Immunobiology of Gestational Diabetes Mellitus in Post-Medawar Era

Although the concepts related to fetal immune tolerance proposed by Sir Peter Medawar in the 1950s have not withstood the test of time, they revolutionized our current understanding of the immunity at the maternal-fetal interface. An important extension of the original Medawar paradigm is the investigation into the underlying mechanisms for adverse pregnancy outcomes, including recurrent spontaneous abortion, preterm birth, preeclampsia and gestational diabetes mellitus (GDM). Although a common pregnancy complication with systemic symptoms, GDM still lacks understanding of immunological perturbations associated with the pathological processes, particularly at the maternal-fetal interface. GDM has been characterized by low grade systemic inflammation that exacerbates maternal immune responses. In this regard, GDM may also entail mild autoimmune pathology by dysregulating circulating and uterine regulatory T cells (Tregs). The aim of this review article is to focus on maternal-fetal immunological tolerance phenomenon and discuss how local or systemic inflammation has been programmed in GDM. Specifically, this review addresses the following questions: Does the inflammatory or exhausted Treg population affecting the Th17:Treg ratio lead to the propensity of a pro-inflammatory environment? Do glycans and glycan-binding proteins (mainly galectins) contribute to the biology of immune responses in GDM? Our understanding of these important questions is still elementary as there are no well-defined animal models that mimic all the features of GDM or can be used to better understand the mechanistic underpinnings associated with this common pregnancy complication. In this review, we will leverage our preliminary studies and the literature to provide a conceptualized discussion on the immunobiology of GDM.

Maternal exposure to an enrichment environment promotes uterine vascular remodeling and prevents embryo loss in mice.

Aim: Implantation-related events are crucial for pregnancy success. In particular, defects in vascular remodeling at the maternal-fetal interface are associated with spontaneous miscarriage and recurrent pregnancy loss. Physical activity and therapies oriented to reduce stress improve pregnancy outcomes. In animal models, environmental stimulation and enrichment are associated with enhanced well-being, cognitive function and stress resilience. Here we studied whether exposure of BALB/c mice to an enriched environment (EE) regulates crucial events during early gestation at the maternal-fetal interface. Method: Pregnant BALB/c mice were exposed to the EE that combines non-invasive stimuli from the sensory pathway with voluntary physical activity. The pregnancy rate was evaluated. Implantation sites were investigated microscopically and macroscopically. Vascular adaptation parameters at the maternal-fetal interface were analyzed. Results: We found that exposure to the EE prevented pregnancy loss between gestational days 7 and 15. Also, it increased the diameter of the uterine artery and decreased the wall:lumen ratio of the mesometrial decidual vessels, suggesting that EE exposure promotes vascular remodeling. Moreover, it increased nitric oxide synthase activity and inducible nitric oxide synthase expression, as well as prostaglandin F2α production and endoglin expression in the implantation sites. Conclusion: Exposure of pregnant females to the EE regulates uterine physiology, promoting vascular remodeling during early gestation. These adaptations might contribute to preventing embryo loss. Our results highlight the importance of the maternal environment for pregnancy success. The design of an “EE-like” protocol for humans could be considered as a new non-pharmacologic strategy to prevent implantation failure and recurrent miscarriage.

Inhibition of HMGB1 Ameliorates the Maternal-Fetal Interface Destruction in Unexplained Recurrent Spontaneous Abortion by Suppressing Pyroptosis Activation

Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the mechanisms are unclear. Our previous studies have found that high mobility group box 1 (HMGB1) molecules are highly expressed at the maternal-fetal interface of unexplained recurrent spontaneous abortion (URSA) patients. The purpose of this study was to further detect the expression of HMGB1 and pyroptosis in decidual tissue of URSA patients, and explore the potential mechanism of the protective role of HMGB1 in URSA patients and mouse model. The decidua tissues of 75 URSA patients and 75 women who actively terminated pregnancy were collected, and URSA mouse models were established and treated with HMGB1 inhibitor-aspirin. The expression of HMGB1, and their receptors (RAGE, TLR2, TLR4), pyroptosis-associated proteins (NLRP-3, caspase-1, GSDMD) and NF-κB was examined at the maternal-fetal interface of human and mouse. Our study found that HMGB1, NLRP-3, Caspase-1, GSDMD, RAGE, TLR2 and TLR4 were highly expressed and NF-κB signaling pathway were activated in the decidua tissue of URSA group. Moreover, immune cell disorder and co-localization of HMGB1 and macrophages were found at the maternal-fetal interface of URSA mice. However, HMGB1, TLR2, TLR4, NF-κB, and pyroptosis-associated proteins can be down-regulated by administering low-dose aspirin. These data may indicate that highly expressed HMGB1 was actively secreted by macrophages and then activated pyroptosis through the TLR2/TLR4-NF-κB pathway to cause aseptic inflammation, leading to the occurrence and development of URSA. Moreover, low-dose aspirin can reduce HMGB1 protein levels of serum and decidual in URSA.

Prenatal stress, anxiety and depression alter transcripts, proteins and pathways associated with immune responses at the maternal-fetal interface

During pregnancy, the immune system is modified to allow developmental developmental tolerance of the semi-allogeneic fetus and placenta to term. Pregnant women suffering from stress, anxiety and depression show dysfunctions of their immune system that may be responsible for fetal and/or newborn disorders, provided that provided that placental gene regulation is compromised. The present study explored the effects of maternal chronic self-perceived stress, anxiety and depression during pregnancy on the expression of immune related-genes and pathways in term placenta. Pregnancies were clinically monitored with the Beck’s Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 divided patients into two groups: Index group (≥10, n = 11) and a Control group (<10, n = 11), whose placentae were sampled at delivery. The placental samples were subjected to RNA-Sequencing, demonstrating that stress, anxiety and depression during pregnancy induced a major downregulation of placental transcripts related to immune processes such as T-cell regulation, interleukin and cytokine signaling or innate immune responses. Expression differences of main immune related genes such as CD46, CD15, CD8α & β ILR7α and CCR4 among others, were found in the index group (P < 0.05). Moreover, the key immune-like pathway involved in humoral and cellular immunity named “Primary immunodeficiency” was significantly downregulated in the index group compared to controls. Our results show that mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy. These findings may help unveil mechanisms ruling the impact of maternal psychiatric symptoms and lead to new prevention/intervention strategies in complicated pregnancies.

Identification and Validation of Immune-Related Genes and Immune Cell Infiltration in Preeclampsia

Background Preeclampsia (PE) is a complex multisystem disease and its etiology remains unclear. The aim of this study was to identify potential immune-related diagnostic genes for PE, analyze the role of immune cell infiltration in PE, and explore the mechanism underlying PE-induced disruption of immune tolerance at the maternal-fetal interface. Methods We used the PE dataset GES25906 from Gene Expression Omnibus and immune-related genes from ImmPort database. The differentially expressed genes (DEGs) were identified using the “limma” package, and the differentially expressed immune-related genes (DEIGs) were extracted from the DEGs and immune-related genes using Venn diagrams. The potential functions of DEIGs were determined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Furthermore, the protein–protein interaction network was obtained from the STRING database, and it was visualized using Cytoscape software. Least absolute shrinkage and selection operator logistic regression was used to verify the diagnostic markers of PE and build a predicting model. The model was validated using datasets GSE66273 and GSE75010. Finally, CIBERSORT was used to evaluate the infiltration of immune cells in PE tissues. Results Six genes (ACTG1, ENG, IFNGR1, ITGB2, NOD1, and SPP1) enriched in Th17 cell differentiation, cytokine-cytokine receptor interaction, innate immune response, and positive regulation of MAPK cascade pathways were identified, and a predicting model was built. Datasets GSE66273 and GSE75010 were used to validate the model, and the area under the curve was 0.8333 and 0.8107, respectively. Immune cell infiltration analysis revealed an increase in plasma cells and gamma delta T cells and a decrease in resting natural killer cells in the high score group according to the predictive model risk values. Conclusions We developed a risk model to predict PE and proved that immune imbalance at the maternal-fetal interface plays a key role in the pathogenesis of PE.

A proteomic atlas of ligand-receptor interactions at the ovine maternal-fetal interface reveals the role of histone lactylation in uterine remodeling

Well-orchestrated maternal-fetal crosstalk occurs via secreted ligands, interacting receptors, and coupled intracellular pathways between the conceptus and endometrium, and is essential for successful embryo implantation. However, previous studies mostly focus on either the conceptus or the endometrium in isolation. The lack of integrated analysis impedes our understanding of early maternal-fetal crosstalk. Herein, focusing on ligand–receptor complexes and coupled pathways at the maternal-fetal interface in sheep, we provide the first comprehensive proteomic map of ligand-receptor pathway cascades essential for embryo implantation. We demonstrate that these cascades are associated with cell adhesion and invasion, redox homeostasis, and the immune response. Candidate interactions and their physiological roles were further validated by functional experiments. We reveal the physical interaction of albumin and claudin 4 and their roles in facilitating embryo attachment to endometrium. We also demonstrate a novel function of enhanced conceptus glycolysis in remodeling uterine receptivity by inducing endometrial histone lactylation, a newly identified histone modification. Results from in vitro and in vivo models supported the essential role of lactate in inducing endometrial H3K18 lactylation and in regulating redox homeostasis and apoptotic balance to ensure successful implantation. By reconstructing a map of potential ligand-receptor pathway cascades at the maternal-fetal interface, our study presents new concepts for understanding molecular and cellular mechanisms that fine-tune conceptus-endometrium crosstalk during implantation. This provides more direct and accurate insights for developing potential clinical intervention strategies to improve pregnancy outcomes following both natural and assisted conception.