Multiomic immune clockworks of pregnancy

Peterson, Laura S.; Stelzer, Ina A.; Tsai, Amy S.; Ghaemi, Mohammad Sajjad; Han, Xiaoyuan; Ando, Kazuo; Winn, Virginia D.; Martinez, Nadine; Contrepois, Kévin; Moufarrej, Mira N.; Quake, Stephen R.; Relman, David A.; Snyder, M; Shaw, Gary M.; Stevenson, David K.; Wong, Ronald J.; Arck, Petra C.; Angst, Martin S.; Aghaeepour, Nima; Gaudillière, Brice

doi:10.1007/s00281-019-00772-1

Cited by 57 publications

(56 citation statements)

References 197 publications

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“…Yet most of our understanding of the pathways involved in labor originates from studies investigating single pathways or mediators by comparing preterm and term pregnancies in humans and various animal models. As multiomic assessments are now underway to evaluate the plausibility of immunological findings [146], the power of biological signatures predictive of preterm birth may soon be within reach and will inform novel approaches of early prediction and therapeutic interventions. Hence, understanding of molecular mechanisms will likely experience rapid developments in the near future, hereby enabling the identification of women at risk and the development of early prevention strategies of PTB.…”

Section: Resultsmentioning

confidence: 99%

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

2020

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Preterm birth (PTB) complicates 5–18% of pregnancies globally and is a leading cause of maternal and fetal morbidity and mortality. Most PTB is spontaneous and idiopathic, with largely undefined causes. To increase understanding of PTB, much research in recent years has focused on using animal models to recapitulate the pathophysiology of PTB. Dysfunctions of maternal immune adaptations have been implicated in a range of pregnancy pathologies, including PTB. A wealth of evidence arising from mouse models as well as human studies is now available to support that PTB results from a breakdown in fetal-maternal tolerance, along with excessive, premature inflammation. In this review, we examine the current knowledge of the bidirectional communication between fetal and maternal systems and its role in the immunopathogenesis of PTB. These recent insights significantly advance our understanding of the pathogenesis of PTB, which is essential to ultimately designing more effective strategies for early prediction and subsequent prevention of PTB.

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Section: Resultsmentioning

confidence: 99%

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

2020

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“…It would be helpful to get a better understanding of the function of all regulatory T cells present in the decidua, to be able to recognize their relevance in healthy and complicated pregnancies. As such, the use of multiple omics techniques to identify the decidual microenvironment by a holistic approach could give insights in the presence, frequency, and distribution of the different types of Tregs in pregnancy [ (32,202,203); van der Zwan et al, submitted]. It is important to note that the time point of sampling is a crucial factor in such experiments, given the dynamic nature of the placental microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells in Pregnancy: It Is Not All About FoxP3

et al. 2020

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In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed.

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“…interactions and temporal changes affect various organ systems, such as the cardiovascular, respiratory, endocrine system or metabolic systems, and, more recently, pivotal immunological adaptions and changes in the human microbiome became evident. [1][2][3][4][5] Physiological adaptions of the immune system during pregnancy play a central role in implantation and placentation, promotion of fetal growth and initiation of labour and delivery. 2 Deviations from the norm of this fine-tuned immune clock may lead to dysregulation in biological networks and cause various pregnancy-associated complications with their immediate consequences for the mother and fetus.…”

Section: Open Accessmentioning

confidence: 99%

“…However, there is a need for longitudinal, multiomics profiling studies that may further contribute to the understanding of physiological adaptions, the interconnections of various biological systems and their significance in pregnancy-associated complications. 3 Research, in particular high-end research, is often biased towards high-income countries. 9 This imbalance is aggravated by the fact that, due to population based differences, results are often not generalisable, 10 populations living in resource-constrained settings are more affected by the consequences of pregnancy-associated complications (eg, inadequate access to safe iatrogenic birth or lack of advanced neonatal care) and have different epidemiological patterns of communicable diseases.…”

Section: Open Accessmentioning

confidence: 99%

Cohort profile: molecular signature in pregnancy (MSP): longitudinal high-frequency sampling to characterise cross-omic trajectories in pregnancy in a resource-constrained setting

et al. 2020

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PurposeA successful pregnancy relies on the interplay of various biological systems. Deviations from the norm within a system or intersystemic interactions may result in pregnancy-associated complications and adverse pregnancy outcomes. Systems biology approaches provide an avenue of unbiased, in-depth phenotyping in health and disease. The molecular signature in pregnancy (MSP) cohort was established to characterise longitudinal, cross-omic trajectories in pregnant women from a resource constrained setting. Downstream analysis will focus on characterising physiological perturbations in uneventful pregnancies, pregnancy-associated complications and adverse outcomes.ParticipantsFirst trimester pregnant women of Karen or Burman ethnicity were followed prospectively throughout pregnancy, at delivery and until 3 months post partum. Serial high-frequency sampling to assess whole blood transcriptomics and microbiome composition of the gut, vagina and oral cavity, in conjunction with assessment of gene expression and microbial colonisation of gestational tissue, was done for all cohort participants.Findings to date381 women with live born singletons averaged 16 (IQR 15–18) antenatal visits (13 094 biological samples were collected). At 5% (19/381) the preterm birth rate was low. Other adverse events such as maternal febrile illness 7.1% (27/381), gestational diabetes 13.1% (50/381), maternal anaemia 16.3% (62/381), maternal underweight 19.2% (73/381) and a neonate born small for gestational age 20.2% (77/381) were more often observed than preterm birth.Future plansResults from the MSP cohort will enable in-depth characterisation of cross-omic molecular trajectories in pregnancies from a population in a resource-constrained setting. Moreover, pregnancy-associated complications and unfavourable pregnancy outcomes will be investigated at the same granular level, with a particular focus on population relevant needs such as effect of tropical infections on pregnancy. More detailed knowledge on multiomic perturbations will ideally result in the development of diagnostic tools and ultimately lead to targeted interventions that may disproportionally benefit pregnant women from this resource-limited population.Trial registration numberNCT02797327.

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Multiomic immune clockworks of pregnancy

Cited by 57 publications

References 197 publications

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

Regulatory T Cells in Pregnancy: It Is Not All About FoxP3

Cohort profile: molecular signature in pregnancy (MSP): longitudinal high-frequency sampling to characterise cross-omic trajectories in pregnancy in a resource-constrained setting

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