Predicting Spontaneous Preterm Birth Using the Immunome.

Throughout pregnancy, the maternal peripheral circulation contains valuable information reflecting pregnancy progression, detectable as tightly regulated immune dynamics. Local immune processes at the maternal-fetal interface and other reproductive and non-reproductive tissues are likely to be the pacemakers for this peripheral immune "clock." This cellular immune status of pregnancy can be leveraged for the early risk assessment and prediction of spontaneous preterm birth (sPTB). Systems immunology approaches to sPTB subtypes and cross-tissue (local and peripheral) interactions, as well as integration of multiple biological data modalities promise to improve our understanding of preterm birth pathobiology and identify potential clinically actionable biomarkers.

Visualization of maternal IL-17a across the placental membrane.

IL-17a is a pro-inflammatory cytokine produced primarily by T helper-17 cells. Several studies have shown that maternal IL-17a, associated with maternal immune activation (MIA), affects the developing brain. However, the mechanisms underlying maternal IL-17a signaling remain partially unknown. This study detected trans-placental IL-17a passage using luminescent activity studies and an in vitro transfer assay. First, the luminescent activity was observed using LiCoR dye-conjugated IL-17a injected into pregnant mice. IL-17a luminescent activity was highly detected in the placenta and isolated fetus, but positive control IgG and negative control IgM showed low or no luminescence in the placenta and fetus, respectively. Next, IL-17a transmission across the placenta was investigated using a transwell experiment with trophoblast BeWo cells and primary trophoblast cells. Significant amounts of IL-17a were detected in the lower compartment. And in various placenta cell lines, IL-17a treatment significantly increased IL-17RA mRNA expression. However, it did not affect IL-17RC mRNA expression.This study showed that elevated IL-17a increased the IL-17RA expression in the trophoblast and may accumulate in the placenta. Furthermore, these results indicate the molecular basis of an important role in IL-17a/IL-17RA in the maternal placenta.

Neutrophil depletion in the pre-implantation phase impairs pregnancy index, placenta and fetus development.

Maternal neutrophils cells are players in gestational tolerance and fetus delivery. Nonetheless, their actions in each phase of the pregnancy are unknown. We here investigated the role of maternal neutrophil depletion before the blastocyst implantation phase and outcomes in the pregnancy index, placenta, and fetus development. Neutrophils were pharmacologically depleted by i.p. injection of anti-Gr1 (anti-neutrophils; 200 µg) 24 hours after plug visualization in allogeneic-mated C57BL/6/BALB/c mice. Depletion of peripheral neutrophils lasted until 48 hours after anti-Gr1 injection (gestational day 1.5-3.5). On gestational day 5.5, neutrophil depletion impaired the blastocyst implantation, as 50% of pregnant mice presented reduced implantation sites. On gestational day 18.5, neutrophil depletion reduced the pregnancy rate and index, altered the placenta disposition in the uterine horns, and modified the structure of the placenta, detected by reduced junctional zone, associated with decreased numbers of giant trophoblast cells, spongiotrophoblast. Reduced number of placenta cells labeled for vascular endothelial growth factor (VEGF), platelet-endothelial cell adhesion molecule (PECAM-1), and intercellular cell adhesion molecule (ICAM-1), important markers of angiogenesis and adhesiveness, were detected in neutrophil depleted mice. Furthermore, neutrophil depletion promoted a higher frequency of monocytes, natural killers, and T regulatory cells, and lower frequency of cytotoxic T cells in the blood, and abnormal development of offspring. Associated data obtained herein highlight the pivotal role of neutrophils actions in the early stages of pregnancy, and address further investigations on the imbricating signaling evoked by neutrophils in the trophoblastic interaction with uterine epithelium.

Up-and-down immunity of pregnancy in humans.

One part of the human placenta in early pregnancy is particularly important for local immunity: the decidua basalis, which is transformed endometrium located at the site of embryo implantation . This placental bed tissue contains both maternal uterine immune cells, including decidual natural killer (NK) cells, the dominant leukocyte population exhibiting a unique phenotype, and fetal extravillous trophoblast which comes into direct contact with maternal decidual cells . To establish a successful placental development and healthy pregnancy outcome, the maternal immune system must tolerate paternal antigens expressed by trophoblast cells yet remain efficient for clearing any local pathogen infection. This review deals mainly with decidual NK cells. A key element, among others, to achieve such dual functions is the direct interaction between activating and inhibitory receptors expressed by decidual NK cells and their specific ligands presented by trophoblast or other decidual cells. Depending whether maternal decidual cells and trophoblast are infected by viruses, the balance between activating and inhibitory receptor signals mediated by decidual NK cell-trophoblast cross-talk results in tolerance (healthy pregnancy) or specific killing (pathogen-infected cells).

Immune regulatory network in successful pregnancy and reproductive failures.

Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies, their frequency and function are reduced in reproductive defects such as recurrent miscarriage and preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine. Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg, γd T cell, Breg, MDSC, and NKT cells in pregnancy outcome.

Potential cytokine biomarkers in autism spectrum disorders.

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by impairments in three core behavioral areas. As prevalence rates for ASD continue to rise there is also increasing interest in finding biomarkers associated with ASD. The use of biomarkers could help identify those at risk for ASD or ASD-associated comorbid conditions and help to predict the developmental course of these children. Due to the heterogeneity of ASD, biomarkers may help to identify subpopulations within ASD that share similar traits or profiles. Such work could lead to specialized therapy and help to develop biomarkers whereby the benefits of treatments/therapies for individuals could be monitored over time and through clinical trials. Over the last 10 years, the evidence of immune involvement in ASD has been steadily growing and many investigators have begun to look at possible immune biomarkers, such as immune cytokine profiles, in children with ASD.