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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809077

RESUMO

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14+ monocytes and co-cultures of CD4+ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission.


Assuntos
Vesículas Extracelulares/genética , Imunidade/genética , Esclerose Múltipla/genética , Proteoma/genética , Comunicação Celular/genética , Técnicas de Cocultura , Citocinas/genética , Decídua/imunologia , Decídua/metabolismo , Vesículas Extracelulares/imunologia , Feminino , Humanos , Imunomodulação/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Placenta/imunologia , Placenta/metabolismo , Gravidez , Linfócitos T Reguladores/imunologia , Trofoblastos/imunologia , Trofoblastos/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805739

RESUMO

As most recently demonstrated by the SARS-CoV-2 pandemic, congenital and perinatal infections are of significant concern to the pregnant population as compared to the general population. These outcomes can range from no apparent impact all the way to spontaneous abortion or fetal infection with long term developmental consequences. While some pathogens have developed mechanisms to cross the placenta and directly infect the fetus, other pathogens lead to an upregulation in maternal or placental inflammation that can indirectly cause harm. The placenta is a temporary, yet critical organ that serves multiple important functions during gestation including facilitation of fetal nutrition, oxygenation, and prevention of fetal infection in utero. Here, we review trophoblast cell immunology and the molecular mechanisms utilized to protect the fetus from infection. Lastly, we discuss consequences in the placenta when these protections fail and the histopathologic result following infection.


Assuntos
Imunidade , Placenta/imunologia , Placenta/virologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Viroses/imunologia , Vírus/imunologia , Feminino , Feto/imunologia , Feto/virologia , Humanos , Placenta/patologia , Gravidez , Trofoblastos/imunologia , Trofoblastos/virologia
4.
Int J Mol Sci ; 22(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578919

RESUMO

Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved in trophoblast cell-cell fusion (aka syncytialization). Here we will review and summarize several of the mechanisms that support healthy maternal-fetal immune interactions specifically at syncytiotrophoblast interfaces.


Assuntos
Trofoblastos/imunologia , Animais , Vilosidades Coriônicas/imunologia , Vesículas Extracelulares/imunologia , Feminino , Humanos , Imunidade , Placenta/imunologia , Placentação , Gravidez , Receptores Toll-Like/imunologia
5.
J Med Virol ; 93(5): 2769-2773, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33559937

RESUMO

The coronavirus disease 2019 (COVID-19), which had spread to the world from Wuhan (China) in late December, was announced as a pandemic by the World Health Organization in March 2020. In addition to acute respiratory syndrome symptoms, this virus also affects nonrespiratory organs, according to existing data. ACE2 and TMPRSS2, which play a critical role in the entrance of SARS-COV-2 into the cell, are coexpressed in placental development stages, so the placenta also carries a risk for this virus. Many studies have shown that this virus causes some histopathological changes in the placenta. The vertical transmission of the virus is not yet clear, but available data have shown that the indirect effects of the virus can be seen on the fetus. This article focuses on revealing the effects of the virus on the placenta in all aspects.


Assuntos
/epidemiologia , Placenta/virologia , Complicações Infecciosas na Gravidez/epidemiologia , /genética , /imunologia , /transmissão , Síndrome da Liberação de Citocina/imunologia , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa , Placenta/citologia , Placenta/imunologia , Placenta/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transplante de Células-Tronco
6.
Early Hum Dev ; 155: 105322, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571742

RESUMO

From the moment of the identification of SARS-CoV-2 as an etiological agent of the severe clinical pictures of pneumonia that were being slowly observed all over the world, numerous studies have been conducted to increase the knowledge about what was an unknown virus until then. The efforts were mainly aimed to acquire epidemiological, microbiological, pathogenetic, clinical, diagnostic, therapeutic and preventive information in order to increase the available weapons to fight an infection which was rapidly taking on the characteristics of the pandemic. Given the topicality of the problem, not everything has yet been fully understood and clarified, especially in the maternal-fetal­neonatal field, where we are beginning to question what could be the outcomes of newborn babies born to mothers who contracted SARS-CoV-2 infection during pregnancy. Thus, the aim of this review is to analyze the long-term outcomes of this infection that could affect the offspring, regardless of a possible maternal-fetal transmission, focusing on, above all, the role of maternal immune activation and the expression of the Angiotensin-converting enzyme 2 (ACE2) in particular at the placental level.


Assuntos
/complicações , Doenças do Recém-Nascido/virologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Imunidade Adaptativa , /imunologia , /transmissão , Feminino , Desenvolvimento Fetal , Humanos , Recém-Nascido , Doenças do Recém-Nascido/embriologia , Doenças do Recém-Nascido/metabolismo , Transmissão Vertical de Doença Infecciosa , Placenta/imunologia , Placenta/metabolismo , Gravidez , Fatores de Tempo
7.
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
8.
Cell ; 184(3): 628-642.e10, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33476549

RESUMO

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.


Assuntos
Anticorpos Antivirais/imunologia , Imunoglobulina G/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Complicações Infecciosas na Gravidez/imunologia , /imunologia , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Terceiro Trimestre da Gravidez/imunologia , Receptores de IgG/imunologia , Células THP-1
9.
Science ; 371(6526): 271-276, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446553

RESUMO

Type I interferon (IFN) signaling in fetal tissues causes developmental abnormalities and fetal demise. Although pathogens that infect fetal tissues can induce birth defects through the local production of type I IFN, it remains unknown why systemic IFN generated during maternal infections only rarely causes fetal developmental defects. Here, we report that activation of the guanine nucleotide-binding protein-coupled estrogen receptor 1 (GPER1) during pregnancy is both necessary and sufficient to suppress IFN signaling and does so disproportionately in reproductive and fetal tissues. Inactivation of GPER1 in mice halted fetal development and promoted fetal demise, but only in the context of maternal inflammation. Thus, GPER1 is a central regulator of IFN signaling during pregnancy that allows dynamic antiviral responses in maternal tissues while also preserving fetal health.


Assuntos
Doenças Fetais/imunologia , Inflamação/imunologia , Troca Materno-Fetal/imunologia , Complicações Infecciosas na Gravidez/imunologia , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Benzodioxóis/farmacologia , Sistemas CRISPR-Cas , Feminino , Doenças Fetais/virologia , Feto/imunologia , Feto/virologia , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Placenta/imunologia , Placenta/virologia , Gravidez , Quinolinas/farmacologia , Receptores Estrogênicos/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores
10.
Nature ; 589(7842): 442-447, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33361811

RESUMO

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.


Assuntos
Diabetes Gestacional/imunologia , Morte Fetal/etiologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Linfócitos T Reguladores/imunologia , Timo/imunologia , Adipócitos/patologia , Animais , Proliferação de Células , Diabetes Gestacional/etiologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Células Epiteliais/imunologia , Feminino , Feto/imunologia , Feto/metabolismo , Feto/patologia , Glucose/metabolismo , Intolerância à Glucose/genética , Humanos , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Placenta/imunologia , Placenta/patologia , Gravidez , Receptor Ativador de Fator Nuclear kappa-B/deficiência , Receptor Ativador de Fator Nuclear kappa-B/genética , Linfócitos T Reguladores/citologia , Timo/citologia , Fatores de Transcrição/metabolismo
11.
Viruses ; 13(1)2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374185

RESUMO

Human cytomegalovirus (CMV) is a major cause of nonhereditary adverse birth outcomes, including hearing and visual loss, neurologic deficits, and intrauterine growth retardation (IUGR), and may contribute to outcomes such as stillbirth and preterm delivery. However, the mechanisms by which CMV could cause adverse birth outcomes are not fully understood. This study reviewed proposed mechanisms underlying the role of CMV in stillbirth, preterm birth, and IUGR. Targeted literature searches were performed in PubMed and Embase to identify relevant articles. Several potential mechanisms were identified from in vitro studies in which laboratory-adapted and low-passage strains of CMV and various human placental models were used. Potential mechanisms identified included impairment of trophoblast progenitor stem cell differentiation and function, impairment of extravillous trophoblast invasiveness, dysregulation of Wnt signaling pathways in cytotrophoblasts, tumor necrosis factor-α mediated apoptosis of trophoblasts, CMV-induced cytokine changes in the placenta, inhibition of indoleamine 2,3-dioxygenase activity, and downregulation of trophoblast class I major histocompatibility complex molecules. Inherent challenges for the field remain in the identification of suitable in vivo animal models. Nonetheless, we believe that our review provides useful insights into the mechanisms by which CMV impairs placental development and function and how these changes could result in adverse birth outcomes.


Assuntos
Infecções por Citomegalovirus/transmissão , Infecções por Citomegalovirus/virologia , Citomegalovirus/fisiologia , Complicações Infecciosas na Gravidez/virologia , Biomarcadores , Diferenciação Celular , Feminino , Expressão Gênica , Humanos , Troca Materno-Fetal , Placenta/imunologia , Placenta/metabolismo , Placenta/virologia , Gravidez , Resultado da Gravidez , Nascimento Prematuro/etiologia , Natimorto/epidemiologia , Trofoblastos/metabolismo , Trofoblastos/virologia , Via de Sinalização Wnt
12.
Front Immunol ; 11: 572567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101294

RESUMO

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.


Assuntos
Decídua/imunologia , Placenta/imunologia , Viroses/imunologia , Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Dengue/imunologia , Dengue/patologia , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/patologia , Hepatite E/imunologia , Hepatite E/patologia , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Febre Lassa/imunologia , Febre Lassa/patologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Gravidez
13.
Nat Commun ; 11(1): 5332, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087697

RESUMO

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Pancreáticas/imunologia , Fatores de Transcrição/imunologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-A1/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Placenta/imunologia , Gravidez , Prognóstico , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/genética
14.
Proc Natl Acad Sci U S A ; 117(40): 24964-24973, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958663

RESUMO

Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.


Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Inflamação/genética , Vírus da Influenza A/genética , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Feminino , Feto/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Vírus da Influenza A/patogenicidade , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Glicoproteínas de Membrana/genética , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Placenta/irrigação sanguínea , Placenta/imunologia , Placenta/virologia , Gravidez , Linfócitos T/imunologia , Linfócitos T/virologia , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética
15.
Mol Immunol ; 126: 143-152, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32829203

RESUMO

A viral infection is detected through germline-encoded pattern-recognition receptors (PRRs) leading to the production of interferons (IFNs) and proinflammatory cytokines. The objective of this study was to investigate the expression of retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) in response to viral infection and the selected cytokine responses in the human term placenta. Placental villi and decidual explants were infected with human cytomegalovirus (CMV) or vesicular stomatitis virus (VSV) and cultured ex vivo to study viral infection. To evaluate DDX58 (RIG-I), IFIH1 (MDA5), and DHX58 (LGP2) expression, quantitative real-time PCR (qRT-PCR) was used. The expression of RLRs was detected by Western blotting. Cytokine and chemokine production, as well as RLR protein levels, were quantified using ELISA. The increased expression of both RIG-I and MDA5 and the enhanced secretion of IFN-ß were observed in response to VSV infection compared to mock-infected tissues. CMV infection resulted in higher transcript levels of DDX58 and IFIH1, while no changes in the cytokine production were observed. Our results indicate that RIG-I and MDA5 are specifically expressed in chorionic villi and deciduae in response to VSV infection. These findings suggest that RLRs may play a key role in pathogen recognition and the immune response against intrauterine viral transmission.


Assuntos
Proteína DEAD-box 58/metabolismo , Transmissão Vertical de Doença Infecciosa , Helicase IFIH1 Induzida por Interferon/metabolismo , Placenta/imunologia , Complicações Infecciosas na Gravidez/imunologia , Animais , Linhagem Celular , Citomegalovirus/imunologia , Feminino , Humanos , Interferon beta/imunologia , Interferon beta/metabolismo , Camundongos , Placenta/metabolismo , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Terceiro Trimestre da Gravidez , RNA Helicases/metabolismo , Técnicas de Cultura de Tecidos , Vesiculovirus/imunologia
16.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R195-R202, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32640833

RESUMO

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational day (GD) 12, rats were chronically infused with placental antiangiogenic factors sFlt-1 and sEng to induce HELLP syndrome. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another group of NP and HELLP rats on GD13 was used as a control for FasL antibody, and all rats were euthanized on GD19 after blood pressure measurement. Plasma and placentas were collected to assess inflammation, apoptosis, and the degree of placental debris activation of endothelial cells. Administration of MFL4 to HELLP rats significantly decreased blood pressure compared with untreated HELLP rats and HELLP rats infused with IgG and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were significantly attenuated in response to MFL4 infusion, as were levels of placental and circulating TNFα when compared with untreated HELLP rats and HELLP rats infused with IgG. Endothelial cells exposed to placental debris and media from HP + MFL4 rats secreted significantly less endothelin-1 compared with stimulated endothelial cells from HELLP placentas. Neutralization of FasL is associated with decreased MAP and improvement in placental inflammation and endothelial damage in an animal model of HELLP syndrome.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Endotelina-1/sangue , Proteína Ligante Fas/imunologia , Síndrome HELLP/tratamento farmacológico , Placenta/fisiopatologia , Animais , Modelos Animais de Doenças , Proteína Ligante Fas/sangue , Feminino , Síndrome HELLP/sangue , Síndrome HELLP/imunologia , Síndrome HELLP/fisiopatologia , Imunoglobulina G , Placenta/imunologia , Gravidez , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
17.
Eur J Obstet Gynecol Reprod Biol ; 252: 605-609, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32620513

RESUMO

This review evaluates whether pregnancy is a risk factor for COVID-19 by looking at the expression of immune markers such as immune cells and cytokines in order to have a better understanding on the pathophysiology of the disease, thus reducing maternal deaths. Pregnant women are more at risk of contracting COVID-19 due to their weakened immune system. Studies demonstrate that COVID-19 is an immune condition which is marked by reduced lymphocytes and elevated selected proinflammatory cytokines. Similar immune expression has been demonstrated in pregnancy by several studies. In addition, the placenta has been shown to possess ACE2 receptors on the villous cytotrophoblast and the syncytiotrophoblast and findings suggest that the coronavirus enters the host cells via these ACE2 receptors. The immune response in pregnancy increases the risk of contracting COVID-19. Both normal pregnancy and COVID-19 are marked by decreased lymphocytes, NKG2A inhibitory receptors, and increased ACE2, IL-8, IL-10, and IP-10 it therefore safer to conclude that pregnancy is a risk factor for COVID-19 development. Furthermore, the presence of the ACE2 receptors in the placenta may increase the risk of mother to baby transmission of the virus. Therefore, more studies investigating the link between pregnancy and COVID-19 are needed.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Complicações Infecciosas na Gravidez/imunologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Citocinas/sangue , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa , Pandemias , Peptidil Dipeptidase A/imunologia , Placenta/imunologia , Placenta/virologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/virologia , Fatores de Risco
18.
Cells ; 9(8)2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32722449

RESUMO

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage, and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.


Assuntos
Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa , Placenta/imunologia , Placenta/virologia , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/imunologia , Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Recém-Nascido , MicroRNAs/genética , MicroRNAs/metabolismo , Pandemias , Placenta/metabolismo , Placenta/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia
19.
Clin Immunol ; 217: 108510, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32544611

RESUMO

Children, because of having an immature immune system, are usually more prone than the adults to the microbial infections and have more severe symptoms, which is especially true for the newborns, and very young children. However, the review of clinical data from the current COVID-19 pandemic indicates otherwise. We discuss here what are the main features and components of children's immune system, the role of maternal transmission of immunity, and what are the possible explanations for the seemingly lower infection rate and severity of COVI-19 in children.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Sistema Imunitário/virologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Adulto , Fatores Etários , Betacoronavirus/patogenicidade , Criança , Pré-Escolar , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Citocinas/imunologia , Resistência à Doença , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Leite Humano/imunologia , Placenta/imunologia , Placenta/virologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez
20.
Proc Natl Acad Sci U S A ; 117(27): 15772-15777, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581122

RESUMO

During pregnancy, invading HLA-G+ extravillous trophoblasts (EVT) play a key role in placental development, uterine spiral artery remodeling, and prevention of detrimental maternal immune responses to placental and fetal antigens. Failures of these processes are suggested to play a role in the development of pregnancy complications, but very little is known about the underlying mechanisms. Here we present validated methods to purify and culture primary HLA-G+ EVT from the placental disk and chorionic membrane from healthy term pregnancy. Characterization of HLA-G+ EVT from term pregnancy compared to first trimester revealed their unique phenotypes, gene expression profiles, and differing capacities to increase regulatory T cells (Treg) during coculture assays, features that cannot be captured by using surrogate cell lines or animal models. Furthermore, clinical variables including gestational age and fetal sex significantly influenced EVT biology and function. These methods and approaches form a solid basis for further investigation of the role of HLA-G+ EVT in the development of detrimental placental inflammatory responses associated with pregnancy complications, including spontaneous preterm delivery and preeclampsia.


Assuntos
Antígenos HLA-G/imunologia , Imunidade Inata/genética , Placentação/imunologia , Pré-Eclâmpsia/imunologia , Linhagem Celular , Movimento Celular/imunologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Humanos , Relações Materno-Fetais , Placenta/imunologia , Placenta/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Primeiro Trimestre da Gravidez , Trofoblastos/imunologia
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