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1.
J Reprod Immunol ; 145: 103305, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33725526

RESUMO

Air pollution is associated with preterm birth (PTB), potentially via inflammation. We recently showed the mixture benzene, toluene, ethylbenzene, and xylene (BTEX) is associated with PTB. We examined if ambient BTEX exposure is associated with mid-pregnancy inflammation in a sample of 140 African-American women residing in Detroit, Michigan. The Geospatial Determinants of Health Outcomes Consortium study collected outdoor air pollution measurements in Detroit; these data were coupled with Michigan Air Sampling Network measurements to develop monthly BTEX concentration estimates at a spatial density of 300 m2. First trimester and mid-pregnancy BTEX exposure estimates were assigned to maternal address. Mid-pregnancy (mean 21.3 ± 3.7 weeks gestation) inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin [IL]-6, IL-10, IL-1ß, and tumor necrosis factor-α) were measured with enzyme immunoassays. After covariate adjustment, for every 1-unit increase in first trimester BTEX, there was an expected mean increase in log-transformed IL-1ß of 0.05 ± 0.02 units (P = 0.014) and an expected mean increase in log-transformed tumor necrosis factor-α of 0.07 ± 0.02 units (P = 0.006). Similarly, for every 1-unit increase in mid-pregnancy BTEX, there was a mean increase in log IL-1ß of 0.06 ± 0.03 units (P = 0.027). There was no association of either first trimester or mid-pregnancy BTEX with high-sensitivity C-reactive protein, IL-10, or IL-6 (all P > 0.05). Ambient BTEX exposure is associated with inflammation in mid-pregnancy in African-American women. Future studies examining if inflammation mediates associations between BTEX exposure and PTB are needed.

2.
Bioinformatics ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33693506

RESUMO

MOTIVATION: COVID-19 has several distinct clinical phases: a viral replication phase, an inflammatory phase, and in some patients, a hyper-inflammatory phase. High mortality is associated with patients developing cytokine storm syndrome. Treatment of hyper-inflammation in these patients using existing, approved therapies with proven safety profiles could address the immediate need to reduce mortality. RESULTS: We analyzed the changes in the gene expression, pathways and putative mechanisms induced by SARS-CoV2 in NHBE, and A549 cells, as well as COVID-19 lung vs. their respective controls. We used these changes to identify FDA approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. We identified methylprednisolone (MP) as a potential leading therapy. The results were then confirmed in five independent validation data sets including Vero E6 cells, lung and intestinal organoids, as well as additional patient lung sample vs. their respective controls. Finally, the efficacy of MP was validated in an independent clinical study. Thirty-day all-cause mortality occurred at a significantly lower rate in the MP-treated group compared to control group (29.6% vs. 16.6%, p = 0.027). Clinical results confirmed the in silico prediction that MP could improve outcomes in severe cases of COVID-19. A low number needed to treat (NNT = 5) suggests MP may be more efficacious than dexamethasone or hydrocortisone. AVAILABILITY: iPathwayGuide is available at https://ipathwayguide.advaitabio.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

3.
Front Immunol ; 12: 631044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613576

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has been raging around the world since January 2020. Pregnancy places the women in a unique immune scenario which may allow severe COVID-19 disease. In this regard, the potential unknown effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mothers and fetuses have attracted considerable attention. There is no clear consistent evidence of the changes in the immune status of pregnant women after recovery from COVID-19. In this study, we use multiparameter flow cytometry and Luminex assay to determine the immune cell subsets and cytokines, respectively, in the peripheral blood and umbilical cord blood from pregnant women recovering from COVID-19 about 3 months (n=5). Our results showed decreased percentages of Tc2, Tfh17, memory B cells, virus-specific NK cells, and increased percentages of naive B cells in the peripheral blood. Serum levels of IL-1ra and MCP-1 showed a decreased tendency in late recovery stage (LRS) patients. Meanwhile, there was no significant difference in immune cell subsets in the umbilical cord blood. The placentas from LRS patients showed increased CD68+ macrophages infiltration and mild hypoxic features. The inflammatory damage of the placenta may be related to the antiviral response. Since the receptors, ACE2 and TMPRSS2, utilized by SARS-CoV-2 are not co-expressed in the placenta, so it is extremely rare for SARS-CoV-2 to cause infection through this route and the impact on the fetus is negligible.


Assuntos
Linfócitos B/imunologia , Sangue Fetal/imunologia , Centro Germinativo/imunologia , Placenta/imunologia , Células Th17/imunologia , /metabolismo , Autoantígenos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Memória Imunológica , Imunofenotipagem , Células Matadoras Naturais , Gravidez , Receptores de Interleucina-1/metabolismo , Serina Endopeptidases/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-33255777

RESUMO

Volatile organic compounds (VOCs) are a group of aromatic or chlorinated organic chemicals commonly found in manufactured products that have high vapor pressure, and thus vaporize readily at room temperature. While airshed VOCs are well studied and have provided insights into public health issues, we suggest that belowground VOCs and the related vapor intrusion process could be equally or even more relevant to public health. The persistence, movement, remediation, and human health implications of subsurface VOCs in urban landscapes remain relatively understudied despite evidence of widespread contamination. This review explores the state of the science of subsurface movement and remediation of VOCs through groundwater and soils, the linkages between these poorly understood contaminant exposure pathways and health outcomes based on research in various animal models, and describes the role of these contaminants in human health, focusing on birth outcomes, notably low birth weight and preterm birth. Finally, this review provides recommendations for future research to address knowledge gaps that are essential for not only tackling health disparities and environmental injustice in post-industrial cities, but also protecting and preserving critical freshwater resources.

5.
J Leukoc Biol ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33242368

RESUMO

The SARS-CoV-2 pandemic has led to hundreds of thousands of deaths and billions of dollars in economic damage. The immune response elicited from this virus is poorly understood. An alarming number of cases have arisen where COVID-19 patients develop complications on top of the symptoms already associated with SARS, such as thrombosis, injuries of vascular system, kidney, and liver, as well as Kawasaki disease. In this review, we have used a bioinformatics approach to elucidate the immune response triggered by SARS-CoV-2 infection in primary human lung epithelial and transformed human lung alveolar. Additionally, we have examined the potential mechanism behind several complications that have been associated with COVID-19 and determined that a specific cytokine storm is leading to excessive neutrophil recruitment. These neutrophils are directly leading to thrombosis, organ damage, and complement activation via neutrophil extracellular trap release.

6.
J Reprod Immunol ; 142: 103214, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33152658

RESUMO

Alterations in the number and protein/gene expression of Hofbauer cells (HBCs) may play a role in microbial-driven/cytokine-mediated placental inflammation, and in subsequent pregnancy complications such as villitis, histologic chorioamnionitis, and the fetal inflammatory response syndrome. Pyroptosis is an inflammatory form of cell death mediated by the inflammasome, a multi-protein complex which drives the processing and secretion of interleukin 1 beta (IL-1ß). Pyroptosis can be triggered by bacterial lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in non-placental macrophages through activation of the NLRP3 inflammasome. However, the role of inflammasome activation and pyroptosis in HBC pathophysiology remains unclear. HBCs isolated from human term placentas were treated with or without LPS or ATP, alone or in combination. Treatment of HBCs with both LPS and ATP induced the rapid secretion of high levels of IL-1ß and at the same time, cell death associated with nuclear condensation and cellular swelling. HBC treatment with both LPS and ATP induced caspase-1 activation, gasdermin D (GSDMD) cleavage, which mediates pyroptosis, and IL-1ß processing. Caspase-1 activation, GSDMD cleavage, IL-1ß processing, and IL-1ß secretion were all significantly reduced following NLRP3 knockdown; inhibition of caspase-1; and inhibition of P2X7, the receptor that mediates K+ efflux. Together, our data indicate that LPS and ATP treatment stimulated NLRP3 inflammasome activation and pyroptosis in HBCs leading to the rapid release of IL-1ß. Since the localization of HBCs confers a unique ability to influence microbial-associated placental and fetal inflammation, these studies suggest a key role for the inflammasome and pyroptosis in mediating HBC driven inflammation.

7.
Hum Reprod ; 35(11): 2454-2466, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33107565

RESUMO

STUDY QUESTION: What is the mechanism of Tim-3+ regulatory T (Treg)-cell accumulation in the decidua during early pregnancy and is its disruption associated with recurrent pregnancy loss (RPL)? SUMMARY ANSWER: IL-27 and Gal-9 secreted by trophoblasts activate the Tim-3 signaling pathway in CD4+ T cells and Treg cells and so promote accumulation of Tim-3+ Treg cells, the abnormal expression of IL-27 and Gal-9 is associated with impaired immunologic tolerance in RPL patients. WHAT IS KNOWN ALREADY: Tim-3+ Treg cells are better suppressors of Teff cell proliferation, and display higher proliferative activity than Tim-3- Treg cells. Tim-3+ Treg cells are tissue-specific promoters of T-cell dysfunction in many tumors. These cells express a unique factor that influences and shapes the tumor microenvironment. STUDY DESIGN, SIZE, DURATION: The animal study included 80 normal pregnant mice. In human study, decidua tissues in the first trimester for flow cytometry analysis were collected from 32 normal pregnant women and 23 RPL patients. Placenta tissues for immunohistochemistry analysis were collected from 15 normal pregnant women. Placenta tissues for western blot analysis were collected from 5 normal pregnant women, 5 RPL patients and 5 women who have experienced one miscarriage. Blood samples for in vitro experiments were collected from 30 normal pregnant women. This study was performed between January 2017 and March 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we investigated the kinetics of Tim-3+ CD4+ T-cell accumulation, and the proportions of Tim-3+ Treg cells throughout murine pregnancies using flow cytometry. We compared Tim-3 expression on decidual CD4+ T cells and Treg cells during normal pregnancies with expression on the same cell populations in women suffering from RPL. IL-27 and Gal-9 transcription and protein expression in the placenta were determined by RT-PCR and western blot, respectively. An in vitro co-culture model consisting of peripheral CD4+ T cells and primary trophoblasts from early pregnancy was used to mimic the maternal-fetal environment. MAIN RESULTS AND THE ROLE OF CHANCE: The percentage of Tim-3+ Treg cells present in mouse uteri fluctuates as gestation proceeds but does not change in the spleen. Levels of Tim3+ Treg cells in uteri peaked at pregnancy Day 6.5 (E 6.5), then progressively diminished, and fell to non-pregnant levels by E18.5. In pregnant mice, Tim-3+ Treg cells constituted 40-70% of Treg cells in uteri but were present at much lower abundance in spleens. About 60% of decidual Treg cells were Tim-3 positive at E6.5. Of these decidual Tim3+ Treg cells, nearly 90% were PD-1 positive. However, only about 16% of Tim3- Treg cells expressed PD-1. Blocking the Tim-3 signaling pathway decreased the proportion of Treg cells and led to embryo resorption. Moreover, much lower Tim-3 expression was observed on CD4+ T cells and Treg cells in women who had suffered from RPL at 6-9 gestational weeks compared with those who had normal pregnancies at matched gestations. In a normal pregnancy, Tim-3 expression on decidual CD4+ T cells is induced initially by IL-27. Then Gal-9-Tim-3 interaction promotes differentiation of decidual Tim-3+ CD4+ T cells into Treg cells. IL-27 and Gal-9 cooperatively induced Tim-3+ Treg cells in vitro. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: We did not investigate the kinetics of human decidual Tim-3+ CD4+ T and Tim-3+ Treg cell populations throughout pregnancy due to limited availability of second and third trimester decidua. In addition, functional suppressive data on the decidual Tim-3+ Treg cells are lacking due to limited and low quantities of these cells in decidua. WIDER IMPLICATIONS OF THE FINDINGS: These findings might have therapeutic clinical implications in RPL. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the National Natural Science Foundation of China (No. 81871186) and National Key Research & Developmental Program of China (2018YFC1003900, 2018YFC1003904). The authors declare no conflict of interest.

8.
Placenta ; 100: 122-132, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927240

RESUMO

INTRODUCTION: The limited cell number of primary trophoblasts and contamination of trophoblast cell lines promote us to develop a novel stable trophoblast cell line. METHOD OF STUDY: Primary trophoblast cells were isolated from first-trimester placenta and telomerase-induced immortalization was used to immortalize these cells. Subsets of cells were then evaluated by flow cytometry using CK7, HLA-G, CD45 and CD14, specific markers for trophoblast cells, extra-villous trophoblast, pan leucocyte and monocyte/macrophage, respectively. Immunofluorescence staining and immunocytochemistry were used to detect CK7 expression in trophoblast cells. The level of secreted human Chorionic Gonadotropin (hCG) was measured by electrochemiluminescence (ECL). The Bio-Plex MAGPIX System was used to analyze the cytokines and chemokines produced by AL07 cell line. RESULTS: We were able to isolate primary trophoblast cells from several first-trimester placentas. One clone, AL07 trophoblast cells, isolated from a week 7 placenta, was morphologically stable and positive for the expression of CK7 by immunofluorescence and immunocytochemistry staining. Characterization of AL07 cells reveled that they are CD45 or CD14 negative and had constitutive secretion of hCG and low HLA-G expression. Furthermore, clone AL07 secret high levels of several cytokines and chemokines, including IL-6, IL-8 and VEGF, and moderately secreted MCP-1 IP-10 and RANTES. DISCUSSION: We report the successful isolation, immortalization and characterization of AL07 cells, a novel cell clone isolated from first trimester human placenta. The clone is free of contamination of immune cells, and exhibits similar cytokine profile as other trophoblast cell lines. This new cytotrophoblast-like AL07 cell, can be a valuable tool for in-vitro trophoblast studies in the future.

10.
Am J Reprod Immunol ; : e13348, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32946159

RESUMO

PROBLEM: It is unknown whether maternal cytokine production differs between twin and singleton gestations in the implantation phase. A difference in maternal serum cytokine concentrations in twins would imply a dose-response to the invading embryos, as opposed to a general immune reaction. METHOD OF STUDY: A prospective longitudinal cohort of women aged 18-45 at an academic fertility center undergoing in vitro fertilization and embryo transfer (IVF-ET) underwent routine collection of serial serum samples starting 9 days after ET and then approximately every 48 hours thereafter. Cryopreserved aliquots of these samples were assayed for interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and C-X-C motif chemokine ligand 10 (CXCL10) using the SimplePlex immunoassay platform. Pregnancies were followed until delivery. Serial measures of serum concentrations of IL-10, CXCL10, and TNF-α in singleton or di-di twin pregnancies from 9 to 15 days after IVF-ET were compared. RESULTS: Maternal serum levels of CXCL10 are significantly lower in women with di-di twin pregnancies in early implantation compared to those with singleton gestation (day 9-11, P = .02). Serum levels of TNF-α and IL-10 were comparable at all studied time points (P > .05). CONCLUSION: Maternal serum levels of CXCL10 are significantly lower in the earliest implantation phase in di-di twins compared to singleton conceptions. Given the known anti-angiogenic role of CXCL10, we hypothesize that lower CXCL10 levels in twin implantations allow an environment that is conducive for the greater vascularization required for the establishment of dual placentation in di-di twins.

11.
J Obstet Gynaecol Res ; 46(10): 1958-1966, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32779342

RESUMO

At the end of 2019, a new coronavirus disease, COVID-19, emerged and quickly spread around the world. Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the causative virus of this disease, belongs to the ß-coronavirus family, together with SARS and middle east respiratory syndrome, and has similar biological characteristics to these viruses. For obstetricians, the susceptibility and prognoses of pregnant women and the effects of the infection on the fetus have been the focus of attention; however, at present, the seriousness of the disease in pregnant women is not apparent, and COVID-19 does not increase the rate of miscarriage, stillbirth, preterm labor or teratogenicity. Even so, carriers might transmit SARS-CoV-2 to pregnant women. Thus, we must keep in mind that all medical personnel must understand and maintain standard precautions in their clinical and laboratory practices.


Assuntos
Betacoronavirus , Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/virologia , Feminino , Humanos , Pandemias , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia
12.
Am J Reprod Immunol ; 84(5): e13304, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32662111

RESUMO

Caused by a novel type of virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) constitutes a global public health emergency. Pregnant women are considered to have a higher risk of severe morbidity and even mortality due to their susceptibility to respiratory pathogens and their particular immunologic state. Several studies assessing SARS-CoV-2 infection during pregnancy reported adverse pregnancy outcomes in patients with severe conditions, including spontaneous abortion, preterm labor, fetal distress, cesarean section, preterm birth, neonatal asphyxia, neonatal pneumonia, stillbirth, and neonatal death. However, whether these complications are causally related to SARS-CoV-2 infection is not clear. Here, we reviewed the scientific evidence supporting the contributing role of Treg/Th17 cell imbalance in the uncontrolled systemic inflammation characterizing severe cases of COVID-19. Based on the recognized harmful effects of these CD4+ T-cell subset imbalances in pregnancy, we speculated that SARS-CoV-2 infection might lead to adverse pregnancy outcomes through the deregulation of otherwise tightly regulated Treg/Th17 ratios, and to subsequent uncontrolled systemic inflammation. Moreover, we discuss the possibility of vertical transmission of COVID-19 from infected mothers to their infants, which could also explain adverse perinatal outcomes. Rigorous monitoring of pregnancies and appropriate measures should be taken to prevent and treat early eventual maternal and perinatal complications.

13.
Oncoimmunology ; 9(1): 1758869, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32566387

RESUMO

Ovarian cancer accounts for most deaths from gynecologic malignancies. Although more than 80% of patients respond to first-line standard of care, most of these responders present with recurrence and eventually succumb to carcinomatosis and chemotherapy-resistant disease. To improve patient survival, new modalities must, therefore, target or prevent recurrent disease. Here we describe for the first time a novel syngeneic mouse model of recurrent high-grade serous ovarian cancer (HGSOC), which allows immunotherapeutic interventions in a time course relevant to human carcinomatosis and disease course. Using this model, we demonstrate the efficacy of Transimmunization (TI), a dendritic cell (DC) vaccination strategy that uses autologous and physiologically derived DC loaded with autologous whole tumor antigens. TI has been proven successful in the treatment of human cutaneous T cell lymphoma and we report for the first time its in vivo efficacy against an intra-peritoneal solid tumor. Given as a single therapy, TI is able to elicit an effective anti-tumor immune response and inhibit immune-suppressive crosstalks with sufficient power to curtail tumor progression and establishment of carcinomatosis and recurrent disease. Specifically, TI is able to inhibit the expansion of tumor-associated macrophages as well as myeloid-derived suppressive cells consequently restoring T cell immune-surveillance. These results demonstrate the possible value of TI in the management of ovarian cancer and other intra-peritoneal tumors.

14.
J Leukoc Biol ; 108(3): 983-998, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32386458

RESUMO

Decidual macrophages are in close contact with trophoblast cells during placenta development, and an appropriate crosstalk between these cellular compartments is crucial for the establishment and maintenance of a healthy pregnancy. During different phases of gestation, macrophages undergo dynamic changes to adjust to the different stages of fetal development. Trophoblast-secreted factors are considered the main modulators responsible for macrophage differentiation and function. However, the phenotype of these macrophages induced by trophoblast-secreted factors and the factors responsible for their polarization has not been elucidated. In this study, we characterized the phenotype and function of human trophoblast-induced macrophages. Using in vitro models, we found that human trophoblast-educated macrophages were CD14+ CD206+ CD86- and presented an unusual transcriptional profile in response to TLR4/LPS activation characterized by the expression of type I IFN-ß expression. IFN-ß further enhances the constitutive production of soluble programmed cell death ligand 1 (PD-L1) from trophoblast cells. PD-1 blockage inhibited trophoblast-induced macrophage differentiation. Soluble PD-L1 (sPD-L1) was detected in the blood of pregnant women and increased throughout the gestation. Collectively, our data suggest the existence of a regulatory circuit at the maternal fetal interface wherein IFN-ß promotes sPD-L1 expression/secretion by trophoblast cells, which can then initiate a PD-L1/PD-1-mediated macrophage polarization toward an M2 phenotype, consequently decreasing inflammation. Macrophages then maintain the expression of sPD-L1 by the trophoblasts through IFN-ß production induced through TLR4 ligation.

15.
Sci Rep ; 10(1): 5785, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238853

RESUMO

The process of implantation, trophoblast invasion and placentation demand continuous adaptation and modifications between the trophoblast (embryonic) and the decidua (maternal). Within the decidua, the maternal immune system undergoes continued changes, as the pregnancy progress, in terms of the cell population, phenotype and production of immune factors, cytokines and chemokines. Human chorionic gonadotropin (hCG) is one of the earliest hormones produced by the blastocyst and has potent immune modulatory effects, especially in relation to T cells. We hypothesized that trophoblast-derived hCG modulates the immune population present at the maternal fetal interface by modifying the cytokine profile produced by the stromal/decidual cells. Using in vitro models from decidual samples we demonstrate that hCG inhibits CXCL10 expression by inducing H3K27me3 histone methylation, which binds to Region 4 of the CXCL10 promoter, thereby suppressing its expression. hCG-induced histone methylation is mediated through EZH2, a functional member of the PRC2 complex. Regulation of CXCL10 expression has a major impact on the capacity of endometrial stromal cells to recruit CD8 cells. We demonstrate the existence of a cross talk between the placenta (hCG) and the decidua (CXCL10) in the control of immune cell recruitment. Alterations in this immune regulatory function, such as during infection, will have detrimental effects on the success of the pregnancy.

16.
J Reprod Immunol ; 139: 103122, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32244166

RESUMO

The 2019 novel coronavirus disease (COVID-19) was first detected in December 2019 and became epidemic in Wuhan, Hubei Province, China. COVID-19 has been rapidly spreading out in China and all over the world. The virus causing COVID-19, SARS-CoV-2 has been known to be genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV) but distinct from it. Clinical manifestation of COVID-19 can be characterized by mild upper respiratory tract infection, lower respiratory tract infection involving non-life threatening pneumonia, and life-threatening pneumonia with acute respiratory distress syndrome. It affects all age groups, including newborns, to the elders. Particularly, pregnant women may be more susceptible to COVID-19 since pregnant women, in general, are vulnerable to respiratory infection. In pregnant women with COVID-19, there is no evidence for vertical transmission of the virus, but an increased prevalence of preterm deliveries has been noticed. The COVID-19 may alter immune responses at the maternal-fetal interface, and affect the well-being of mothers and infants. In this review, we focused on the reason why pregnant women are more susceptible to COVID-19 and the potential maternal and fetal complications from an immunological viewpoint.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Complicações Infecciosas na Gravidez/imunologia , China , Infecções por Coronavirus/patologia , Feminino , Humanos , Pandemias , Pneumonia Viral/patologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Nascimento Prematuro/etiologia
17.
J Reprod Immunol ; 140: 103126, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32289593

RESUMO

The maternal-fetal interface possesses innate immune strategies to protect against infections. We previously reported that prior viral infection of human fetal membranes (FMs) in vitro and mouse FMs in vivo sensitized the tissue to low dose bacterial LPS leading to augmented inflammation. The objective of this study was to examine FM production of type I interferons (IFNs) and IFN-stimulated genes (ISGs) in the context of this polymicrobial model. Human FM explants and pregnant C57BL/6 mice were treated with or without low dose LPS following exposure to media or the γ-herpes virus, MHV-68. FM RNA was analyzed by qRT-PCR for type I IFNs, ISGs, upstream signaling, and MHV-68 open reading frames (ORFs). Pre-exposure to MHV-68 followed by LPS treatment inhibited the ability of LPS to induce human FM type I IFNs (IFNA, IFNB); ISGs (OAS, MxA, APOBEC3G) and upstream signaling mediators (RIG-I, TBK-1). Signaling mediators IRF-3 and IRF-7 were also reduced. In mouse FMs, pre-exposure to MHV-68 followed by LPS treatment reduced the ability of LPS to upregulate Ifna, Ifnb, Mxa, Irf7, and also reduced Irf3. MHV-68 infection of FMs induced ORF45 which targets IRF-7, and this was further augmented in response to a combination of MHV-68 and LPS. Together, these findings indicate that a viral infection blunts FM type I IFN production and signaling in response to LPS leading to a suppressed ISG response. Our studies suggest that a viral infection inhibits this protective FM response by negatively regulating IRF-7 through ORF45, leaving the maternal-fetal interface vulnerable to further viral attack.

18.
Front Immunol ; 11: 279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32180770

RESUMO

Aerobic glycolysis is a recognized feature shared by tumors, leading to the accumulation of lactic acid in their local microenvironments. Like the tumors, the blastocysts, placenta, trophoblasts and decidual immune cells can also produce a large amount of lactic acid through aerobic glycolysis during the early pregnancy. Moreover, the placenta expresses the transporters of the lactic acid. While several studies have described the role of lactic acid in the tumor microenvironment, especially lactic acid's modulation of immune cells, the role of lactic acid produced during pregnancy is still unclear. In this paper, we reviewed the scientific evidence detailing the effects of lactic acid in the tumor microenvironment. Based on the influence of the lactic acid on immune cells and tumors, we proposed that lactic acid released in the unique uterine environment could have similar effects on the trophoblast cells and immune cells during the early pregnancy.

19.
Oncogene ; 39(20): 3965-3979, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205869

RESUMO

Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.


Assuntos
Carcinogênese/metabolismo , Transição Epitelial-Mesenquimal , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/biossíntese , Neoplasias Ovarianas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Elementos de Resposta , Proteína 1 Relacionada a Twist/biossíntese , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Complexo Repressor Polycomb 1/genética , Transcrição Genética , Proteína 1 Relacionada a Twist/genética
20.
Placenta ; 91: 59-65, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32174308

RESUMO

INTRODUCTION: Placental viral infections are associated with fetal inflammation and adverse pregnancy outcomes. However, there have been limited studies on how placental macrophages in the villous and adjacent fetal umbilical endothelial cells respond to a viral insult. This study aimed to evaluate the communication between Hofbauer cells (HBCs) and human umbilical vein endothelial cells (HUVECs) during a viral infection. METHODS: HBCs were either uninfected or infected with the γ-herpesvirus, MHV-68, and the conditioned medium (CM) collected. HUVECs were exposed to HBC CM and the levels of the pro-neutrophilic response markers: IL-8; E-selectin; intercellular adhesion molecule 1 (ICAM-1); and vascular adhesion molecule 1 (VCAM-1) measured by ELISA and qPCR. The role of HBC-derived IL-1ß was investigated using an IL-1ß blocking antibody (Ab) or IL-1 receptor antagonist (IL-1Ra). RESULTS: MHV-68 infection of HBCs induced a significant increase in IL-1ß secretion. CM from infected HBCs induced HUVEC expression of IL-8, E-selectin, VCAM-1, ICAM-1 mRNA, and secretion of IL-8. The HUVEC response to the CM of MHV-infected HBCs was inhibited by a neutralizing IL-1ß Ab and by IL-1Ra. DISCUSSION: Virally-induced HBC IL-1ß activates HUVECs to generate a pro-neutrophilic response. This novel cell-cell communication pathway may play an important role in the genesis of fetal inflammation associated with placental viral infection.

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