RESUMO
Adaptive immune cells with regulatory function reportedly mediate immune escape in a variety of tumors. Little is known regarding the relevance of the most prominent regulatory cell populations, namely Foxp3+ T regulatory cells (Tregs) and CD19+IL-10+ B regulatory cells (Bregs), for neuroblastoma (NB) survival. After establishing a novel immunocompetent syngeneic NB mouse model where orthotopic tumors can be generated after intrarenal injection of NB975A cells, we studied the importance of Tregs and Bregs in Foxp3-DTR mice whose Tregs can be depleted by diphtheria toxin (DT) application as well as in CD19-specific IL-10 deficient mice that lack IL-10+ Bregs (CD19cre+/- × IL-10fl/fl mice). We observed Foxp3 Treg cells in tumors from wild type mice. On the contrary, Bregs or B cells were scarce. Specific depletion of Tregs in Foxp3-DTR mice resulted in an 85% reduction of tumor volume and weight compared to DT-treated wild type mice and untreated Foxp3-DTR mice. In contrast, NB tumor growth was not affected in CD19-specific IL-10 deficient mice. Similarly, mice lacking mature B cells (µMT mice) and CD19 deficient mice (CD19cre mice) showed no change in growth pattern of NB tumors. In Treg-depleted mice, reduced tumor growth was associated with an increased concentration of IFN-gamma, TNF-alpha, IL-4, IL-6, and IL-10 in isolated splenocytes. In summary, transient ablation of Tregs but not absence of Bregs hindered the growth of NB, strongly suggesting the therapeutic potential of targeting Tregs for this aggressive childhood tumor.
Assuntos
Linfócitos B Reguladores , Neuroblastoma , Animais , Antígenos CD19 , Linfócitos B Reguladores/metabolismo , Toxina Diftérica/metabolismo , Toxina Diftérica/farmacologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neuroblastoma/metabolismo , Linfócitos T Reguladores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.
Assuntos
Didrogesterona/administração & dosagem , Fase Luteal/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Animais , Suplementos Nutricionais , Implantação do Embrião/efeitos dos fármacos , Feminino , Fertilização in vitro/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Parto/efeitos dos fármacos , Placenta/efeitos dos fármacos , Gravidez , Taxa de Gravidez , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Técnicas de Reprodução AssistidaRESUMO
Immune cells adapt their phenotypic and functional characteristics in response to the tissue microenvironment within which they traffic and reside. The fetomaternal interface, consisting of placental trophoblasts and the maternal decidua, is a highly specialized tissue with a unique and time-limited function: to nourish and support development of the semiallogeneic fetus and protect it from inflammatory or immune-mediated injury. It is therefore important to understand how immune cells within these tissues are educated and adapt to fulfill their biological functions. This review article focuses on the local regulatory mechanisms ensuring that both innate and adaptive immune cells appropriately support the early events of implantation and placental development through direct involvement in promoting immune tolerance of fetal alloantigens, suppressing inflammation, and remodeling of maternal uterine vessels to facilitate optimal placental function and fetal growth.
Assuntos
Microambiente Celular/imunologia , Desenvolvimento Fetal/imunologia , Feto/imunologia , Placentação/imunologia , Animais , Feminino , Humanos , GravidezRESUMO
The aim of this study was to analyze whether dermal exposure to benzophenone 3 (BP-3) during pregnancy affects critical parameters of pregnancy, and whether this exposure may affect the outcome of a second pregnancy in mice. Pregnant mice were exposed to 50-mg BP-3/kg body weight/day or olive oil (vehicle) from gestation day (gd) 0 to gd6 by dermal exposure. High-frequency ultrasound imaging was used to follow up fetal and placental growth in vivo. Blood flow parameters in uterine and umbilical arteries were analyzed by Doppler measurements. Mice were killed at gd5, gd10, and gd14 on the first pregnancy, and at gd10 and 14 on the second pregnancy. The weight of the first and second progenies was recorded, and sex ratio was analyzed. BP-3 levels were analyzed in serum and amniotic fluid. BP-3 reduced the fetal weight at gd14 and feto-placenta index of first pregnancy, with 16.13% of fetuses under the 5th percentile; arteria uterina parameters showed altered pattern at gd10. BP-3 was detected in serum 4 h after the exposure at gd6, and in amniotic fluid at gd14. Offspring weight of first progeny was lower in BP-3 group. Placenta weights of BP-3 group were decreased in second pregnancy. First and second progenies of mothers exposed to BP-3 showed a higher percentage of females (female sex ratio). Dermal exposure to low dose of BP-3 during early pregnancy resulted in an intrauterine growth restriction (IUGR) phenotype, disturbed sex ratio and alterations in the growth curve of the offspring in mouse model.
Assuntos
Benzofenonas/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/induzido quimicamente , Razão de Masculinidade , Protetores Solares/toxicidade , Administração Cutânea , Líquido Amniótico/metabolismo , Animais , Benzofenonas/administração & dosagem , Benzofenonas/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/fisiopatologia , Idade Gestacional , Masculino , Exposição Materna , Troca Materno-Fetal , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Placentação/efeitos dos fármacos , Gravidez , Medição de Risco , Protetores Solares/administração & dosagem , Protetores Solares/metabolismoRESUMO
Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/metabolismo , Hipocampo/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hormônio Liberador de Gonadotropina/metabolismo , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Fosforilação , RNA Mensageiro/biossíntese , Transdução de Sinais , Sinapses/genética , Sinapses/metabolismoRESUMO
The pregnancy hormone, human chorionic gonadotropin (hCG), is crucially involved in processes such as implantation and placentation, two milestones of pregnancy whose successful progress is a prerequisite for adequate fetal growth. Moreover, hCG determines fetal fate by regulating maternal innate and adaptive immune responses allowing the acceptance of the foreign fetal antigens. As one of the first signals provided by the embryo to its mother, hCG has the potential to regulate very early pregnancy-driven immune responses, allowing the establishment and preservation of fetal tolerance. This mini review focuses on how hCG modulates the adaptive arm of the immune system including dendritic cells as key regulators of adaptive immune responses.
Assuntos
Gonadotropina Coriônica/metabolismo , Desenvolvimento Fetal/imunologia , Tolerância Imunológica , Fatores Imunológicos/metabolismo , Imunomodulação , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Gravidez , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
T helper type 17 (Th17) and regulatory T (Treg) cells are active players in the establishment of tolerance and defence. These attributes of the immune system enmesh to guarantee the right level of protection. The healthy immune system, on the one hand, recognizes and eliminates dangerous non-self pathogens and, on the other hand, protects the healthy self. However, there are circumstances where this fine balance is disrupted. In fact, in situations such as in pregnancy, the foreign fetal antigens challenge the maternal immune system and Treg cells will dominate Th17 cells to guarantee fetal survival. In other situations such as autoimmunity, where the Th17 responses are often overwhelming, the immune system shifts towards an inflammatory profile and attacks the healthy tissue from the self. Interestingly, autoimmune patients have meliorating symptoms during pregnancy. This connects with the antagonist role of Th17 and Treg cells, and their specific profiles during these two immune challenging situations. In this review, we put into perspective the Th17/Treg ratio during pregnancy and autoimmunity, as well as in pregnant women with autoimmune conditions. We further review existing systems biology approaches that study specific mechanisms of these immune cells using mathematical modelling and we point out possible future directions of investigation. Understanding what maintains or disrupts the balance between these two opponent yet reciprocal cells in healthy physiological settings, sheds light into the development of innovative pharmacological approaches to fight pregnancy loss and autoimmunity.
Assuntos
Gravidez/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Aborto Habitual/imunologia , Animais , Doenças Autoimunes/etiologia , Autoimunidade , Feminino , Humanos , Modelos Teóricos , Pré-Eclâmpsia/imunologia , Complicações na Gravidez/etiologia , Nascimento Prematuro/imunologiaRESUMO
The pregnancy hormone human Chorionic Gonadotropin (hCG) reportedly modulates innate and adaptive immune responses and contributes thereby to fetal survival. More precisely, hCG has been shown to support human Treg cell homing into the fetal-maternal interface and enhance number and function of Treg cells in murine pregnancy. Here, we aimed to study whether hCG and hCG-producing human trophoblast cell lines induce Treg cells from CD4+FOXP3- T cells and promote T cell suppressive activity. CD4+FOXP3- T cells were isolated from peripheral blood of normal pregnant women and cultured in the presence of hCG-producing (JEG-3, HTR-8) and non-producing (SWAN-71) cell lines. To confirm the participation of hCG in Treg cell conversion, the experiments were performed in the presence of anti-hCG and additional experiments were run with recombinant or urine-purified hCG. After culture the number of CD4+FOXP3+ Treg cells as well as the suppressive capacity of total T cells was assessed. hCG-producing JEG-3 cells as well as recombinant and urine-purified hCG induced CD4+FOXP3+ Treg cells from CD4+FOXP3- T cells. Blockage of hCG impaired Treg cell induction. Moreover, hCG-producing JEG-3 cells increased suppressive activity of CD4+FOXP3- T cells through an antigen-independent pathway. Our results propose another mechanism through which hCG modulates the female immune system during pregnancy in favor of the fetus.
RESUMO
Normal pregnancy is characterized by an early expansion of regulatory T cells (Tregs), which is known to contribute to fetal tolerance. However, mechanisms and factors behind Treg expansion are not yet defined. Recently, we proposed that the pregnancy hormone human chorionic gonadotropin (hCG) efficiently attracts human Tregs to trophoblasts, favoring their accumulation locally. In this study, we hypothesized that hCG not only acts as a chemoattractant of Tregs but also plays a central role in pregnancy-induced immune tolerance. Virgin, normal pregnant, and abortion-prone female mice were treated either with 10 IU/ml hCG or PBS at days 0, 2, 4, and 6 of pregnancy. The hCG effect on Treg frequency and cytokine secretion was determined in Foxp3(gfp) females. hCG impact on Treg suppressive capacity was studied in vitro. In vivo, we investigated whether hCG enhances Treg suppressive capacity indirectly by modulating dendritic cell maturation in an established mouse model of disturbed fetal tolerance. Application of hCG increased Treg frequency in vivo and their suppressive activity in vitro. In females having spontaneous abortions, hCG provoked not only an augmentation of Treg numbers, but also normalized fetal abortion rates. hCG-generated Tregs were fully functional and could confer tolerance when adoptively transferred. hCG also retained dendritic cells in a tolerogenic state that is likely to contribute to both Treg expansion and prevention of abortion. Our results position hCG in a novel, so far unknown role as modulator of immune tolerance during pregnancy.
Assuntos
Gonadotropina Coriônica/fisiologia , Tolerância Imunológica/fisiologia , Proteínas da Gravidez/fisiologia , Gravidez/imunologia , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos TransgênicosRESUMO
Recognition of foreign paternal antigens expressed in the semi-allogeneic fetus by maternal immune cells is a requirement for successful pregnancy. However, despite intensive research activity during the last decades, the precise mechanisms contributing to the acceptance of the paternal alloantigens are still puzzling and pregnancy remains a fascinating phenomenon. Moreover, most studies focused on the maternal and fetal contribution to pregnancy success, and relatively little is known about the paternal involvement. In the current review, we address the contribution of paternal-derived factors to fetal-tolerance induction. First, we discuss data suggesting that in both humans and mice, the female body gets prepared for a pregnancy in every cycle, also in regard to male alloantigens delivered at coitus. Then, we provide an overview about factors present in seminal fluid and how these factors influence immune responses in the female reproductive tract. We further discuss ways of paternal alloantigen presentation and identify the immune modulatory properties of seminal fluid-derived factors with a special focus on Treg biology. Finally, we highlight the therapeutic potential of seminal fluid in different clinical applications.
Assuntos
Feto/imunologia , Sêmen/imunologia , Animais , Feminino , Humanos , Masculino , Camundongos , Gravidez , Linfócitos T Reguladores/imunologiaRESUMO
The enzyme heme oxygenase-1 (HO-1) is pivotal in reproductive processes, particularly in placental and vascular development. This study investigated the role of HO-1 and its byproduct, carbon monoxide (CO), in trophoblastic spheroid implantation. In order to deepen our understanding of the role of HO-1 during implantation, we conducted in vivo experiments on virgin and pregnant mice, aiming to unravel the cellular and molecular mechanisms. Using siRNA, HO-1 was knocked down in JEG-3 and BeWo cells and trophoblastic spheroids were generated with or without CO treatment. Adhesion assays were performed after transferring the spheroids to RL-95 endometrial epithelial cell layers. Additionally, angiogenesis, stress, and toxicity RT2-Profiler™ PCR SuperArray and PCR analyses were performed in uterine murine samples. HO-1 knockdown by siRNA impeded implantation in the 3D culture model, but this effect could be reversed by CO. Uteruses from virgin Hmox1-/- females exhibited altered expression of angiogenesis and stress markers. Furthermore, there was a distinct expression pattern of cytokines and chemokines in uteruses from gestation day 14 in Hmox1-/- females compared to Hmox1+/+ females. This study strongly supports the essential role of HO-1 during implantation. Moreover, CO appears to have the potential to compensate for the lack of HO-1 during the spheroid attachment process. The absence of HO-1 results in dysregulation of angiogenesis and stress-related genes in the uterus, possibly contributing to implantation failure.
Assuntos
Heme Oxigenase-1 , Placenta , Gravidez , Feminino , Camundongos , Animais , Heme Oxigenase-1/metabolismo , Placenta/metabolismo , Linhagem Celular Tumoral , Angiogênese , Útero/metabolismo , RNA Interferente Pequeno/metabolismo , Expressão GênicaRESUMO
Immune homeostasis is key to guarantee that the immune system can elicit effector functions against pathogens and at the same time raise tolerance towards other antigens. A disturbance of this delicate balance may underlie or at least trigger pathologies. Endocrine disrupting chemicals (EDCs) are increasingly recognized as risk factors for immune dysregulation. However, the immunotoxic potential of specific EDCs and their mixtures is still poorly understood. Thus, we aimed to investigate the effect of bisphenol A (BPA) and benzophenone-3 (BP-3), alone and in combination, on in vitro differentiation of T helper (TH)17 cells and regulatory T (Treg) cells. Naïve T cells were isolated from mouse lymphoid tissues and differentiated into the respective TH population in the presence of 0.001-10 µM BP-3 and/or 0.01-100 µM BPA. Cell viability, proliferation and the expression of TH lineage specific transcription factors and cytokines was measured by flow cytometry and CBA/ELISA. Moreover, the transcription of hormone receptors as direct targets of EDCs was quantified by RT-PCR. We found that the highest BPA concentration adversely affected TH cell viability and proliferation. Moreover, the general differentiation potential of both TH populations was not altered in the presence of both EDCs. However, EDC exposure modulated the emergence of TH17 and Treg cell intermediate states. While BPA and BP-3 promoted the development of TH1-like TH17 cells under TH17-differentiating conditions, TH2-like Treg cells occurred under Treg polarization. Interestingly, differential effects could be observed in mixtures of the two tested compounds compared with the individual compounds. Notably, estrogen receptor ß expression was decreased under TH17-differentiating conditions in the presence of BPA and BP-3 as mixture. In conclusion, our study provides solid evidence for both, the immune disruptive potential and the existence of cumulative effects of real nature EDC mixtures on T cell in vitro differentiation.
Assuntos
Compostos Benzidrílicos , Benzofenonas , Diferenciação Celular , Fenóis , Linfócitos T Reguladores , Células Th17 , Fenóis/toxicidade , Fenóis/farmacologia , Animais , Compostos Benzidrílicos/toxicidade , Benzofenonas/farmacologia , Benzofenonas/toxicidade , Diferenciação Celular/efeitos dos fármacos , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/citologia , Células Th17/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Células CultivadasRESUMO
Endocrine disrupting chemicals (EDCs) possess the capability to interfere with the endocrine system by binding to hormone receptors, for example on immune cells. Specific effects have already been described for individual substances, but the impact of exposure to chemical mixtures during pregnancy on maternal immune regulation, placentation and fetal development is not known. In this study, we aimed to investigate the combined effects of two widespread EDCs, bisphenol A (BPA) and benzophenone-3 (BP-3), at allowed concentrations on crucial pregnancy processes such as implantation, placentation, uterine immune cell populations and fetal growth. From gestation day (gd) 0 to gd10, female mice were exposed to 4 µg/kg/d BPA, 50 mg/kg/d BP-3 or a BPA/BP-3 mixture. High frequency ultrasound and Doppler measurements were used to determine intrauterine fetal development and hemodynamic parameters. Furthermore, uterine spiral artery remodeling and placental mRNA expression were studied via histology and CHIP-RT-PCR, respectively. Effects of EDC exposure on multiple uterine immune cell populations were investigated using flow cytometry. We found that exposure to BP-3 caused intrauterine growth restriction in offspring at gd14, while BPA and BPA/BP-3 mixture caused varying effects. Moreover, placental morphology at gd12 and placental efficiency at gd14 were altered upon BP-3 exposure. Placental gene transcription was altered particularly in female offspring after in utero exposure to BP-3. Flow cytometry analyses revealed an increase in uterine T cells and NK cells in BPA and BPA/BP-3-treated dams at gd14. Doppler measurements revealed no effect on uterine hemodynamic parameters and spiral artery remodeling was not affected following EDC exposure. Our results provide evidence that exposure to BPA and BP-3 during early gestation affects fetal development in a sex-dependent manner, placental function and immune cell frequencies at the feto-maternal interface. These results call for inclusion of studies addressing pregnancy in the risk assessment of environmental chemicals.
Assuntos
Benzofenonas , Fenóis , Placenta , Placentação , Gravidez , Feminino , Camundongos , Animais , Placenta/metabolismo , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/metabolismo , Desenvolvimento FetalRESUMO
Ovarian cancer has the highest mortality rate among female reproductive tract malignancies. A complex network, including the interaction between tumor and immune cells, regulates the tumor microenvironment, survival, and growth. The role of mast cells (MCs) in ovarian tumor pathophysiology is poorly understood. We aimed to understand the effect of MCs on tumor cell migration and growth using in vitro and in vivo approaches. Wound healing assays using human tumor cell lines (SK-OV-3, OVCAR-3) and human MCs (HMC-1) were conducted. Murine ID8 tumor cells were injected into C57BL6/J wildtype (WT) and MC-deficient C57BL/6-KitW-sh/W-sh (KitW-sh) mice. Reconstitution of KitW-sh was performed by the transfer of WT bone marrow-derived MCs (BMMCs). Tumor development was recorded by high-frequency ultrasonography. In vitro, we observed a diminished migration of human ovarian tumor cells upon direct or indirect MC contact. In vivo, application of ID8 cells into KitW-sh mice resulted in significantly increased tumor growth compared to C57BL6/J mice. Injection of BMMCs into KitW-sh mice reconstituted MCs and restored tumor growth. Our data show that MCs have a suppressive effect on ovarian tumor growth and may serve as a new therapeutic target.
RESUMO
OBJECTIVE: Pregnancy is characterized by well-defined immunological adaptions within the maternal immune cell compartment allowing the survival of a genetically disparate individual in the maternal womb. Phenotype and function of immune cells are largely determined by intracellular processing of external stimuli. Ubiquitinating and deubiquitinating enzymes are known to critically regulate immune signaling either by modulating the stability or the interaction of the signaling molecules. Accordingly, if absent, critical physiological processes may be perturbed such as fetal tolerance induction. Based on previous findings that mice hemizygous for the deubiquitinating enzyme otubain 1 (OTUB1) do not give rise to homozygous progeny, here, we investigated whether partial OTUB1 deficiency influences fetal-wellbeing in a syngeneic or an allogeneic pregnancy context accompanied by changes in the dendritic cell (DC) and T cell compartment. RESULTS: We observed increased fetal rejection rates in allogeneic pregnant OTUB1 heterozygous dams but not syngeneic pregnant OTUB1 heterozygous dams when compared to OTUB1 wildtype dams. Fetal demise in allogeneic pregnancies was not associated with major changes in maternal peripheral and local DC and T cell frequencies. Thus, our results suggest that OTUB1 confers fetal protection, however, this phenotype is independent of immune responses involving DC and T cells.
Assuntos
Enzimas Desubiquitinantes , Transplante de Células-Tronco Hematopoéticas , Feminino , Camundongos , Gravidez , Animais , Cisteína Endopeptidases/genética , Linfócitos T , Células Dendríticas , Tolerância ImunológicaRESUMO
Breastfeeding is associated with long-term wellbeing including low risks of infectious diseases and non-communicable diseases such as asthma, cancer, autoimmune diseases and obesity during childhood. In recent years, important advances have been made in understanding the human breast milk (HBM) composition. Breast milk components such as, non-immune and immune cells and bioactive molecules, namely, cytokines/chemokines, lipids, hormones, and enzymes reportedly play many roles in breastfed newborns and in mothers, by diseases protection and shaping the immune system of the newborn. Bioactive components in HBM are also involved in tolerance and appropriate inflammatory response of breastfed infants if necessary. This review summarizes the current literature on the relationship between mother and her infant through breast milk with regard to disease protection. We will shed some light on the mechanisms underlying the roles of breast milk components in the maintenance of health of both child and mother.
Assuntos
Leite Humano , Mães , Aleitamento Materno , Criança , Feminino , Humanos , Sistema Imunitário , Imunidade Ativa , Lactente , Recém-NascidoRESUMO
Spiral-artery (SA) remodeling is a fundamental process during pregnancy that involves the action of cells of the initial vessel, such as vascular smooth-muscle cells (VSMCs) and endothelial cells, but also maternal immune cells and fetal extravillous trophoblast cells (EVTs). Mast cells (MCs), and specifically chymase-expressing cells, have been identified as key to a sufficient SA-remodeling process in vivo. However, the mechanisms are still unclear. The purpose of this study is to evaluate the effects of the MC line HMC-1 and recombinant human chymase (rhuCMA1) on human primary uterine vascular smooth-muscle cells (HUtSMCs), a human trophoblast cell line (HTR8/SV-neo), and human umbilical-vein endothelial cells (HUVEC) in vitro. Both HMC-1 and rhuCMA1 stimulated migration, proliferation, and changed protein expression in HUtSMCs. HMC-1 increased proliferation, migration, and changed gene expression of HTR8/SVneo cells, while rhuCMA treatment led to increased migration and decreased expression of tissue inhibitors of matrix metalloproteinases. Additionally, rhuCMA1 enhanced endothelial-cell-tube formation. Collectively, we identified possible mechanisms by which MCs/rhuCMA1 promote SA remodeling. Our findings are relevant to the understanding of this crucial step in pregnancy and thus of the dysregulated pathways that can lead to pregnancy complications such as fetal growth restriction and preeclampsia.
Assuntos
Mastócitos , Trofoblastos , Quimases/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Miócitos de Músculo Liso/metabolismo , Fenótipo , Gravidez , Trofoblastos/metabolismoRESUMO
By promoting tissue invasion, cell growth and angiogenesis, the Y-box binding protein (YB-1) became famous as multifunctional oncoprotein. However, this designation is telling only part of the story. There is one particular time in life when actual tumorigenic-like processes become undoubtedly welcome, namely pregnancy. It seems therefore reasonable that YB-1 plays also a crucial role in reproduction, and yet this biological aspect of the cold-shock protein has been overlooked for many years. To overcome this limitation, we would like to propose a new perspective on YB-1 and emphasize its pivotal functions in healthy pregnancy and pregnancy-related complications. Moreover, we will discuss findings obtained from cancer research in the light of reproductive events to elucidate the importance of YB-1 at the feto-maternal interface.
RESUMO
An equilibrium between proinflammatory and anti-inflammatory immune responses is essential for maternal tolerance of the fetus throughout gestation. To study the participation of fetal tissue-derived factors in this delicate immune balance, we analyzed the effects of human chorionic gonadotropin (hCG) on murine Treg cells and Th17 cells in vitro, and on pregnancy outcomes, fetal and placental growth, blood flow velocities and remodeling of the uterine vascular bed in vivo. Compared with untreated CD4+CD25+ T cells, hCG increased the frequency of Treg cells upon activation of the LH/CG receptor. hCG, with the involvement of IL-2, also interfered with induced differentiation of CD4+ T cells into proinflammatory Th17 cells. In already differentiated Th17 cells, hCG induced an anti-inflammatory profile. Transfer of proinflammatory Th17 cells into healthy pregnant mice promoted fetal rejection, impaired fetal growth and resulted in insufficient remodeling of uterine spiral arteries, and abnormal flow velocities. Our works show that proinflammatory Th17 cells have a negative influence on pregnancy that can be partly avoided by in vitro re-programming of proinflammatory Th17 cells with hCG.
Assuntos
Linfócitos T Reguladores , Células Th17 , Animais , Gonadotropina Coriônica/farmacologia , Gonadotropina Coriônica/fisiologia , Feminino , Humanos , Interleucina-2 , Camundongos , Placenta , GravidezRESUMO
BACKGROUND: Different periodontal treatment methods (quadrant-wise debridement, scaling and root planing (Q-SRP), full-mouth scaling (FMS), full-mouth disinfection (FMD), and FMD with adjuvant erythritol air-polishing (FMDAP)) were applied in periodontitis patients (stage III/IV). The study objective (substudy of ClinicalTrials.gov Identifier: NCT03509233) was to compare the impact of treatments on subgingival colonization. METHODS: Forty patients were randomized to the treatment groups. Periodontal parameters and subgingival colonization were evaluated at baseline and 3 and 6 months after treatment. RESULTS: Positive changes in clinical parameters were recorded in every treatment group during the 3-month follow-up period, but did not always continue. In three groups, specific bacteria decreased after 3 months; however, this was associated with a renewed increase after 6 months (FMS: Porphyromonas gingivalis; FMD: Eubacterium nodatum, Prevotella dentalis; and FMDAP: uncultured Prevotella sp.). CONCLUSIONS: The benefit of all clinical treatments measured after 3 months was associated with a decrease in pathogenic bacteria in the FMS, FMD, and FMDAP groups. However, after 6 months, we observed further improvement or some stagnation in clinical outcomes accompanied by deterioration of the microbiological profile. Investigating the subgingival microbiota might help appraise successful periodontal treatment and implement individualized therapy.