During pregnancy, the immune systems of mother and offspring are challenged by their close adjacency to balance tolerance and rejection. After birth the neonate has to continue this balance towards ...its new environment by tolerating commensals while rejecting pathogens and towards its developing tissues to avoid inflammatory damage while overcoming immunosuppression. Our group was the first to link immunosuppressive features of myeloid derived suppressor cells (MDSC) to materno-fetal tolerance, neonatal susceptibility to infection and inflammation control. Here we summarize recent advances in this dynamic field.
Newborns and especially preterm infants are much more susceptible to infections than adults. Due to immature adaptive immunity, especially innate immune cells play an important role in a newborn's ...infection defense. Neonatal neutrophils exhibit profound differences in their functionality compared to neutrophils of adults. In particular, neonates possess a relevant population of suppressive neutrophils, which not only inhibit but also specifically modulate the function of T-cells. In this study, we investigated whether neonatal neutrophils are already involved in T-cell development in the thymus. For this purpose, we used a newly developed model of antibody-mediated immune cell depletion in which we administered a depleting antibody to pregnant and then lactating dams. Using this method, we were able to sufficiently deplete Ly6G-positive neutrophils in offspring. We demonstrated that the depletion of neutrophils in newborn mice resulted in altered peripheral T-cell homeostasis with a decreased CD4+/CD8+ T-cell ratio and decreased expression of CD62L. Neutrophil depletion even affected T-cell development in the thymus, with increased double positive thymocytes and a decreased CD4+/CD8+ single positive thymocyte ratio. Altogether, we demonstrated a previously unknown mechanism mediating neutrophils' immunomodulatory effects in newborns.
Abortions are the most important reason for unintentional childlessness. During pregnancy, maternal immune cells are in close contact to cells of the semi-allogeneic fetus. Dysregulation of the ...maternal immune system leading to defective adaptation to pregnancy often plays a role in pathogenesis of abortions. Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress functions of other immune cells, especially T-cells, thereby negatively affecting diseases such as cancer, sepsis or trauma. They seem, however, also necessary for maintenance of maternal-fetal tolerance. Mechanisms regulating MDSC expansion and function during pregnancy are only incompletely understood. In tumor environment, hypoxia is crucial for MDSC accumulation and activation. Hypoxia is also important for early placenta and embryo development. Effects of hypoxia are mediated through hypoxia-inducible factor 1α (HIF-1α). In the present study we aimed to examine the role of HIF-1α in myeloid cells for MDSC accumulation and MDSC function during pregnancy and for pregnancy outcome. We therefore used a mouse model with targeted deletion of HIF-1α in myeloid cells (myeloid HIF-KO) and analyzed blood, spleens and uteri of pregnant mice at gestational day E 10.5 in comparison to non-pregnant animals and wildtype (WT) animals. Further we analyzed pregnancy success by determining rates of failed implantation and abortion in WT and myeloid HIF-KO animals. We found that myeloid HIF-KO in mice led to an abrogated MDSC accumulation in the pregnant uterus and to impaired suppressive activity of MDSC. While expression of chemokine receptors and integrins on MDSC was not affected by HIF-1α, myeloid HIF-KO led to increased apoptosis rates of MDSC in the uterus. Myeloid-HIF-KO resulted in increased proportions of non-pregnant animals after positive vaginal plug and increased abortion rates, suggesting that activation of HIF-1α dependent pathways in MDSC are important for maintenance of pregnancy.
Establishing and maintaining maternal‐fetal tolerance is essential for a successful pregnancy; failure of immunological adaptation to pregnancy leads to severe complications such as abortion or ...preterm delivery. Myeloid‐derived suppressor cells (MDSCs) are innate immune cells that suppress T‐cell responses, expand during pregnancy and thus may play a role in tolerance induction. Human leucocyte antigen G (HLA‐G) is a major histocompatibility complex (MHC) I molecule with immune‐modulatory properties, which is expressed during pregnancy. Here, we investigated the impact of HLA‐G on MDSCs accumulation and activation in pregnant women. We demonstrate that granulocytic MDSCs (GR‐MDSCs) express receptors for HLA‐G, namely immunoglobulin‐like transcript (ILT) 2 and 4, and that ILT4‐expression by GR‐MDSCs is regulated during pregnancy. Stimulation with soluble HLA‐G (sHLA‐G) increased suppressive activity of GR‐MDSCs, induced MDSCs from peripheral blood mononuclear cells (PBMCs) and led to phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and induction of indoleamine‐2,3‐dioxygenase (IDO) in myeloid cells. Effects of sHLA‐G on MDSC accumulation were mediated through ILT4. These results suggest an interaction between MDSCs and HLA‐G in humans as a potential mechanism for maintaining maternal‐fetal tolerance. Modulating MDSC function during pregnancy via HLA‐G might provide new opportunities for a therapeutic manipulation of immunological pregnancy complications.
In an in‐vitro study we showed that soluble HLA‐G (sHLA‐G) induced myeloid‐derived suppressor cells (MDSCs) from human peripheral blood mononuclear cells and increases their suppressive activity during pregnancy. MDSC expansion was mediated through the receptor ILT4 and accompanied by a phosphorylation of STAT3. Targeting MDSCs via HLA‐G could be a new strategy for treatment of immunologycal pregnancy complications.
The study aims to investigate the attitudes of medical students regarding the importance and relevance of vaccinations, whether vaccinations should be compulsory and how to employ a new teaching ...concept to deal with vaccination-critical parents. This mixed-method study consists of a quantitative questionnaire and focus groups. Quantitative data were analysed by calculating the descriptive statistics, and interviews were analysed using Mayring's content analysis. A total of 170 medical students completed the questionnaire, and 59 students participated in 9 focus groups. Students reported that they felt more confident dealing with vaccination-critical parents after learning the new teaching concept. Similar results were found for medical students prior to and during the pandemic. During the pandemic, medical students viewed vaccinations for several diseases, such as measles or COVID-19, as important (range: M = 3.56, SD = 0.54 to M = 3.97, SD = 0.17). Similar results were found for medical students prior to the pandemic (range: M = 3.26, SD = 0.77 to M = 3.94, SD = 0.24). In the focus groups, however, medical students displayed controversial attitudes regarding compulsory vaccinations. While the medical students agreed on the use of vaccination for highly infectious diseases, their level of agreement decreased depending on the severity of the disease. Practical recommendations that come out of the study are creating a trustful relationship with and delivering information to patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tolerance induction toward the semiallogeneic fetus is crucial to enable a successful pregnancy; its failure is associated with abortion or preterm delivery. Skewing T cell differentiation toward a ...Th2-dominated phenotype seems to be pivotal in maternal immune adaption, yet underlying mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that mediate T cell suppression and are increased in cord blood of healthy newborns and in peripheral blood of pregnant women. In this study, we demonstrate that granulocytic MDSCs (GR-MDSCs) accumulate in human placenta of healthy pregnancies but are diminished in patients with spontaneous abortions. Placental GR-MDSCs effectively suppressed T cell responses by expression of arginase I and production of reactive oxygen species and were activated at the maternal-fetal interface through interaction with trophoblast cells. Furthermore, GR-MDSCs isolated from placenta polarized CD4(+) T cells toward a Th2 cytokine response. These results highlight a potential role of GR-MDSCs in inducing and maintaining maternal-fetal tolerance and suggest them as a promising target for therapeutic manipulation of pregnancy complications.
During pregnancy, maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead ...to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. In the present study we analyzed the impact of the murine MHC class Ib molecule Qa-2 on pregnancy outcome
. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by a disturbed trophoblast invasion and altered spiral artery remodeling as well as protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused imbalanced immunological adaptation to pregnancy with altered immune cell and especially T-cell homeostasis, reduced T
numbers and decreased accumulation and functional activation of myeloid-derived suppressor cells. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for treatment of immunological pregnancy complications.
Infections are the main cause of death in preterm infants. Causative agents often descend from the intestinal flora of the infected neonate, indicating insufficient protection by the mucosal barrier. ...Breast milk (BM) contains different subsets of immune cells. We recently showed that BM contains significant numbers of myeloid-derived suppressor cells (MDSC)-immune cells that actively suppress pro-inflammatory immune responses-and hypothesized that the transfer of BM-MDSC may modulate the mucosal immunity of the newborn.
Percentages of MDSC in the BM from mothers of 86 preterm infants between 23 + 0 and 36 + 6 weeks of gestation during their first five postnatal weeks were analyzed by flow cytometry and correlated with maternal and infant characteristics.
Percentages of BM-MDSC positively correlated with gestational age and postnatal age. The expression of activation markers on BM-MDSC did not change with gestational age, but it decreased with postnatal age. Mothers who received antepartum tocolytics had lower percentages of BM-MDSC, and infant's sex strongly influenced percentages of BM-MDSC.
Our results point toward a role of BM-MDSC for immune regulation in the neonatal gut, making them a potential target of immune-based therapies shortly after birth.
Neutrophils are classically characterized as merely reactive innate effector cells. However, the microbiome is known to shape the education and maturation process of neutrophils, improving their ...function and immune-plasticity. Recent reports demonstrate that murine neutrophils possess the ability to exert adaptive responses after exposure to bacterial components such as LPS (Gram-negative bacteria) or LTA (Gram-positive bacteria). We now ask whether small extracellular vesicles (EVs) from the gut may directly mediate adaptive responses in neutrophils in vitro. Murine bone marrow-derived neutrophils were primed in vitro by small EVs of high purity collected from colon stool samples, followed by a second hit with LPS. We found that low-dose priming with gut microbiota-derived small EVs enhanced pro-inflammatory sensitivity as indicated by elevated levels of TNF-α, IL-6, ROS and MCP-1 and increased migratory and phagocytic activity. In contrast, high-dose priming resulted in a tolerant phenotype, marked by increased IL-10 and decreased transmigration and phagocytosis. Alterations in TLR2/MyD88 as well as TLR4/MyD88 signaling were correlated with the induction of adaptive cues in neutrophils in vitro. Taken together, our study shows that small EVs from stools can drive adaptive responses in neutrophils in vitro and may represent a missing link in the gut-immune axis.
Background Preterm delivery is a leading cause of neonatal morbidity and death. It often results from chorioamnionitis, which is a complication of bacterial vaginosis. Probiotics are effective in the ...treatment of bacterial vaginosis in women who were not pregnant; studies in pregnant woman are missing. Objective The purpose of this study was to evaluate whether an oral probiotic food supplement supports the maintenance or restoration of a normal vaginal microbiota during pregnancy. Study Design We conducted a randomized, placebo-controlled, triple-blind, parallel group trial. Oral Lactobacillus rhamnosus GR-1and L reuteri RC-14 (109 colony-forming units) or placebo were administered for 8 weeks to women with <12 completed weeks of pregnancy. Participants were enrolled at Tuebingen University Hospital and 10 recruiting gynecologic practices. Vaginal swabs were taken before and after intervention and analyzed according to the Nugent scoring system. Telephone interviews were performed before and after intervention and after delivery. Primary outcome was the proportion of swabs with normal Nugent score (<4) after intervention, compared by Fisher’s exact test in an intention-to-treat analysis. Results Three hundred twenty pregnant women were enrolled. Vaginal swabs were analyzed from 290 women before and 271 women after intervention. The proportion of normal vaginal microbiota decreased from 82.6 to 77.8% in the treatment group and from 79.1 to 74.3% in the placebo group, with no significant difference across groups after intervention ( P =.297). Conclusion Oral probiotics may be suitable for implementation in antenatal care but, as administered here, had no effect on vaginal health during mid gestation. Other application routes or probiotic preparations may be more effective in supporting vaginal microbiota during pregnancy.
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