bims-reprim Biomed News
on Reproductive immunology
Issue of 2021–01–24
eight papers selected by
Iva Filipovic, Karolinska Institutet
  1. Aging and CMV discordance are associated with increased immune diversity between monozygotic twins.
  2. Single-cell Immune Landscape of Human Recurrent Miscarriage.
  3. Immune Tolerance of the Human Decidua.
  4. Male Fetal Sex Affects Uteroplacental Angiogenesis in Growth Restriction Mouse Model†.
  5. Compromised SARS-CoV-2-specific placental antibody transfer.
  6. SARS-CoV-2 placentitis: An uncommon complication of maternal COVID-19.
  7. Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity.
  8. Obstetric Outcomes of SARS-CoV-2 Infection in Asymptomatic Pregnant Women.
  1. Immun Ageing. 2021 Jan 18. 18(1): 5
    Aging and CMV discordance are associated with increased immune diversity between monozygotic twins.
    Zheng Yan, Holden T Maecker, Petter Brodin, Unni C Nygaard, Shu Chen Lyu, Mark M Davis, Kari C Nadeau, Sandra Andorf.
       BACKGROUND: Broadly, much of variance in immune system phenotype has been linked to the influence of non-heritable factors rather than genetics. In particular, two non-heritable factors: aging and human cytolomegavirus (CMV) infection, have been known to account for significant inter-individual immune variance. However, many specific relationships between them and immune composition remain unclear, especially between individuals over narrower age ranges. Further exploration of these relationships may be useful for informing personalized intervention development.
    RESULTS: To address this need, we evaluated 41 different cell type frequencies by mass cytometry and identified their relationships with aging and CMV seropositivity. Analyses were done using 60 healthy individuals, including 23 monozygotic twin pairs, categorized into young (12-31 years) and middle-aged (42-59 years). Aging and CMV discordance were associated with increased immune diversity between monozygotic twins overall, and particularly strongly in various T cell populations. Notably, we identified 17 and 11 cell subset frequencies as relatively influenced and uninfluenced by non-heritable factors, respectively, with results that largely matched those from studies on older-aged cohorts. Next, CD4+ T cell frequency was shown to diverge with age in twins, but with lower slope than in demographically similar non-twins, suggesting that much inter-individual variance in this cell type can be attributed to interactions between genetic and environmental factors. Several cell frequencies previously associated with memory inflation, such as CD27- CD8+ T cells and CD161+ CD4+ T cells, were positively correlated with CMV seropositivity, supporting findings that CMV infection may incur rapid aging of the immune system.
    CONCLUSIONS: Our study confirms previous findings that aging, even within a relatively small age range and by mid-adulthood, and CMV seropositivity, both contribute significantly to inter-individual immune diversity. Notably, we identify several key immune cell subsets that vary considerably with aging, as well as others associated with memory inflation which correlate with CMV seropositivity.
    Keywords:  Aging; Cytomegalovirus; Human immunology; Mass cytometry (CyTOF); Monozygotic twins
    DOI:  https://doi.org/10.1186/s12979-021-00216-1
  2. Genomics Proteomics Bioinformatics. 2021 Jan 19. pii: S1672-0229(21)00003-6. [Epub ahead of print]
    Single-cell Immune Landscape of Human Recurrent Miscarriage.
    Feiyang Wang, Wentong Jia, Mengjie Fan, Xuan Shao, Zhilang Li, Yongjie Liu, Yeling Ma, Yu-Xia Li, Rong Li, Qiang Tu, Yan-Ling Wang.
      Successful pregnancy in placental mammals substantially depends on the establishment of maternal immune tolerance to the semi-allogenic fetus. Disorders in this process are tightly associated with adverse pregnancy outcomes including recurrent miscarriage (RM). However, an in-depth understanding of the systematic and decidual immune environment in RM remains largely lacking. In this study, we utilized single-cell RNA-sequencing (scRNA-seq) to comparably analyze the cellular and molecular signatures of decidual and peripheral leukocytes in normal and unexplained RM pregnancies at the early stage of gestation. Integrative analysis identifies 22 distinct cell clusters in total, and a dramatic difference in leukocyte subsets and molecular properties in RM cases is revealed. Specifically, the cytotoxic properties of CD8+ effector T cells, nature killer (NK), and mucosal-associated invariant T (MAIT) cells in peripheral blood indicates apparently enhanced pro-inflammatory status, and the population proportions and ligand-receptor interactions of the decidual leukocyte subsets demonstrate preferential immune activation in RM patients. The molecular features, spatial distribution, and the developmental trajectories of five decidual NK (dNK) subsets have been elaborately illustrated. In RM patients, a dNK subset that supports embryonic growth is diminished in proportion, while the ratio of another dNK subset with cytotoxic and immune-active signature is significantly increased. Notably, a unique pro-inflammatory CD56+CD16+ dNK subset substantially accumulates in RM decidua. These findings reveal a comprehensive cellular and molecular atlas of decidual and peripheral leukocytes in human early pregnancy and provide an in-depth insight into the immune pathogenesis for early pregnancy loss.
    Keywords:  Decidual and peripheral leukocytes; Developmental trajectory; Early pregnancy; Recurrent miscarriage; Single-cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.gpb.2020.11.002
  3. J Clin Med. 2021 Jan 18. pii: E351. [Epub ahead of print]10(2):
    Immune Tolerance of the Human Decidua.
    Hiromi Murata, Susumu Tanaka, Hidetaka Okada.
      The endometrium is necessary for implantation, complete development of the placenta, and a successful pregnancy. The endometrium undergoes repeated cycles of proliferation, decidualization (differentiation), and shedding during each menstrual cycle. The endometrium-including stromal, epithelial, vascular endothelial, and immune cells-is both functionally and morphologically altered in response to progesterone, causing changes in the number and types of immune cells. Immune cells make up half of the total number of endometrial cells during implantation and menstruation. Surprisingly, immune tolerant cells in the endometrium (uterine natural killer cells, T cells, and macrophages) have two conflicting functions: to protect the body by eliminating pathogenic microorganisms and other pathogens and to foster immunological change to tolerate the embryo during pregnancy. One of the key molecules involved in this control is the cytokine interleukin-15 (IL-15), which is secreted by endometrial stromal cells. Recently, it has been reported that IL-15 is directly regulated by the transcription factor heart- and neural crest derivatives-expressed protein 2 in endometrial stromal cells. In this review, we outline the significance of the endometrium and immune cell population during menstruation and early pregnancy and describe the factors involved in immune tolerance and their involvement in the establishment and maintenance of pregnancy.
    Keywords:  endometrial stromal cells; endometrium; galectin 9; heart- and neural crest derivatives-expressed protein 2 (HAND2); immune tolerance; interleukin-15 (IL15); macrophages; regulatory T cells (Treg); uterine natural killer cells
    DOI:  https://doi.org/10.3390/jcm10020351
  4. Biol Reprod. 2021 Jan 18. pii: ioab006. [Epub ahead of print]
    Male Fetal Sex Affects Uteroplacental Angiogenesis in Growth Restriction Mouse Model†.
    Jessica F Hebert, Jess A Millar, Rahul Raghavan, Amie Romney, Jason E Podrabsky, Monique Y Rennie, Allison Felker, Perrie O'Tierney-Ginn, Mayu Morita, Elizabeth A DuPriest, Terry K Morgan.
      Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age (SGA) babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[-6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer cell (uNK) phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional micro-computed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.
    Keywords:  angiogenesis; intrauterine growth restriction; placenta; placental transport
    DOI:  https://doi.org/10.1093/biolre/ioab006
  5. Cell. 2020 Dec 23. pii: S0092-8674(20)31749-9. [Epub ahead of print]
    Compromised SARS-CoV-2-specific placental antibody transfer.
    Caroline Atyeo, Krista M Pullen, Evan A Bordt, Stephanie Fischinger, John Burke, Ashlin Michell, Matthew D Slein, Carolin Loos, Lydia L Shook, Adeline A Boatin, Laura J Yockey, David Pepin, Marie-Charlotte Meinsohn, Ngoc Minh Phuong Nguyen, Maeva Chauvin, Drucilla Roberts, Ilona T Goldfarb, Juan D Matute, Kaitlyn E James, Lael M Yonker, Lisa M Bebell, Anjali J Kaimal, Kathryn J Gray, Douglas Lauffenburger, Andrea G Edlow, Galit Alter.
      SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.
    Keywords:  Fc-receptor; SARS-CoV-2; antibodies; fucose; glycosylation; hypergammablobulinemia; infection; inflammation; placental transfer; pregnancy; trimester
    DOI:  https://doi.org/10.1016/j.cell.2020.12.027
  6. Placenta. 2021 Jan 11. pii: S0143-4004(21)00020-5. [Epub ahead of print]104 261-266
    SARS-CoV-2 placentitis: An uncommon complication of maternal COVID-19.
    Laura Linehan, Keelin O'Donoghue, Susan Dineen, Jessica White, John R Higgins, Brendan Fitzgerald.
      We present a case of third trimester pregnancy complicated by SARS-CoV-2 infection and subsequent reduced fetal movements, resulting in emergency Caesarean delivery with demonstrable placental SARS-CoV-2 placentitis. We show through illustration of this case and literature review that SARS-Co-V-2 placentitis is an uncommon but readily recognisable complication of maternal SARS-CoV-2 infection that may be a marker of potential vertical transmission and that may have the capacity to cause fetal compromise through a direct injurious effect on the placenta.
    Keywords:  Histiocytic intervillositis; Placental pathology; Placentitis; SARS-CoV-2; Vertical transmission
    DOI:  https://doi.org/10.1016/j.placenta.2021.01.012
  7. Sci Rep. 2021 Jan 19. 11(1): 1773
    Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity.
    Z Shen, M Rodriguez-Garcia, M V Patel, C R Wira.
      Regulation of endometrial (EM) CD8+T cells is essential for successful reproduction and protection against pathogens. Suppression of CD8+T cells is necessary for a tolerogenic environment that promotes implantation and pregnancy. However, the mechanisms regulating this process remain unclear. Sex hormones are known to control immune responses directly on immune cells and indirectly through the tissue environment. When the actions of estradiol (E2), progesterone (P) and TGFβ on EM CD8+T cells were evaluated, cytotoxic activity, perforin and granzymes were directly suppressed by E2 and TGFβ but not P. Moreover, incubation of polarized EM epithelial cells with P, but not E2, increased TGFβ secretion. These findings suggest that E2 acts directly on CD8+T cell to suppress cytotoxic activity while P acts indirectly through induction of TGFβ production. Understanding the mechanisms involved in regulating endometrial CD8+T cells is essential for optimizing reproductive success and developing protective strategies against genital infections and gynecological cancers.
    DOI:  https://doi.org/10.1038/s41598-021-81380-8
  8. Viruses. 2021 01 15. pii: E112. [Epub ahead of print]13(1):
    Obstetric Outcomes of SARS-CoV-2 Infection in Asymptomatic Pregnant Women.
    Monica Cruz-Lemini, Elena Ferriols Perez, Maria Luisa de la Cruz Conty, Africa Caño Aguilar, Maria Begoña Encinas Pardilla, Pilar Prats Rodríguez, Marta Muner Hernando, Laura Forcen Acebal, Pilar Pintado Recarte, Maria Del Carmen Medina Mallen, Noelia Perez Perez, Judit Canet Rodriguez, Ana Villalba Yarza, Olga Nieto Velasco, Pablo Guillermo Del Barrio Fernandez, Carmen Maria Orizales Lago, Beatriz Marcos Puig, Begoña Muñoz Abellana, Laura Fuentes Ricoy, Agueda Rodriguez Vicente, Maria Jesus Janeiro Freire, Macarena Alferez Alvarez-Mallo, Cristina Casanova Pedraz, Onofre Alomar Mateu, Cristina Lesmes Heredia, Juan Carlos Wizner de Alva, Alma Posadas San Juan, Montserrat Macia Badia, Cristina Alvarez Colomo, Antonio Sanchez Muñoz, Laia Pratcorona Alicart, Ruben Alonso Saiz, Monica Lopez Rodriguez, Maria Carmen Barbancho Lopez, Marta Ruth Meca Casbas, Oscar Vaquerizo Ruiz, Eva Moran Antolin, Maria Jose Nuñez Valera, Camino Fernandez Fernandez, Albert Tubau Navarra, Alejandra Maria Cano Garcia, Susana Soldevilla Perez, Irene Gattaca Abasolo, Jose Adanez Garcia, Alberto Puertas Prieto, Rosa Ostos Serna, Maria Del Pilar Guadix Martin, Monica Catalina Coello, Silvia Espuelas Malon, Jose Antonio Sainz Bueno, Maria Reyes Granell Escobar, Sara Cruz Melguizo, Oscar Martinez Perez, On Behalf Of The Spanish Obstetric Emergency Group.
      Around two percent of asymptomatic women in labor test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Spain. Families and care providers face childbirth with uncertainty. We determined if SARS-CoV-2 infection at delivery among asymptomatic mothers had different obstetric outcomes compared to negative patients. This was a multicenter prospective study based on universal antenatal screening for SARS-CoV-2 infection. A total of 42 hospitals tested women admitted for delivery using polymerase chain reaction, from March to May 2020. We included positive mothers and a sample of negative mothers asymptomatic throughout the antenatal period, with 6-week postpartum follow-up. Association between SARS-CoV-2 and obstetric outcomes was evaluated by multivariate logistic regression analyses. In total, 174 asymptomatic SARS-CoV-2 positive pregnancies were compared with 430 asymptomatic negative pregnancies. No differences were observed between both groups in key maternal and neonatal outcomes at delivery and follow-up, with the exception of prelabor rupture of membranes at term (adjusted odds ratio 1.88, 95% confidence interval 1.13-3.11; p = 0.015). Asymptomatic SARS-CoV-2 positive mothers have higher odds of prelabor rupture of membranes at term, without an increase in perinatal complications, compared to negative mothers. Pregnant women testing positive for SARS-CoV-2 at admission for delivery should be reassured by their healthcare workers in the absence of symptoms.
    Keywords:  SARS-CoV-2; asymptomatic infection; coronavirus; delivery; maternal complications; perinatal outcomes; pregnancy
    DOI:  https://doi.org/10.3390/v13010112
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