Search Results (11)

Cell migration capacity represents an essential function of the immune system. Pregnancy involves numerous morphogenetic events, angiogenesis, the establishment of intercellular connections, and complex interactions between maternal and fetal immune systems—all requiring precisely coordinated and regulated migratory processes. Chemokines serve as master regulators of cellular migration and communication during pregnancy, with functions extending far beyond classical immunological roles. Physiological chemokine levels maintain feto-maternal tolerance through precise spatiotemporal regulation, while their dysregulation leads to catastrophic pregnancy complications such as preeclampsia and preterm birth. The chemokine system exhibits remarkable complexity through functional redundancy and promiscuity of receptors and ligands; alternative splicing generating protein diversity; decoy receptors enabling the fine-tuning of chemokine concentrations; and heterocomplex formation creating novel biological functions. Chemokines show significant promise as diagnostic and prognostic biomarkers, while specific receptor–ligand pairs represent therapeutic targets for managing pathological and life-threatening conditions during pregnancy. Thus, the chemokine system constitutes both a fundamental biological mechanism supporting pregnancy and a promising translational target for addressing complex clinical challenges in obstetric complications. To fully harness the potential of this system, it is essential to understand both its evolutionarily conserved core functions and its gestational stage-specific adaptations. Full article

Background: Hofbauer cells (HBCs) are fetal-origin macrophages in the placental villous stroma that contribute to immune tolerance at the feto–maternal interface. They predominantly display an M2 phenotype, characterized by CD206 expression. Methods: Using immunohistochemistry and morphometric analysis, we quantified HBCs, assessed CD206 intensity and morphology, and evaluated apoptotic body accumulation in placental villi. Comparisons were made among pregnancies complicated by type 1 diabetes mellitus (T1DM), gestational diabetes mellitus (GDM), and normoglycemic controls, as well as between male and female fetuses. Results: Significant effects of maternal diabetes and fetal sex on CD206 intensity were observed ([diagnosis: F = 2773.00, p < 0.0001; sex: F = 12.19, p = 0.0005]), with a strong interaction (F = 165.40, p < 0.0001). In controls, CD206 intensity was higher in female than male fetuses (p < 0.0001). Across groups, CD206 intensity decreased progressively from controls to GDM and T1DM, with a more pronounced reduction in females. Reduced CD206 was associated with elongation and irregular HBC morphology and increased IL-1β (r = −0.392, p = 0.003; r = −0.609, p < 0.0001) suggesting less tolerogenic phenotype. For apoptotic bodies, significant main effects of maternal diabetes and fetal sex were detected ([diagnosis: F = 97.16, p < 0.0001; sex: F = 15.88, p = 0.0001]). Accumulation increased progressively from controls to GDM and T1DM, with higher counts in males. Conclusions: Maternal diabetes is associated with reduced CD206 intensity, altered HBC morphology, and accumulation of apoptotic bodies in placental villi. Our results suggest greater HBC plasticity, potentially contributing to a tolerogenic placental environment in females. Full article

Since the first published report of experimental kidney transplantation in dogs in 1902, there were many experimental and clinical trials of organ transplantation, with many sacrifices. After the establishment of the surgical technique and the discovery of immunosuppressive drugs, transplantation became the definitive treatment strategy for patients with terminal organ failure. However, this is not a common therapy method due to the difficulty of solving the fundamental issues behind organ transplantation, including the shortage of donor graft, potential risks of transplant surgery and economic capability. The pre- and post-transplant management of recipients is another critical issue that may affect transplant outcome. Most liver transplant recipients experience post-transplant complications, including infection, acute/chronic rejection, metabolic syndrome and the recurrence of hepatocellular carcinoma. Therefore, the early prediction and diagnosis of these complications may improve overall and disease-free survival. Furthermore, how to induce operational tolerance is the key to achieving the ultimate goal of transplantation. In this review, we focus on liver transplantation, which is known to achieve operational tolerance in some circumstances, and the mechanical similarities and differences between liver transplant immunology and fetomaternal tolerance, autoimmunity or tumor immunity are discussed. Full article

Introduction: Trophoblast-derived angiogenic factors are considered to play an important role in the pathophysiology of various complications of pregnancy. Human Leukocyte Antigen-G (HLA-G) belongs to the non-classical human major histocompatibility complex (MHC-I) molecule and has membrane-bound and soluble forms. HLA-G is primarily expressed by extravillous cytotrophoblasts located in the placenta between the maternal and fetal compartments and plays a pivotal role in providing immune tolerance. The aim of this study was to establish a relationship between concentrations of soluble HLA-G (sHLA-G) in maternal serum and amniotic fluid at 16–22 weeks of gestation and the sonographic measurements of fetal and placental growth. Materials and methods: sHLA-G in serum and amniotic fluid, as well as fetal biometric data and placental volume and perfusion indices, were determined in 41 singleton pregnancies with no complications. The level of sHLA-G (U/mL) was tested with a sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results: The sHLA-G levels were unchanged both in amniotic fluid and serum during mid-pregnancy. The sHLA-G level in serum correlated positively with amniotic sHLA-G level (β = 0.63, p < 0.01). Serum sHLA-G level was significantly correlated with abdominal measurements (β = 0.41, p < 0.05) and estimated fetal weight (β = 0.41, p < 0.05). Conversely, amniotic sHLA-G level and placental perfusion (VI: β = −0.34, p < 0.01 and VFI: β = −0.44, p < 0.01, respectively) were negatively correlated. A low amniotic sHLA-G level was significantly associated with nuchal translucency (r = −0.102, p < 0.05). Conclusions: sHLA-G assayed in amniotic fluid might be a potential indicator of placental function, whereas the sHLA-G level in serum can be a prognostic factor for feto-placental insufficiency. Full article

Preeclampsia is the leading cause of maternal–fetal morbidity worldwide. The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PreE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and T helper (T_H) cell alterations in mice consistent with human PreE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory (Treg) cells, and promote tolerance. In mice, DCregs prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PreE in mice. C57BL/6J females were infused with AVP (24 ng/h) or saline throughout gestation via an osmotic minipump. Bone-marrow-derived DCregs were injected into AVP-infused dams at the time of the pump implantation or on gestational day (GD) 7. The blood pressure of the mice was taken throughout their pregnancy. The maternal urine proteins and T_H-associated cytokines in maternal and fetal tissues were measured on GD 18. The treatment with DCregs effectively prevented the elevation of maternal blood pressure, proteinuria, and fetal growth restriction that were observed in AVP-infused dams. Furthermore, we noted a reduction in the pro-inflammatory T_H-associated cytokines IFNγ and IL-17, while anti-inflammatory cytokines IL-4, IL-10, and TGFβ showed an increase following DCreg treatment. These outcomes provide strong evidence supporting the potential of DCregs as a valuable therapeutic approach in addressing PreE. Full article

Erythroid cells are emerging players in immunological regulation that have recently been shown to play a crucial role in fetomaternal tolerance in mice. In this work, we set ourselves the goal of discovering additional information about the molecular mechanisms of this process. We used flow cytometry to study placental erythroid cells’ composition and BioPlex for the secretome profiling of 23 cytokines at E12.5 and E19.5 in both allogeneic and syngeneic pregnancies. We found that (1) placental erythroid cells are mainly represented by CD45⁺ erythroid cells; (2) the secretomes of CD71⁺ placental erythroid cells differ from the ones in syngeneic pregnancy; (3) CCL2, CCL3, CCL4 and CXCL1 chemokines were secreted on each day of embryonic development and in both types of pregnancy studied. We believe that these chemokines lure placental immune cells towards erythroid cells so that erythroid cells can induce anergy in those immune cells via cell-bound ligands such as PD-L1, enzymes such as ARG1, and secreted factors such as TGFβ-1. Full article

Immune tolerance at the feto-maternal interface is crucial for the growth of the semi-allograft fetus in the womb. The outcome of pregnancy is dependent on a fine balance between various immunological forces. For a long time, the potential role of the immune system in pregnancy disorders has remained enigmatic. Current evidence has revealed that natural killer (NK) cells are the predominant immune cell population in the uterine decidua. NK cells cooperate with T-cells to provide an optimal microenvironment for the growth of the developing fetus by producing cytokines, chemokines, and angiogenic factors. These factors support trophoblast migration and angiogenesis which regulates the process of placentation. NK cells differentiate between “self” and “non-self” through their surface receptors known as killer-cell immunoglobulin-like receptors (KIRs). They induce immune tolerance through communication via their KIR and fetal human leucocyte antigens (HLA). KIRs are surface receptors of NKs that comprise both activating and inhibiting receptors. Due to the wide diversity manifested by its genes, the KIR repertoire is different in each individual. Significant evidence has implicated KIRs in recurrent spontaneous abortion (RSA); however, maternal KIR gene diversity in RSA is still unclear. Research has shown that immunological aberrancies including activating KIRs, NK abnormalities, and T cell downregulation are risk factors for RSA. In this review, we discuss relevant data from experimental studies on NK cell abnormalities, KIR, and T-cells in the incidence of recurrent spontaneous abortion. Full article

In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase^®, the World Health Organization’s spontaneous reporting system. We performed raw and subgroup disproportionality analyses using the reporting odds ratio and comparing ICIs with the entire database, other antineoplastic agents, and other antineoplastic agents gathered in VigiBase^® since 2011. Across 103 safety reports referring to ICI exposure during the peri-pregnancy period, 56 reported pregnancy-related outcomes, of which 46 were without concomitant drugs as potential confounding factors. No signals of disproportionate reporting were found for spontaneous abortion, fetal growth restriction, and prematurity. In light of the expanding indications of ICIs, continuous surveillance by clinicians and pharmacovigilance experts is warranted, along with pharmacoepidemiological studies on other sources of real-world evidence, such as birth records, to precisely assess ICI exposure during the peri-pregnancy period and further characterize relevant outcomes. Full article

B cells and in particular IL-10-secreting B cells emerge as important players in immune balance during pregnancy. We have recently revealed that CD19-deficient (CD19^−/−), B cell-specific IL-10-deficient (BIL-10^−/−) and B cell-deficient µMT pregnant mice are highly susceptible to LPS-induced preterm birth (PTB). We aimed to analyze the ability of IL-10-secreting cells to protect from PTB and the underlying mechanisms. Wild type (WT), CD19^−/−, BIL-10^−/− and µMT mice were treated with LPS at gd16 and the cellular immune response was investigated 24 h later. LPS-treated BIL-10^−/− dams showed a more pronounced PTB phenotype compared to WT, CD19^−/− and µMT females, and increased inflammatory and reduced anti-inflammatory mediator concentrations in the peritoneal cavity and serum. CD19^−/−, BIL-10^−/− and µMT mice displayed altered immune cell population frequencies in the blood and uterus with lower numbers of IL-10-secreting B cells and T cells. BIL-10^−/− mothers presented decreased frequencies of uterine CD4+CD25+Foxp3+ Treg cells. Co-stimulatory molecules are critical for feto-maternal tolerance and IL-10 secretion. We found dysregulated PD-1 expression in peripheral blood and ICOS expression in the uterus of CD19^−/−, BIL-10^−/− and µMT dams. Our data show that B cell-specific IL-10-signaling is essential for a balanced maternal immune response to an inflammatory stimulant that cannot be hampered without IL-10-secreting B cells. Full article

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that suppress immune responses in cancer, infection, and trauma. They mainly act by inhibiting T-cells, natural-killer cells, and dendritic cells, and also by inducing T-regulatory cells, and modulating macrophages. Although they are mostly associated with adverse prognosis of the underlying disease entity, they may display positive effects in specific situations, such as in allogeneic hematopoietic stem cell transplantation (HSCT), where they suppress graft-versus-host disease (GVHD). They also contribute to the feto-maternal tolerance, and in the fetus growth process, whereas several pregnancy complications have been associated with their defects. Human umbilical cord blood (UCB) is a source rich in MDSCs and their myeloid progenitor cells. Recently, a number of studies have investigated the generation, isolation, and expansion of UCB-MDSCs for potential clinical application associated with their immunosuppressive properties, such as GVHD, and autoimmune and inflammatory diseases. Given that a significant proportion of UCB units in cord blood banks are not suitable for clinical use in HSCT, they might be used as a significant source of MDSCs for research and clinical purposes. The current review summarizes the roles of MDSCs in the UCB, as well as their promising applications. Full article

Galectins are a family of conserved soluble proteins defined by an affinity for β-galactoside structures present on various glycoconjugates. Over the past few decades, galectins have been recognized as important factors for successful implantation and maintenance of pregnancy. An increasing number of studies have demonstrated their involvement in trophoblast cell function and placental development. In addition, several lines of evidence suggest their important roles in feto-maternal immune tolerance regulation and angiogenesis. Changed or dysregulated galectin expression is also described in pregnancy-related disorders. Although the data regarding galectins’ clinical relevance are still at an early stage, evidence suggests that some galectin family members are promising candidates for better understanding pregnancy-related pathologies, as well as predicting biomarkers. In this review, we aim to summarize current knowledge of galectins in early pregnancy as well as in pregnancy-related pathologies. Full article