/10.1111/aji.13502

J Reprod Immunol. 2021 Sep 20. pii: S0165-0378(21)00154-6. [Epub ahead of print]148 103424

Reduced frequency of perforin-positive CD8+ T cells in menstrual effluent of endometriosis patients.

Timo Schmitz, Verena Hoffmann, Elisabeth Olliges, Alina Bobinger, Roxana Popovici, Elfriede Nößner, Karin Meissner.

Endometriosis is a widespread disease and commonly reduces the life quality of those affected. Scientific literature indicates different underlying immunological changes. Frequently examined tissues are peripheral blood, endometrial tissue and peritoneal fluid. Yet, knowledge on immunological differences in menstrual effluent (ME) is scarce. In this study, between January 2018 and August 2019, 12 women with endometriosis (rASRM classification: stages I-IV) and 11 healthy controls were included. ME was collected using menstrual cups and venous blood samples (PB) were taken. Mononuclear cells were obtained from ME (MMC) and PB (PBMC) and analyzed using flow cytometry. Concentrations of cell adhesion molecules (ICAM-I and VCAM-I) and cytokines (IL-6, IL-8 and TNF-α) were measured using ELISA. CD8 + T cells obtained from ME were significantly less often perforin-positive in women with endometriosis compared to healthy controls. A comparison between MMC and PBMC revealed that MMC contained significantly less T cells and more B cells. The CD4/CD8 ratio was significantly higher in MMC, and Tregs were significantly less frequently in MMC. In ME, T cells and NK cells expressed significantly more CD69. NK cells obtained from ME were predominantly CD56bright/CD16dim and had a lower frequency of perforin + cells compared to PBMC NK cells. Moreover, ICAM-1 plasma levels were significantly reduced in women with endometriosis compared to healthy controls. In conclusion, CD8 + T cells obtained from the ME were significantly less perforin-positive in endometriosis patients indicating a reduced cytotoxic potential. MMC are distinctively different from PBMC and, thus, seem to be of endometrial origin.

Keywords: Endometriosis; Menstrual effluent; Perforin; T cells

DOI: https://doi.org/10.1016/j.jri.2021.103424

Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2109252118. [Epub ahead of print]118(40):

Deficiency of PARP-1 and PARP-2 in the mouse uterus results in decidualization failure and pregnancy loss.

Andrew M Kelleher, Rohit Setlem, Françoise Dantzer, Francesco J DeMayo, John P Lydon, W Lee Kraus.

Miscarriage is a common complication of pregnancy for which there are few clinical interventions. Deficiency in endometrial stromal cell decidualization is considered a major contributing factor to pregnancy loss; however, our understanding of the underlying mechanisms of decidual deficiency are incomplete. ADP ribosylation by PARP-1 and PARP-2 has been linked to physiological processes essential to successful pregnancy outcomes. Here, we report that the catalytic inhibition or genetic ablation of PARP-1 and PARP-2 in the uterus lead to pregnancy loss in mice. Notably, the absence of PARP-1 and PARP-2 resulted in increased p53 signaling and an increased population of senescent decidual cells. Molecular and histological analysis revealed that embryo attachment and the removal of the luminal epithelium are not altered in uterine Parp1, Parp2 knockout mice, but subsequent decidualization failure results in pregnancy loss. These findings provide evidence for a previously unknown function of PARP-1 and PARP-2 in mediating decidualization for successful pregnancy establishment.

Keywords: ADP-ribosylation; PARP-1; PARP-2; pregnancy; uterus

DOI: https://doi.org/10.1073/pnas.2109252118