RESUMO
Successful pregnancy relies on the adaptation of immune responses that allow the fetus to grow and develop in the uterus despite being recognized by maternal immune cells. Dendritic cells (DCs) are central to the control of immune tolerance, and their state of activation at the maternal-decidual interface is critical to the feto-maternal immunological equilibrium. So far, the involvement of circulating DCs has been investigated poorly. Therefore, in this study we investigated whether, during healthy human pregnancy, peripheral blood DCs (PBDCs) undergo changes that may be relevant to the adaptation of maternal immune responses that allow fetal tolerance. In a cross-sectional study, we analysed PBDCs by six-colour flow cytometry on whole blood samples from 47 women during healthy pregnancy progression and 24 non-pregnant controls. We demonstrated that both myeloid and plasmacytoid PBDCs undergo a state of incomplete activation, more evident in the third trimester, characterized by increased expression of co-stimulatory molecules and cytokine production but lacking human leucocyte antigen (HLA)-DR up-regulation. To investigate the contribution of soluble circulating factors to this phenomenon, we also performed culture experiments showing that sera from pregnant women added to control DCs conditioned a similar incomplete activation that was associated with reduced DC allostimulatory capacity, supporting the in vivo relevance of our findings. We also obtained evidence that the glycoprotein hormone activin-A may contribute to DC incomplete activation. We suggest that the changes of PBDCs occurring during late pregnancy may aid the comprehension of the immune mechanisms operated by the maternal immune system to maintain fetal tolerance.
Assuntos
Células Dendríticas/imunologia , Ativinas/farmacologia , Ativinas/fisiologia , Adulto , Apresentação de Antígeno , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Citocinas/biossíntese , Citocinas/classificação , Citocinas/genética , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/genética , Humanos , Tolerância Imunológica/imunologia , Inflamação , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Teste de Cultura Mista de Linfócitos , Troca Materno-Fetal , Gravidez , Terceiro Trimestre da Gravidez , Proteínas Recombinantes/farmacologia , Regulação para Cima , Adulto JovemRESUMO
Ovarian, endometrial and breast cancers are associated with several risk factors, such as low parity, infertility, early age at menarche, and late age at menopause. Frequently most of these risk factors coexist in infertile patients and some studies suggested that the different infertility causes can be involved in cancer risk development. In particular case-control and cohort studies investigated the possible role of ovulatory disorders, endometriosis and unexplained infertility in increasing the risk of this disease. Most studies have shown no overall increased risk in invasive ovarian cancer in subfertile patients, although nulliparity has been consistently associated with increased rates of ovarian tumor, in particular with borderline and endometrioid cancers in patients with a history of endometriosis. Different studies reported that infertile women are not at risk for breast cancer. However, women affected by infertility may be more at risk for endometrial cancer, particularly if affected by ovulatory disorders. Moreover, infertility is now often treated with medical devices that could by themselves modify the hormonal environment and be cofactors in the cellular changes towards cancer development. However, although early studies suggested that infertility medications were associated to increased risk in ovarian cancer, subsequent studies have been mainly reassuring, although suggesting that type and duration of medical treatment can increase the malignancy risk. An increased risk of endometrial cancer in patients undergoing infertility treatment has been reported, as expected by the similar structure shared by clomiphene and tamoxiphene. Since breast cancer is widely recognized as having a hormonal etiology, a possible role of fertility medications to promote cancer has been hypothesized. However, many large studies were not able to find an associated risk of breast cancer. In conclusion, nowadays, firm answers about the precise effects of infertility and its treatment on cancer risk are not available but findings are generally reassuring. Further studies about fertility drug treatments on larger populations may offer in the future longer follow-up and more precise data with better adjustments for confounding factors.
Assuntos
Infertilidade Feminina/complicações , Neoplasias/etiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/etiologia , Feminino , Humanos , Infertilidade Feminina/epidemiologia , Modelos Biológicos , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etiologia , Indução da Ovulação/efeitos adversos , Fatores de RiscoRESUMO
Understanding the mechanisms of disease responsible for the syndrome of preeclampsia as well as early risk assessment is still a major challenge. The concentrations of circulating proteins in maternal blood such as placental growth factor, soluble vascular endothelial growth factor receptor-1 and soluble endoglin are altered weeks before the onset of clinical symptoms of the syndrome. Recently, other proteins in maternal serum, such as activin A, inhibin A, PAPP-A, and PP13 have been suggested to be of value in first trimester risk assessment. Since preeclampsia is a syndrome, it seems unlikely that a single test will predict all forms of preeclampsia. This realization has led to the formulation of a new conceptual framework suggesting that a combination of markers (biochemical and/or biophysical) may be required to conduct comprehensive risk assessment for the syndrome.
Assuntos
Biomarcadores , Marcadores Genéticos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , Educação , Feminino , Humanos , Pré-Eclâmpsia/genética , Valor Preditivo dos Testes , Gravidez , Fatores de RiscoRESUMO
The thermogenic activity of brown adipose tissue (BAT) is heavily dependent on high perfusion, through its dense vascular system. Angiogenesis must go hand-in-hand with BAT functions, but little is known about the factors controlling it. In the present study we demonstrate that: (a) vascular endothelial growth factor (VEGF) is synthesised and released in brown adipocytes in culture; (b) VEGF mRNA isoforms and protein appear in dispersed mature brown adipocytes and whole tissue; (c) VEGF expression is increased in BAT from cold-exposed rats, and in cultured brown adipocytes exposed to noradrenaline and the beta3-adrenoceptor agonists; (e) BAT from genetically obese (falfa) rats exhibits reduced expression of VEGF as well as a change in the ratio of mRNA isoforms. It is concluded that sympathetic control of VEGF expression via noradrenaline acting on beta3-adrenoceptors plays a major role in developmental and adaptive angiogenesis, and defects in this contribute to the reduced thermogenic capacity of BAT in genetic obesity.
Assuntos
Tecido Adiposo Marrom/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Regulação da Expressão Gênica , Linfocinas/metabolismo , Obesidade/metabolismo , Sistema Nervoso Simpático/metabolismo , Tecido Adiposo Marrom/irrigação sanguínea , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/imunologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Temperatura Baixa , Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Linfocinas/genética , Linfocinas/imunologia , Masculino , Neovascularização Fisiológica , Norepinefrina/farmacologia , Obesidade/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptores Adrenérgicos beta/fisiologia , Receptores Adrenérgicos beta 3 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Despite the success of assisted reproduction technologies (ART) in allowing conception in couples with infertility problems, a growing body of evidence points to implication of ART on fetal birth weight alterations, fetal malformations, chromosomal aneuploidies and syndromes related to genomic imprinting modifications. Different causes can be accounted for to explain the increased risk of fetal defects. Pregnancies generated by ART differ from spontaneously achieved pregnancies in that gametes and embryos are cultured in vitro, more than one conceptus is transferred into the uterine cavity, and the time of transfer is different to what occurs in normal conditions. Epigenetic reprogramming of gene expression has been advocated in relation to the gamete and embryo manipulation, with a significant role of genomic imprinting in determining changes in fetal growth. Moreover, the maternal environment, with the ovarian hyperstimulation of the beginning of pregnancy, could alter the maternal response to the early phases of trophoblast invasion. There are suggestions that placental weights and placental/fetal weight ratios are increased in these pregnancies resembling the model of maternal undernutrition in the early phases of pregnancy. Therefore concern has also arisen around the possible long term and transgenerational effects of assisted reproduction procedures and studies should be carried out to evaluate these possibilities.
Assuntos
Desenvolvimento Embrionário e Fetal , Doenças Fetais , Técnicas de Reprodução Assistida/efeitos adversos , Adulto , Feminino , Doenças Fetais/epidemiologia , Doenças Fetais/etiologia , Humanos , GravidezAssuntos
Adipócitos Marrons/fisiologia , Adipócitos Brancos/fisiologia , Apoptose/fisiologia , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/citologia , Adipócitos Brancos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 8/genética , Caspase 8/metabolismo , Cicloeximida/farmacologia , Fragmentação do DNA , Regulação da Expressão Gênica , Obesidade/fisiopatologia , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Inanição/fisiopatologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Endothelial dysfunction typical of preeclampsia (PE) is the result of an excessive maternal inflammatory response to pregnancy. We investigated PTX3 in maternal, fetal and placental compartments in complicated pregnancies. Maternal blood samples were collected during the third trimester in 53 PE, 43 IUGR (intrauterine growth restriction) and 50 normal pregnancies. Fetal samples were collected from the umbilical vein in 26 PE, 23 IUGR and 26 normal pregnancies at elective cesarean section. Pattern and site of expression of PTX3 were studied by immunohistochemistry (IHC) on placenta, decidual bed and maternal peritoneum. PE and IUGR pregnancies had significantly higher maternal PTX3 levels compared to normal pregnancies, with IUGR significantly lower than PE. Maternal peritoneum expressed a significantly higher signal in the endothelium of pathological compared to normal pregnancies. The maternal increase of PTX3 correlated with the severity of disease with higher PTX3 concentrations in severe PE. Increased PTX3 levels in PE and IUGR mothers, together with IHC data represent the expression of altered endothelial function on the maternal side. IUGR fetuses had higher PTX3 values than controls and the increase was related to IUGR severity, likely reflecting the hypoxic environment. These data confirm the relevance of PTX3 in support the hypothesis that PE is a disease associated with altered maternal endothelial function. The PTX3 increase in IUGR fetuses deserves further investigation.
Assuntos
Proteína C-Reativa/metabolismo , Endotélio Vascular/fisiopatologia , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/fisiopatologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/fisiopatologia , Componente Amiloide P Sérico/metabolismo , Regulação para Cima , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Decídua/irrigação sanguínea , Decídua/metabolismo , Decídua/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Sangue Fetal , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Humanos , Peritônio/irrigação sanguínea , Peritônio/metabolismo , Peritônio/patologia , Placenta/irrigação sanguínea , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Índice de Gravidade de Doença , Doenças Vasculares/etiologia , Adulto JovemRESUMO
BACKGROUND: Animal models and experimental studies suggest a role for paracrine prolactin (PRL) signalling in decidualization and embryo implantation. We investigated the expression of endometrial prolactin (e-PRL) and prolactin receptor (PRL-R) in the endometrium of women affected by unexplained infertility (UI) and repeated miscarriages (RM). METHODS: Patients (n = 24) were divided into three groups: RM, n = 5; UI, n = 11; controls, n = 8. Endometrial samples were collected at the time of hysteroscopy in the late luteal phase. The presence of transcripts of e-PRL and PRL-R was investigated by qualitative RT-PCR. Pattern and site of expression of e-PRL were studied by immunohistochemistry. RESULTS: PRL-R mRNA was detected in all endometrial samples of the three groups. PRL gene expression was detected in all control samples, only in three of five samples of the RM group and in four of 11 samples of the UI group. RT-PCR results were largely confirmed by immunohistochemistry, study groups showing a defect of expression of e-PRL. CONCLUSIONS: In this pilot study we report a lack of expression of endometrial prolactin during the 'implantation window' in some patients affected by unexplained infertility and repeated miscarriages. These data, in association with those obtained in experimental animals, suggest that the lack of endometrial PRL expression is involved in reproduction failure.