bims-reprim 2021-10-24 papers

Issue of 2021‒10‒24
five papers selected by
Iva Filipovic
Karolinska Institutet

J Immunol. 2021 Oct 18. pii: ji2100649. [Epub ahead of print]

Maternal Monocytes Respond to Cell-Free Fetal DNA and Initiate Key Processes of Human Parturition.

Nazanin Yeganeh Kazemi, Bohdana Fedyshyn, Shari Sutor, Yaroslav Fedyshyn, Svetomir Markovic, Elizabeth Ann L Enninga.

Throughout gestation, the maternal immune system is tightly modulated to allow growth of a semiallogeneic fetus. During the third trimester, the maternal immune system shifts to a proinflammatory phenotype in preparation for labor. What induces this shift remains unclear. Cell-free fetal DNA (cffDNA) is shed by the placenta and enters maternal circulation throughout pregnancy. Levels of cffDNA are increased as gestation progresses and peak before labor, coinciding with a shift to proinflammatory maternal immunity. Furthermore, cffDNA is abnormally elevated in plasma from women with complications of pregnancy, including preterm labor. Given the changes in maternal immunity at the end of pregnancy and the role of sterile inflammation in the pathophysiology of spontaneous preterm birth, we hypothesized that cffDNA can act as a damage-associated molecular pattern inducing an inflammatory cytokine response that promotes hallmarks of parturition. To test this hypothesis, we stimulated human maternal leukocytes with cffDNA from primary term cytotrophoblasts or maternal plasma and observed significant IL-1β and CXCL10 secretion, which coincides with phosphorylation of IFN regulatory factor 3 and caspase-1 cleavage. We then show that human maternal monocytes are crucial for the immune response to cffDNA and can activate bystander T cells to secrete proinflammatory IFN-γ and granzyme B. Lastly, we find that the monocyte response to cffDNA leads to vascular endothelium activation, induction of myometrial contractility, and PGE2 release in vitro. Our results suggest that the immune response to cffDNA can promote key features of the parturition cascade, which has physiologic consequences relevant to the timing of labor.

DOI: https://doi.org/10.4049/jimmunol.2100649

Biol Reprod. 2021 Oct 23. pii: ioab197. [Epub ahead of print]

Transcriptome changes in maternal peripheral blood during term parturition mimic perturbations preceding spontaneous Preterm birth†.

Nardhy Gomez-Lopez, Roberto Romero, Jose Galaz, Gaurav Bhatti, Bogdan Done, Derek Miller, Corina Ghita, Kenichiro Motomura, Marcelo Farias-Jofre, Eunjung Jung, Roger Pique-Regi, Sonia S Hassan, Tinnakorn Chaiworapongsa, Adi L Tarca.

The complex physiologic process of parturition includes the onset of labor, which requires the orchestrated stimulation of a common pathway involving uterine contractility, cervical ripening, and chorioamniotic membrane activation. However, the labor-specific processes taking place in these tissues have limited use as predictive biomarkers unless they can be probed in non-invasive samples, such as the peripheral blood. Herein, we utilized a transcriptomic dataset to assess labor-specific changes in the peripheral blood of women who delivered at term. We identified a set of genes that were differentially expressed with labor and enriched for immunological processes, and these gene expression changes were strongly correlated with results from prior studies, providing in silico validation of our findings. We then identified significant correlations between labor-specific transcriptomic changes in the maternal circulation and those reported in the chorioamniotic membranes, myometrium, and cervix of women at term, demonstrating that tissue-specific labor signatures are partly mirrored in the peripheral blood. Last, we demonstrated a significant overlap between the peripheral blood transcriptomic changes in term parturition and those observed in asymptomatic women prior to the diagnosis of preterm prelabor rupture of membranes who delivered preterm. Collectively, we provide evidence that the normal process of labor at term is characterized by a unique immunological expression signature, which may serve as a useful tool for assessing labor status and potentially identifying women at risk for preterm birth.

Keywords: Parturition; cervix; chorioamniotic membranes; fetal membranes; immune response; inflammation; myometrium; placenta; preterm labor; uterus

DOI: https://doi.org/10.1093/biolre/ioab197

Front Immunol. 2021 ;12 741518

IFNγ-Producing γ/δ T Cells Accumulate in the Fetal Brain Following Intrauterine Inflammation.

Emma L Lewis, Natalia Tulina, Lauren Anton, Amy G Brown, Paige M Porrett, Michal A Elovitz.

Intrauterine inflammation impacts prenatal neurodevelopment and is linked to adverse neurobehavioral outcomes ranging from cerebral palsy to autism spectrum disorder. However, the mechanism by which a prenatal exposure to intrauterine inflammation contributes to life-long neurobehavioral consequences is unknown. To address this gap in knowledge, this study investigates how inflammation transverses across multiple anatomic compartments from the maternal reproductive tract to the fetal brain and what specific cell types in the fetal brain may cause long-term neuronal injury. Utilizing a well-established mouse model, we found that mid-gestation intrauterine inflammation resulted in a lasting neutrophil influx to the decidua in the absence of maternal systemic inflammation. Fetal immunologic changes were observed at 72-hours post-intrauterine inflammation, including elevated neutrophils and macrophages in the fetal liver, and increased granulocytes and activated microglia in the fetal brain. Through unbiased clustering, a population of Gr-1+ γ/δ T cells was identified as the earliest immune cell shift in the fetal brain of fetuses exposed to intrauterine inflammation and determined to be producing high levels of IFNγ when compared to γ/δ T cells in other compartments. In a case-control study of term infants, IFNγ was found to be elevated in the cord blood of term infants exposed to intrauterine inflammation compared to those without this exposure. Collectively, these data identify a novel cellular immune mechanism for fetal brain injury in the setting of intrauterine inflammation.

Keywords: IFNγ; fetal brain injury; intrauterine inflammation; maternal-fetal interface; neuroimmune activation; tissue-specific immunity; γ/δ T cell

DOI: https://doi.org/10.3389/fimmu.2021.741518

Cells. 2021 Oct 08. pii: 2693. [Epub ahead of print]10(10):

Maternal B Cell-Intrinsic MyD88 Signaling Mediates LPS-Driven Intrauterine Fetal Death.

Mandy Busse, Susanne Plenagl, Norina Kim Jutta Campe, Andreas J Müller, Kerry Tedford, Anne Schumacher, Ana Claudia Zenclussen.

Immunological networks balance tolerance towards paternal alloantigens during pregnancy with normal immune response to pathogens. Subclinical infections can impact this balance and lead to preterm birth or even intrauterine fetal death (IUFD). We recently showed that loss of maternal B cells renders murine fetuses susceptible to IUFD after LPS exposure. Since the signaling pathway involved in this B-cell mediated response remains unclear, we aimed to understand the participation of MyD88 in this response using B-cell-specific MyD88-deficient (BMyD88-/-) mice. B cells isolated from wild-type (WT), BMyD88-/-, CD19-/- and MyD88-/- dams on gestational day (gd) 10 responded differently to LPS concerning cytokine secretion. In vivo LPS challenge on gd 10 provoked IUFD in CD19-/- mothers with functional MyD88, while fetuses from BMyD88-/- and MyD88-/- mice were protected. These outcomes were associated with altered cytokine levels in the maternal serum and changes in CD4+ T-cell responses. Overall, the loss of MyD88 signaling in maternal B cells prevents the activation of cytokine release that leads to IUFD. Thus, while MyD88 signaling in maternal B cells protects the mother from infection, it ultimately kills the fetus. Understanding the cellular mechanisms underlying infection-driven pregnancy complications is the first step to designing powerful therapeutic strategies in the future.

Keywords: B cells; inflammation; intrauterine fetal death; pregnancy

DOI: https://doi.org/10.3390/cells10102693

Front Immunol. 2021 ;12 770242

Editorial: Adaptive Immunity in Pregnancy.

Marie-Pierre Piccinni, Sarah Anne Robertson, Shigeru Saito.

Keywords: T helper cells; T reg cells; maternal-fetal immune tolerance; placenta; pregnancy; spontaneous abortion

DOI: https://doi.org/10.3389/fimmu.2021.770242