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1.
Sheng Li Xue Bao ; 72(1): 11-19, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32099980

RESUMO

Immune tolerance at maternal-fetal interface is the basis for establishment and maintenance of successful pregnancy. T cells are pivotal compositions of uterine decidual immune cells, which are required to mediate anti-infection immunity and protect embryos from external antigens attack. T cells also participate in the complex immune regulation process of maternal acceptance of semi-allogeneic embryos, and play an important role in regulating embryo implantation and maintaining pregnancy. Its dysfunction may lead to early pregnancy failures or mid-late pregnancy complications. This review summarizes the compositions, phenotypic characteristics and functions of decidual T cells at the maternal-fetal interface in recent years, and further describes the regulation of decidual CD4+ and CD8+ T cells in maternal-fetal immune tolerance as well as the molecular mechanisms of abnormal regulation leading to early pregnancy failures. Through the in-depth understanding the mechanism of maternal-fetal immune regulation, it supplies a novel concept on maternal-fetal immune tolerance and new clues for the immunotherapy of pregnancy-related diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Decídua/imunologia , Tolerância Imunológica , Troca Materno-Fetal/imunologia , Feminino , Feto , Humanos , Gravidez
2.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31548323

RESUMO

Group B Streptococcus (GBS) is an opportunistic bacterial pathogen that contributes to miscarriage, preterm birth, and serious neonatal infections. Studies have indicated that some multilocus sequence types (STs) of GBS are more likely to cause severe disease than others. We hypothesized that the ability of GBS to elicit varying host responses in maternal decidual tissue during pregnancy is an important factor regulating infection and disease severity. To address this hypothesis, we utilized an antibody microarray to compare changes in production and activation of host signaling proteins in decidualized telomerase-immortalized human endometrial stromal cells (dT-HESCs) following infection with GBS strains from septic neonates or colonized mothers. GBS infection increased levels of total and phosphorylated mitogen-activated protein kinase (MAPK) family members such as p38 and JNK and induced nuclear factor kappa B (NF-κB) pathway activation. Infection also altered the regulation of additional proteins that mediate cell death and inflammation in a strain-specific manner, which could be due to the observed variation in attachment to and invasion of the decidual stromal cells and ability to lyse red blood cells. Further analyses confirmed array results and revealed that p38 promotes programmed necrosis in dT-HESCs. Together, the observed signaling changes may contribute to deregulation of critical developmental signaling cascades and inflammatory responses following infection, both of which could trigger GBS-associated pregnancy complications.


Assuntos
Decídua/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular , Decídua/citologia , Decídua/microbiologia , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/imunologia , Tipagem de Sequências Multilocus , NF-kappa B/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/microbiologia , Complicações Infecciosas na Gravidez/patologia , Infecções Estreptocócicas/microbiologia , Streptococcus agalactiae/classificação
3.
Artigo em Inglês | MEDLINE | ID: mdl-31285174

RESUMO

During human pregnancy, trophoblast cells, the main cellular component of the placenta, invade deeply into uterine blood vessels and the modified endometrium (decidua). Hence, the maternal immune system must adapt to it. A successful pregnancy requires the tolerance of genetically different (allogenic) cells while the mother's immune competence is maintained. This tolerance is ensured through multiple overlapping and occasionally redundant innate and adaptive immune mechanisms. The present article aims to provide a broad overview on uterine immune cell components and the phenotypical and functional changes that they experience during pregnancy. Particularly, we seek to highlight very recent findings in functional adaptations to pregnancy in immune cell populations encountered in the decidua. These adaptations not only ensure tolerance to allogenic trophoblast cells but also promote optimal placental and fetal growth, simultaneously endeavoring to maintain immune surveillance to provide defense against infections.


Assuntos
Imunidade Adaptativa , Decídua , Placenta , Trofoblastos , Decídua/imunologia , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Útero
4.
Arch Immunol Ther Exp (Warsz) ; 67(5): 295-309, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286151

RESUMO

Macrophages (MФs) are the leukocytes produced from differentiation of monocytes and are located in almost all tissues of human body. They are involved in various processes, such as phagocytosis, innate and adaptive immunity, proinflammatory (M1) and anti-inflammatory (M2) activity, depending on the tissue microenvironment. They play a crucial role in pregnancy, and their dysfunction or alteration of polarity is involved in pregnancy disorders, like preeclampsia, recurrent spontaneous abortion, infertility, intrauterine growth restriction, and preterm labor. About 50-60% of decidual leukocytes are natural killer (NK) cells followed by MФs (the second largest population). MФs are actively involved in trophoblast invasion, tissue and vascular remodeling during early pregnancy, besides their role as major antigen-presenting cells in the decidua. These cells have different phenotypes and polarities in different stages of pregnancy. They have also been observed to enhance tumor growth by their anti-inflammatory activity (M2 type) and prevent immunogenic rejection. Targeted alteration of polarity (M1-M2 or vice versa) could be a major focus in the future treatment of pregnancy complications. This review is focused on the role of MФs in pregnancy, their involvement in pregnancy disorders, and decidual MФs as possible therapeutic targets for the treatment of pregnancy complications.


Assuntos
Decídua/imunologia , Macrófagos/fisiologia , Complicações na Gravidez/imunologia , Gravidez/imunologia , Animais , Implantação do Embrião/imunologia , Feminino , Humanos , Tolerância Imunológica , Macrófagos/imunologia , Macrófagos/patologia , Complicações na Gravidez/patologia , Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
J Immunol Res ; 2019: 3128010, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263712

RESUMO

Successful pregnancy requires a tightly-regulated equilibrium of immune cell interactions at the maternal-fetal interface (i.e., the decidual tissues), which plays a central role in the inflammatory process of labor. Most of the innate immune cells in this compartment have been well characterized; however, adaptive immune cells are still under investigation. Herein, we performed immunophenotyping of the decidua basalis and decidua parietalis to determine whether exhausted and senescent T cells are present at the maternal-fetal interface and whether the presence of pathological (i.e., preterm) or physiological (i.e., term) labor and/or placental inflammation alter such adaptive immune cells. In addition, decidual exhausted T cells were sorted to test their functional status. We found that (1) exhausted and senescent T cells were present at the maternal-fetal interface and predominantly expressed an effector memory phenotype, (2) exhausted CD4+ T cells increased in the decidua parietalis as gestational age progressed, (3) exhausted CD4+ and CD8+ T cells decreased in the decidua basalis of women who underwent labor at term compared to those without labor, (4) exhausted CD4+ T cells declined with the presence of placental inflammation in the decidua basalis of women with preterm labor, (5) exhausted CD8+ T cells decreased with the presence of placental inflammation in the decidua basalis of women who underwent labor at term, (6) both senescent CD4+ and CD8+ T cells declined with the presence of placental inflammation in the decidua basalis of women who underwent preterm labor, and (7) decidual exhausted T cells produced IFNγ and TNFα upon in vitro stimulation. Collectively, these findings indicate that exhausted and senescent T cells are present at the human maternal-fetal interface and undergo alterations in a subset of women either with labor at term or preterm labor and placental inflammation. Importantly, decidual T cell function can be restored upon stimulation.


Assuntos
Trabalho de Parto/imunologia , Troca Materno-Fetal/imunologia , Trabalho de Parto Prematuro/imunologia , Placenta/imunologia , Linfócitos T/imunologia , Adulto , Biomarcadores , Senescência Celular/imunologia , Decídua/imunologia , Decídua/metabolismo , Feminino , Humanos , Imunofenotipagem , Trabalho de Parto/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Contagem de Linfócitos , Trabalho de Parto Prematuro/metabolismo , Placenta/metabolismo , Gravidez , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Adulto Jovem
6.
J Immunol Res ; 2019: 3836942, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236420

RESUMO

Pregnancy is an immunological enigma where paternal antigens are present at the fetomaternal interface. What regulates the local immunotolerance, which is necessary to prevent rejection of the conceptus, is still under strong investigation. Gamma/delta T cells are believed to play a role in the local regulation of this immunotolerance towards the semiallogenic fetus. Gamma/delta T cells from the uterus and spleen of pregnant and nonpregnant mice were analyzed by flow cytometry. We confirmed that the rate of γδT cells in the decidua increases during murine pregnancy and half of decidual γδT cells are CD4+. Furthermore, we found a unique association of CD4 or CD8 coreceptor expression with their γδTCR intensity, where in all investigated groups CD4- or CD8-positive γδT cells seemed principally to be γδTCRdim. In addition, compared to peripheral γδT lymphocytes, a greater proportion of decidual γδT cells expressed the cytotoxic marker CD107a and markers of Th1 or Th2 polarization (TIM-3, TIM-1), where decidual γδTCRbright cells were characterized by high TIM-3 and TIM-1 receptor expression. On the other hand, no difference in the expression of CD160, a receptor with dual function affecting cytotoxicity and T cell inhibition, was detected. Within lymphocytes expressing CD107a, TIM-1, or CD160, the rate of γδT cells was significantly higher in the decidua. According to our results, cytotoxic potential of decidual γδTCRbright cells could be regulated by TIM-3 ligation, while the TIM-1 receptor seems to be able to influence the Th1-Th2 balance at the fetomaternal interface. These mechanisms could play a part in the active maternal immunotolerance towards the fetus, allowing an efficient protection against pathogens during healthy murine pregnancy.


Assuntos
Decídua/imunologia , Decídua/metabolismo , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Imunomodulação , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Feminino , Expressão Gênica , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/genética , Imunofenotipagem , Camundongos , Especificidade de Órgãos , Gravidez , Receptores de Antígenos de Linfócitos T gama-delta/genética , Baço/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
7.
Mol Biol (Mosk) ; 53(2): 303-310, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31099780

RESUMO

Soluble human leukocyte antigen G (sHLA-G) plays a key role in pregnancy through interaction with decidual natural killer (dNK) cell inhibitory receptors at the maternal-fetal interface. To demonstrate the possible role of sHLA-G during the pregnancy with Toxoplasma gondii infection, we compared the concentration of a murine functional homolog of sHLA-G, Qa-2, in T. gondii infected and non-infected pregnant C57BL/6 mice, and that of sHLA-G in BeWo culture supernatant. In addition, the levels of KIR2DL4 expressed on human dNK cells and NKG2A in pregnant mice were evaluated. We showed that T. gondii infection result in significant increase in the level of Qa-2 and NKG2A in pregnant mice. sHLA-G and KIR2DL4 in human samples were also significantly upregulated under the condition of T. gondii infection. The further treatment with sHLA-G antibody could reduce the expression level of KIR2DL4 which was upregulated by T. gondii infection. In summary, sHLA-G could upregulate the expression level of KIR2DL4 which lead to excessive immunological tolerance, and further contributed to T. gondii immunity escaping and affecting fetus via vertical transmission which may lead to adverse outcomes.


Assuntos
Antígenos HLA-G/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transmissão Vertical de Doença Infecciosa , Toxoplasmose/imunologia , Toxoplasmose/transmissão , Animais , Decídua/imunologia , Feminino , Antígenos HLA-G/química , Antígenos de Histocompatibilidade Classe I/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Solubilidade , Toxoplasma
8.
Mol Med Rep ; 19(4): 2620-2626, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720083

RESUMO

A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS­7) has been revealed to serve an important role in inflammation­associated diseases. However, the role of ADAMTS­7 in spontaneous abortion (SA) remains unclear. In the present study, human and mouse decidual tissues were used to detect the expression of ADAMTS­7 and cartilage oligomeric matrix protein (COMP) in mice with lipopolysaccharide (LPS)­induced abortion (10 mice/group), and in SA humans and the corresponding control group (21 participants in the SA group and 15 participants in the control group). The results revealed that ADAMTS­7 expression was upregulated and that COMP expression was downregulated in the mouse decidual tissue of the LPS­induced abortion group, when compared with that of the normal control group. The results were further confirmed by western blot analysis and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis, which revealed increased ADAMTS­7 and decreased COMP expression at the protein and mRNA levels in mice treated with LPS. Additionally, the expression of ADAMTS­7 was negatively correlated with the expression of COMP in mice, with a correlation coefficient of ­0.936 (P<0.001). In addition, the expression of ADAMTS­7 and COMP exhibited was similar in the decidual tissue of SA patients when compared with the levels observed in the tissues of the normal control participants, as demonstrated by increased ADAMTS­7 expression and decreased COMP expression. Western blotting and RT­qPCR analysis revealed that ADAMTS­7 was increased and COMP was decreased in the decidual tissue of SA subjects. The correlation analysis of ADAMTS­7 and COMP in human decidual tissue also revealed a similar result, with a correlation coefficient of ­0.836 (P<0.001). The results of the present study demonstrated that ADAMTS­7 was upregulated and COMP was downregulated in the decidual tissues of humans and mice with SA, and a negative correlation was identified between the expression levels of ADAMTS­7 and COMP, thereby providing novel evidence for a better understanding of the pathogenesis of SA, which may lead to improvements in the clinical pregnancy outcomes of these individuals.


Assuntos
Aborto Espontâneo/etiologia , Proteína de Matriz Oligomérica de Cartilagem/genética , Regulação da Expressão Gênica , Proteína ADAMTS7/genética , Proteína ADAMTS7/metabolismo , Adulto , Animais , Biomarcadores , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Decídua/imunologia , Decídua/metabolismo , Decídua/patologia , Feminino , Humanos , Imuno-Histoquímica , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Camundongos , Gravidez
9.
BMC Pregnancy Childbirth ; 19(1): 74, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782114

RESUMO

BACKGROUND: Our goal with this study was to investigate the contribution of PD-1/PD-L1 immune-checkpoint pathway to maternal immunotolerance mechanisms. METHODS: Thirteen healthy pregnant women and 10 non-pregnant controls were involved in this project. PBMCs and DICs were isolated from peripheral blood and from decidual tissues. After the characterization of different immune cell subsets, we used fluorochrome-conjugated monoclonal antibodies to measure the expression level of PD-1, PD-L1, NKG2D, and CD107a molecules by flow cytometry. RESULTS: We measured significant alternations in the proportion of decidual immune cell subsets compared to the periphery. Elevated PD-1 expression by decidual CD8+ T, CD4+ T, and NKT-like cells were also detected accompanied by the increased PD-L1 expression by decidual CD4+ T, Treg, NKT-like and CD56 + NK cell subsets compared to peripheral blood. The cytotoxic potential was significantly higher in PD-1- decidual immune cells compared to the periphery, however we measured a significantly lower cytotoxicity in the decidual PD-1+ CD8+ T cells compared with the peripheral subsets. An activation receptor NKG2D expression was decreased by the PD-1+ CD8+ T subsets in the first trimester compared to non-pregnant condition but the expression level of the decidual counterparts was significantly elevated compared to the periphery. The cytotoxic potential of decidual PD1/NKG2D double positive CD8+ T cells was significantly decreased compared to the peripheral subsets. CONCLUSIONS: Based on our results we assume that PD-1/PD-L1 pathway might have a novel role in the maintaining of the local immunological environment. Accompanied by NKG2D activating receptor this checkpoint interaction could regulate decidual CD8 Tc cell subsets and may contribute maternal immunotolerance.


Assuntos
Antígeno B7-H1/imunologia , Histocompatibilidade Materno-Fetal/imunologia , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Adulto , Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Decídua/imunologia , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Gravidez
10.
Mucosal Immunol ; 12(3): 624-631, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30755717

RESUMO

Group 3 innate lymphoid cells (ILC3) have been detected in both murine and human decidual tissues where they are thought to play a relevant role in the induction and maintenance of pregnancy. However, limited information exists on the molecular mechanisms that regulate these cells, including immune checkpoints. Here, we show that ILC3 express the inhibitory checkpoints programmed cell death (PD-1) and T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) during the first trimester of pregnancy and that these receptors could regulate production of cytokines, including IL-22, IL-8, and TNF-α, induced by IL-23. We also show that the intermediate extravillous trophoblast (iEVT) expresses high levels of the PD-1-ligand PD-L1, suggesting that PD-1/PD-L1 interaction may regulate ILC3 function at the feto-maternal interface. Our present data provide the first evidence that human decidual ILC3 express a functional PD-1. It is possible that an altered expression or function of PD-1 may break the immune-tolerance resulting in pregnancy failure.


Assuntos
Decídua/imunologia , Linfócitos/imunologia , Gravidez , Receptor de Morte Celular Programada 1/metabolismo , Trofoblastos/metabolismo , Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Feminino , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Imunidade Inata , Circulação Placentária , Transdução de Sinais
11.
Int J Mol Sci ; 20(3)2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30764544

RESUMO

Pregnancy is a state where high and stage-dependent plasticity of the maternal immune system is necessary in order to equilibrate between immunosuppression of harmful responses towards the fetus and ability to fight infections. TCR γδ cells have been implicated in the responses in infectious diseases, in the regulation of immune responses, and in tissue homeostasis and repair. The variety of functions makes γδ T cells a particularly interesting population during pregnancy. In this study, we investigated the proportion, phenotype and TCR γ and δ repertoires of γδ T cells at the maternal⁻fetal interface and in the blood of pregnant women using FACS, immunohistochemistry and spectratyping. We found an enrichment of activated and terminally differentiated pro-inflammatory γδ T-cell effectors with specific location in the human decidua during early pregnancy, while no significant changes in their counterparts in the blood of pregnant women were observed. Our spectratyping data revealed polyclonal CDR3 repertoires of the δ1, δ2 and δ3 chains and γ2, γ3, γ4 and γ5 chains and oligoclonal and highly restricted CDR3γ9 repertoire of γδ T cells in the decidua and blood of pregnant women. Early pregnancy induces recruitment of differentiated pro-inflammatory γδ T-cell effectors with diverse TCR repertoires at the maternal⁻fetal interface.


Assuntos
Decídua/imunologia , Feto/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Feminino , Humanos , Tolerância Imunológica , Ativação Linfocitária , Gravidez , Receptores de Antígenos de Linfócitos T gama-delta/análise , Receptores de Antígenos de Linfócitos T gama-delta/sangue
12.
Cell Immunol ; 336: 75-82, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30665661

RESUMO

Obesity is seen as a low grade inflammatory state, and is associated with adverse pregnancy outcomes. Disturbed macrophage characteristics might be essential in obesity associated pregnancy pathology via effects on the regulation of angiogenesis and placental development. This study aims to address the effects of maternal obesity on macrophage subsets in the decidua of women with term uncomplicated pregnancies. Macrophages were isolated from the decidua basalis and decidua parietalis of women with pre-gravid BMI < 25 (control) and BMI > 30 (obese). Macrophages were characterized and quantified using multi-color flow cytometry. Placentas of 10 obese and 10 control women after an uncomplicated term pregnancy were included. The decidua parietalis, but not decidua basalis, showed significantly lower levels of M1-type (HLA-DR+, CD163-) macrophages (p < 0.05) in obese women (4,3% of total macrophages) compared to control women (5,3% of total macrophages). The lower levels of M1 macrophages, considered to be pro-inflammatory, might indicate a mechanism to compensate for the pro-inflammatory environment in obese women to ensure healthy pregnancy outcomes.


Assuntos
Decídua/imunologia , Macrófagos/classificação , /imunologia , Adulto , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Feminino , Antígenos HLA-DR/análise , Humanos , Gravidez , Receptores de Superfície Celular/análise
13.
Cell Death Dis ; 10(1): 15, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30622243

RESUMO

The single and/or combination use of immune checkpoint blockade therapies in human infectious diseases and cancer are rapidly expanding. Despite early efforts, substantial uncertainty remains about the safety and efficacy of immune checkpoint blockade in some populations. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin mucin-3 (Tim-3) are the major targetable co-inhibitory receptors on T cells. Here we showed that in animal studies, treatment with either CTLA-4- or Tim-3-blocking antibody caused greater susceptibility to fetal loss with altered cytokine profiles by decidual CD4+T (dCD4+T) cells. CTLA-4 and Tim-3 pathways appeared to play key roles in maintaining maternal-fetal tolerance by regulating the function of dCD4+T cells. In addition, the abnormality in number and functionality of dCTLA-4+Tim-3+CD4+T cells was associated with miscarriage. These findings underscored the important roles of the CTLA-4 and Tim-3 pathways in regulating dCD4+T cells function and maintaining normal pregnancy. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care.


Assuntos
Aborto Espontâneo/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Citocinas/metabolismo , Decídua/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Animais , Anticorpos/efeitos adversos , Anticorpos/uso terapêutico , Antígeno CTLA-4/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Tolerância Imunológica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Gravidez
14.
Biochem Biophys Res Commun ; 508(2): 354-360, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30503343

RESUMO

PROBLEM: Recurrent spontaneous abortion (RSA) is associated with immune imbalance at the maternal-fetal interface. Decidual immune cells and cytokines expressed at this interface regulate the response of the maternal immune system to the fetus. However, the populations and cytokine expression levels of these lymphocytes in miscarriage with normal and abnormal chromosome karyotypes remain unclear. METHODS: We assessed the populations and cytokine expression levels of Natural Killer (NK), Natural Killer T (NKT), Helper T (Th) and Cytotoxic T (Tc) cells in the decidua of RSA by flow cytometry and simultaneously analyzed the fetal chromosome karyotypes of these miscarriages. RESULTS: Flow cytometry showed no significant difference between RSA and normal pregnancy in the percentages of Th, Tc, NK, and NKT cells. Type-1 cells decreased significantly in the decidua of normal pregnancy, and NK2 and NKT2 cells increased significantly in the normal pregnancy group. We also found no difference in the lymphocyte composition and the proportion of types 1 and 2 subsets of the four lymphocytes in the decidua between RSA with abnormal chromosome karyotypes of villous trophoblasts (RSA-A) and RSA with normal chromosome karyotypes of villous trophoblasts (RSA-N), but the proportion of type-1 cells in both groups was significantly higher than that in normal pregnancy. CONCLUSION: No difference existed between the type-1 immune response of RSA in normal and abnormal chromosome karyotypes of villous trophoblasts.


Assuntos
Aborto Habitual/genética , Aborto Habitual/imunologia , Aberrações Cromossômicas , Decídua/imunologia , Subpopulações de Linfócitos/imunologia , Aborto Habitual/patologia , Adulto , Estudos de Casos e Controles , Vilosidades Coriônicas/imunologia , Vilosidades Coriônicas/patologia , Citocinas/metabolismo , Decídua/patologia , Feminino , Humanos , Cariótipo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Subpopulações de Linfócitos/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Gravidez , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Trofoblastos/imunologia , Trofoblastos/patologia , Adulto Jovem
15.
EBioMedicine ; 39: 531-539, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30579870

RESUMO

BACKGROUND: Decidual natural killer (dNK) cells are the predominant lymphocytes accumulated at the maternal-fetal interface. Regulatory mechanism of dNK cells in preeclampsia, a gestational complication characterized by high blood pressure and increased proteinuria occurring after 20 weeks pregnancy, is not completely understood. METHODS: Multi-parameter flow cytometry is applied to investigate the phenotype and function of dNK cells freshly isolated from decidual samples or conditionally cultured by TGFb stimulation. FINDINGS: In preeclampsia, we documented elevated numbers of CD56+ CD3- dNK cells in close proximity to Foxp3+ regulatory T (Treg) cells within the decidua. In vitro experiments using dNK cells from early gestation showed that dNK activation (IFNG, IL-8 and CD107a) can be downregulated by Treg cells. The expression of these markers by dNK cells was significantly lower in preeclampsia. We also observed a positive correlation between the expression of dNK activation receptors (NKp30 and NKG2D) and the expression of IFNG in specific dNK subsets. TGFb levels are increased in the decidua of preeclamptic pregnancies. We analyzed co-expression of activation (IFNG/IL-8/CD107a) and angiogenic (VEGF) markers in dNK cells. TGFb treatment reduced while blockade of TGFb increased co-expression of these markers. INTERPRETATION: Our findings suggest that elevated decidual TGFb1 supresses the activation of specific subsets of dNK which in turn contributes to the uteroplacental pathology associated with the onset of preeclampsia.


Assuntos
Decídua/imunologia , Células Matadoras Naturais/imunologia , Pré-Eclâmpsia/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/química , Decídua/metabolismo , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-8/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Gravidez , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/farmacologia
16.
Biomed Pharmacother ; 109: 1478-1487, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551399

RESUMO

AIM: Natural killer (NK) cells, as key regulatory cells, accumulate at the maternal-fetal interface in large numbers. This study explored the effect of miR-30e on regulating the activity and function of peripheral blood NK cells (PB-NK cells) and decidua NK cells (D-NK cells) by targeting PRF1 in immune tolerance of maternal-fetal interface. METHODS: Expressions of miR-30e in PB and decidua tissues from 49 patients with recurrent spontaneous abortion and 52 normal pregnant women were measured using PCR. NK cells were isolated from PB and decidua tissues and identified by flow cytometry (FCM). In PB-NK cells and D-NK cells activated by IFN-α, expressions of miR-30e and PRF1 were determined by PCR and Western blot. Negative controls of miR-30e mimics/inhibitors and siRNA against PRF1 were transfected in PB-NK cells and D-NK cells. Expressions of miR-30e and PRF1 were determined and their relationship was verified. Expressions of KIR2DL1, NKp44, IFN-γ, TNF-α, IL-4 and IL-10 were determined by FCM. Cytotoxicity kit was used to identify the cytotoxicity of NK cells. PCR and ELISA were employed to measure expression of VEGF, Ang-2 and PGF in D-NK cells. RESULTS: After activation by IFN-α, D-NK cells and PB-NK cells showed decreased miR-30e expression and increased PRF1 expression in normal non-pregnant women. PRF1 is a target gene of miR-30e and miR-30e negatively regulated PRF1 expression. The treatment of miR-30e mimics elevated KIR2DL1 expression and decreased NKp44 expression in PB-NK or D-NK cells. Moreover, up-regulation of miR-30e expression suppressed cytotoxicity, corresponding to increased expression of IL-4and IL-10 and reduced expression of IFN-γ and TNF-α in PB-NK and D-NK cells, as well as enhanced expression of VEGF, Ang-2 and PGF in D-NK cells. Transfection of miR-30e inhibitors could reverse the tendencies. CONCLUSION: Up-regulated miR-30e can reduce the cytotoxicity of PB-NK cells and D-NK cells by targeting PRF1, whereby inhibiting Th1 tolerance phenotype and inducing Th2 immunodominance. miR-30e may be contributive to creating a micro-immune tolerance environment of maternal-fetal interface.


Assuntos
Tolerância Imunológica/imunologia , Células Matadoras Naturais/imunologia , MicroRNAs/imunologia , Perforina/imunologia , Aborto Habitual/imunologia , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Decídua/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Gravidez , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/imunologia
17.
Front Immunol ; 9: 2880, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574149

RESUMO

Heterologous immunity of virus-specific T cells poses a potential barrier to transplantation tolerance. Cross-reactivity to HLA-A and -B molecules has broadly been described, whereas responses to allo-HLA-C have remained ill defined. In contrast to the transplant setting, HLA-C is the only polymorphic HLA molecule expressed by extravillous trophoblasts at the maternal-fetal interface during pregnancy. Uncontrolled placental viral infections, accompanied by a pro-inflammatory milieu, can alter the activation status and stability of effector T cells. Potential cross-reactivity of maternal decidual virus-specific T cells to fetal allo-HLA-C may thereby have detrimental consequences for the success of pregnancy. To explore the presence of cross-reactivity to HLA-C and the other non-classical HLA antigens expressed by trophoblasts, HLA-A and -B-restricted CD8+ T cells specific for Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, and Influenza virus were tested against target cells expressing HLA-C, -E, and -G molecules. An HLA-B*08:01-restricted EBV-specific T cell clone displayed cross-reactivity against HLA-C*01:02. Furthermore, cross-reactivity of HLA-C-restricted virus-specific CD8+ T cells was observed for HCMV HLA-C*06:02/TRA CD8+ T cell lines and clones against HLA-C*03:02. Collectively, these results demonstrate that cross-reactivity against HLA-C can occur and thereby may affect pregnancy outcome.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Decídua/imunologia , Antígenos HLA-C/imunologia , Isoantígenos/imunologia , Troca Materno-Fetal/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Reações Cruzadas , Decídua/citologia , Feminino , Antígenos HLA-C/metabolismo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Gravidez , Resultado da Gravidez , Trofoblastos/imunologia , Trofoblastos/metabolismo , Vírus/imunologia
18.
Nature ; 563(7731): 347-353, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30429548

RESUMO

During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.


Assuntos
Comunicação Celular , Feto/citologia , Histocompatibilidade Materno-Fetal/imunologia , Placenta/citologia , Placenta/metabolismo , Gravidez/imunologia , Análise de Célula Única , Comunicação Celular/imunologia , Diferenciação Celular/genética , Decídua/citologia , Decídua/imunologia , Decídua/metabolismo , Feminino , Feto/imunologia , Feto/metabolismo , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Ligantes , Placenta/imunologia , RNA Citoplasmático Pequeno/genética , Análise de Sequência de RNA , Células Estromais/citologia , Células Estromais/metabolismo , Transcriptoma , Trofoblastos/citologia , Trofoblastos/imunologia , Trofoblastos/metabolismo
19.
J Immunol ; 201(9): 2551-2556, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275046

RESUMO

NK cells accumulate in adult murine and human uteri during decidualization induced physiologically, pathologically, or experimentally. Adoptive transfer studies indicate that uterine NK (uNK) cells arise from circulating progenitors. However, virgin uteri contain few circulating NK1.1+CD49a- conventional NK cells, whereas NK1.1+CD49a+ tissue-resident NK (trNK) cells are abundant. In this study, we employed a novel, immune-competent NK cell-specific reporter mouse to track accumulation of uNK cells during unmanipulated pregnancies. We identified conventional NK and trNK cells accumulating in both decidua basalis and myometrium. Only trNK cells showed evidence of proliferation. In parabiosis studies using experimentally induced deciduomata, the accumulated uNK cells were proliferating trNK cells; migrating NK cells made no contribution. Together, these data suggest proliferating trNK cells are the source of uNK cells during endometrial decidualization.


Assuntos
Movimento Celular/imunologia , Proliferação de Células/fisiologia , Decídua/citologia , Células Matadoras Naturais/imunologia , Prenhez , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Decídua/imunologia , Feminino , Proteínas de Fluorescência Verde/genética , Células Matadoras Naturais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Parabiose , Gravidez
20.
Front Immunol ; 9: 2087, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283441

RESUMO

Adaptive immune system, principally governed by the T cells-dendritic cells (DCs) nexus, is an essential mediator of gestational fetal tolerance and protection against infection. However, the exact composition and dynamics of DCs and T cell subsets in gestational tissues are not well understood. These are controlled in human physiology by a complex interplay of alloantigen distribution and presentation, cellular/humoral active and passive tolerance, hormones/chemokines/angiogenic factors and their gradients, systemic and local microbial communities. Reductive discrimination of these factors in physiology and pathology of model systems and humans requires simplification of the model and increased resolution of interrogative technologies. As a baseline, we have studied the gestational tissue dynamics in the syngeneic C57BL/6 mice, as the simplest immunological environment, and focused on validating the approach to increased data density and computational analysis pipeline afforded by highly polychromatic flow cytometry and machine learning interpretation. We mapped DC and T cell subsets, and comprehensively examined their maternal (decidual)-fetal (placental) interface dynamics. Both frequency and composition of decidual DCs changed across gestation, with a dramatic increase in myeloid DCs in early pregnancy, and exclusion of plasmacytoid DCs. CD4+ T cells, in contrast, were lower at all gestational ages and an unusual CD4-CD8-TCRαß+group was prominent at mid-pregnancy. Dimensionality reduction with machine learning-aided clustering revealed that CD4-CD8- T cells were phenotypically different from CD4+ and CD8+ T cells. Additionally, divergence between maternal decidual and fetal placental compartment was prominent, with absence of DCs from the placenta, but not decidua or embryo. These results provide a novel framework and a syngeneic baseline on which the specific role of alloantigen/tolerance, polymicrobial environment, and models of pregnancy pathology can be precisely modeled and analyzed.


Assuntos
Imunidade Adaptativa/imunologia , Decídua/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Placenta/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Células Cultivadas , Decídua/citologia , Feminino , Feto/imunologia , Idade Gestacional , Humanos , Masculino , Camundongos Endogâmicos C57BL , Placenta/citologia , Gravidez , Útero/citologia , Útero/imunologia
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