American Journal of Reproductive Immunology最新文献

Problem: Although it is still uncertain whether Severe Acute Respiratory Coronavirus (SARS-CoV-2) placental infection and vertical transmission occur, inflammation during early pregnancy can have devastating consequences for gestation itself and the growing fetus. If and how SARS-CoV-2-specific immune cells negatively affect placenta functionality is still unknown.

Method of study: We stimulated peripheral blood mononuclear cells (PBMCs) from women of reproductive age with SARS-CoV-2 peptides and cocultured them with trophoblast spheroids (HTR-8/SVneo and JEG-3) to dissect if SARS-CoV-2-activated immune cells can interfere with trophoblast functionality. The activation and cytokine profile of the PBMCs were determined using multicolor flow cytometry. The functionality of trophoblast spheroids was assessed using microscopy, enzyme-linked immunosorbent assay (ELISA), and RT-qPCR.

Results: SARS-CoV-2 S and M peptides significantly activated PBMCs (monocytes, NK cells, and T cells with memory subsets) and induced the upregulation of proinflammatory cytokines, such as IFNγ. The activated PBMCs did not impact the viability, growth rate, and invasion capabilities of trophoblast spheroids. Furthermore, the hormonal production of hCG by JEG-3 spheroids was not compromised upon coculture with the activated PBMCs. mRNA transcript levels of genes involved in trophoblast spheroid functional pathways were also not dysregulated after coculture.

Conclusions: Together, the findings of our in vitro coculture model, although not fully representative of in vivo conditions, strongly support the claim that the interaction of SARS-CoV-2-activated peripheral blood immune cells with trophoblast cells at the fetal-maternal interface does not negatively affect trophoblast functionality. This goes in hand with the recommendation of vaccinating pregnant women in their first trimester.

Preeclampsia is one of the most severe obstetric complications, yet its pathogenesis remains unclear. Decidual natural killer (dNK) cells, the most abundant immune cells at the maternal-fetal interface, are closely associated with preeclampsia due to abnormalities in their quantity, phenotype, and function. This review summarizes the molecular mechanisms by which dNK cells regulate extravillous trophoblast (EVT) invasion, promote uterine spiral artery remodeling, and maintain immune tolerance. Furthermore, it explores how disruptions in these mechanisms and changes in the decidual microenvironment alter dNK cell properties, driving the progression of preeclampsia. Understanding the mechanisms of dNK cells and identifying potential therapeutic targets may provide new insights for clinical intervention.

Objectives: Given the ongoing challenges regarding the specific roles of viral infections in cancer etiology, or as cancer co-morbidities, this study assessed potential associations between anti-viral, T-cell receptor (TCR) complementarity domain region-3 (CDR3s), and clinical outcomes for ovarian cancer.

Methods: TCR CDR3s were isolated from ovarian cancer specimens for a determination of which patients had anti-viral CDR3s and whether those patients had better or worse outcomes.

Results: Analyses revealed that patients with exact matches of anti-Epstein-Barr virus (EBV) CDR3 amino acid sequences exhibited better outcomes for both overall and disease-specific survival. However, better outcomes were not observed when assessing anti-viral CDR3s representing cytomegalovirus, influenza A, or Sars-CoV-2. Due to previous occurrences of the occasional misdiagnoses of lymphoma as ovarian cancer, the frequency of anti-EBV CDR3s in lymphoma patients was determined. These frequencies were relatively high, particularly for diffuse large B-cell lymphoma.

Conclusions: These findings (i) underscore the potential value of anti-EBV immune responses in terms of patient outcomes; (ii) raise questions about the potential value of anti-EBV immunotherapies; and (iii) support further inquiry into the relationship between EBV infection and previously reported cases of ovary-resident lymphoma.

Background: Preeclampsia is a severe, multisystem complication that affects 2%-5% of pregnancies, and is a leading cause of fetal and maternal morbidity and mortality worldwide. Preeclampsia may have devastating results on maternal health and may affect offspring's immediate and long-term health. Previous studies have examined the impact of maternal preeclampsia on the long-term health outcomes of offspring, many of these studies have been limited by confounding factors that could bias the results. The classic way of analyzing the relationship between maternal preeclampsia and long-term infectious morbidity of the offspring, which typically involves comparing the rates of infectious disease hospitalization between the exposed and unexposed groups, may not be sufficient due to the potential influence of unmeasured confounding factors.

Objective: To study the association between maternal preeclampsia and long-term offspring infectious morbidity, while employing sibling-matched analysis to maximize confounder control.

Study design: A retrospective cohort was conducted, including parous women, who were diagnosed with preeclampsia in one pregnancy. A sibling-matched analysis was performed, so that one sibling was, and the other was not, prenatally exposed to maternal preeclampsia. Incidence of the offspring hospitalization with infectious morbidities were compared between the siblings, as well as the time to first hospitalization with such a diagnosis. Multivariable survival analysis was performed to adjust for confounding variables.

Results: Offspring of mothers with preeclampsia (n = 4272) were significantly (p < 0.001) at a higher risk for long-term infectious hospitalization compared to offspring of mothers without preeclampsia (n = 4272), with a hazard ratio of 1.324 (95% CI 1.168-1.503) after adjusting for maternal age, gestational age, and mode of delivery.

Conclusions: Offspring born following pregnancies complicated with preeclampsia are at increased risk for infectious morbidity, even while rigorously adjusting for confounders in a sibling analysis.

Problem: Aging alters immune function in women and can lead increased risk of infections, particularly in the female reproductive tract (FRT).

Method of study: To determine how aging affects innate immune responses in the cervical stroma of the FRT, we isolated endocervical (CX) and ectocervical (ECX) stromal fibroblasts and determine if their expression of multiple pattern recognition receptors (PRRs) and responses to viral stimulation varied with menopause and age.

Results: Constitutive expression of most PRRs did not vary with age or menopausal status in either cell type. However, the expression of TLR7, MDA5, and NOD2 by ECX stromal fibroblasts significantly increased in post-menopausal women, while the expression of NOD1 by CX stromal fibroblast also significantly increased in post-menopausal women. When stratified by age, the expression of TLR6 by CX stromal fibroblasts, and MDA5 and NOD2 by ECX stromal fibroblasts increased significantly with increasing age. Stimulation with the dsRNA viral mimic HMW poly (I:C), a ligand for MDA5, resulted in significantly increased expression of the Type I interferons (IFN) IFNβ and IFNε, the Type III interferon IFNλ1, and interferon-stimulated genes (ISGs) MxA, OAS2, and ISG15 in both cell populations. However, upregulation of IFNβ, IFNλ1, MxA, OAS2, and ISG15 in response to poly (I:C) significantly declined with increasing post-menopausal age in ECX stromal fibroblasts. There was no effect of age or menopause on either IFN or ISG expression in CX stromal fibroblasts.

Conclusion: Overall, these studies demonstrate that ECX and CX fibroblasts are phenotypically distinct populations and that increasing post-menopausal age reduces IFN and ISG upregulation in ECX stromal fibroblasts in response to viral stimulation, potentially leading to decreased protection against incoming viral pathogens in older post-menopausal women.

Recurrent pregnancy loss (RPL) represents a complication of pregnancy occurring in 1%-3% of all couples trying to conceive. About 50%-60% of RPL cases remain idiopathic, therefore therapeutic strategies seem empirical and based on unproven evidence. We investigated the efficacy of corticosteroids in women with RPL. We conducted a systematic review and meta-analysis, up to August 2024, in the PubMed, Scopus, and Web of Science databases, including studies on idiopathic RPL women and comparing corticosteroids versus control treatment. Primary outcome was the ongoing pregnancy rate beyond 12 weeks of gestation; secondary outcomes were live birth rate (LBR), stillbirth, birth weight, incidence of preeclampsia and/or gestational diabetes, gestational age at delivery, and fetal abnormalities. Four studies comprising 417 RPL women randomly assigned to steroid or control treatment were included. We found that oral corticosteroids significantly increase the ongoing pregnancy rate beyond 12 weeks of gestation compared to the control group (log OR [odds ratio] = 1.49 [0.32, 2.67], p = 0.01), with high heterogeneity (I² = 75%), and improve LBR (log OR = 0.9 [0.11, 1.69], p = 0.03), with low heterogeneity (I² = 0.05%). However, the limited number of studies significantly limits the strength of the findings. Also, the benefit/risk assessment of the use of corticosteroids in early pregnancy for RPL is still unclear.

Background: Alterations in lipid metabolism were reported to impact human fertility; however, there is limited evidence on the association of lipid metabolism with embryo implantation as well as the etiology of recurrent implantation failure (RIF), especially regarding arachidonic acid metabolism.

Methods: Experimental verification research (16 RIF patients and 30 control patients) based on GEO database analysis (24 RIF patients and 24 control patients). The methods in bioinformatics included differential gene screening, functional enrichment analysis, protein-protein interaction network, cluster analysis, weighted gene co-expression network analysis, and so forth. RIF patients were recruited for the experimental validation section. The endometrial samples in the mid-luteal phase were collected and subjected to quantitative real-time PCR detection.

Results: Genes related to oxidative stress were differentially expressed and 17 different types of immune cells exhibited diverse infiltration in three RIF subgroups with different arachidonic acid metabolism. HPGDS, ALOX12, and TBXAS1 showed a strong positive correlation with the infiltration of NK cell, on the contrary, GGT6, PLA2G12A, and PTGS2 showed a strong negative correlation. The overall expression of AAMRGs was positively correlated with the infiltration of activated CD8 T cell, macrophage, natural killer cell, and T follicular helper cell.

Conclusions: The cluster of arachidonic acid metabolism-related genes (AAMRGs) was abnormally expressed and positively associated with excessive oxidative stress as well as extensive infiltration of immune cells, including NK cells among RIF patients. Considering the high heterogeneity of the etiology of RIF, our study utilized the expression of AAMRGs as a typing basis to provide a new understanding of endometrial receptivity from the perspective of lipid metabolism and immune regulation in unexplained RIF couples, providing directions for its etiology and future basic research.

Problem: COVID-19 during pregnancy is linked to increased maternal morbidity and a higher incidence of preterm births (PTBs), yet the underlying mechanisms remain unclear. Cellular senescence, characterized by the irreversible cessation of cell division, is a critical process in placental function, and its dysregulation has been implicated in pregnancy complications like PTB. Senescence can be induced by various stressors, including oxidative stress, DNA damage, and viral infections.

Method of study: In this study, we determined whether COVID-19 had an impact on placental senescence. We examined placentas from women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 10 term, 4 preterm) compared to uninfected controls (n = 10 term, 3 preterm). The placentas were analyzed for SARS-CoV-2 infection (spike and nucleocapsid viral proteins), markers of DNA damage (γH2AX) and oxidative stress (ROS), and senescence (telomere length, cell cycle regulators, and senescence-associated secretory phenotype [SASP]).

Results: Although no overall differences in cellular senescence markers were observed between the COVID-19 positive and negative groups, we found increased secreted SASP markers. Confocal microscopy of placentas from COVID-19 positive cases revealed localized areas of oxidative stress and DNA damage colocalized with SARS-CoV-2 spike protein.

Conclusions: These findings indicate that SARS-CoV-2 infection induces localized focal placental damage, warranting further investigation into its impact on maternal and perinatal outcomes.

Problem: This study aims to evaluate the role of the systemic immune-inflammation index (SII) and the systemic immune-response index (SIRI) in predicting adverse perinatal outcomes (APO) in pregnant women with antiphospholipid syndrome (APS).

Methods: This is a retrospective case-control study at the tertiary center, between January 2015 and January 2023. The study included APS cases and a low-risk control group. Pregnant women with APS (n = 52) and controls (n = 104) were compared between SII and SIRI values taken in the first trimester (1) and the last month before birth (2). It was examined whether these indexes predicted APO in cases with APS.

Results: In the APS group, SII and SIRI values taken in the first trimester (1) and in the last month before birth (2) were significantly lower than in the control group (p = 0.015, p = 0.023, p = 0.001, p = 0.001, respectively). The small for gestational age (SGA) rate was 30.8% and the stillbirth rate was 11.5% in the APS group (p = 0.017, p = 0.001). The optimum cutoff values for SGA were 584.97 (75% sensitivity, 77.8% specificity), 688.50 (62.5% sensitivity, 62.9% specificity), and 1.02 (56.3% sensitivity, 77.8% specificity) for SII 1, SII 2, and SIRI 1, respectively. The optimum cutoff value for stillbirth was 1.23 for SIRI 2 (83.3% sensitivity, 89.1% specificity, p = 0.004).

Conclusion: Pregnant women with APS had decreased blood indices in the first trimester and the last month before birth compared to the control group. In cases with APS, these indices can predict APOs like SGA and stillbirth.

Purpose: Characterized as a prevalent sexually transmitted infection, Chlamydia trachomatis is intimately associated with reproductive tract complications, including pelvic inflammatory disease (PID) and infertility. However, the causal relationships between C. trachomatis infection and reproductive tract complications remain elusive.

Methods: To investigate the causal relationships between C. trachomatis antibodies and seven reproductive tract complications, we conducted a bidirectional Mendelian randomization (MR) analysis. The fundamental data were originated from the genome-wide association studies (GWAS) database. While the influences of C. trachomatis antibodies on reproductive tract complications such as tubal factor infertility (TFI) and PID have been assessed, the reverse MR analysis examined how these complications impacted C. trachomatis antibodies.

Results: The forward MR analysis revealed that the upregulation of MOMP A antibodies was significantly associated with a reduced risk of TFI (OR = 0.932, p = 0.007), while MOMP D antibodies were associated with a reduced risk of ectopic pregnancy (EP) (OR = 0.923, p = 0.005). However, no significant causal interactions were identified for other reproductive complications. Moreover, the reverse MR analysis indicated that cervicitis was significantly correlated with lower MOMP A antibody levels (OR = 0.900, p = 0.016).

Conclusions: This study demonstrates the protective effects of C. trachomatis antibodies, particularly MOMP A and MOMP D, against TFI and EP, respectively. It also emphasizes the potential role of cervical inflammation in shaping immune responses to C. trachomatis. These insights provide a foundation for future research to develop immune-targeted therapies and integrated approaches for preventing and managing C. trachomatis-related reproductive tract complications.