RESUMO
Pregnancy alters B cell development and function. B cell activation is initiated by antigens binding to the BCR leading to B cell survival, proliferation, antigen presentation and antibody production. We performed a genome-wide transcriptome profiling of splenic B cells from pregnant (P) and non-pregnant (NP) mice and identified 1136 genes exhibiting differential expression in B cells from P mice (625 up- and 511 down-regulated) compared to NP animals. In silico analysis showed that B cell activation through BCR seems to be lowered during pregnancy. RT-qPCR analysis confirmed these data. Additionally, B cells from pregnant women stimulated in vitro through BCR produced lower levels of inflammatory cytokines compared to non-pregnant women. Our results suggest that B cells acquire a state of hypo-responsiveness during gestation, probably as part of the maternal immune strategy for fetal tolerance but also open new avenues to understand why pregnant women are at highest risk for infections.
Assuntos
Linfócitos B , Transcriptoma , Animais , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Ativação Linfocitária , Camundongos , GravidezRESUMO
Preterm birth (PTB), defined as birth occurring before 37 weeks of pregnancy, affects 5-18% of pregnancies and is the leading cause of neonatal morbidity and mortality worldwide. Although PTB is considered a syndrome, infection-induced inflammation accounts for up to 50% of all cases. Despite the effort to reduce the incidence of PTB, it continues to rise worldwide and current approaches for preventing or treating PTB are largely unsatisfactory. Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. It is well known that probiotics can modulate the host immune system exerting a potent anti-inflammatory activity. The main aim of this work was to evaluate the capacity of the probiotic Lactobacillus kefiri (Lk48) to prevent preterm birth in mice. C57BL/6 female mice were treated with Lk48 or vehicle a week before and during pregnancy and were challenged with LPS (10 µg), a dose known to induce PTB on gestational day 16. Percentages of PTB as well as stillbirth were evaluated. We observed that oral administration of Lk48 significantly reduced the occurrence of LPS-induced PTB and stillbirth as well as improved post-natal development. This protective effect was associated with a reduction in leucocyte infiltration and reduced inflammation-induced damage in reproductive tissue. Besides, Lk48 treatment also modulated the diversity of vaginal microbiota. Our results demonstrated that prophylactic consumption of probiotic L. kefiri prevented LPS-induced PTB and still birth in mice and opens new avenues for exploring novel and promising strategies for preventing PTB in humans.
Assuntos
Endotoxinas/toxicidade , Lactobacillus/química , Nascimento Prematuro/prevenção & controle , Probióticos/administração & dosagem , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/patologia , NatimortoRESUMO
Maternal lifestyle affects both mother health and pregnancy outcome in humans. Several studies have demonstrated that interventions oriented toward reducing stress and anxiety have positive effects on pregnancy complications such as preeclampsia, excessive gestational weight, gestational diabetes and preterm birth. In this work, we showed that the environmental enrichment (EE), defined as a noninvasive and biologically significant stimulus of the sensory pathway combined with voluntary physical activity, prevented preterm birth (PTB) rate by 40% in an inflammatory mouse model induced by the systemic administration of bacterial lipopolysaccharide (LPS). Furthermore, we found that EE modulates maternal metabolism and produces an anti-inflammatory environment that contributes to pregnancy maintenance. In pregnant mice uterus, EE reduces the expression of TLR4 and CD14 (the LPS receptor and its coactivator protein), preventing the LPS-induced increase in PGE2 and PGF2α release and nitric oxide synthase (NOS) activity. In cervical tissue, EE inhibits cervical ripening events, such as PGE2 release, matrix metalloproteinase (MMP)-9 increased activity and neutrophil recruitment, therefore conserving cervical function. It seems that EE exposure could mimic the stress and anxiety-reducing techniques mentioned above, explaining, at least partially, the beneficial effects of having a healthy lifestyle before and during gestation. Furthermore, we propose that designing an EE protocol for humans could be a noninvasive and preventive therapy for pregnancy complications, averting pre-term birth occurrence and dreaded sequelae that are present in the offspring born too soon.
Assuntos
Nascimento Prematuro/prevenção & controle , Estresse Psicológico/prevenção & controle , Animais , Corticosterona/sangue , Modelos Animais de Doenças , Meio Ambiente , Feminino , Estilo de Vida Saudável , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos , Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/etiologia , Estresse Psicológico/complicações , Receptor 4 Toll-Like/metabolismo , Útero/metabolismoRESUMO
The amniotic fluid provides mechanical protection and immune defense against pathogens to the fetus. Indeed, components of the innate and adaptive immunity, including B cells, have been described in the amniotic fluid. However, limited information concerning phenotype and functionality of amniotic fluid B cells is available. Hence, we aimed to perform a full phenotypical and functional characterization of amniotic fluid B cells in normal pregnancy and in a mouse model of preterm birth. Phenotypic analysis depicted the presence of two populations of amniotic fluid B cells: an immature population, resembling B1 progenitor cells and a more mature population. Further isolation and in vitro co-culture with a bone marrow stroma cell line demonstrated the capacity of the immature B cells to mature. This was further supported by spontaneous production of IgM, a feature of the B1 B cell sub-population. An additional in vitro stimulation with lipopolysaccharide induced the activation of amniotic fluid B cells as well as the production of pro and anti-inflammatory cytokines. Furthermore, amniotic fluid B cells were expanded in the acute phase of LPS-induced preterm birth. Overall our data add new insight not only on the phenotype and developmental stage of the amniotic fluid B1 B cells but especially on their functionality. This provides important information for a better understanding of their role within the amniotic fluid as immunological protective barrier, especially with regard to intraamniotic infection and preterm birth.
Assuntos
Líquido Amniótico/imunologia , Linfócitos B/imunologia , Citocinas/metabolismo , Inflamação/fisiopatologia , Nascimento Prematuro/imunologia , Líquido Amniótico/efeitos dos fármacos , Líquido Amniótico/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Feminino , Imunoglobulina M/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Gravidez , Nascimento Prematuro/metabolismo , Nascimento Prematuro/patologiaRESUMO
In mammals, hormonal regulation during gestation is crucial for embryo implantation and pregnancy success. This regulation is controlled through the level of progesterone (P4) that blocks the activity of the hypothalamic-hypophyseal-gonadal (HHG) axis. Previous studies in the pregnant South American plains vizcacha, Lagostomus maximus, have shown that the HHG axis activates around mid-gestation, promoting pre-ovulatory follicle formation. However, the characterization of the hormonal dynamics throughout gestation and its ovarian correlation has not been studied in depth. We studied the ovarian dynamics of L. maximus and its correlation with the hormonal profile during gestation, analyzing serum levels of P4, 17ß-estradiol (E2), 4Δ-androstenedione (A4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) as well as the ovarian distribution and expression of their receptors. Additionally, we have analyzed the folliculogenesis and accessory corpora lutea (ACL) formation. P4 showed two concentration peaks reaching its highest level at mid-gestation decreasing at 91-100days post-coitum. P4 decrease is followed by an increase of circulating levels of A4, E2, FSH and LH and with an elevated number of antral/pre-ovulatory follicles which express PGR, ESR1, ESR2, AR, LHR and FSHR. In addition, ACL with oocyte retention and cytoplasmic lipid droplets in luteal cells were detected at this time point. These results show that in L. maximus the decrease of P4 level from mid-gestation enables follicular recruitment until pre-ovulatory stage and the development of functional ACL.
Assuntos
Ecossistema , Hormônios/metabolismo , Folículo Ovariano/metabolismo , Roedores/metabolismo , Animais , Corpo Lúteo/metabolismo , Corpo Lúteo/ultraestrutura , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Folículo Ovariano/citologia , Período Pós-Parto , Gravidez , Receptores de Superfície Celular/metabolismoRESUMO
STUDY QUESTION: What is the role of the endocannabinoid system (eCS) in the alterations of the endocrine system in a murine model of lipopolysaccharide (LPS)-induced miscarriage? SUMMARY ANSWER: In 7-days pregnant wild type, but not cannabinoid receptor type 1 knockout (CB1-KO) mice, LPS increased COX-2 expression and prostaglandin F2α (PGF2α) production in the uterus leading to lower expression of prolactin receptor in the ovary and a marked regression of corpora lutea (CL), suggesting that the eCS mediates the deleterious effects of LPS on reproductive events. WHAT IS KNOWN ALREADY: Appropriate systemic progesterone levels are critical for a successful pregnancy outcome. Precocious loss of luteal progesterone (P4) secretion leads to miscarriage in rodents. We have previously shown that LPS administration to pregnant mice induces embryonic resorption accompanied by a dramatic decrease in systemic progesterone levels in a murine model of inflammatory miscarriage, with the eCS mediating these LPS-induced deleterious effects. STUDY DESIGN SAMPLES/MATERIALS, METHODS: CD1 wild-type (WT) and CB1-KO mice were randomly allocated to Vehicle (saline; i.p.) or LPS (0.5 µg/g body weight; i.p.) treated groups: (WT-Vehicle; WT-LPS; CB1-KO-Vehicle and CB1-KO-LPS). A single injection was given on day 7 of pregnancy and tissues (blood, ovary, uterus) were collected 6, 12, 24 and 48 h later. P4 and PGF2α plasma levels were determined by radioimmunoassay. Cyclooxygenase-2 (COX-2) mRNA (RT-PCR) and protein (Western blot) content in uterus was assayed. COX-2 and prolactin receptor (PrlR) mRNA levels in the ovary were assayed by RT-PCR. Tissue morphology of the CL was assessed by haematoxylin-eosin staining. MAIN RESULTS AND THE ROLE OF CHANCE: Treatment of 7-day pregnant WT mice with LPS induced a P4 withdrawal (p < 0.05), increased in uterine COX-2 mRNA and protein expression (p < 0.05) as well as an increase in uterine PGF2α production (p < 0.05). These changes were absent in LPS-treated 7-day pregnant CB1-KO mice. In ovarian tissues, LPS treatment to 7-day pregnant WT mice induced a downregulation of PrlR mRNA expression (p < 0.05) together with an increase in COX-2 mRNA expression (p < 0.05) and PGF2α content (p < 0.05). These effects were absent in the CB1-KO mice. Collectively, our results suggest a role for the eCS mediating LPS-induced deleterious effects on reproductive tissues. LIMITATIONS, REASONS FOR CAUTION: An important caveat of this study is the endocrine differences between mice and humans during pregnancy (e.g. P4 is produced by the CL throughout pregnancy in mice, whereas this is not the case in humans), which limits the extrapolation of the results presented here. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insights in the role of the endocannabinoid system in the physiopathology of reproduction as well as the role of this endogenous system as a mediator of LPS deleterious effects on reproductive tissues. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: Dr Ana María Franchi was funded by Agencia Nacional para la Promoción Científica y Tecnológica (PICT 2010/0813 and PICT 2013/0097) and by Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 2012/0061). The authors have no competing interests.
Assuntos
Aborto Espontâneo/tratamento farmacológico , Aborto Espontâneo/metabolismo , Endocanabinoides/metabolismo , Lipopolissacarídeos/toxicidade , Fase Luteal/metabolismo , Progesterona/metabolismo , Animais , Corpo Lúteo/metabolismo , Feminino , Luteólise/metabolismo , Camundongos , Camundongos Knockout , Gravidez , RadioimunoensaioRESUMO
The success of eutherian mammal evolution was certainly supported by the ability of the already existing immune system to adapt to the presence of the semi-allogeneic fetus without losing the capability to defend the mother against infections. This required the acquisition of highly regulated and coordinated immunological mechanisms. Failures in the development of these strategies not only lead to the interruption of pregnancy but also compromise maternal health. Alongside changes on the cytokine profile - expansion of tolerogenic dendritic and regulatory T cells - a profound adaptation of the B cell compartment during pregnancy was recently described. Among others, the suppression of B cell lymphopoiesis and B cell lymphopenia were proposed to be protective mechanisms tending to reduce the occurrence of autoreactive B cells that might recognize fetal structures and put pregnancy on risk. On the other hand, expansion of the pre-activated marginal zone (MZ) B cell phenotype was described as a compensatory strategy launched to overcome B cell lymphopenia thus ensuring a proper defense. In this work, using an animal model of pregnancy disturbances, we demonstrated that the suppression of B cell lymphopoiesis as well as splenic B cell lymphopenia occur independently of pregnancy outcome. However, only animals undergoing normal pregnancies, but not those suffering from pregnancy disturbances, could induce an expansion and activation of the MZ B cells. Hence, our results clearly show that MZ B cells, probably due to the production of natural protective antibodies, participate in the fine balance of immune activation required for pregnancy well-being.
Assuntos
Linfócitos B/imunologia , Tecido Linfoide/imunologia , Mucosa/imunologia , Resultado da Gravidez , Aborto Espontâneo/imunologia , Animais , Fator Ativador de Células B/sangue , Linfócitos B/fisiologia , Feminino , Feto/imunologia , Tolerância Imunológica/imunologia , Imunoglobulinas/sangue , Linfopoese/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Modelos Animais , Gravidez , Útero/imunologiaRESUMO
Pregnancy hides an immunological riddle combining two antagonistic characteristics of immunology: the existence of a tolerance that allows the gestation of a semiallogeneic fetus and proper protection against pathogens threatening the health of the immunocompromised mother. Despite the fundamental role that B cells play in orchestrating an immune response, their behavior in the context of pregnancy has been barely investigated. Here we demonstrate that numbers of pre/pro and immature B cells were progressively diminished in the bone marrow (BM) of pregnant mice, leading to a reduced influx of B cells in blood and spleen. Correspondingly, lower levels of B cell-activating factor of the TNF family were observed in serum of pregnant mice. In contrast to immature B cells, mature B cells were accumulated in the BM during pregnancy. Accordingly, higher numbers of mature B cells were observed in the lymph nodes draining the uterus as well as in the peritoneal cavity of pregnant mice, both tissues in close contact with the fetuses. Despite an increase in spleen size, pregnant mice showed lower numbers of splenic B cells, which was mirrored by lower numbers of immature and FO B cells. However, marginal zone B cells in the spleen increased during pregnancy. Additionally, serum IgM, IgA, and IgG3 titers were elevated in pregnant mice. Collectively, our data show how the B cell compartment adapts to the presence of the semiallogeneic fetus during gravidity.
Assuntos
Adaptação Fisiológica/imunologia , Linfócitos B/fisiologia , Diferenciação Celular , Gravidez/imunologia , Animais , Linfócitos B/citologia , Células da Medula Óssea/imunologia , Diferenciação Celular/imunologia , Feminino , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez/sangue , Baço/citologia , Baço/imunologiaRESUMO
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults, predominantly females. This was partially attributed to sex differences in immunity, which are influenced by changes in sex hormones occurring during women's life, among other factors. Furthermore, MS patients experience significant improvement in their symptoms during pregnancy when levels of female sex-hormones significantly increase. This phenomenon was attributed to immune adaptations occurring during gestation which are regulated by paternal antigens and sex hormones. The human chorionic gonadotropin (hCG) was shown to have strong immunosuppressive abilities. We aimed to analyze here the capacity of the hCG to regulate pro- and anti-inflammatory cytokine production by PBMC from MS patients. PBMC isolated from 17 MS patients receiving IFNß1a treatment were cultured with or without recombinant or urinary hCG. Cytokine production in the supernatants was assessed using a CBA array and cytokine production by lymphocytes and expression of co-stimulatory molecules in B-lymphocytes were evaluated by flow cytometry. hCG reduced the production of TNF by PBMC from MS patients while lowering the percentages of TNF producing T cells and diminishing the production of TNF by B cells. hCG significantly boosted the production of IL-10 by regulatory T cells and CD19high B cells from MS patients. Furthermore, hCG treatment lowered the percentages of CD80+CD86+ expressing B cells within PBMC from MS patients. Overall, our results described a novel and not yet explored mechanisms of action of hCG in the context of MS.
Assuntos
Gonadotropina Coriônica , Esclerose Múltipla , Humanos , Feminino , Adulto , Esclerose Múltipla/imunologia , Masculino , Células Cultivadas , Citocinas/metabolismo , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Gravidez , Interleucina-10/metabolismo , Interferon beta/metabolismoRESUMO
During mammalian pregnancy, the immune system defies a double challenge: to tolerate the foreign growing fetus and to fight off infections that could affect both mother and fetus. Minimal disturbances to the fine equilibrium between immune activation and tolerance would compromise fetal survival. Here, we show that regulatory B10 cells are important for pregnancy tolerance in mice. The frequency of these cells increases during normal murine pregnancies, while mice presenting spontaneous abortion do not show elevated levels of regulatory B10 cells. When B10 cells are transferred to the abortion-prone mice, dendritic cells are kept in an immature state, and regulatory T cells increase, thus avoiding immunological rejection of the fetuses. In vitro, we could identify IL-10 secreted by B10 cells as the main mediator of these salutary effects. Our data add an important piece of information to the complex immune crosstalk during pregnancy. This study opens novel lines of work to better understand how to help women who have trouble in maintaining a pregnancy.
Assuntos
Aborto Espontâneo/prevenção & controle , Linfócitos B Reguladores/transplante , Modelos Animais de Doenças , Síndromes de Imunodeficiência/terapia , Interleucina-10/metabolismo , Aborto Espontâneo/etiologia , Animais , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Cruzamentos Genéticos , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Regulação da Expressão Gênica , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Knockout , Gravidez , Baço/citologia , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Systemic lupus erythematosus is a debilitating autoimmune disease characterized by uncontrolled activation of adaptive immunity, particularly B cells, which predominantly affects women in a 9 to 1 ratio compared to men. This stark sex disparity strongly suggests a role for female sex hormones in the disease's onset and progression. Indeed, it is widely recognized that estradiol not only enhances the survival of autoreactive B cells but also stimulates the production of autoantibodies associated with systemic lupus erythematosus, such as anti-nuclear antibodies and anti-dsDNA antibodies. Clinical manifestations of systemic lupus erythematosus typically emerge after puberty and persist throughout reproductive life. Furthermore, symptoms often exacerbate during the premenstrual period and pregnancy, as increased levels of estradiol can contribute to disease flares. Despite being fertile, women with lupus face a heightened risk of pregnancy-related complications, including pregnancy loss and stillbirth, which significantly surpass the rates observed in the healthy population. Therefore, this review aims to summarize and discuss the existing literature on the influence of female sex hormones on B-cell activation in patients with systemic lupus erythematosus, with a particular emphasis on their impact on pregnancy loss.
Assuntos
Aborto Habitual , Lúpus Eritematoso Sistêmico , Complicações na Gravidez , Gravidez , Masculino , Humanos , Feminino , Lúpus Eritematoso Sistêmico/complicações , Autoanticorpos , Complicações na Gravidez/diagnóstico , Estradiol , Aborto Habitual/etiologiaRESUMO
B cells are a heterogeneous cell population with differential ontogeny, anatomical location, and functions. B1 B cells are a distinct subpopulation characterized by their unique capacity of self-renewal, the production of large quantities of IL-10, and the ability to secrete protective, anti-inflammatory natural antibodies (NAbs), presumably upon down-regulation of CD1d expression. Although natural antibodies are thought to be protective, due to their polyreactivity, their participation in certain autoimmune diseases has been suggested. In the context of pregnancy, the role of B1 B cells has been discussed controversially. While in human pregnancies B1 B cells and natural/polyreactive antibodies they produce are involved in the development of preeclampsia, in mice they promote healthy gestation and fetal protection. In this work, we aimed to functionally characterize the splenic B1 B cell population during pregnancy in mice. Functional enrichment analysis using only up-regulated transcripts from a transcriptomic profile performed on total splenic B cells from pregnant compared to non-pregnant mice showed augmented cell cycle and DNA replication pathways. Proliferation studies by flow cytometry showed augmented Ki-67 proliferation marker expression and percentages of B1 B cells. Furthermore, B1 B cells produced higher levels of IL-10 and lower levels of TNF-α leading to an increased IL-10/TNF-α ratio and showing an immunoregulatory phenotype. Finally, we observed lower expression of CD1d on B1 B cells, suggesting a higher capacity to produce NAbs in the context of pregnancy. In summary, our results showed not only an expanded and proliferative splenic B1 B cell population during pregnancy but also the acquisition of immunomodulatory capacities suggesting its critical role in the intricate process of pregnancy tolerance.
Assuntos
Interleucina-10 , Fator de Necrose Tumoral alfa , Animais , Linfócitos B , Feminino , Interleucina-10/metabolismo , Contagem de Linfócitos , Camundongos , Gravidez , Baço , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Probiotics can modulate the host immune system and keep a healthy microbiota thus enhancing the integrity of the mucosal epithelium. They were proven to be useful as therapeutic strategies for a variety of inflammatory diseases. Preterm birth is a multicausal complication where the early inflammatory cascade activation affects both the mother and the fetus and may have an irreversibly impact on infant development. Prevention of preterm birth is a challenge that calls for different strategies targeting its diverse etiologies. For the past decade, novel and numerous studies investigated the role of probiotics for the prevention of preterm birth given their above-mentioned abilities. This allows a wider approach to the multifactorial causes of preterm birth. In this sense, probiotic administration was shown to be inversely related to the rate of preterm birth. In this review, we discuss the latest reports involving probiotics and preterm birth, and the chances of probiotics becoming a therapeutic strategy for the prevention of pregnancy-associated pathologies like preterm birth shortly.
Assuntos
Microbiota , Nascimento Prematuro , Probióticos , Criança , Feminino , Humanos , Recém-Nascido , Mães , Gravidez , Nascimento Prematuro/prevenção & controle , Probióticos/uso terapêuticoRESUMO
The production of pro-inflammatory cytokines during inflammatory processes has been associated with preterm birth (PTB) and fetal injury in humans and mice. We previously demonstrated that exposition to an enriched environment (EE), defined as a noninvasive and biological significant stimulus of the sensory pathway combined with voluntary physical activity, prevented PTB and perinatal death induced by the systemic administration of bacterial lipopolysaccharide (LPS) in mice. This work aimed to analyze whether EE modulates the immune response to the inflammatory process induced by LPS in peripheral blood and the amniotic fluid (AF). We observed that EE modulated maternal white blood cell count and its response to LPS. Furthermore, we found higher levels of IL-10 and a higher percentage of B cells in AF from EE exposed mothers compared to controls. Albeit LPS significantly increased IL-6 levels in AF from both groups, it was 3.6 times higher in control environment (CE) exposed group when compared to EE. Similarly, levels of IL-22 were significantly increased by LPS in both groups, but it was 6.7 times higher in EE group. Interestingly, levels of PGE2 in AF were only increased in the EE-LPS treated group, and a positive correlation between IL-22 and PGE2 levels was observed. During lactation, EE prevented LPS-induced delay in physical landmarks analyzed to assess offspring development. Our results suggest that EE modulates the immune response to systemic LPS-administration protecting the offspring. We propose that an EE-like protocol could be designed for pregnant women aiming at preventing the sequelae present in premature children.
Assuntos
Líquido Amniótico/imunologia , Morte Perinatal/prevenção & controle , Condicionamento Físico Animal , Nascimento Prematuro/prevenção & controle , Animais , Linfócitos B/imunologia , Desenvolvimento Infantil , Modelos Animais de Doenças , Feminino , Estilo de Vida Saudável , Humanos , Recém-Nascido , Lactação/imunologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Contagem de Linfócitos , Camundongos , Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/imunologiaRESUMO
Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.
Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Gravidez/imunologia , Nascimento Prematuro/imunologia , Doença Aguda , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para CimaRESUMO
BACKGROUND: Germ cell number during ovarian organogenesis is regulated through programmed cell death. We investigated the expression of germ-cell-specific VASA protein, apoptosis-related proteins BAX and BCL-2 and DNA fragmentation in developing human ovaries from gestation week 12 to term. METHODS: Human fetal ovaries from 13 women undergoing spontaneous abortion were fixed, paraffin-embedded and processed for immunohistochemistry to analyse temporal and cellular localization of VASA, BCL-2 and BAX, and to detect apoptosis by TUNEL assay. RESULTS: VASA showed a differential pattern of expression throughout the differentiation and proliferative phase and prophase I to finally associate with Balbiani's body in primordial and primary follicles. BCL-2 was detected from week 12 to 17 and became undetectable thereafter. Strong BAX signal was detected in oogonia and oocytes from week 12 to term. Low levels (Assuntos
Apoptose/fisiologia
, RNA Helicases DEAD-box/metabolismo
, Células Germinativas/química
, Ovário/embriologia
, Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
, Proteína X Associada a bcl-2/metabolismo
, Aborto Espontâneo
, Fragmentação do DNA
, Feminino
, Humanos
, Imuno-Histoquímica
, Marcação In Situ das Extremidades Cortadas
, Ovário/citologia
, Gravidez
RESUMO
Pregnant women are at high risk for severe influenza disease outcomes, yet insights into the underlying mechanisms are limited. Here, we present models of H1N1 infection in syngenic and allogenic pregnant mice; infection in the latter mirrors the severe course of 2009 pandemic influenza in pregnant women. We found that the anti-viral immune response in the pregnant host was significantly restricted as compared to the non-pregnant host. This included a reduced type I interferon response as well as impaired migration of CD8+ T cells into the lung. The multi-faceted failure to mount an anti-viral response in allogenic pregnant mice resulted in a less stringent selective environment that promoted the emergence of 2009 H1N1 virus variants that specifically counteract type I interferon response and mediate increased viral pathogenicity. These insights underscore the importance of influenza vaccination compliance in pregnant women and may open novel therapeutic avenues.
Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Mutação , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Gravidez , Seleção Genética , VirulênciaRESUMO
Abiraterone provides significant survival advantages in prostate cancer (PC), however, the current understanding of the molecular mechanisms of abiraterone is still limited. Therefore, the abiraterone impact on androgen receptor (AR)-positive LNCaP and AR-negative PC-3 cells was assessed by cellular and molecular analyses. The present study demonstrated, that abiraterone treatment significantly decreased cell growth, AR expression, and AR activity of AR-positive LNCaP cells. Notably, AR-negative PC-3 cells exhibited comparable reductions in cellular proliferation, associated with DNA fragmentation and pro-apoptotic modulation of p21, caspase-3, survivin, and transforming growth factor ß (TGFß). Our observations suggest that the attenuation of AR signaling is not the only rationale to explain the abiraterone anticancer activity. Abiraterone efficacy may play a more global role in PC progression control than originally hypothesized. In this regard, abiraterone is not only a promising drug for treatment of AR-negative PC stages, even more, abiraterone may represent an alternative for treatment of other malignancies besides prostate cancer.
Assuntos
Androstenos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Survivina , Fator de Crescimento Transformador beta/metabolismoRESUMO
During mammalian pregnancy, highly specialized mechanisms of immune tolerance are triggered in order to allow the semi-allogeneic fetus to grow within the maternal uterus in harmony with the maternal immune system. Among other mechanisms, changes in the endocrine status have been proposed to be at least part of the machinery responsible for the induction of immune tolerance during pregnancy. Indeed, pregnancy-associated hormones, estradiol, progesterone, and human chorionic gonadotropin are known to confer immune suppressive capacity to innate as well as adaptive immune cells. Regulatory B cells, a subpopulation of B lymphocytes with strong immunosuppressive functions, were shown to expand during pregnancy. Furthermore, it is well-known that some women suffering from multiple sclerosis, significantly improve their symptoms during pregnancy and this was attributed to the effect of female sex hormones. Accordingly, estradiol protects mice from developing experimental autoimmune encephalomyelitis by triggering the expansion and activation of regulatory B cells. In this review, we discuss different mechanisms associated with the development, activation, and function of regulatory B cells with a special focus on those involving pregnancy-associated hormones.