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1.
Mol Ther Nucleic Acids ; 18: 518-532, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31671345

RESUMO

Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment.

2.
Fertil Steril ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31718829

RESUMO

OBJECTIVE: To investigate whether chronic endometritis (CE) affects the immune status of peripheral blood and endometrium in patients with recurrent reproductive failure (RRF). DESIGN: Retrospective study. SETTING: Private fertility center. PATIENTS(S): A total of 524 RRF patients, including 324 women with recurrent miscarriage (RM) and 200 women with recurrent implantation failure (RIF). INTERVENTION(S): Peripheral blood and endometrium samples were collected in the midluteal phase before in vitro fertilization treatment or pregnancy. The number of peripheral T, natural killer (NK), and B cells, as well as cytotoxicity of NK cells and expression of TH1 cytokines were analyzed with the use of flow cytometry, and uterine immune cells were subjected to immunohistochemistry. MAIN OUTCOME MEASURE(S): Peripheral immune cells, cytokines, NK cytotoxicity, and endometrial immune cells were compared in RRF patients with versus without CE. RESULT(S): The proportion and function of the analyzed immune cell subsets in peripheral blood as well as the percentages of CD56+ NK cells, CD163+ M2 macrophages, and CD1a+ immature dendritic cells in the endometrium were not significantly altered between non-CE and CE patients, whereas the proportions of uterine CD68+ macrophages, CD83+ mature dendritic cells, CD8+ T cells, and Foxp3+ regulatory T cells were significantly elevated in CE patients. After antibiotic treatment, the percentage of CD68+ macrophages, CD83+ mature dendritic cells, CD8+ T cells, and Foxp3+ regulatory T cells in endometrium were significantly reduced in patients with cured CE. CONCLUSION(S): CE contributes to elevated endometrial infiltration levels of immune cells. The excessive presence of endometrial immune cells in CE patients may be involved in reduced endometrial receptivity and recurrent pregnancy failures.

3.
Reproduction ; 158(3): 247-255, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31284267

RESUMO

During pregnancy, the maternal immune system must tolerate the persistence of semi-allogeneic fetus in the maternal tissue. Inadequate recognition of fetal antigens may lead to pregnancy complications, such as recurrent miscarriage (RM) and recurrent implantation failure (RIF). Dendritic cells (DCs) are key regulators of protective immune responses and the development and maintenance of tolerance. Regarding that DCs are important in the establishment of immune tolerance in human pregnancy, it would be important to study the microenvironment in which DCs reside or are activated may affect their functions toward tolerance rather than active immune response. IL-10 plays a critical role in the maintenance of normal pregnancy, and the increased production of IL-10 is associated with successful pregnancy. In this study, we provide an in-depth comparison of the phenotype and cytokine production by DC-10 and other DC subsets, such as iDC and mDC. CD14+ monocyte-derived DCs were differentiated in the presence of IL-10 (DC-10) in vitro from ten normal fertile controls, six RM women and seven RIF women, and characterized for relevant markers. DC-10 was characterized by relatively low expression of costimulatory molecule CD86, as well as MHC class II molecule HLA-DR, high expression of tolerance molecules HLA-G, ILT2, ILT4 and immunosuppressive cytokine IL-10, but produced little or no proinflammatory cytokines, such as TNF-α, IL-6 and IL-12p70. Our study provides a better understanding of the phenotypical properties of DC-10, which may participate in the complex orchestration that leads to maternal immune tolerance and homeostatic environment in human pregnancy.

4.
Fertil Steril ; 112(2): 250-257.e1, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31103286

RESUMO

OBJECTIVE: To evaluate whether maternal chronic hepatitis B virus (HBV) infection affects pregnancy outcomes in infertile patients undergoing their first in vitro fertilization (IVF) treatment. DESIGN: A retrospective case control study. SETTING: Fertility center. PATIENT(S): Female patients, comprising 8,550 infertile women including 180 HBsAg+HBeAg+, 714 HBsAg+HBeAg-, and 7,656 HBsAg seronegative controls undergoing their first IVF treatments. INTERVENTION(S): Clinical characteristics, pregnancy and neonatal outcomes were analyzed by Kruskal-Wallis test, analysis of variance, or chi-square test. Logistic regression was employed to verify the contribution of maternal HBV to clinical pregnancy, live birth, and miscarriage. MAIN OUTCOME MEASURE(S): Primary outcome: live-birth rate; secondary outcomes: implantation, clinical pregnancy, and miscarriage rates. RESULT(S): An increased duration of infertility and more secondary infertility and ovulatory disorders were observed in the HBV patients. The implantation rate was statistically significantly lower in the HBsAg+HBeAg- group compared with the controls. However, the clinical pregnancy rate, miscarriage rate, live-birth rate, neonatal outcomes, and pregnancy complications showed no statistically significant differences among the groups. The logistic regression analysis showed that HBV infection status did not affect the clinical pregnancy, miscarriage, or live-birth rates, unlike maternal age, endometrial thickness, and use of high-quality embryos. CONCLUSION(S): Hepatitis B virus infection is not an independent contributor to pregnancy outcomes, although it is associated with prolonged infertility duration, a high frequency of secondary infertility and ovulatory disorders, and a reduced implantation rate.


Assuntos
Fertilização In Vitro , Hepatite B Crônica/terapia , Infertilidade Feminina/terapia , Complicações Infecciosas na Gravidez/terapia , Resultado da Gravidez , Aborto Espontâneo/epidemiologia , Adulto , Estudos de Casos e Controles , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Humanos , Infertilidade Feminina/complicações , Infertilidade Feminina/epidemiologia , Nascimento Vivo/epidemiologia , Masculino , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Taxa de Gravidez , Estudos Retrospectivos
5.
Am J Reprod Immunol ; 81(3): e13083, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604518

RESUMO

PROBLEM: Does hepatitis B infection affect peripheral blood immune response in women with reproductive failure? METHOD OF STUDY: Two hundred and twenty-seven women, including 10 HBsAg+ HBeAg+ , 27 HBsAg+ HBeAg- hepatitis sero-positive women, and 190 women without HBV infection, formed the study population. Their peripheral immune responses containing lymphocyte subsets, cytokine production, expression of cell surface markers and intracellular toxicity molecules, and pregnancy outcomes were retrospectively compared. RESULTS: Comparing with HBsAg+ HBeAg- carriers and HBsAg- group, HBsAg+ HBeAg+ group had lower rates of CD3+ CD4+ helper T cells (31.7% vs 38.0% and 36.8%, P < 0.05, respectively), but higher frequency of CD19+ B cells (17.8% vs 14.0% and 13.2%, P < 0.05 and P < 0.01, respectively). NK cells in HBsAg+ HBeAg+ patients showed lower cytotoxic activity than that in two other groups (P < 0.05). Comparing with HBsAg- patients, HBsAg+ HBeAg+ group exhibited decreased expression of the activating receptor NKG2D (56.2% vs 66.1%, P < 0.05), as well as reduced expression of granzyme B (54.8% vs 70.5%, P < 0.05), perforin (49.9% vs 65.0%, P < 0.05), and granulysin (52.0% vs 67.9%, P < 0.01). Generally, a higher clinical pregnancy rate (85.7% vs 56.9%) and higher early miscarriage rate (33.3% vs 20.3%) were noticed in HBsAg+ HBeAg+ group than HBsAg- group. CONCLUSION: Chronic HBV infection alters peripheral immune responses by upregulating B-cell frequency, decreasing CD3+ CD4+ helper T cells, and decreasing peripheral NK function and toxicity. These may influence pregnancy outcome on HBV-infected patients, and the pathogenesis of HBV infection on pregnancy outcome deserves to be further studied.

6.
Semin Immunopathol ; 40(2): 157-174, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29071391

RESUMO

The emerging field of immunometabolism has substantially progressed over the last years and provided pivotal insights into distinct metabolic regulators and reprogramming pathways of immune cell populations in various immunological settings. However, insights into immunometabolic reprogramming in the context of reproduction are still enigmatic. During pregnancy, the maternal immune system needs to actively adapt to the presence of the fetal antigens, i.e., by functional modifications of distinct innate immune cell subsets, the generation of regulatory T cells, and the suppression of an anti-fetal effector T cell response. Considering that metabolic pathways have been shown to affect the functional role of such immune cells in a number of settings, we here review the potential role of immunometabolism with regard to the molecular and cellular mechanisms necessary for successful reproduction. Since immunometabolism holds the potential for a therapeutic approach to alter the course of immune diseases, we further highlight how a targeted metabolic reprogramming of immune cells may be triggered by maternal anthropometric or nutritional aspects.


Assuntos
Fenômenos do Sistema Imunológico/fisiologia , Redes e Vias Metabólicas/imunologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/imunologia , Animais , Feminino , Humanos , Gravidez
7.
J Reprod Immunol ; 124: 44-53, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29055791

RESUMO

The maternal-fetal interface undergoes dynamic changes to allow the fetus to grow and develop in the uterus, despite being recognized by the maternal immune cells. Within the innate immune system, decidual natural killer cells and antigen presenting cells (including macrophages and dendritic cells) that comprise a large proportion of the decidual leukocyte populations play an important role in modulating trophoblast invasion, angiogenesis and vascular remodeling. On the other hand, within the adaptive immune system, CD8+ T cells, effector CD4+ T cells, Foxp3+ regulatory T cells and CD4+HLA-G+ suppressor T cells are identified as potential players in maintaining immune tolerance toward the semi-allogeneic fetus. This review discusses how these key immune cells contribute to pregnancy outcome and the complex interactions between the innate and adaptive immune system during human pregnancy.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Decídua/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T Reguladores/imunologia , Imunidade Adaptativa , Animais , Decídua/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Imunidade Inata , Circulação Placentária , Gravidez
8.
J Reprod Immunol ; 122: 14-20, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28804023

RESUMO

The relevance of antiphospholipid (aPL), antinuclear (ANA) or antithyroid (ATA) antibodies in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are controversial. The present study aims to investigate which autoantibodies are associated with the pregnancy outcome of patients undergoing first IVF/ICSI treatment. A total of 3763 IVF/ICSI patients were recruited from January to December 2015. Forty-five patients positive for aPL presenting adverse outcomes in their first cycle received low-dose aspirin treatment before the second transfer. Logistic regression analyses were performed to assess any association between autoantibodies and IVF/ICSI outcomes. The aCL-IgG was significantly associated with live birth rate (OR 0.58, 95% CI 0.36-0.96, p<0.05) and miscarriage rate (OR 2.04, 95% CI 1.23-3.40, p<0.01). The aCL-IgM was associated with miscarriage rate (OR 2.14, 95% CI 1.29-3.54, p<0.01). The aß2GPI-IgG was associated with implantation rate and clinical pregnancy rate (OR 0.61, 95% CI 0.24-0.96, p<0.05; OR 0.40, 95% CI 0.13-0.87, p<0.05, respectively). After the low-dose aspirin treatment, the live birth rate (37.0% vs. 19.1%, p<0.05) increased significantly in patients with positive for aPL. In contrary, the aß2GPI-IgM, ANA, anti-thyroglobulin (aTG) and anti-thyroperoxidase (aTPO) antibodies had no association with IVF/ICSI outcome. It is suggested that the presence of aCL-IgG, aCL-IgM and aß2GPI-IgG might exert a detrimental effect on IVF/ICSI outcomes. Low-dose aspirin treatment could be useful for patients positive for these antibodies. Therefore, it is suggested that these antibodies should be assessed prior to IVF/ICSI treatment.


Assuntos
Aspirina/uso terapêutico , Fertilização In Vitro , Infertilidade Feminina/terapia , Adulto , Autoanticorpos/sangue , Coeficiente de Natalidade , Estudos de Coortes , Implantação do Embrião , Feminino , Humanos , Nascimento Vivo , Gravidez , Taxa de Gravidez , Estudos Prospectivos , Injeções de Esperma Intracitoplásmicas
9.
Am J Reprod Immunol ; 78(2)2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28508475

RESUMO

CD8+ T cells are the main candidates to recognize and respond to fetal HLA-C at the fetal-maternal interface, but data on the amount of peripheral CD8+ T cells and their functions during the window of implantation in recurrent implantation failure (RIF) patients are limited. Peripheral blood was obtained from 56 women with RIF and 16 fertile women in the mid-luteal phase of the menstrual cycle, and the CD8+ T cells were determined by FACS analysis. No statistical differences in the proportion of peripheral CD8+ T cells were observed among the women with RIF and the control group. However, the levels of IFN-γ+ and TNF-α+ CD8+ T cells in the RIF group were significantly higher than those in the control group. The cytolytic activity and regulatory proportion of CD8+ T cells in RIF were similar to that in the control group. Our data indicated that the elevated expression levels of IFN-γ and TNF-α in peripheral CD8+ T cells may contribute to an impaired immune tolerance in women with RIF.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Implantação do Embrião/imunologia , Infertilidade Feminina/imunologia , Adulto , Feminino , Humanos , Tolerância Imunológica , Interferon gama/imunologia , Fator de Necrose Tumoral alfa/imunologia
10.
Am J Reprod Immunol ; 78(2)2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28224680

RESUMO

Inhibitor of DNA-binding protein 3 (Id3) is required for tumor angiogenesis and regulatory T-cell generation. However, the involvement of Id3 in unexplained repeated implantation failure (RIF) and recurrent miscarriage (RM) remains poorly understood. Immunohistochemistry was used to identify Id3, CD34, CTLA-4, and FOXP3 in the endometrium taken from the women with RIF (n=16), RM (n=16) and matched controls (n=8). The images were acquired and analyzed by the Vectra® automated quantitative pathology imaging system. Percentage of Id3+ cells was significantly higher in the endometrium of women with RIF and RM compared with controls. The numbers of Id3+ and CD34+ vessels in the endometrium were positively correlated in control but not in RIF or RM. Percentages of CTLA-4+ cells, but not FOXP3+ cells, were significantly increased in the endometrium of RIF and RM women than those in controls. We found aberrant expressions of endometrial Id3 and CTLA-4 in peri-implantation endometrium of women with RIF and RM, suggesting the negative roles of these angiogenesis and immune tolerance markers involving in regulating endometrium receptivity.


Assuntos
Aborto Habitual/metabolismo , Antígeno CTLA-4/metabolismo , Implantação do Embrião , Endométrio/metabolismo , Proteínas Inibidoras de Diferenciação/metabolismo , Proteínas de Neoplasias/metabolismo , Adulto , Feminino , Humanos , Gravidez
11.
Am J Reprod Immunol ; 77(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28044377

RESUMO

PROBLEM: Human chorionic gonadotropin (hCG) and regulatory T cells (Tregs) have been suggested to play important roles during the initial stage of pregnancy. However, the clinical relevance and mechanism of the effects of hCG on Treg functions in women with recurrent implantation failure (RIF) remain to be elucidated. METHOD OF STUDY: Thirty-four RIF and twenty-three control women were included in the study. Endometrial and peripheral Tregs were analyzed by immunohistochemistry and flow cytometry, respectively. Tregs were generated from naïve CD4+ T cells by stimulation with anti-CD3/CD28 in the presence or absence of hCG, and the subsets were analyzed by flow cytometry, Western blotting, and qPCR. RESULTS: The percentages of endometrial FOXP3+ Tregs and peripheral CCR4+ FOXP3+ Tregs were significantly lower in the women with RIF than in the healthy controls. In addition, the percentages of CCR4+ FOXP3+ Tregs and TGF-ß-expressing FOXP3+ Tregs were increased following the stimulation of naïve CD4+ T cells with anti-CD3/CD28, and these increases were concomitant with AKT and ERK dephosphorylation. CONCLUSIONS: The results of this study provide novel evidence supporting a role of hCG in regulating the differentiation of peripheral FOXP3+ Tregs. The alterations of circulating Tregs may positively affect the pregnancy outcomes of patients with a history of RIF.


Assuntos
Gonadotropina Coriônica/metabolismo , Endométrio/imunologia , Infertilidade Feminina/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Movimento Celular , Células Cultivadas , Implantação do Embrião , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Gravidez , Resultado da Gravidez , Receptores CCR4/metabolismo , Receptores do LH/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
12.
Am J Reprod Immunol ; 76(6): 432-438, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27696575

RESUMO

PROBLEM: We aimed to investigate the modulatory effects of vitamin D on peripheral blood cellular immune response in patients with recurrent miscarriage (RM). METHOD OF STUDY: The effect of vitamin D on the number of peripheral blood cells, T helper 1 (Th1) cytokines, and NK cytotoxicity was measured in 99 women with RM. RESULTS: The percentage of CD19+ B cells and NK cytotoxicity at an effector-to-target cell (E:T) ratio of 50:1, 25:1, and 12.5:1 were significantly higher in the vitamin D insufficiency group (VDI) than in the vitamin D normal group (VDN) (P<.05 each). The proportion of TNF-α-expressing Th cells was significantly higher in the vitamin D deficiency group (VDD) than in VDN (P<.05). However, there were no significant differences between VDI and VDD. This dysregulation was significantly reduced with 1,25(OH)2 D supplementation. CONCLUSION: The data suggest that the abnormalities of cellular immune response were observed in RM patients with a low vitamin D level, which could be regulated to some extent with 1,25(OH)2 D supplementation.


Assuntos
Aborto Habitual/imunologia , Calcitriol/administração & dosagem , Fatores Imunológicos/administração & dosagem , Deficiência de Vitamina D/imunologia , Aborto Habitual/dietoterapia , Aborto Habitual/genética , Aborto Habitual/patologia , Administração Oral , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Estudos de Casos e Controles , Citotoxicidade Imunológica , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Gravidez , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/patologia
13.
Am J Reprod Immunol ; 76(4): 326-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27545493

RESUMO

PROBLEM: Dendritic cells (DCs) have been reported to play an important role in pregnancy. However, the role of DCs in recurrent pregnancy loss (RPL) has not been investigated well. METHOD OF STUDY: Forty-three women affected by RPL and 16 fertile controls were recruited from June 2013 to December 2014. The peripheral blood DCs subsets, including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), the levels (%) of CD80(+) , CD86(+) , and CD200(+) DCs were analyzed using flow cytometry. RESULTS: The levels of total DCs, mDCs, and CD86(+) DCs were significantly higher (all P<.05); however, the level of CD200(+) DCs in the RPL group was significantly lower than that of the control group (P<.05). The logistical regression analyses showed that the elevated level of mDCs was significantly associated with RPL after adjustment for age (OR: 1.14, 95% CI, 1.01-1.29, P<.05). CONCLUSION: The elevated level of mDCs was significantly associated with RPL, which might lead to the intervention of targeted immunosuppression in women with RPL.


Assuntos
Aborto Habitual/imunologia , Células Sanguíneas/imunologia , Células Dendríticas/imunologia , Células Mieloides/imunologia , Adulto , Antígenos CD/metabolismo , Estudos de Casos e Controles , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Gravidez
14.
Nat Immunol ; 16(11): 1195-203, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26390157

RESUMO

Sumoylation regulates many cellular processes, but its role in signaling via the T cell antigen receptor (TCR) remains unknown. We found that the kinase PKC-θ was sumoylated upon costimulation with antigen or via the TCR plus the coreceptor CD28, with Lys325 and Lys506 being the main sumoylation sites. We identified the SUMO E3 ligase PIASxß as a ligase for PKC-θ. Analysis of primary mouse and human T cells revealed that sumoylation of PKC-θ was essential for T cell activation. Desumoylation did not affect the catalytic activity of PKC-θ but inhibited the association of CD28 with PKC-θ and filamin A and impaired the assembly of a mature immunological synapse and central co-accumulation of PKC-θ and CD28. Our findings demonstrate that sumoylation controls TCR-proximal signaling and that sumoylation of PKC-θ is essential for the formation of a mature immunological synapse and T cell activation.


Assuntos
Isoenzimas/metabolismo , Proteína Quinase C/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/enzimologia , Linfócitos T/imunologia , Animais , Sítios de Ligação , Antígenos CD28/metabolismo , Diferenciação Celular , Células Cultivadas , Filaminas/metabolismo , Células HEK293 , Humanos , Sinapses Imunológicas/metabolismo , Isoenzimas/química , Isoenzimas/deficiência , Isoenzimas/genética , Células Jurkat , Ativação Linfocitária , Lisina/química , Camundongos , Camundongos Knockout , Mutagênese Sítio-Dirigida , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteína Quinase C/química , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Proteína Quinase C-theta , Transdução de Sinais , Sumoilação , Linfócitos T/citologia , Células Th2/citologia , Células Th2/enzimologia , Células Th2/imunologia
15.
Reprod Biomed Online ; 31(6): 823-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26371706

RESUMO

Limited information is available on the balance state of pro- and anti-inflammatory cytokines in patients with recurrent implantation failure (RIF). This study assessed the pro- and anti-inflammatory cytokines in plasma of 34 patients with RIF, compared with those of 25 women with a successful pregnancy in the first IVF/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycle. The IFN-γ, IL-1ß, IL-6 and IL-4 concentrations were higher, whereas the TGF-ß1 concentration was lower in the RIF group compared with the control group. Furthermore, the ratios of pro-inflammatory and anti-inflammatory cytokines IFN-γ/IL-4, IFN-γ/IL-10, IFN-γ/TGF-ß1, IL-6/IL-10, IL-6/TGF-ß1, IL-1ß/TGF-ß1 and TNF-α/TGF-ß1 were higher in the RIF group (all P < 0.01). The results suggested a shift toward a pro-inflammatory state in peripheral blood of the patients with RIF.


Assuntos
Aborto Habitual/sangue , Anti-Inflamatórios/sangue , Citocinas/sangue , Mediadores da Inflamação/sangue , Aborto Habitual/epidemiologia , Adulto , Estudos de Casos e Controles , Implantação do Embrião , Perda do Embrião/sangue , Perda do Embrião/epidemiologia , Feminino , Fertilização In Vitro/métodos , Humanos , Masculino , Gravidez , Injeções de Esperma Intracitoplásmicas
16.
Int J Environ Res Public Health ; 12(9): 10352-61, 2015 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-26308040

RESUMO

Thyroid autoimmunity (TAI), which is defined as the presence of autoantibodies against thyroid peroxidase (TPO) and/or thyroglobulin (TG), is related to repeated implantation failure (RIF). It is reported that TAI was involved in reproductive failure not only through leading thyroid function abnormality, but it can also be accompanied with immune imbalance. Therefore, this study was designed to investigate the association of thyroid function, immune status and TAI in women with RIF. Blood samples were drawn from 72 women with RIF to evaluate the prevalence of TAI, the thyroid function, the absolute numbers and percentages of lymphocytes. The prevalence of thyroid function abnormality in RIF women with TAI was not significantly different from that in RIF women without TAI (c(2) = 0.484, p > 0.05). The absolute number and percentage of T cells, T helper (Th) cells, B cells and natural killer (NK) cells were not significantly different in RIF women with TAI compared to those without TAI (all p > 0.05). The percentage of T cytotoxicity (Tc) cells was significantly decreased in RIF women with TAI compared to those without TAI (p < 0.05). Meanwhile, Th/Tc ratio was significantly increased (p < 0.05). These results indicated that the decreased Tc percentage and increased Th/Tc ratio may be another influential factor of adverse pregnancy outcomes in RIF women with TAI.


Assuntos
Implantação do Embrião , Infertilidade Feminina/imunologia , Linfócitos T Citotóxicos/imunologia , Tireoidite Autoimune/imunologia , Adulto , Autoanticorpos/sangue , Linfócitos B/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/terapia , Iodeto Peroxidase/imunologia , Células Matadoras Naturais/imunologia , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Tireoglobulina/imunologia , Testes de Função Tireóidea
17.
Reprod Biomed Online ; 28(5): 582-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24631166

RESUMO

The aim of this study was to evaluate the effects of quarter zona-pellucida (ZP) opening by laser-assisted hatching (QLAH) on the clinical outcomes following transfer of vitrified-warmed blastocysts developed from low-grade cleavage-stage embryos in patients with all high-grade and fair-grade cleavage-stage embryos transferred without achieving pregnancy. Patients were randomized into two groups: QLAH (n=101) and control (n=102). The implantation and clinical pregnancy rates were significantly higher in the QLAH group compared with the control group (P=0.021 and P=0.034, respectively). The live birth rate of the QLAH group was also higher, although not significantly. When the clinical outcomes according to the day of blastocyst vitrification were compared between the groups, the implantation, clinical pregnancy and live birth rates of the QLAH group were significantly higher (P<0.05) than those of the control group for day 6 blastocysts, but not for day 5 or day 5/day 6 blastocysts. These results suggest that QLAH improves the clinical outcomes of vitrified-warmed blastocysts, especially of day 6 vitrified blastocysts, developed from low-grade cleavage-stage embryos.


Assuntos
Blastocisto/efeitos da radiação , Fase de Clivagem do Zigoto/efeitos da radiação , Fertilização In Vitro/métodos , Infertilidade/diagnóstico , Infertilidade/terapia , Lasers , Adulto , Feminino , Fertilização In Vitro/estatística & dados numéricos , Humanos , Masculino , Gravidez , Taxa de Gravidez , Gravidez Múltipla/estatística & dados numéricos , Prognóstico , Resultado do Tratamento , Vitrificação
18.
J Immunol ; 190(8): 4027-36, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23514740

RESUMO

TNFR-associated factor (TRAF)6 is an essential ubiquitin E3 ligase in immune responses, but its function in adaptive immunity is not well understood. In this study, we show that TRAF6 is recruited to the peripheral ring of the T cell immunological synapse in Jurkat T cells or human primary CD4(+) T cells conjugated with staphylococcal enterotoxin E-pulsed B cells. This recruitment depends on TRAF6 interacting with linker for activation of T cells (LAT) via its TRAF domain. Although LAT was indispensable for TCR/CD28-induced TRAF6 ubiquitination and its ligase activity, RNA interference-induced TRAF6 knockdown in T cells decreased TCR/CD28-induced LAT ubiquitination, tyrosine phosphorylation, and association with tyrosine kinase ZAP70. Overexpression of TRAF6 or its catalytically inactive form C70A promoted and decreased, respectively, LAT tyrosine phosphorylation upon stimulation. Moreover, LAT was ubiquitinated at Lys(88) by TRAF6 via K63-linked chain. In addition, TRAF6 was required for and synergized with LAT to promote the TCR/CD28-induced activation of NFAT. These results reveal a novel function and mechanism of TRAF6 action in the TCR-LAT signaling pathway distinct from its role in TCR-induced NF-κB activation, indicating that LAT also plays an adapter role in TCR/CD28-induced activation of TRAF6.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Membrana/metabolismo , Mapeamento de Interação de Proteínas/métodos , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais/imunologia , Fator 6 Associado a Receptor de TNF/fisiologia , Antígenos CD28/fisiologia , Células HEK293 , Humanos , Células Jurkat , Fosforilação/imunologia , Cultura Primária de Células , Fator 6 Associado a Receptor de TNF/deficiência , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação/imunologia
19.
Cell Signal ; 24(8): 1556-64, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22513115

RESUMO

NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) complex, is an essential adaptor both for inflammation stimuli and TCR-induced NF-κB activation. However, the exact mechanism of its function has not been fully understood. Here, we report that knockdown of NEMO by RNA interference in Jurkat E6.1 cells enhanced TCR-induced NF-κB report gene activity and IL-2 production by promotion of IκBα degradation and p65 nuclear translocation, whereas inhibited TNF-α and LPS-induced IκBα degradation without influencing the phosphorylation of MAPKs. In human primary T and Jurkat E6.1 cells, both CD3/CD28 and PMA/Ionomycin induced NF-κB activation showed a para-curve correlation with the dosage of small interfering RNA targeting NEMO (siNEMO): the NF-κB report gene activity was increased along with ascending doses of transfected siNEMO and reached the highest activity when knockdown about 70% of NEMO, then turned to decline and gradually be blocked once almost thoroughly knockdown of NEMO. Meanwhile, TNF-α induced NF-κB was always inhibited no matter how much NEMO was knockdown. Subcellular fractionation results suggested that upon CD3/CD28 costimulation, NEMO and IKKß may not cotranslocate to cytoskeleton fraction as a conventional NEMO/IKK complex with a static stoichiometric ratio, instead the ratio of NEMO: IKKß continuously shift from high to low. Depletion of NEMO accelerated TCR-induced cytoskeleton translocation of IKKß. Altogether, this study suggests that NEMO may function as a rheostat exerting a negative action on TCR-induced NF-κB activation and differentially regulates TNF-α and TCR-induced NF-κB pathways.


Assuntos
Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Células Jurkat , Dados de Sequência Molecular
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