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Sample records for active maternal immune

  1. Maternal Immunization

    PubMed Central

    Chu, Helen Y.; Englund, Janet A.

    2014-01-01

    Maternal immunization has the potential to protect the pregnant woman, fetus, and infant from vaccine-preventable diseases. Maternal immunoglobulin G is actively transported across the placenta, providing passive immunity to the neonate and infant prior to the infant's ability to respond to vaccines. Currently inactivated influenza, tetanus toxoid, and acellular pertussis vaccines are recommended during pregnancy. Several other vaccines have been studied in pregnancy and found to be safe and immunogenic and to provide antibody to infants. These include pneumococcus, group B Streptococcus, Haemophilus influenzae type b, and meningococcus vaccines. Other vaccines in development for potential maternal immunization include respiratory syncytial virus, herpes simplex virus, and cytomegalovirus vaccines. PMID:24799324

  2. Maternal immune activation: Implications for neuropsychiatric disorders.

    PubMed

    Estes, Myka L; McAllister, A Kimberley

    2016-08-19

    Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This Review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also discussed. Finally, the need for more research in this nascent field and the implications for identifying and developing new treatments for individuals at heightened risk for neuroimmune disorders are considered. PMID:27540164

  3. Maternal immunization

    PubMed Central

    Moniz, Michelle H; Beigi, Richard H

    2014-01-01

    Maternal immunization holds tremendous promise to improve maternal and neonatal health for a number of infectious conditions. The unique susceptibilities of pregnant women to infectious conditions, as well as the ability of maternally-derived antibody to offer vital neonatal protection (via placental transfer), together have produced the recent increased attention on maternal immunization. The Advisory Committee on Immunization Practices (ACIP) currently recommends 2 immunizations for all pregnant women lacking contraindication, inactivated Influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap). Given ongoing research the number of vaccines recommended during pregnancy is likely to increase. Thus, achieving high vaccination coverage of pregnant women for all recommended immunizations is a key public health enterprise. This review will focus on the present state of vaccine acceptance in pregnancy, with attention to currently identified barriers and determinants of vaccine acceptance. Additionally, opportunities for improvement will be considered. PMID:25483490

  4. Maternal Immune Activation Disrupts Dopamine System in the Offspring

    PubMed Central

    Luchicchi, Antonio; Lecca, Salvatore; Melis, Miriam; De Felice, Marta; Cadeddu, Francesca; Frau, Roberto; Muntoni, Anna Lisa; Fadda, Paola; Devoto, Paola

    2016-01-01

    Background: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. Methods: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. Results: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. Conclusions: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology. PMID:26819283

  5. Maternal immune activation and abnormal brain development across CNS disorders.

    PubMed

    Knuesel, Irene; Chicha, Laurie; Britschgi, Markus; Schobel, Scott A; Bodmer, Michael; Hellings, Jessica A; Toovey, Stephen; Prinssen, Eric P

    2014-11-01

    Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies. PMID:25311587

  6. Maternal immune activation increases seizure susceptibility in juvenile rat offspring.

    PubMed

    Yin, Ping; Zhang, Xin-Ting; Li, Jun; Yu, Lin; Wang, Ji-Wen; Lei, Ge-Fei; Sun, Ruo-Peng; Li, Bao-Min

    2015-06-01

    Epidemiological data suggest a relationship between maternal infection and a high incidence of childhood epilepsy in offspring. However, there is little experimental evidence that links maternal infection with later seizure susceptibility in juvenile offspring. Here, we asked whether maternal immune challenge during pregnancy can alter seizure susceptibility and seizure-associated brain damage in adolescence. Pregnant Sprague-Dawley rats were treated with lipopolysaccharide (LPS) or normal saline (NS) on gestational days 15 and 16. At postnatal day 21, seizure susceptibility to kainic acid (KA) was evaluated in male offspring. Four groups were studied, including normal control (NS-NS), prenatal infection (LPS-NS), juvenile seizure (NS-KA), and "two-hit" (LPS-KA) groups. Our results demonstrated that maternal LPS exposure caused long-term reactive astrogliosis and increased seizure susceptibility in juvenile rat offspring. Compared to the juvenile seizure group, animals in the "two-hit" group showed exaggerated astrogliosis, followed by worsened spatial learning ability in adulthood. In addition, prenatal immune challenge alone led to spatial learning impairment in offspring but had no effect on anxiety. These data suggest that prenatal immune challenge causes a long-term increase in juvenile seizure susceptibility and exacerbates seizure-induced brain injury, possibly by priming astroglia. PMID:25982885

  7. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

    PubMed

    Marques, Andrea Horvath; Bjørke-Monsen, Anne-Lise; Teixeira, Antônio L; Silverman, Marni N

    2015-08-18

    Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying

  8. Maternal immune activation affects litter success, size and neuroendocrine responses related to behavior in adult offspring.

    PubMed

    French, Susannah S; Chester, Emily M; Demas, Gregory E

    2013-07-01

    It is increasingly evident that influences other than genetics can contribute to offspring phenotype. In particular, maternal influences are an important contributing factor to offspring survival, development, physiology and behavior. Common environmental pathogens such as viral or bacterial microorganisms can induce maternal immune responses, which have the potential to alter the prenatal environment via multiple independent pathways. The effects of maternal immune activation on endocrine responses and behavior are less well studied and provide the basis for the current study. Our approach in the current study was two-pronged: 1) quantify sickness responses during pregnancy in adult female hamsters experiencing varying severity of immune responsiveness (i.e., differing doses of lipopolysaccharide [LPS]), and 2) assess the effects of maternal immune activation on offspring development, immunocompetence, hormone profiles, and social behavior during adulthood. Pregnancy success decreased with increasing doses of LPS, and litter size was reduced in LPS dams that managed to successfully reproduce. Unexpectedly, pregnant females treated with LPS showed a hypothermic response in addition to the more typical anorexic and body mass changes associated with sickness. Significant endocrine changes related to behavior were observed in the offspring of LPS-treated dams; these effects were apparent in adulthood. Specifically, offspring from LPS treated dams showed significantly greater cortisol responses to stressful resident-intruder encounters compared with offspring from control dams. Post-behavior cortisol was elevated in male LPS offspring relative to the offspring of control dams, and was positively correlated with the frequency of bites during agonistic interactions, and cortisol levels in both sexes were related to defensive behaviors, suggesting that changes in hypothalamo-pituitary-adrenal axis responsiveness may play a regulatory role in the observed behavioral

  9. Normal Human Pregnancy Results in Maternal Immune Activation in the Periphery and at the Uteroplacental Interface

    PubMed Central

    Yesayan, Maria N.; Kahn, Daniel A.

    2014-01-01

    Pregnancy poses a unique challenge to the human immune system: the semi-allogeneic fetus must be protected from maternal immune attack while immunity towards pathogens is maintained. Breakdown in maternal-fetal tolerance can lead to pregnancy-specific diseases with potentially high degrees of morbidity and mortality for both the mother and her fetus. Various immune cell-types could mediate these functions, but a comprehensive evaluation of the peripheral and local maternal T cell and regulatory T cell compartments in normal human pregnancy is lacking. In this case-control study, we apply the Human Immunology Project Consortium proposed gating strategies to samples from healthy 3rd trimester human subjects compared with healthy non-pregnant controls. The proportions of HLA-DR+ and CD38+ effector- and effector memory CD8 T cells are significantly increased in the peripheral blood of pregnant women. Utilizing a novel technique that takes advantage of the standard protocol for intrauterine cleanup after cesarean section, we isolate lymphocytes resident at the uteroplacental interface (UPI). At the UPI, the CD4 and CD8 T cell compartments largely mirror the peripheral blood, except that the proportion of HLA-DR+ activated T regulatory cells is significantly increased in direct proportion to an observed increase in the number of activated CD8 T cells. We find that cryopreservation and delayed sample processing (>12 hours) decreases our ability to identify regulatory T cell subsets. Further, the Consortium proposed method for Treg identification underrepresents Resting and Cytokine Tregs compared with Activated Tregs, thus skewing the entire population. Better understanding of the changes in the immune system during pregnancy in the peripheral blood and at the uteroplacental interface are essential for progress in treatment of pregnancy diseases such as pre-eclampsia and recurrent miscarriage. PMID:24846312

  10. Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice.

    PubMed

    Zhang, Zhi; van Praag, Henriette

    2015-03-01

    Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation. PMID:25449671

  11. Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders

    PubMed Central

    Coiro, Pierluca; Padmashri, Ragunathan; Suresh, Anand; Spartz, Elizabeth; Pendyala, Gurudutt; Chou, Shinnyi; Jung, Yoosun; Meays, Brittney; Roy, Shreya; Gautam, Nagsen; Alnouti, Yazen; Li, Ming; Dunaevsky, Anna

    2016-01-01

    Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment. PMID:26218293

  12. Maternal Immune Activation Leads to Selective Functional Deficits in Offspring Parvalbumin Interneurons

    PubMed Central

    Canetta, Sarah; Bolkan, Scott; Padilla-Coreano, Nancy; Song, LouJin; Sahn, Ryan; Harrison, Neil; Gordon, Joshua A.; Brown, Alan; Kellendonk, Christoph

    2015-01-01

    Summary Abnormalities in prefrontal GABAergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to maternal immune activation, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders. PMID:26830140

  13. Maternal Immune Activation Alters Nonspatial Information Processing in the Hippocampus of the Adult Offspring

    PubMed Central

    Ito, Hiroshi T.; Smith, Stephen E. P.; Hsiao, Elaine; Patterson, Paul H.

    2010-01-01

    The observation that maternal infection increases the risk for schizophrenia in the offspring suggests that the maternal immune system plays a key role in the etiology of schizophrenia. In a mouse model, maternal immune activation (MIA) by injection of poly(I:C) yields adult offspring that display abnormalities in a variety of behaviors relevant to schizophrenia. As abnormalities in the hippocampus are a consistent observation in schizophrenia patients, we examined synaptic properties in hippocampal slices prepared from the offspring of poly(I:C)- and saline-treated mothers. Compared to controls, CA1 pyramidal neurons from adult offspring of MIA mothers display reduced frequency and increased amplitude of miniature excitatory postsynaptic currents. In addition, the specific component of the temporoammonic pathway that mediates object-related information displays increased sensitivity to dopamine. To assess hippocampal network function in vivo, we used expression of the immediate early gene, c-Fos, as a surrogate measure of neuronal activity. Compared to controls, the offspring of poly(I:C)-treated mothers display a distinct c-Fos expression pattern in area CA1 following novel object, but not novel location, exposure. Thus, the offspring of MIA mothers may have an abnormality in modality-specific information processing. Indeed, the MIA offspring display enhanced discrimination in a novel object recognition, but not in an object location, task. Thus, analysis of object and spatial information processing at both synaptic and behavioral levels reveals a largely selective abnormality in object information processing in this mouse model. Our results suggest that altered processing of object-related information may be part of the pathogenesis of schizophrenia-like cognitive behaviors. PMID:20227486

  14. Dietary docosahexaenoic acid alleviates autistic-like behaviors resulting from maternal immune activation in mice.

    PubMed

    Weiser, Michael J; Mucha, Brittany; Denheyer, Heather; Atkinson, Devon; Schanz, Norman; Vassiliou, Evros; Benno, Robert H

    2016-03-01

    The prevalence of autism spectrum disorders over the last several decades has risen at an alarming rate. Factors such as broadened clinical definitions and increased parental age only partially account for this precipitous increase, suggesting that recent changes in environmental factors may also be responsible. One such factor could be the dramatic decrease in consumption of anti-inflammatory dietary omega-3 (n-3) polyunsaturated fatty acids (PUFAs) relative to the amount of pro-inflammatory omega-6 (n-6) PUFAs and saturated fats in the Western diet. Docosahexaenoic acid (DHA) is the principle n-3 PUFA found in neural tissue and is important for optimal brain development, especially during late gestation when DHA rapidly and preferentially accumulates in the brain. In this study, we tested whether supplementation of a low n-3 PUFA diet with DHA throughout development could improve measures related to autism in a mouse model of maternal immune activation. We found that dietary DHA protected offspring from the deleterious effects of gestational exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid on behavioral measures of autism and subsequent adulthood immune system reactivity. These data suggest that elevated dietary levels of DHA, especially during pregnancy and nursing, may help protect normal neurodevelopment from the potentially adverse consequences of environmental insults like maternal infection. PMID:26703213

  15. The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice.

    PubMed

    Tsukada, Tsuyoshi; Simamura, Eriko; Shimada, Hiroki; Arai, Takuma; Higashi, Nobuaki; Akai, Takuya; Iizuka, Hideaki; Hatta, Toshihisa

    2015-01-01

    Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis. PMID:26043040

  16. Reduced maternal levels of common viruses during pregnancy predict offspring psychosis: potential role of enhanced maternal immune activity?

    PubMed

    Canuti, Marta; Buka, Stephen; Jazaeri Farsani, Seyed Mohammad; Oude Munnink, Bas B; Jebbink, Maarten F; van Beveren, Nico J M; de Haan, Lieuwe; Goldstein, Jill; Seidman, Larry J; Tsuang, Ming T; Storosum, Jitschak G; van der Hoek, Lia

    2015-08-01

    Viral infections during the prenatal or early childhood periods are one of the environmental factors which might play an etiological role in psychoses. Several studies report higher antibody levels against viruses during pregnancy in blood of mothers of offspring with psychotic disorders, but the presence of such viruses has never been demonstrated. The goal of this study was to investigate the potential association between viral infections during pregnancy and progeny with psychotic disorders and, for this purpose, we performed a nested case-control study involving pregnant mothers of offspring with schizophrenia or bipolar disorder with psychotic features (cases, N=43) and pregnant women with healthy offspring (controls, N=95). Since several potential viral candidates have been suggested in prior work, a broad-spectrum virus detection system was necessary. A metagenomic analysis performed with the virus discovery method VIDISCA-454 revealed only common blood-associated viruses in all cohorts. However, a significantly lower viral prevalence was detected in the group of cases and in the sub-population of pregnant mothers of offspring with schizophrenia (p<0.05). Consistent with the existing inverse correlation between the level of these viruses and the immunocompetence of an individual, we hypothesized the presence of a higher immune activity during pregnancy in mothers whose offspring later develop a psychotic disorder as compared to controls. Combining our results with previously available literature data on antibody levels during the gestation period suggests that a more prominent maternal immune activity can be considered a risk factor for developing psychosis. PMID:26004694

  17. Maternal immune activation evoked by polyinosinic:polycytidylic acid does not evoke microglial cell activation in the embryo

    PubMed Central

    Smolders, Silke; Smolders, Sophie M. T.; Swinnen, Nina; Gärtner, Annette; Rigo, Jean-Michel; Legendre, Pascal; Brône, Bert

    2015-01-01

    Several studies have indicated that inflammation during pregnancy increases the risk for the development of neuropsychiatric disorders in the offspring. Morphological brain abnormalities combined with deviations in the inflammatory status of the brain can be observed in patients of both autism and schizophrenia. It was shown that acute infection can induce changes in maternal cytokine levels which in turn are suggested to affect fetal brain development and increase the risk on the development of neuropsychiatric disorders in the offspring. Animal models of maternal immune activation reproduce the etiology of neurodevelopmental disorders such as schizophrenia and autism. In this study the poly (I:C) model was used to mimic viral immune activation in pregnant mice in order to assess the activation status of fetal microglia in these developmental disorders. Because microglia are the resident immune cells of the brain they were expected to be activated due to the inflammatory stimulus. Microglial cell density and activation level in the fetal cortex and hippocampus were determined. Despite the presence of a systemic inflammation in the pregnant mice, there was no significant difference in fetal microglial cell density or immunohistochemically determined activation level between the control and inflammation group. These data indicate that activation of the fetal microglial cells is not likely to be responsible for the inflammation induced deficits in the offspring in this model. PMID:26300736

  18. Early infections by myxoma virus of young rabbits (Oryctolagus cuniculus) protected by maternal antibodies activate their immune system and enhance herd immunity in wild populations

    PubMed Central

    2014-01-01

    The role of maternal antibodies is to protect newborns against acute early infection by pathogens. This can be achieved either by preventing any infection or by allowing attenuated infections associated with activation of the immune system, the two strategies being based on different cost/benefit ratios. We carried out an epidemiological survey of myxomatosis, which is a highly lethal infectious disease, in two distant wild populations of rabbits to describe the epidemiological pattern of the disease. Detection of specific IgM and IgG enabled us to describe the pattern of immunity. We show that maternal immunity attenuates early infection of juveniles and enables activation of their immune system. This mechanism associated with steady circulation of the myxoma virus in both populations, which induces frequent reinfections of immune rabbits, leads to the maintenance of high immunity levels within populations. Thus, myxomatosis has a low impact, with most infections being asymptomatic. This work shows that infection of young rabbits protected by maternal antibodies induces attenuated disease and activates their immune system. This may play a major role in reducing the impact of a highly lethal disease when ecological conditions enable permanent circulation of the pathogen. PMID:24589193

  19. Early infections by myxoma virus of young rabbits (Oryctolagus cuniculus) protected by maternal antibodies activate their immune system and enhance herd immunity in wild populations.

    PubMed

    Marchandeau, Stéphane; Pontier, Dominique; Guitton, Jean-Sébastien; Letty, Jérôme; Fouchet, David; Aubineau, Jacky; Berger, Francis; Léonard, Yves; Roobrouck, Alain; Gelfi, Jacqueline; Peralta, Brigitte; Bertagnoli, Stéphane

    2014-01-01

    The role of maternal antibodies is to protect newborns against acute early infection by pathogens. This can be achieved either by preventing any infection or by allowing attenuated infections associated with activation of the immune system, the two strategies being based on different cost/benefit ratios. We carried out an epidemiological survey of myxomatosis, which is a highly lethal infectious disease, in two distant wild populations of rabbits to describe the epidemiological pattern of the disease. Detection of specific IgM and IgG enabled us to describe the pattern of immunity. We show that maternal immunity attenuates early infection of juveniles and enables activation of their immune system. This mechanism associated with steady circulation of the myxoma virus in both populations, which induces frequent reinfections of immune rabbits, leads to the maintenance of high immunity levels within populations. Thus, myxomatosis has a low impact, with most infections being asymptomatic. This work shows that infection of young rabbits protected by maternal antibodies induces attenuated disease and activates their immune system. This may play a major role in reducing the impact of a highly lethal disease when ecological conditions enable permanent circulation of the pathogen. PMID:24589193

  20. Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure.

    PubMed

    Hollins, Sharon L; Zavitsanou, Katerina; Walker, Frederick Rohan; Cairns, Murray J

    2016-08-01

    Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders. PMID:26923065

  1. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice

    PubMed Central

    Schwartzer, J J; Careaga, M; Onore, C E; Rushakoff, J A; Berman, R F; Ashwood, P

    2013-01-01

    It is becoming increasingly apparent that the causes of autism spectrum disorders (ASD) are due to both genetic and environmental factors. Animal studies provide important translational models for elucidating specific genetic or environmental factors that contribute to ASD-related behavioral deficits. For example, mouse research has demonstrated a link between maternal immune activation and the expression of ASD-like behaviors. Although these studies have provided insights into the potential causes of ASD, they are limited in their ability to model the important interactions between genetic variability and environmental insults. This is of particular concern given the broad spectrum of severity observed in the human population, suggesting that subpopulations may be more susceptible to the adverse effects of particular environmental insults. It is hypothesized that the severity of effects of maternal immune activation on ASD-like phenotypes is influenced by the genetic background in mice. To test this, pregnant dams of two inbred strains (that is, C57BL/6J and BTBR T+tf/J) were exposed to the viral mimic polyinosinic-polycytidylic acid (polyI:C), and their offspring were tested for the presence and severity of ASD-like behaviors. To identify differences in immune system regulation, spleens were processed and measured for alterations in induced cytokine responses. Strain-treatment interactions were observed in social approach, ultrasonic vocalization, repetitive grooming and marble burying behaviors. Interestingly, persistent dysregulation of adaptive immune system function was only observed in BTBR mice. Data suggest that behavioral and immunological effects of maternal immune activation are strain-dependent in mice. PMID:23481627

  2. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.

    PubMed

    Canetta, S; Bolkan, S; Padilla-Coreano, N; Song, L J; Sahn, R; Harrison, N L; Gordon, J A; Brown, A; Kellendonk, C

    2016-07-01

    Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders. PMID:26830140

  3. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C

    PubMed Central

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID:26742695

  4. Maternal antibodies and infant immune responses to vaccines.

    PubMed

    Edwards, Kathryn M

    2015-11-25

    Infants are born with immature immune systems, making it difficult for them to effectively respond to the infectious pathogens encountered shortly after birth. Maternal antibody is actively transported across the placenta and serves to provide protection to the newborn during the first weeks to months of life. However, maternal antibody has been shown repeatedly to inhibit the immune responses of young children to vaccines. The mechanisms for this inhibition are presented and the impact on ultimate immune responses is discussed. PMID:26256526

  5. Modeling rates of infection with transient maternal antibodies and waning active immunity: application to Bordetella pertussis in Sweden.

    PubMed

    Feng, Zhilan; Glasser, John W; Hill, Andrew N; Franko, Mikael A; Carlsson, Rose-Marie; Hallander, Hans; Tüll, Peet; Olin, Patrick

    2014-09-01

    Serological surveys provide reliable information from which to calculate forces (instantaneous rates) of infection, but waning immunity and clinical consequences that depend on residual immunity complicate interpretation of results. We devised a means of calculating these rates that accounts for passively acquired maternal antibodies that decay or active immunity that wanes, permitting re-infection. We applied our method to pertussis (whooping cough) in Sweden, where vaccination was discontinued from 1979 to 1995. A national cross-sectional serosurvey of antibodies to pertussis toxin, which peak soon after infection and then decay, was conducted shortly after vaccination resumed. Together with age-specific contact rates in Finland, contemporary forces of infection enable us to evaluate the recent assertion that the probability of infection upon contact is age-independent. We find elevated probabilities among children, adolescents and young adults, whose contacts may be more intimate than others. Products of contact rates and probabilities of infection permit transmission modeling and estimation of the intrinsic reproduction number. In contrast to another recent estimate, ours approximates the ratio of life expectancy and age at first infection. Our framework is sufficiently general to accommodate more realistic sojourn distributions and additional lifetime infections. PMID:24768867

  6. Do prenatal immune activation and maternal iron deficiency interact to affect neurodevelopment and early behavior in rat offspring?

    PubMed

    Harvey, Louise; Boksa, Patricia

    2014-01-01

    Infection and iron deficiency are common during pregnancy and studies have described altered brain development in the offspring as a result of these individual maternal exposures. Both exposures have been identified as risk factors for schizophrenia yet they have never been modeled simultaneously. We developed a rat model of prenatal immune activation on a background of maternal iron deficiency to determine whether these factors interact to affect neurodevelopment and early behavior in offspring. Pregnant rats were placed on iron sufficient (IS) or iron deficient (ID) diets from E2 to P7, and administered LPS or saline on E15/16. Iron was reduced in liver, spleen, serum and placenta from ID dams by E15. LPS administration on E15 caused greater induction of serum interleukin-6 and tumor necrosis factor-α in ID dams compared to IS dams. Offspring (P0, P7) from ID dams had reduced iron in spleen, liver and brain compared to IS, which normalized by P21. Pups from ID dams showed differences in forelimb grasp and acoustic startle, whilst pups from LPS dams displayed differences in grip ability, geotaxis reflex, cliff avoidance and acoustic startle. Offspring from LPS dams displayed reduced locomotor activity at P7 and P60; offspring from ID dams showed no change. Our findings show effects of prenatal LPS and maternal iron deficiency were additive, such that offspring exposed to both insults displayed more neurodevelopmental abnormalities than offspring exposed to one alone. Yet surprisingly there was no interaction between factors, suggesting independent mechanisms of action. PMID:24064370

  7. Changes in Astroglial Markers in a Maternal Immune Activation Model of Schizophrenia in Wistar Rats are Dependent on Sex

    PubMed Central

    de Souza, Daniela F.; Wartchow, Krista M.; Lunardi, Paula S.; Brolese, Giovana; Tortorelli, Lucas S.; Batassini, Cristiane; Biasibetti, Regina; Gonçalves, Carlos-Alberto

    2015-01-01

    Data from epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. We evaluated whether the administration of LPS to rat dams during late pregnancy affects astroglial markers (S100B and GFAP) of the offspring in later life. The frontal cortex and hippocampus were compared in male and female offspring on postnatal days (PND) 30 and 60. The S100B protein exhibited an age-dependent pattern of expression, being increased in the frontal cortex and hippocampus of the MIA group at PND 60, while at PND 30, male rats presented increased S100B levels only in the frontal cortex. Considering that S100B secretion is reduced by elevation of glutamate levels, we may hypothesize that this early increment in frontal cortex tissue of males is associated with elevated extracellular levels of glutamate and glutamatergic hypofunction, an alteration commonly associated with SCZ pathology. Moreover, we also found augmented GFAP in the frontal cortex of the LPS group at PND 30, but not in the hippocampus. Taken together data indicate that astroglial changes induced by MIA are dependent on sex and brain region and that these changes could reflect astroglial dysfunction. Such alterations may contribute to our understanding of the abnormal neuronal connectivity and developmental aspects of SCZ and other psychiatric disorders. PMID:26733814

  8. Changes in Astroglial Markers in a Maternal Immune Activation Model of Schizophrenia in Wistar Rats are Dependent on Sex.

    PubMed

    de Souza, Daniela F; Wartchow, Krista M; Lunardi, Paula S; Brolese, Giovana; Tortorelli, Lucas S; Batassini, Cristiane; Biasibetti, Regina; Gonçalves, Carlos-Alberto

    2015-01-01

    Data from epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. We evaluated whether the administration of LPS to rat dams during late pregnancy affects astroglial markers (S100B and GFAP) of the offspring in later life. The frontal cortex and hippocampus were compared in male and female offspring on postnatal days (PND) 30 and 60. The S100B protein exhibited an age-dependent pattern of expression, being increased in the frontal cortex and hippocampus of the MIA group at PND 60, while at PND 30, male rats presented increased S100B levels only in the frontal cortex. Considering that S100B secretion is reduced by elevation of glutamate levels, we may hypothesize that this early increment in frontal cortex tissue of males is associated with elevated extracellular levels of glutamate and glutamatergic hypofunction, an alteration commonly associated with SCZ pathology. Moreover, we also found augmented GFAP in the frontal cortex of the LPS group at PND 30, but not in the hippocampus. Taken together data indicate that astroglial changes induced by MIA are dependent on sex and brain region and that these changes could reflect astroglial dysfunction. Such alterations may contribute to our understanding of the abnormal neuronal connectivity and developmental aspects of SCZ and other psychiatric disorders. PMID:26733814

  9. The Suppression of Maternal–Fetal Leukemia Inhibitory Factor Signal Relay Pathway by Maternal Immune Activation Impairs Brain Development in Mice

    PubMed Central

    Tsukada, Tsuyoshi; Simamura, Eriko; Shimada, Hiroki; Arai, Takuma; Higashi, Nobuaki; Akai, Takuya; Iizuka, Hideaki; Hatta, Toshihisa

    2015-01-01

    Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)–placental ACTH–fetal LIF signaling relay pathway (maternal–fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal–fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal–fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis. PMID:26043040

  10. Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice

    PubMed Central

    Washington, James; Kumar, Udaya; Medel-Matus, Jesus-Servando; Shin, Don; Sankar, Raman; Mazarati, Andrey

    2015-01-01

    Maternal immune activation (MIA) results in the development of autism in the offspring via hyperactivation of IL-6 signaling. Furthermore, experimental studies showed that the MIA-associated activation of interleukin-1β (IL-1β) concurrently with IL-6 increases the rate and the severity of hippocampal kindling in mice, thus offering an explanation for autism-epilepsy comorbidity. We examined whether epileptic phenotype triggered by prenatal exposure to IL-6 and IL-1β combination is restricted to kindling or whether it is reproducible in another model of epilepsy, whereby spontaneous seizures develop following kainic acid (KA)- induced status epilepticus. We also examined whether in mice prenatally exposed to IL-6 and IL-6+IL-1β, the presence of spontaneous seizures would exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57bl/6j mice received daily injections of IL-6, IL-1β or IL-6+IL-1β combination. At postnatal day 40, male offspring was examined for the presence of social behavioral deficit and status epilepticus was induced by intrahippocampal KA injection. After six weeks of monitoring for spontaneous seizures, sociability was tested again. Both IL-6 and IL-6+IL-1β offspring presented with social behavioral deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6+IL-1β exacerbated the severity of KA-induced epilepsy. Increased severity of epilepsy in the IL-6+IL-1β mice correlated with the improvement of autism-like behavior. We conclude that complex and not necessarily agonistic relationships exist between epileptic and autism-like phenotypes in an animal model of MIA coupled with KA-induced epilepsy, and that the nature of these relationships depends on components of MIA involved. PMID:26103532

  11. Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation.

    PubMed

    Hemmerle, Ann M; Ahlbrand, Rebecca; Bronson, Stefanie L; Lundgren, Kerstin H; Richtand, Neil M; Seroogy, Kim B

    2015-10-01

    Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to the development of alterations of relevance to neuropsychiatric diseases. PMID:26206493

  12. On the maternal transmission of immunity: a 'molecular attention' hypothesis.

    PubMed

    Anderson, R W

    1995-01-01

    Maternally-derived antibodies can provide passive protection to their offspring. More subtle phenomena associated with maternal antibodies concern their influence in shaping the immune repertoire and priming the neonatal immune response. These phenomena suggest that maternal antibodies play a role in the education of the neonatal immune system. The educational effects are thought to be mediated by idiotypic interactions among antibodies and B cells in the context of an idiotypic network. This paper proposes that maternal antibodies trigger localized idiotypic network activity that serves to amplify and translate information concerning the molecular shapes of potential antigens. The triggering molecular signals are contained in the binding regions of the antibody molecules. These antibodies form complexes and are taken up by antigen presenting cells or retained by follicular dendritic cells and thereby incorporated into more traditional cellular immune memory mechanisms. This mechanism for maternal transmission of immunity is termed the molecular attention hypothesis and is contrasted to the dynamic memory hypothesis. Experiments are proposed that may help indicate which models are more appropriate and will further our understanding of these intriguing natural phenomena. Finally, analogies are drawn to attention in neural systems. PMID:7727708

  13. Implantation: mutual activity of sex steroid hormones and the immune system guarantee the maternal-embryo interaction.

    PubMed

    Gnainsky, Yulia; Dekel, Nava; Granot, Irit

    2014-09-01

    Implantation is strictly dependent on the mutual interaction between a receptive endometrium and the blastocyst. Hence, synchronization between blastocyst development and the acquisition of endometrial receptivity is a prerequisite for the success of this process. This review depicts the cellular and molecular events that coordinate these complex activities. Specifically, the involvement of the sex steroid hormones, estrogen and progesterone, as well as components of the immune system, such as cytokines and specific blood cells, is elaborated. PMID:24959815

  14. Maternal immunity enhances Mycoplasma hyopneumoniae vaccination induced cell-mediated immune responses in piglets

    PubMed Central

    2014-01-01

    Background Passively acquired maternal derived immunity (MDI) is a double-edged sword. Maternal derived antibody-mediated immunity (AMI) and cell-mediated immunity (CMI) are critical immediate defenses for the neonate; however, MDI may interfere with the induction of active immunity in the neonate, i.e. passive interference. The effect of antigen-specific MDI on vaccine-induced AMI and CMI responses to Mycoplasma hyopneumoniae (M. hyopneumoniae) was assessed in neonatal piglets. To determine whether CMI and AMI responses could be induced in piglets with MDI, piglets with high and low levels of maternal M. hyopneumoniae-specific immunity were vaccinated against M. hyopneumoniae at 7 d of age. Piglet M. hyopneumoniae-specific antibody, lymphoproliferation, and delayed type hypersensitivity (DTH) responses were measured 7 d and 14 d post vaccination. Results Piglets with M. hyopneumoniae-specific MDI failed to show vaccine-induced AMI responses; there was no rise in M. hyopneumoniae antibody levels following vaccination of piglets in the presence of M. hyopneumoniae-specific MDI. However, piglets with M. hyopneumoniae-specific MDI had primary (antigen-specific lymphoproliferation) and secondary (DTH) M. hyopneumoniae-specific CMI responses following vaccination. Conclusions In this study neonatal M. hyopneumoniae-specific CMI was not subject to passive interference by MDI. Further, it appears that both maternal derived and endogenous CMI contribute to M. hyopneumoniae-specific CMI responses in piglets vaccinated in the face of MDI. PMID:24903770

  15. Alpha 2 macroglobulin is a maternally-derived immune factor in amphioxus embryos: New evidence for defense roles of maternal immune components in invertebrate chordate.

    PubMed

    Pathirana, Anjalika; Diao, Mingyue; Huang, Shibo; Zuo, Lingling; Liang, Yujun

    2016-03-01

    In fish, a series of maternal derived immune components have been identified in their eggs or embryos at very early stages, which are proposed to provide protections to themselves against pathogenic attacks from hostile environment. The phenomenon of maternal immunity has been also recorded in several invertebrate species, however, so far, very limited information about the maternal immune molecules are available. In this study, it was demonstrated maternal alpha2 macroglobulin (A2m) protein, an important innate immune factor, exists in the fertilized eggs of amphioxus Branchiostoma japonicum, an invertebrate chordate. Maternal mRNA of A2m was also detected in amphioxus embryos at very early developing stages. In addition, it was recorded that the egg lysate prepared from the newly fertilized eggs can inhibit the growth of both Gram-negative bacterium Escherichia coli and Gram-positive bacterium Staphylococcus aureus in a concentration dependent manner. The bacteriostatic activity can be reduced notably after precipitated A2m with anti-A2m antibody. Thus maternal A2m is partly attributed to the bacteriostatic activity. It was further demonstrated that recombinant A2m can bind to E. coli cells directly. All these points come to a result that A2m is a maternal immune factor existing in eggs of invertebrate chordate, which may be involved in defense their embryos against harmful microbes' attacks. PMID:26796816

  16. Timing of Maternal Immunization Affects Immunological and Behavioral Outcomes of Adult Offspring in Siberian Hamsters (Phodopus sungorus).

    PubMed

    French, Susannah S; Chester, Emily M; Demas, Gregory E

    2016-07-01

    Maternal influences are an important contributing factor to offspring survival, development, and behavior. Common environmental pathogens can induce maternal immune responses and affect subsequent development of offspring. There are likely sensitive periods during pregnancy when animals are particularly vulnerable to environmental disruption. Here we characterize the effects of maternal immunization across pregnancy and postpartum on offspring physiology and behavior in Siberian hamsters (Phodopus sungorus). Hamsters were injected with the antigen keyhole limpet hemocyanin (KLH) (1) prior to pairing with a male (premating), (2) at separation (postmating), (3) at midpregnancy, or (4) after birth (lactation). Maternal food intake, body mass, and immunity were monitored throughout gestation, and litters were measured weekly for growth until adulthood when social behavior, hormone concentrations, and immune responses were determined. We found that immunizations altered maternal immunity throughout pregnancy and lactation. The effects of maternal treatment differed between male and female offspring. Aggressive behavior was enhanced in offspring of both sexes born to mothers treated postmating and thus early in pregnancy relative to other stages. In contrast, maternal treatment and maternal stage differentially affected innate immunity in males and females. Offspring cortisol, however, was unaffected by maternal treatment. Collectively, these data demonstrate that maternal immunization affects offspring physiology and behavior in a time-dependent and sex-specific manner. More broadly, these findings contribute to our understanding of the effects of maternal immune activation, whether it be from environmental exposure or immunization, on immunological and behavioral responses of offspring. PMID:27320639

  17. Transfer of Maternal Antimicrobial Immunity to HIV-Exposed Uninfected Newborns

    PubMed Central

    Abu-Raya, Bahaa; Smolen, Kinga K.; Willems, Fabienne; Kollmann, Tobias R.; Marchant, Arnaud

    2016-01-01

    The transfer of maternal immune factors to the newborn is critical for protection from infectious disease in early life. Maternally acquired passive immunity provides protection until the infant is beyond early life’s increased susceptibility to severe infections or until active immunity is achieved following infant’s primary immunization. However, as reviewed here, human immunodeficiency virus (HIV) infection alters the transfer of immune factors from HIV-infected mothers to the HIV-exposed newborns and young infants. This may relate to the immune activation in HIV-infected pregnant women, associated with the production of inflammatory cytokines at the maternofetal interface associated with inflammatory responses in the newborn. We also summarize mother-targeting interventions to improve the health of infants born to HIV-infected women, such as immunization during pregnancy and reduction of maternal inflammation. Maternal immunization offers the potential to compensate for the decreased transplacentally transferred maternal antibodies observed in HIV-exposed infants. Current data suggest reduced immunogenicity of vaccines in HIV-infected pregnant women, possibly reducing the protective impact of maternal immunization for HIV-exposed infants. Fortunately, levels of antibodies appear preserved in the breast milk of HIV-infected women, which supports the recommendation to breast-feed during antiretroviral treatment to protect HIV-exposed infants.

  18. The Effect of Maternal Helminth Infection on Maternal and Neonatal Immune Function and Immunity to Tuberculosis

    PubMed Central

    Gebreegziabiher, Dawit; Desta, Kassu; Desalegn, Girmay; Howe, Rawleigh; Abebe, Markos

    2014-01-01

    Background M. tuberculosis and helminth infection each affects one third of the world population. Helminth infections down regulate cell mediated immune responses and this may contribute to lower efficacy of BCG vaccination and higher prevalence of tuberculosis. Objective To determine the effect of maternal helminth infection on maternal and neonatal immune function and immunity to TB. Methods In this cross sectional study, eighty five pregnant women were screened for parasitic and latent TB infections using Kato-Katz and QFT-GIT tests, respectively. IFN-γ and IL-4 ELISpot on Cord blood Mononuclear Cells, and total IgE and TB specific IgG ELISA on cord blood plasma was performed to investigate the possible effect of maternal helminth and/or latent TB co-infection on maternal and neonatal immune function and immunity to TB. Result The prevalence of helminth infections in pregnant women was 27% (n = 23), with Schistosoma mansoni the most common helminth species observed (20% of women were infected). Among the total of 85 study participants 25.8% were QFT-GIT positive and 17% had an indeterminate result. The mean total IgE value of cord blood was significantly higher in helminth positive than negative women (0.76 vs 0.47, p = 0.042). Cross placental transfer of TB specific IgG was significantly higher in helminth positive (21.9±7.9) than negative (12.3±5.1), p = 0.002) Latent TB Infection positive participants. The IFN-γ response of CBMCs to ESAT-6/CFP-10 cocktail (50 vs 116, p = 0.018) and PPD (58 vs 123, p = 0.02) was significantly lower in helminth positive than negative participants. There was no significant difference in IL-4 response of CBMCs between helminth negative and positive participants. Conclusions Maternal helminth infection had a significant association with the IFN-γ response of CBMCs, total IgE and cross placental transfer of TB specific IgG. Therefore, further studies should be conducted to determine the effect of these

  19. Maternal and developmental immune challenges alter behavior and learning ability of offspring

    PubMed Central

    Grindstaff, Jennifer L.; Hunsaker, Veronica R.; Cox, Shelby N.

    2012-01-01

    Stimulation of the offspring immune response during development is known to influence growth and behavioral phenotype. However, the potential for maternal antibodies to block the behavioral effects of immune activation during the neonatal period has not been assessed. We challenged female zebra finches (Taeniopygia guttata) prior to egg laying and then challenged offspring during the nestling and juvenile periods with one of two antigens (keyhole limpet hemocyanin (KLH) or lipopolysaccharide (LPS)). We then tested the effects of maternal and neonatal immune challenges on offspring growth rates and neophobia and learning ability of offspring during adulthood. Neonatal immune challenge depressed growth rates. Neophobia of adult offspring was influenced by a combination of maternal treatment, offspring treatment, and offspring sex. Males challenged with LPS during the nestling and juvenile periods had reduced learning performance in a novel foraging task; however, female learning was not impacted. Offspring challenged with the same antigen as mothers exhibited similar growth suppression and behavioral changes as offspring challenged with a novel antigen. Thus, developmental immune challenges have long-term effects on the growth and behavioral phenotype of offspring. We found limited evidence that matching of maternal and offspring challenges reduces the effects of immune challenge in the altricial zebra finch. This may be a result of rapid catabolism of maternal antibodies in altricial birds. Our results emphasize the need to address sex differences in the long-term effects of developmental immune challenge and suggest neonatal immune activation may be one proximate mechanism underlying differences in adult behavior. PMID:22522078

  20. Maternal immunization efforts of the National Institutes of Health.

    PubMed

    Rubin, Fran A; Koso-Thomas, Marion; Isaacs, Maggie Brewinski; Piper, Jeanna; Read, Jennifer; Nesin, Mirjana

    2015-11-25

    Over the last 35 years, efforts at the National Institutes of Health (NIH) to protect mothers and their infants against infectious diseases have involved a bench-to-bedside approach. Basic and translational research that provided a foundation for clinical trials of vaccines in pregnancy include natural history and vaccine antigen identification studies. Development of laboratory assays and reagents have been funded by NIAID; these are critical for the advancement of vaccine candidates through the preclinical and clinical steps along the maternal immunization research pathway to support vaccine efficacy. Animal models of maternal immunization have been developed to evaluate efficacy of vaccine candidates. Clinical studies required development of maternal immunization protocols to address specific pregnancy related issues, for enrollment and safety assessment of mothers and their infants. NIH has organized and participated in meetings, workshops and other collaborative efforts with partners have advanced maternal immunization efforts. Partners have included many institutes and offices at NIH as well as other Department of Health and Human Services agencies and offices (Food and Drug Administration, Centers for Disease Control and Prevention, National Vaccine Program Office), World Health Organization, academic investigators, Biotech and pharmaceutical companies, and nonprofit organizations such as the Bill and Melinda Gates Foundation. These research and development partnership are essential for advancing maternal immunization. Continued efforts are needed to promote maternal immunization to protect pregnant women and their infants against vaccine-preventable infectious disease, especially in resource-limited settings where the burden of infections is high. PMID:26458798

  1. Strategies To Boost Maternal Immunization To Achieve Further Gains In Improved Maternal And Newborn Health.

    PubMed

    Steedman, Mark R; Kampmann, Beate; Schillings, Egbert; Al Kuwari, Hanan; Darzi, Ara

    2016-02-01

    Despite the indisputable successes of the United Nations Millennium Development Goals, which include goals on improving maternal health and reducing child mortality, millions of mothers and newborns still die tragically and unnecessarily each year. Many of these deaths result from vaccine-preventable diseases, since obstacles such as cost and accessibility have hampered efforts to deliver efficacious vaccines to those most in need. Additionally, many vaccines given to mothers and children under age five are not suitable for newborns, since their maturing immune systems do not respond optimally during the first few months of life. Maternal immunization-the process by which a pregnant woman's immune system is fortified against a particular disease and the protection is then transferred to her unborn child-has emerged as a strategy to prevent many unnecessary maternal and newborn deaths. We review vaccines that are already used for maternal immunization, analyze vaccines under development that could be used for maternal immunization strategies in the future, and recommend that policy makers use maternal immunization for improved maternal and newborn health. PMID:26858385

  2. [Trophoblast: conductor of the maternal immune tolerance].

    PubMed

    Mesdag, V; Salzet, M; Vinatier, D

    2014-11-01

    Pregnancy is a temporary semi-allograft that survives for nine months. The importance of this event for the survival of the species justifies several tolerance mechanisms that are put into place at the beginning of pregnancy, some of which occur even at the time of implantation. The description of these mechanisms underlines the leadership of the trophoblast. The trophoblast is the conductor of the events, protects himself by expressing specific antigens and regulates the environment of the decidua according to the calendar of the events of the pregnancy The trophoblast and the decidual environment attract the effectors of immunity, almost all present in the decidua. The immunological atmosphere of the decidua evolves during the pregnancy modulating the level of activation of the immunological cells and adapting the level of activation to the stage of the pregnancy. PMID:25063485

  3. Humoral and cellular factors of maternal immunity in swine.

    PubMed

    Salmon, Henri; Berri, Mustapha; Gerdts, Volker; Meurens, François

    2009-03-01

    Immunoglobulins cannot cross the placenta in pregnant sows. Neonatal pigs are therefore agammaglobulinemic at birth and, although immunocompetent, they cannot mount rapid immune responses at systemic and mucosal sites. Their survival depends directly on the acquisition of maternal immunity via colostrum and milk. Protection by maternal immunity is mediated by a number of factors, including specific systemic humoral immunity, involving mostly maternal IgG transferred from blood to colostrum and typically absorbed within the first 36 h of life. Passive mucosal immunity involves local humoral immunity, including the production of secretory IgA (sIgA), which is transferred principally via milk until weaning. The mammary gland (MG) produces sIgA, which is, then secreted into the milk via the poly-Ig receptor (pIgR) of epithelial cells. These antibodies are produced in response to intestinal and respiratory antigens, including pathogens and commensal organisms. Protection is also mediated by cellular immunity, which is transferred via maternal cells present in mammary secretions. The mechanisms underlying the various immunological links between MG and the mucosal surfaces involve hormonally regulated addressins and chemokines specific to these compartments. The enhancement of colostrogenic immunity depends on the stimulation of systemic immunity, whereas the enhancement of lactogenic immunity depends on appropriate stimulation at induction sites, an increase in cell trafficking from the gut and upper respiratory tract to the MG and, possibly, enhanced immunoglobulin production at the effector site and secretion in milk. In addition, mammary secretions provide factors other than immunoglobulins that protect the neonate and regulate the development of mucosal immunity--a key element of postnatal adaptation to environmental antigens. PMID:18761034

  4. Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.

    PubMed

    Hollins, S L; Zavitsanou, K; Walker, F R; Cairns, M J

    2014-01-01

    A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia. PMID:25268256

  5. Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure

    PubMed Central

    Hollins, S L; Zavitsanou, K; Walker, F R; Cairns, M J

    2014-01-01

    A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia. PMID:25268256

  6. Association of aberrant neural synchrony and altered GAD67 expression following exposure to maternal immune activation, a risk factor for schizophrenia

    PubMed Central

    Dickerson, D D; Overeem, K A; Wolff, A R; Williams, J M; Abraham, W C; Bilkey, D K

    2014-01-01

    A failure of integrative processes within the brain, mediated via altered GABAergic inhibition, may underlie several features of schizophrenia. The present study examined, therefore, whether maternal immune activation (MIA), a risk factor for schizophrenia, altered inhibitory markers in the hippocampus and medial prefrontal cortex (mPFC), while also altering electroencephalogram (EEG) coherence between these regions. Pregnant rats were treated with saline or polyinosinic:polycytidylic acid mid-gestation. EEG depth recordings were made from the dorsal and ventral hippocampus and mPFC of male adult offspring. Glutamic decarboxylase (GAD67) levels were separately assayed in these regions using western blot. GAD67 expression was also assessed within parvalbumin-positive cells in the dorsal and ventral hippocampus using immunofluorescence alongside stereological analysis of parvalbumin-positive cell numbers. EEG coherence was reduced between the dorsal hippocampus and mPFC, but not the ventral hippocampus and mPFC, in MIA animals. Western blot and immunofluorescence analyses revealed that GAD67 expression within parvalbumin-positive cells was also reduced in the dorsal hippocampus relative to ventral hippocampus in MIA animals when compared with controls. This reduction was observed in the absence of parvalbumin-positive neuronal loss. Overall, MIA produced a selective reduction in EEG coherence between the dorsal hippocampus and mPFC that was paralleled by a similarly specific reduction in GAD67 within parvalbumin-positive cells of the dorsal hippocampus. These results suggest a link between altered inhibitory mechanisms and synchrony and, therefore point to potential mechanisms via which a disruption in neurodevelopmental processes might lead to pathophysiology associated with schizophrenia. PMID:25072323

  7. Maternal immunization: Optimizing protection for the mother and infant.

    PubMed

    Kachikis, Alisa; Englund, Janet A

    2016-07-01

    Immunizing the pregnant woman to protect both the mother and her infant from infection has been utilized increasingly over the last decade. New outbreaks of pandemic influenza and the resurgence of pertussis have resulted in policy changes and shifts in health authority recommendations for a number of vaccines aimed to protect both pregnant women and their infants in the first months of life. The ability of maternal immunoglobulin IgG antibodies to be transported readily across the healthy intact placenta depends on many different factors including gestational age in the pregnancy, nature and timing of the immunization and presence of maternal HIV or malaria infections. In this paper, the history of maternal immunization is described, and specifically the studies that prompted the recommendations for tetanus, influenza, pertussis, and, when needed, meningococcus vaccines in pregnant women are reviewed. Ongoing research may result in new maternal vaccines against other pathogens including respiratory syncytial virus and group B streptococcus. Both scientific and regulatory considerations remain challenging in licensure of vaccines specifically for maternal immunization. PMID:27233120

  8. Incorporating immunizations into routine obstetric care to facilitate Health Care Practitioners in implementing maternal immunization recommendations

    PubMed Central

    Webb, Heather; Street, Jackie; Marshall, Helen

    2014-01-01

    Immunization against pertussis, influenza, and rubella reduces morbidity and mortality in pregnant women and their offspring. Health care professionals (HCPs) caring for women perinatally are uniquely placed to reduce maternal vaccine preventable diseases (VPDs). Despite guidelines recommending immunization during the perinatal period, maternal vaccine uptake remains low. This qualitative study explored the role of obstetricians, general practitioners, and midwives in maternal vaccine uptake. Semi-structured interviews (n = 15) were conducted with perinatal HCPs at a tertiary maternity hospital in South Australia. HCPs were asked to reflect on their knowledge, beliefs, and practice relating to immunization advice and vaccine provision. Interviews were transcribed and coded using thematic analysis. Data collection and analysis was an iterative process, with collection ceasing with theoretical saturation. Participants unanimously supported maternal vaccination as an effective way of reducing risk of disease in this vulnerable population, however only rubella immunity detection and immunization is embedded in routine care. Among these professionals, delegation of responsibility for maternal immunization was unclear and knowledge about maternal immunization was variable. Influenza and pertussis vaccine prevention measures were not included in standard pregnancy record documentation, information provision to patients was “ad hoc” and vaccinations not offered on-site. The key finding was that the incorporation of maternal vaccinations into standard care through a structured process is an important facilitator for immunization uptake. Incorporating vaccine preventable disease management measures into routine obstetric care including incorporation into the Pregnancy Record would facilitate HCPs in implementing recommendations. Rubella prevention provides a useful “template” for other vaccines. PMID:24509790

  9. The maternal microbiota drives early postnatal innate immune development.

    PubMed

    Gomez de Agüero, Mercedes; Ganal-Vonarburg, Stephanie C; Fuhrer, Tobias; Rupp, Sandra; Uchimura, Yasuhiro; Li, Hai; Steinert, Anna; Heikenwalder, Mathias; Hapfelmeier, Siegfried; Sauer, Uwe; McCoy, Kathy D; Macpherson, Andrew J

    2016-03-18

    Postnatal colonization of the body with microbes is assumed to be the main stimulus to postnatal immune development. By transiently colonizing pregnant female mice, we show that the maternal microbiota shapes the immune system of the offspring. Gestational colonization increases intestinal group 3 innate lymphoid cells and F4/80(+)CD11c(+) mononuclear cells in the pups. Maternal colonization reprograms intestinal transcriptional profiles of the offspring, including increased expression of genes encoding epithelial antibacterial peptides and metabolism of microbial molecules. Some of these effects are dependent on maternal antibodies that potentially retain microbial molecules and transmit them to the offspring during pregnancy and in milk. Pups born to mothers transiently colonized in pregnancy are better able to avoid inflammatory responses to microbial molecules and penetration of intestinal microbes. PMID:26989247

  10. Maternal Education and Immunization Status Among Children in Kenya.

    PubMed

    Onsomu, Elijah O; Abuya, Benta A; Okech, Irene N; Moore, DaKysha; Collins-McNeil, Janice

    2015-08-01

    Child morbidity and mortality due to infectious diseases continues to be a major threat and public health concern worldwide. Although global vaccination coverage reached 90 % for diphtheria, tetanus and pertussis (DTP3) across 129 countries, Kenya and other sub-Saharan countries continue to experience under-vaccination. The purpose of this study was to examine the association between maternal education and child immunization (12-23 months) in Kenya. This study used retrospective cross-sectional data from the 2008-2009 Kenya Demographic and Health Survey for women aged 15-49, who had children aged 12-23 months, and who answered questions about vaccination in the survey (n = 1,707). The majority of the children had received vaccinations, with 77 % for poliomyelitis, 74 % for measles, 94 % for tuberculosis, and 91 % for diphtheria, whooping cough (pertussis), and tetanus. After adjusting for other covariates, women with primary, secondary, and college/university education were between 2.21 (p < 0.01) and 9.10 (p < 0.001) times more likely to immunize their children than those who had less than a primary education. Maternal education is clearly crucial in ensuring good health outcomes among children, and integrating immunization knowledge with maternal and child health services is imperative. More research is needed to identify factors influencing immunization decisions among less-educated women in Kenya. PMID:25636652

  11. Maternal education, child immunizations, and public policy: evidence from the US National Immunization Survey.

    PubMed

    Racine, Andrew D; Joyce, Theodore J

    2007-10-01

    This article measures the independent association of maternal education level and childhood immunization rates in the USA and compares the associations in states that provide free vaccines to all residents (Universal) and those that do not (non-Universal). To do this, the US-based National Immunization Survey data from 1995 to 2003 for children 19-35 months of age were analyzed. Unadjusted estimates of up-to-date status for the 4:3:1:3:3 series and the pneumococcal conjugate vaccine were estimated by the level of maternal education. Linear probability regressions produced adjusted estimates of maternal education effects controlling for covariates. Adjusting for race/ethnicity, income, and other covariates, children of mothers with less than high school education were found to be 7.8% (p<0.05) less likely than children of mothers with college education to be up-to-date for the 4:3:1:3:3 vaccine series. For the newer pneumococcal conjugate vaccine, these children were 4.5% (p<0.05) less likely to be up-to-date. Residence in a Universal state was found to significantly attenuate these effects. As such, higher maternal education, independent of income and race/ethnicity is associated with improved child immunization rates, but subsidizing immunization choices diminishes the disadvantage associated with lower maternal educational achievement. PMID:17643686

  12. Estimating Genetic and Maternal Effects Determining Variation in Immune Function of a Mixed-Mating Snail

    PubMed Central

    Seppälä, Otto; Langeloh, Laura

    2016-01-01

    Evolution of host defenses such as immune function requires heritable genetic variation in them. However, also non-genetic maternal effects can contribute to phenotypic variation, thus being an alternative target for natural selection. We investigated the role of individuals’ genetic background and maternal effects in determining immune defense traits (phenoloxidase and antibacterial activity of hemolymph), as well as in survival and growth, in the simultaneously hermaphroditic snail Lymnaea stagnalis. We utilized the mixed mating system of this species by producing full-sib families in which each parental snail had produced offspring as both a dam and as a sire, and tested whether genetic background (family) and non-genetic maternal effects (dam nested within family) explain trait variation. Immune defense traits and growth were affected solely by individuals’ genetic background. Survival of snails did not show family-level variation. Additionally, some snails were produced through self-fertilization. They showed reduced growth and survival suggesting recessive load or overdominance. Immune defense traits did not respond to inbreeding. Our results suggest that the variation in snail immune function and growth was due to genetic differences. Since immune traits did not respond to inbreeding, this variation is most likely due to additive or epistatic genetic variance. PMID:27551822

  13. Estimating Genetic and Maternal Effects Determining Variation in Immune Function of a Mixed-Mating Snail.

    PubMed

    Seppälä, Otto; Langeloh, Laura

    2016-01-01

    Evolution of host defenses such as immune function requires heritable genetic variation in them. However, also non-genetic maternal effects can contribute to phenotypic variation, thus being an alternative target for natural selection. We investigated the role of individuals' genetic background and maternal effects in determining immune defense traits (phenoloxidase and antibacterial activity of hemolymph), as well as in survival and growth, in the simultaneously hermaphroditic snail Lymnaea stagnalis. We utilized the mixed mating system of this species by producing full-sib families in which each parental snail had produced offspring as both a dam and as a sire, and tested whether genetic background (family) and non-genetic maternal effects (dam nested within family) explain trait variation. Immune defense traits and growth were affected solely by individuals' genetic background. Survival of snails did not show family-level variation. Additionally, some snails were produced through self-fertilization. They showed reduced growth and survival suggesting recessive load or overdominance. Immune defense traits did not respond to inbreeding. Our results suggest that the variation in snail immune function and growth was due to genetic differences. Since immune traits did not respond to inbreeding, this variation is most likely due to additive or epistatic genetic variance. PMID:27551822

  14. Maternal influences on fetal microbial colonization and immune development

    PubMed Central

    Romano-Keeler, Joann; Weitkamp, Jörn-Hendrik

    2014-01-01

    While critical for normal development, the exact timing of establishment of the intestinal microbiome is unknown. For example, although preterm labor and birth have been associated with bacterial colonization of the amniotic cavity and fetal membranes for many years, the prevailing dogma of a sterile intrauterine environment during normal term pregnancies has been challenged more recently. While found to be a key contributor of evolution in the animal kingdom, maternal transmission of commensal bacteria may also constitute a critical process during healthy pregnancies in humans with yet unclear developmental importance. Metagenomic sequencing has elucidated a rich placental microbiome in normal term pregnancies likely providing important metabolic and immune contributions to the growing fetus. Conversely, an altered microbial composition during pregnancy may produce aberrant metabolites impairing fetal brain development and life-long neurological outcomes. Here we review the current understanding of microbial colonization at the feto-maternal interface and explain how normal gut colonization drives a balanced neonatal mucosal immune system, while dysbiosis contributes to aberrant immune function early in life and beyond. We discuss how maternal genetics, diet, medications, and probiotics inform the fetal microbiome in preparation for perinatal and postnatal bacterial colonization. PMID:25310759

  15. Immune Suppression and Immune Activation in Depression

    PubMed Central

    Blume, Joshua; Douglas, Steven D.; Evans, Dwight L.

    2010-01-01

    Depression has been characterized as a disorder of both immune suppression and immune activation. Markers of impaired cellular immunity (decreased natural killer cell cytotoxicity) and inflammation (elevated IL-6, TNFα, CRP) have been associated with depression. These immunological markers have been associated with other medical illnesses, suggesting that immune dysregulation may be a central feature common to both depression and to its frequent medical comorbidities. Yet the significant associations of findings of both immune suppression and immune activation with depression raise questions concerning the relationship between these two classes of immunological observations. Depressed populations are heterogeneous groups, and there may be differences in the immune profiles of populations that are more narrowly defined in terms of symptom profile and/or demographic features. There have been few reports concurrently investigating markers of immune suppression and immune activation in the same depressed individuals. An emerging preclinical literature suggests that chronic inflammation may directly contribute to the pathophysiology of immune suppression in the context of illnesses such as cancer and rheumatoid arthritis. This literature provides us with specific immunoregulatory mechanisms mediating these relationships that could also explain differences in immune disturbances between subsets of depressed individuals We propose a research agenda emphasizing the assessment of these immunoregulatory mechanisms in large samples of depressed subjects as a means to define the relationships among immune findings (suppression and/or activation) within the same depressed individuals and to characterize subsets of depressed subjects based on shared immune profiles. Such a program of research, building on and integrating our knowledge of the psychoneuroimmunology of depression, could lead to innovation in the assessment and treatment of depression and its medical comorbidities

  16. [Management of feto-maternal red cell allo-immunizations].

    PubMed

    Bricca, P; Guinchard, E; Guitton Bliem, C

    2011-04-01

    Feto-maternal red cell alloimmunization is defined by the presence in a pregnant woman of alloantibodies directed against blood group antigens present on the red blood cells of the fetus and inherited from the father. It arises from the immune response to a first contact to these same antigens during a prior transfusion, transplant or pregnancy. The placental transfer and the fixation of the antibodies on the fetal red cells antigenic targets lead to a haemolysis in the fetus and the newborn. The resulting haemolytic disease can show different clinical forms, from a mild anaemia with neonatal hyperbilirubinemia to a major fetal damage with stillbirth caused by hydrops fetalis. The objective of management strategies of feto-maternal alloimmunization is to detect and monitor maternal alloimmunization and to appreciate the effects on the fetus or the newborn. Since a few years, some new non-invasive techniques of surveillance are used, for instance fetal RHD genotyping on maternal plasma and evaluation of fetal anaemia through velocimetry measurement of the blood flow in the middle cerebral artery. The need for a careful postnatal surveillance has to be emphasized due to the neonatal anaemia, which can be prolonged, and to the resurgence of cases of severe neonatal icteruses recently reported by the Académie de Médecine. The policy of prevention of anti-RH1 alloimmunization should also benefit from the evolution of biological techniques by allowing an improved targeting of concerned women. PMID:21397546

  17. Duration of protective immunity conferred by maternal tetanus toxoid immunization: further evidence from Matlab, Bangladesh.

    PubMed Central

    Koenig, M A; Roy, N C; McElrath, T; Shahidullah, M; Wojtyniak, B

    1998-01-01

    OBJECTIVES: Although maternal tetanus immunization has been shown to be highly effective in the prevention of neonatal tetanus, unresolved questions remain concerning the required minimum number of doses and the resulting duration of effective immunity. This study examined the duration of effective immunity against neonatal tetanus provided by maternal tetanus immunization. METHODS: A randomized, double-blind cholera vaccine trial of 41,571 children and nonpregnant adult women carried out in 1974 in the Matlab comparison area of rural Bangladesh provided a unique opportunity to address dose and immunity issues. RESULTS: Children of women who received either 1 or 2 injections of tetanus toxoid experienced 4- to 14-day mortality levels consistently lower than those of children of unimmunized mothers. Analysis of neonatal-tetanus-related mortality showed that 2 injections of tetanus toxoid provided significant protection for subsequent durations of up to 12 or 13 years. CONCLUSIONS: The data demonstrate that a limited-dose regimen of maternal tetanus toxoid provides significant and extended protection against the risk of neonatal tetanus death. PMID:9618617

  18. Intranasal Immunization of Mice to Avoid Interference of Maternal Antibody against H5N1 Infection

    PubMed Central

    Zhang, Fenghua; Peng, Bo; Chang, Haiyan; Zhang, Ran; Lu, Fangguo; Wang, Fuyan; Fang, Fang

    2016-01-01

    Maternally-derived antibodies (MDAs) can protect offspring against influenza virus infection but may also inhibit active immune responses. To overcome MDA- mediated inhibition, active immunization of offspring with an inactivated H5N1 whole-virion vaccine under the influence of MDAs was explored in mice. Female mice were vaccinated twice via the intraperitoneal (IP) or intranasal (IN) route with the vaccine prior to mating. One week after birth, the offspring were immunized twice via the IP or IN route with the same vaccine and then challenged with a lethal dose of a highly homologous virus strain. The results showed that, no matter which immunization route (IP or IN) was used for mothers, the presence of MDAs severely interfered with the active immune response of the offspring when the offspring were immunized via the IP route. Only via the IN immunization route did the offspring overcome the MDA interference. These results suggest that intranasal immunization could be a suitable inoculation route for offspring to overcome MDA interference in the defense against highly pathogenic H5N1 virus infection. This study may provide references for human and animal vaccination to overcome MDA-induced inhibition. PMID:27280297

  19. The evolutionary dynamics of timing of maternal immunity: evaluating the role of age-specific mortality.

    PubMed

    Metcalf, C J E; Jones, J H

    2015-02-01

    If a female survives an infection, she can transfer antibodies against that particular pathogen to any future offspring she produces. The resulting protection of offspring for a period after their birth is termed maternal immunity. Because infection in newborns is associated with high mortality, the duration of this protection is expected to be under strong selection. Evolutionary modelling structured around a trade-off between fertility and duration of maternal immunity has indicated selection for longer duration of maternal immunity for hosts with longer lifespans. Here, we use a new modelling framework to extend this analysis to consider characteristics of pathogens (and hosts) in further detail. Importantly, given the challenges in characterizing trade-offs linked to immune function empirically, our model makes no assumptions about costs of longer lasting maternal immunity. Rather, a key component of this analysis is variation in mortality over age. We found that the optimal duration of maternal immunity is shaped by the shifting balance of the burden of infection between young and old individuals. As age of infection depends on characteristics of both the host and the pathogen, both affect the evolution of duration of maternal immunity. Our analysis provides additional support for selection for longer duration of maternal immunity in long-lived hosts, even in the absence of explicit costs linked to duration of maternal immunity. Further, the scope of our results provides explanations for exceptions to the general correlation between duration of maternal immunity and lifespan, as we found that both pathogen characteristics and trans-generational effects can lead to important shifts in fitness linked to maternal immunity. Finally, our analysis points to new directions for quantifying the trade-offs that drive the development of the immune system. PMID:25611057

  20. Maternal Short-Chain Fructooligosaccharide Supplementation Influences Intestinal Immune System Maturation in Piglets

    PubMed Central

    Le Bourgot, Cindy; Ferret-Bernard, Stéphanie; Le Normand, Laurence; Savary, Gérard; Menendez-Aparicio, Enrique; Blat, Sophie; Appert-Bossard, Emmanuelle; Respondek, Frédérique; Le Huërou-Luron, Isabelle

    2014-01-01

    Peripartum nutrition is crucial for developing the immune system of neonates. We hypothesized that maternal short-chain fructooligosaccharide (scFOS) supplementation could accelerate the development of intestinal immunity in offspring. Thirty-four sows received a standard or a scFOS supplemented diet (10 g scFOS/d) for the last 4 weeks of gestation and the 4 weeks of lactation. Colostrum and milk immunoglobulins (Ig) and TGFβ1 concentrations were evaluated on the day of delivery and at d 6 and d 21 postpartum. Piglet intestinal structure, the immunologic features of jejunal and ileal Peyer's patches, and mesenteric lymph node cells were analysed at postnatal d 21. Short-chain fatty acid concentrations were measured over time in the intestinal contents of suckling and weaned piglets. Colostral IgA (P<0.05) significantly increased because of scFOS and TGFβ1 concentrations tended to improve (P<0.1). IFNγ secretion by stimulated Peyer's patch and mesenteric lymph node cells, and secretory IgA production by unstimulated Peyer's patch cells were increased (P<0.05) in postnatal d 21 scFOS piglets. These differences were associated with a higher proportion of activated CD25+CD4α+ T cells among the CD4+ helper T lymphocytes (P<0.05) as assessed by flow cytometry. IFNγ secretion was positively correlated with the population of activated T lymphocytes (P<0.05). Total short-chain fatty acids were unchanged between groups during lactation but were higher in caecal contents of d 90 scFOS piglets (P<0.05); specifically propionate, butyrate and valerate. In conclusion, we demonstrated that maternal scFOS supplementation modified the intestinal immune functions in piglets in association with increased colostral immunity. Such results underline the key role of maternal nutrition in supporting the postnatal development of mucosal immunity. PMID:25238157

  1. New insights into myeloid-derived suppressor cells and their roles in feto-maternal immune cross-talk.

    PubMed

    Zhao, Ai-Min; Xu, Hai-Jing; Kang, Xiao-Min; Zhao, Ai-Min; Lu, Li-Ming

    2016-02-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress both innate and adaptive immune responses through multiple mechanisms. In recent years, much of our knowledge of the function of MDSCs has come from cancer studies. However, a few recent advances have begun to characterize MDSCs in feto-maternal immune cross-talk. The microenvironment at the fetal-maternal interface is a complex milieu of trophoblasts and maternally-derived cells, which are biased to tolerogenic and Th2-type responses. Current data reveal that MDSCs accumulate at the fetal-maternal interface in healthy pregnancies. Yet, little is known about how MDSCs develop and why the response of MDSCs is heavily granulocytic. In this review, we discuss recent findings on the molecular mechanisms that regulate the expansion and function of MDSCs, in addition to various roles of MDSCs implicated in the modulation of feto-maternal immune cross-talk. Understanding the roles of MDSCs in inducing maternal-fetal tolerance, which is compromised in patients suffering from pregnancy complications, including preeclampsia, intrauterine growth restriction, spontaneous abortion, and preterm birth, we thus propose that the immunomodulatory activity of MDSCs should be carefully considered for the therapeutic approaches targeting pregnancy complications. PMID:26599285

  2. Immunizations: Active vs. Passive

    MedlinePlus

    ... they’ve been exposed. For example, the passive rabies immunization (rabies immune globulin) is commonly used after a certain ... of your pediatrician. There may be variations in treatment that your pediatrician may recommend based on individual ...

  3. Choline is required in the diet of lactating dams to maintain maternal immune function.

    PubMed

    Dellschaft, Neele S; Ruth, Megan R; Goruk, Susan; Lewis, Erin D; Richard, Caroline; Jacobs, René L; Curtis, Jonathan M; Field, Catherine J

    2015-06-14

    Choline demands during lactation are high; however, detailed knowledge is lacking regarding the optimal dietary intake during this critical period. The present study was designed to determine the effects of varying intakes of choline on maternal immune function during lactation. Primiparous Sprague-Dawley rats (n 42) were randomised 24-48 h before birth and fed the following diets for 21 d: choline-devoid (0 g choline/kg diet; D, n 10); 1·0 g choline/kg diet (C1, n 11); 2·5 g choline/kg diet (C2·5, n 10); 6·2 g choline/kg diet (C6, n 11). Splenocytes were isolated and stimulated ex vivo with concanavalin A, lipopolysaccharide (LPS) or CD3/CD28. D and C6 dams had lower final body weight, spleen weight and average pup weight than C1 dams (P< 0·05). There was a linear relationship between free choline concentration in pup stomach contents with maternal dietary choline content (P< 0·001, r² 0·415). Compared with C1 and C2·5, D spleens had a lower proportion of mature T cells and activated suppressor cells, and this resulted in reduced cytokine production after stimulation (P< 0·05). Feeding 6·2 g choline/kg diet resulted in a higher cytokine production after stimulation with CD3/CD28 (P< 0·05). Except for a higher IL-6 production after LPS stimulation with cells from the C2·5 dams (P< 0·05), there were no differences between the C1 and C2·5 dams. For the first time, we show that feeding lactating mothers a diet free of choline has substantial effects on their immune function and on offspring growth. Additionally, excess dietary choline had adverse effects on maternal and offspring body weight but only minimal effects on maternal immune function. PMID:25902853

  4. Effect of age and maternal antibodies on the systemic and mucosal immune response after neonatal immunization in a porcine model

    PubMed Central

    Guzman-Bautista, Edgar R; Garcia-Ruiz, Carlos E; Gama-Espinosa, Alicia L; Ramirez-Estudillo, Carmen; Rojas-Gomez, Oscar I; Vega-Lopez, Marco A

    2014-01-01

    Newborn mammals are highly susceptible to respiratory infections. Although maternal antibodies (MatAb) offer them some protection, they may also interfere with their systemic immune response to vaccination. However, the impact of MatAb on the neonatal mucosal immune response remains incompletely described. This study was performed to determine the effect of ovalbumin (OVA)-specific MatAb on the anti-OVA antibody response in sera, nasal secretions and saliva from specific pathogen-free Vietnamese miniature piglets immunized at 7 or 14 days of age. Our results demonstrated that MatAb increased antigen-specific IgA and IgG responses in sera, and transiently enhanced an early secretory IgA response in nasal secretions of piglets immunized at 7 days of age. In contrast, we detected a lower mucosal (nasal secretion and saliva) anti-OVA IgG response in piglets with MatAb immunized at 14 days of age, compared with piglets with no MatAb, suggesting a modulatory effect of antigen-specific maternal factors on the isotype transfer to the mucosal immune exclusion system. In our porcine model, we demonstrated that passive maternal immunity positively modulated the systemic and nasal immune responses of animals immunized early in life. Our results, therefore, open the possibility of inducing systemic and respiratory mucosal immunity in the presence of MatAb through early vaccination. PMID:24754050

  5. Maternal Milk T Cells Drive Development of Transgenerational Th1 Immunity in Offspring Thymus

    PubMed Central

    Ghosh, Mrinal K.; Nguyen, Virginia; Muller, H. Konrad

    2016-01-01

    Using multiple murine foster-nursing protocols, thereby eliminating placental transfer and allowing a distinction between dam- and pup-derived cells, we show that foster nursing by an immunized dam results in development of CD8+ T cells in nonimmunized foster pups that are specific for Ags against which the foster dam was immunized (Mycobacterium tuberculosis or Candida albicans). We have dubbed this process “maternal educational immunity” to distinguish it from passive cellular immunity. Of the variety of maternal immune cells present in milk, only T cells were detected in pup tissues. Maternal T cells, a substantial percentage of which were CD4+MHC class II+, accumulated in the pup thymus and spleen during the nursing period. Further analysis of maternal cells in the pup thymus showed that a proportion was positive for maternal immunogen-specific MHC class II tetramers. To determine the outcome of Ag presentation in the thymus, the maternal or foster pup origin of immunogen-responding CD8+ cells in foster pup spleens was assessed. Whereas ∼10% were maternally derived in the first few weeks after weaning, all immunogen-responding CD8+ T cells were pup derived by 12 wk of age. Pup-derived immunogen-responsive CD8+ cells persisted until at least 1 y of age. Passive cellular immunity is well accepted and has been demonstrated in the human population. In this study, we show an arguably more important role for transferred immune cells: the direction of offspring T cell development. Harnessing maternal educational immunity through prepregnancy immunization programs has potential for improvement of infant immunity. PMID:27496970

  6. Up regulation of the maternal immune response in the placenta of cattle naturally infected with Neospora caninum.

    PubMed

    Rosbottom, Anne; Gibney, Helen; Kaiser, Peter; Hartley, Catherine; Smith, Robert F; Robinson, Rebecca; Kipar, Anja; Williams, Diana J L

    2011-01-01

    Neospora caninum is an intracellular protozoan parasite which is a major cause of abortion in cattle worldwide. It forms persistent infections which recrudesce during pregnancy leading to foetal infection and in a proportion of cases, abortion. The mechanisms underlying abortion are not understood. In this study, recrudescence of a persistent infection in eight naturally infected cows occurred between 20 and 33 weeks of gestation. Animals were killed at the time of recrudescence and parasites were detected in the placentae and foetuses. An active maternal immune response consisting of an infiltration of CD4+ and CD8+ T cells and a 46-49 fold increase in interferon-γ and interleukin-4 mRNA was detected. Other cytokines, notably interleukin-12 p40, interleukin-10 and tumour necrosis factor-α were also significantly increased and Major Histocompatibility Class II antigen was expressed on maternal and foetal epithelial and stromal fibroblastoid cells. Significantly, despite the presence of an active maternal immune response in the placenta, all the foetuses were alive at the time of maternal euthanasia. There was evidence of parasites within foetal tissues; their distribution was restricted to the central nervous system and skeletal muscle and their presence was associated with tissue necrosis and a non-suppurative inflammatory response involving lymphocytes and macrophages, irrespective of the gestational age of the foetus. Whilst an active maternal immune response to a pathogen in the placenta is generally considered to be damaging to the foetal trophoblast, our findings suggest that the presence of a parasite-induced maternal immune response in the placenta is not detrimental to foetal survival but may contribute to the control of placental parasitosis. PMID:21283810

  7. Up Regulation of the Maternal Immune Response in the Placenta of Cattle Naturally Infected with Neospora caninum

    PubMed Central

    Rosbottom, Anne; Gibney, Helen; Kaiser, Peter; Hartley, Catherine; Smith, Robert F.; Robinson, Rebecca; Kipar, Anja; Williams, Diana J. L.

    2011-01-01

    Neospora caninum is an intracellular protozoan parasite which is a major cause of abortion in cattle worldwide. It forms persistent infections which recrudesce during pregnancy leading to foetal infection and in a proportion of cases, abortion. The mechanisms underlying abortion are not understood. In this study, recrudescence of a persistent infection in eight naturally infected cows occurred between 20 and 33 weeks of gestation. Animals were killed at the time of recrudescence and parasites were detected in the placentae and foetuses. An active maternal immune response consisting of an infiltration of CD4+ and CD8+ T cells and a 46–49 fold increase in interferon-γ and interleukin-4 mRNA was detected. Other cytokines, notably interleukin-12 p40, interleukin-10 and tumour necrosis factor-α were also significantly increased and Major Histocompatibility Class II antigen was expressed on maternal and foetal epithelial and stromal fibroblastoid cells. Significantly, despite the presence of an active maternal immune response in the placenta, all the foetuses were alive at the time of maternal euthanasia. There was evidence of parasites within foetal tissues; their distribution was restricted to the central nervous system and skeletal muscle and their presence was associated with tissue necrosis and a non-suppurative inflammatory response involving lymphocytes and macrophages, irrespective of the gestational age of the foetus. Whilst an active maternal immune response to a pathogen in the placenta is generally considered to be damaging to the foetal trophoblast, our findings suggest that the presence of a parasite-induced maternal immune response in the placenta is not detrimental to foetal survival but may contribute to the control of placental parasitosis. PMID:21283810

  8. Maternal Antibiotic Treatment Impacts Development of the Neonatal Intestinal Microbiome and Antiviral Immunity.

    PubMed

    Gonzalez-Perez, Gabriela; Hicks, Allison L; Tekieli, Tessa M; Radens, Caleb M; Williams, Brent L; Lamousé-Smith, Esi S N

    2016-05-01

    Microbial colonization of the infant gastrointestinal tract (GIT) begins at birth, is shaped by the maternal microbiota, and is profoundly altered by antibiotic treatment. Antibiotic treatment of mothers during pregnancy influences colonization of the GIT microbiota of their infants. The role of the GIT microbiota in regulating adaptive immune function against systemic viral infections during infancy remains undefined. We used a mouse model of perinatal antibiotic exposure to examine the effect of GIT microbial dysbiosis on infant CD8(+) T cell-mediated antiviral immunity. Maternal antibiotic treatment/treated (MAT) during pregnancy and lactation resulted in profound alterations in the composition of the GIT microbiota in mothers and infants. Streptococcus spp. dominated the GIT microbiota of MAT mothers, whereas Enterococcus faecalis predominated within the MAT infant GIT. MAT infant mice subsequently exhibited increased and accelerated mortality following vaccinia virus infection. Ag-specific IFN-γ-producing CD8(+) T cells were reduced in sublethally infected MAT infant mice. MAT CD8(+) T cells from uninfected infant mice also demonstrated a reduced capacity to sustain IFN-γ production following in vitro activation. We additionally determined that control infant mice became more susceptible to infection if they were born in an animal facility using stricter standards of hygiene. These data indicate that undisturbed colonization and progression of the GIT microbiota during infancy are necessary to promote robust adaptive antiviral immune responses. PMID:27036912

  9. Maternal Immune-Mediated Conditions, Autism Spectrum Disorders, and Developmental Delay

    ERIC Educational Resources Information Center

    Lyall, Kristen; Ashwood, Paul; Van de Water, Judy; Hertz-Picciotto, Irva

    2014-01-01

    The maternal immune system may play a role in offspring neurodevelopment. We examined whether maternal autoimmune disease, asthma, and allergy were associated with child autism spectrum disorder (ASD) and developmental delay without autism (DD) using 560 ASD cases, 391 typically developing controls, and 168 DD cases from the CHildhood Autism Risk…

  10. The maternal transfer of bacteria can mediate trans-generational immune priming in insects

    PubMed Central

    Freitak, Dalial; Schmidtberg, Henrike; Dickel, Franziska; Lochnit, Günther; Vogel, Heiko; Vilcinskas, Andreas

    2014-01-01

    Parents invest in their offspring by preparing them for defense against pathogens and parasites that only the parents have encountered, a phenomenon known as trans-generational immune priming. We investigated the underlying mechanism using the established lepidopteran model host Galleria mellonella. When larvae were fed with non-pathogenic bacteria, or the entomopathogenic species Pseudomonas entomophila and Serratia entomophila, the activity of lysozyme and phenoloxidase increased in the hemolymph, and immunity-related genes encoding antibacterial proteins such as gloverin were induced. Remarkably, the ingestion of bacteria by female larvae resulted in the differential expression of immunity-related genes in the eggs subsequently laid by the same females, providing evidence for trans-generational immune priming in G. mellonella. To determine the fate of these ingested microbes, the larval diet was supplemented with bacteria carrying a fluorescent label. We observed these bacteria crossing the midgut epithelium, their entrapment within nodules in the hemocoel, their accumulation within the ovary, and ultimately their deposition in the eggs. Therefore, we propose that trans-generational immune priming in Lepidoptera can be mediated by the maternal transfer of bacteria or bacterial fragments to the developing eggs. PMID:24603099

  11. Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.

    PubMed

    Muc, Magdalena; Kreiner-Møller, Eskil; Larsen, Jeppe M; Birch, Sune; Brix, Susanne; Bisgaard, Hans; Lauritzen, Lotte

    2015-09-28

    Breast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants' blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r -0.25; P=0.004), IL-17 (r -0.24; P=0.005), IL-5 (r -0.21; P=0.014) and IL-13 (r -0.17; P=0.047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r -0.23; P=0.018), IL-17 (r -0.25; P=0.009) and IL-5 (r -0.21; P=0.038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA. PMID:26283408

  12. Protein Nutrition of Southern Plains Small Mammals: Immune Response to Variation in Maternal and Offspring Dietary Nitrogen

    EPA Science Inventory

    Maternal nutrition during pregnancy and postnatal offspring nutrition may influence offspring traits. We investigated the effects of maternal and postweaning offspring dietary nitrogen on immune function and hematology in two species of rodent: the hispid cotton rat (Sigmodon his...

  13. Maternal Antibodies: Clinical Significance, Mechanism of Interference with Immune Responses, and Possible Vaccination Strategies

    PubMed Central

    Niewiesk, Stefan

    2014-01-01

    Neonates have an immature immune system, which cannot adequately protect against infectious diseases. Early in life, immune protection is accomplished by maternal antibodies transferred from mother to offspring. However, decaying maternal antibodies inhibit vaccination as is exemplified by the inhibition of seroconversion after measles vaccination. This phenomenon has been described in both human and veterinary medicine and is independent of the type of vaccine being used. This review will discuss the use of animal models for vaccine research. I will review clinical solutions for inhibition of vaccination by maternal antibodies, and the testing and development of potentially effective vaccines. These are based on new mechanistic insight about the inhibitory mechanism of maternal antibodies. Maternal antibodies inhibit the generation of antibodies whereas the T cell response is usually unaffected. B cell inhibition is mediated through a cross-link between B cell receptor (BCR) with the Fcγ-receptor IIB by a vaccine–antibody complex. In animal experiments, this inhibition can be partially overcome by injection of a vaccine-specific monoclonal IgM antibody. IgM stimulates the B cell directly through cross-linking the BCR via complement protein C3d and antigen to the complement receptor 2 (CR2) signaling complex. In addition, it was shown that interferon alpha binds to the CD21 chain of CR2 as well as the interferon receptor and that this dual receptor usage drives B cell responses in the presence of maternal antibodies. In lieu of immunizing the infant, the concept of maternal immunization as a strategy to protect neonates has been proposed. This approach would still not solve the question of how to immunize in the presence of maternal antibodies but would defer the time of infection to an age where infection might not have such a detrimental outcome as in neonates. I will review successful examples and potential challenges of implementing this concept. PMID

  14. Length of intervals between epidemics: evaluating the influence of maternal transfer of immunity

    PubMed Central

    Garnier, Romain; Gandon, Sylvain; Harding, Karin C; Boulinier, Thierry

    2014-01-01

    The length of intervals between epidemic outbreaks of infectious diseases is critical in epidemiology. In several species of marine mammals and birds, it is pivotal to also consider the life history of the species of concern, as the contact rate between individuals can have a seasonal flux, for example, due to aggregations during the breeding season. Recently, particular interest has been given to the role of the dynamics of immunity in determining the intervals between epidemics in wild animal populations. One potentially powerful, but often neglected, process in this context is the maternal transfer of immunity. Here, we explore theoretically how the transfer of maternal antibodies can delay the recurrence of epidemics using Phocine Distemper in harbor seals as an example of a system in which epidemic outbreaks are followed by pathogen extinction. We show that the presence of temporarily protected newborns can significantly increase the predicted interval between epidemics, and this effect is strongly dependent on the degree of synchrony in the breeding season. Furthermore, we found that stochasticity in the onset of epidemics in combination with maternally acquired immunity increases the predicted intervals between epidemics even more. These effects arise because newborns with maternal antibodies temporarily boost population level immunity above the threshold of herd immunity, particularly when breeding is synchronous. Overall, our results show that maternal antibodies can have a profound influence on the dynamics of wildlife epidemics, notably in gregarious species such as many marine mammals and seabirds. PMID:25035798

  15. Length of intervals between epidemics: evaluating the influence of maternal transfer of immunity.

    PubMed

    Garnier, Romain; Gandon, Sylvain; Harding, Karin C; Boulinier, Thierry

    2014-03-01

    The length of intervals between epidemic outbreaks of infectious diseases is critical in epidemiology. In several species of marine mammals and birds, it is pivotal to also consider the life history of the species of concern, as the contact rate between individuals can have a seasonal flux, for example, due to aggregations during the breeding season. Recently, particular interest has been given to the role of the dynamics of immunity in determining the intervals between epidemics in wild animal populations. One potentially powerful, but often neglected, process in this context is the maternal transfer of immunity. Here, we explore theoretically how the transfer of maternal antibodies can delay the recurrence of epidemics using Phocine Distemper in harbor seals as an example of a system in which epidemic outbreaks are followed by pathogen extinction. We show that the presence of temporarily protected newborns can significantly increase the predicted interval between epidemics, and this effect is strongly dependent on the degree of synchrony in the breeding season. Furthermore, we found that stochasticity in the onset of epidemics in combination with maternally acquired immunity increases the predicted intervals between epidemics even more. These effects arise because newborns with maternal antibodies temporarily boost population level immunity above the threshold of herd immunity, particularly when breeding is synchronous. Overall, our results show that maternal antibodies can have a profound influence on the dynamics of wildlife epidemics, notably in gregarious species such as many marine mammals and seabirds. PMID:25035798

  16. Investment in home-based maternal, newborn and child health records improves immunization coverage in Indonesia.

    PubMed

    Osaki, K; Hattori, T; Kosen, Soewarta; Singgih, Budihardja

    2009-08-01

    Indonesia Demographic and Health Surveys show that the ownership of home-based immunization records among children aged 12-23 months increased from 30.8% in 1997 and 30.7% in 2002-3 to 37% in 2007. In 2002-3, 70.9% of children who owned records had received all vaccines by the time of the survey, whereas 42.9% of children who did not own records had been fully immunized. An Indonesian ministerial decree of 2004 stated that the Maternal and Child Health Handbook (MCH handbook) was to be the only home-based record of maternal, newborn and child health. The increased immunization coverage seen would be a reflection of MCH handbook implementation, through raising awareness of immunization among community and health personnel and children's parents or guardians and allowing more accurate measurement of immunization coverage. PMID:19375141

  17. Cross-fostering to prevent maternal cell transfer did not prevent vaccine-associated enhanced respiratory disease that occurred following heterologous influenza challenge of pigs vaccinated in the presence of maternal immunity.

    PubMed

    Loving, Crystal L; Brockmeier, Susan L; Vincent, Amy L; Gauger, Phillip C; Zanella, Eraldo L; Lager, Kelly M; Kehrli, Marcus E

    2014-09-01

    Whole inactivated virus (WIV) vaccines for influenza A virus (IAV) provide limited cross-protection to diverse antigenic strains that are circulating or may emerge in a population. Maternal vaccination is used to protect neonatal animals from disease through passive transfer of immunity. It is desirable to vaccinate at a young age to induce active immunity that provides protection against infection before maternal immunity wanes. However, maternal-derived immunity (MDI; antibody or cells) can interfere with vaccine priming. Previous work indicates that vaccine-associated enhanced respiratory disease (VAERD) occurs in pigs following heterologous IAV challenge if pigs were previously vaccinated with WIV vaccine in the presence of matched MDI. However, the component of MDI (antibody or cells) that is required for the mispriming of piglet immunity has not been determined. While antibody from colostrum is absorbed into piglet circulation regardless of the sow from which it receives colostrum, transfer of maternal cells requires colostrum from the biological dam. We used cross-fostering (CF) as a tool to determine if maternal cells are required for the mispriming of piglet immunity upon WIV vaccination in the presence of MDI. Piglets vaccinated in the presence of MDI, regardless of CF, displayed characteristics of VAERD following heterologous challenge. MDI alone (no piglet vaccination) did not provide cross-protection against the antigenic variant. However, it did not induce VAERD. WIV vaccination provided complete protection against homologous challenge when delivered to piglets without MDI. Vaccination in the presence of MDI inhibited an increase in hemagglutination inhibiting (HI) antibody titers to vaccine antigen, but did not alter development of total immunoglobulin levels to vaccine virus. Taken together, the cellular component of MDI did not contribute to the mispriming of piglet immunity to WIV vaccine, but maternal-derived antibody (MDA) alone was sufficient

  18. Factors associated with maternal influenza immunization decision-making

    PubMed Central

    Frew, Paula M; Owens, Lauren E; Saint-Victor, Diane S; Benedict, Samantha; Zhang, Siyu; Omer, Saad B

    2014-01-01

    Objective: We examined pregnant women's intention to obtain the seasonal influenza vaccine via a randomized controlled study examining the effects of immunization history, message exposure, and sociodemographic correlates. Methods: Pregnant women ages 18–50 participated in a randomized message framing study from September 2011 through May 2012. Venue-based sampling was used to recruit racial and ethnic minority women throughout Atlanta, Georgia. Key outcomes were evaluated using bivariate and multivariate analyses. Results: History of influenza immunization was positively associated with intent to immunize during pregnancy [OR = 2.31, 90%CI: (1.06, 5.00)]. Significant correlates of intention to immunize included perceived susceptibility to influenza during pregnancy [OR = 3.8, 90% CI: (1.75, 8.36)] and vaccine efficacy [OR = 10.53, 90% CI: (4.34, 25.50)]. Single message exposure did not influence a woman's intent to vaccinate. Conclusions: Prior immunization, perceived flu susceptibility and perceived vaccine effectiveness promoted immunization intent among this population of pregnant minority women. Vaccine efficacy and disease susceptibility are critical to promoting immunization among women with no history of seasonal influenza immunization, while those who received the vaccine are likely to do so again. These findings provide evidence for the promotion of repeated exposure to vaccine messages emphasizing vaccine efficacy, normative support, and susceptibility to influenza. PMID:25483468

  19. Altered immune response in mallard ducklings exposed to lead through maternal transfer in the wild.

    PubMed

    Vallverdú-Coll, Núria; López-Antia, Ana; Martinez-Haro, Monica; Ortiz-Santaliestra, Manuel E; Mateo, Rafael

    2015-10-01

    Lead (Pb) poisoning has caused significant mortality in waterfowl populations worldwide. In spite of having been banned since 2003, prevalence of Pb shot ingestion in mallards (Anas platyrhynchos) from the Ebro delta was still 15.5% in 2011-12. We collected mallard eggs from this area to study the effects of maternally transferred Pb on eggshell properties and on immune response and oxidative balance of ducklings. Eggshell Pb levels were positively correlated with Pb levels in the blood of ducklings. Ducklings with blood Pb levels above 180 ng mL(-1) showed reduced body mass and died during the first week post hatching. Blood Pb levels positively correlated with humoral immune response, endogenous antioxidants and oxidative stress biomarkers, and negatively correlated with cellular immune response. Pb shot ingestion in birds can result in maternal transfer to the offspring that can affect their developing immune system and reduce their survival in early life stages. PMID:26123724

  20. Maternal antibodies in a wild altricial bird: effects on offspring immunity, growth and survival.

    PubMed

    Pihlaja, Marjo; Siitari, Heli; Alatalo, Rauno V

    2006-09-01

    1. In many animals immunity is not fully developed until adulthood but the young still need protection against various sets of pathogens. Thus, bird nestlings are highly dependent on antibodies received from their mother (in the eggs) during their rapid early growth period. The relationship between maternal immunity and the development of neonates' own immunity has been poorly studied. 2. It has been suggested that immune function plays an important part in mediating resource competition between different life-history traits, e.g. growth and reproduction. Maternal investment of antibodies has potentially permanent effects on offspring phenotype. Thus, the trade-offs between the immune function and other important life-history traits in the offspring will also affect the fitness of the mother. 3. Our supplemental feeding experiment in the magpie Pica pica indicates that the immunoglobulin levels of offspring at hatching are dependent on a mother's nutritional condition. In addition, the amount of maternal immunoglobulins transferred to offspring increases along the laying order within a nest. 4. We also found that at the age of 8-10 days the immunoglobulin production of the offspring has already begun. Furthermore, the maternal immunoglobulin levels of the offspring at hatching were positively related to their immunoglobulin levels on day 10. 5. Maternal immunoglobulins did not significantly affect offspring growth, but there was a negative relationship between self-produced immunoglobulins and growth over the first 10 days, indicating a trade-off between these traits. Nestlings' weight, however, had a positive relationship with immunoglobulin production suggesting that the observed trade-off between growth and immunoglobulin production is due to catch-up growth of nestlings with a low hatching weight. We found that within nests nestlings with higher maternal antibody levels had higher survival rate until day 20, but between nests there was an opposite relationship

  1. Drug treatment of malaria infections can reduce levels of protection transferred to offspring via maternal immunity

    PubMed Central

    Staszewski, Vincent; Reece, Sarah E.; O'Donnell, Aidan J.; Cunningham, Emma J. A.

    2012-01-01

    Maternally transferred immunity can have a fundamental effect on the ability of offspring to deal with infection. However, levels of antibodies in adults can vary both quantitatively and qualitatively between individuals and during the course of infection. How infection dynamics and their modification by drug treatment might affect the protection transferred to offspring remains poorly understood. Using the rodent malaria parasite Plasmodium chabaudi, we demonstrate that curing dams part way through infection prior to pregnancy can alter their immune response, with major consequences for offspring health and survival. In untreated maternal infections, maternally transferred protection suppressed parasitaemia and reduced pup mortality by 75 per cent compared with pups from naïve dams. However, when dams were treated with anti-malarial drugs, pups received fewer maternal antibodies, parasitaemia was only marginally suppressed, and mortality risk was 25 per cent higher than for pups from dams with full infections. We observed the same qualitative patterns across three different host strains and two parasite genotypes. This study reveals the role that within-host infection dynamics play in the fitness consequences of maternally transferred immunity. Furthermore, it highlights a potential trade-off between the health of mothers and offspring suggesting that anti-parasite treatment may significantly affect the outcome of infection in newborns. PMID:22357264

  2. Adaptive maternal immune deviations as a ground for autism spectrum disorders development in children.

    PubMed

    Poletaev, Alexander B; Poletaeva, Alina A; Pukhalenko, Alexander I; Zamaleeva, Roza S; Cherepanova, Natalia A; Frizin, Dmitry V

    2014-01-01

    Autism is a vexed problem today. Overall, there is a high frequency of birth children (1:80 - 1:150) with late diagnosed autism spectrum disorders (ASD) and this trend is getting progressively stronger. The causes for the currently increased frequency of ASD and the pathogenesis of ASD are not fully understood yet. One of the most likely mechanisms inducing ASD may be a maternal immune imprinting. This phenomenon is based on transplacental translocation of maternal antibodies of IgG class and, as a consequence, on the epigenetic "tuning" of immune system of the fetus and child. This mechanism provides development of child's anti-infection resistance before meeting with microorganisms, but it can be also a cause of inborn pathology including the ASD appearance. The quantitative changes in maternal blood serum autoantibodies depend on a specific microbial population, or are induced by environmental chemical pollutants in association with some individual features of the maternal metabolism. These immune changes are adaptive in most cases for the maternal organism, but can be pathogenic for the fetus in some cases. We discuss in the present paper the possibilities to predict the risk from abnormal development of nervous system in fetus and early diagnosis of ASD in high-risk group of children. PMID:25181843

  3. Innate Immune Activation in Obesity

    PubMed Central

    Lumeng, Carey N.

    2014-01-01

    The innate immune system is a prewired set of cellular and humoral components that has developed to sense perturbations in normal physiology and trigger responses to restore the system back to baseline. It is now understood that many of these components can also sense the physiologic changes that occur with obesity and be activated. While the exact reasons for this chronic immune response to obesity are unclear, there is strong evidence to suggest that innate inflammatory systems link obesity and disease. Based on this, anti-inflammatory therapies for diseases like type 2 diabetes and metabolic syndrome may form the core of future treatment plans. This review will highlight the components involved in the innate immune response and discuss the evidence that they contribute to the pathogenesis of obesity-associated diseases. PMID:23068074

  4. Maternal natural source vitamin E supplementation on suckling calf performance and immune response

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to determine the effects of maternally supplemented natural-source vitamin E (NSVE) on suckling calf performance and immune response. In a two-year study, one hundred twenty-five Angus-cross beef cows (n = 75/year one, 50/year two) initial BW = 607 kg; initial BCS = 5...

  5. Maternal Immunization with Pneumococcal Surface Protein A Protects against Pneumococcal Infections among Derived Offspring

    PubMed Central

    Hollingshead, Susan K.; Briles, David E.; Yamanaka, Noboru

    2011-01-01

    Pathogen-specific antibody plays an important role in protection against pneumococcal carriage and infections. However, neonates and infants exhibit impaired innate and adaptive immune responses, which result in their high susceptibility to pneumococci. To protect neonates and infants against pneumococcal infection it is important to elicit specific protective immune responses at very young ages. In this study, we investigated the protective immunity against pneumococcal carriage, pneumonia, and sepsis induced by maternal immunization with pneumococcal surface protein A (PspA). Mother mice were intranasally immunized with recombinant PspA (rPspA) and cholera toxin B subunit (CTB) prior to being mated. Anti-PspA specific IgG, predominantly IgG1, was present at a high level in the serum and milk of immunized mothers and in the sera of their pups. The pneumococcal densities in washed nasal tissues and in lung homogenate were significantly reduced in pups delivered from and/or breast-fed by PspA-immunized mothers. Survival after fatal systemic infections with various types of pneumococci was significantly extended in the pups, which had received anti-PspA antibody via the placenta or through their milk. The current findings strongly suggest that maternal immunization with PspA is an attractive strategy against pneumococcal infections during early childhood. (191 words) PMID:22073127

  6. Maternal immunization with pneumococcal surface protein A protects against pneumococcal infections among derived offspring.

    PubMed

    Kono, Masamitsu; Hotomi, Muneki; Hollingshead, Susan K; Briles, David E; Yamanaka, Noboru

    2011-01-01

    Pathogen-specific antibody plays an important role in protection against pneumococcal carriage and infections. However, neonates and infants exhibit impaired innate and adaptive immune responses, which result in their high susceptibility to pneumococci. To protect neonates and infants against pneumococcal infection it is important to elicit specific protective immune responses at very young ages. In this study, we investigated the protective immunity against pneumococcal carriage, pneumonia, and sepsis induced by maternal immunization with pneumococcal surface protein A (PspA). Mother mice were intranasally immunized with recombinant PspA (rPspA) and cholera toxin B subunit (CTB) prior to being mated. Anti-PspA specific IgG, predominantly IgG1, was present at a high level in the serum and milk of immunized mothers and in the sera of their pups. The pneumococcal densities in washed nasal tissues and in lung homogenate were significantly reduced in pups delivered from and/or breast-fed by PspA-immunized mothers. Survival after fatal systemic infections with various types of pneumococci was significantly extended in the pups, which had received anti-PspA antibody via the placenta or through their milk. The current findings strongly suggest that maternal immunization with PspA is an attractive strategy against pneumococcal infections during early childhood. PMID:22073127

  7. Commentary on “Moniz and Beigi's maternal immunization clinical experiences, challenges, and opportunities in vaccine acceptance”

    PubMed Central

    Frew, Paula M

    2014-01-01

    Maternal immunization faces an array of structural, sociocultural, and individual challenges that must be effectively addressed to realize widespread improvements in vaccination uptake. As Moniz and Beigi correctly detail in their review, immunization during this period offers unique opportunity to make substantial improvements in maternal and neonatal health. Moving beyond the existing Health Belief Model, we learn that immunization uptake can be significantly improved by shaping messages, addressing logistical challenges such as out-of-pocket (i.e., “copay”) barriers, and delivering provider education on maternal immunization to encourage future provider recommendations and facilitate the patient convenience of in-office vaccine administration. The resulting approach of “Educate, Recommend, Normalize, Maximize Convenience” is consistent with the evidence on maternal immunization. In its systematic application, such a model may usher in unprecedented opportunity to improve immunization uptake in decades ahead. PMID:25483456

  8. Immune function across generations: integrating mechanism and evolutionary process in maternal antibody transmission.

    PubMed Central

    Grindstaff, Jennifer L; Brodie, Edmund D; Ketterson, Ellen D

    2003-01-01

    The past 30 years of immunological research have revealed much about the proximate mechanisms of maternal antibody transmission and utilization, but have not adequately addressed how these issues are related to evolutionary and ecological theory. Much remains to be learned about individual differences within a species in maternal antibody transmission as well as differences among species in transmission or utilization of antibodies. Similarly, maternal-effects theory has generally neglected the mechanisms by which mothers influence offspring phenotype. Although the environmental cues that generate maternal effects and the consequent effects for offspring phenotype are often well characterized, the intermediary physiological and developmental steps through which the maternal effect is transmitted are generally unknown. Integration of the proximate mechanisms of maternal antibody transmission with evolutionary theory on maternal effects affords an important opportunity to unite mechanism and process by focusing on the links between genetics, environment and physiology, with the ultimate goal of explaining differences among individuals and species in the transfer of immune function from one generation to the next. PMID:14667346

  9. Maternal body size influences offspring immune configuration in an oviparous snake

    PubMed Central

    Brown, Gregory P.

    2016-01-01

    Like most ectothermic vertebrates, keelback snakes (Tropidonophis mairii) do not exhibit parental care. Thus, offspring must possess an immune system capable of dealing with challenges such as pathogens, without assistance from an attendant parent. We know very little about immune system characteristics of neonatal reptiles, including the magnitude of heritability and other maternal influences. To identify sources of variation in circulating white blood cell (WBC) concentrations and differentials, we examined blood smears from 246 hatchling snakes and their field-caught mothers. WBC concentrations were lower in hatchlings than in adults, and hatchlings had more basophils and fewer azurophils than adults. A hatchling keelback's WBC differential was also influenced by its sex and body size. Although hatchling WBC measures exhibited negligible heritability, they were strongly influenced by maternal body size and parasite infection (but not by maternal body condition, relative clutch mass or time in captivity). Larger mothers produced offspring with more azurophils and fewer lymphocytes. The mechanisms and consequences of WBC variation are currently unknown, but if these maternal effects enhance offspring fitness, the impact of maternal body size on reproductive success may be greater than expected simply from allometric increases in the numbers and sizes of progeny. PMID:27069670

  10. Moderate hyperhomocysteinemia and immune activation.

    PubMed

    Schroecksnadel, K; Frick, B; Wirleitner, B; Winkler, C; Schennach, H; Fuchs, D

    2004-02-01

    Moderate hyperhomocysteinemia is associated with an increased risk of atherosclerosis, thrombosis and neurodegenerative diseases. Homocysteine accumulation in the blood can be due to many underlying causes, which may interact with each other, e.g. genetic disposition and B-vitamin status. The role of the sulfur-containing amino acid homocysteine in the pathogenesis of diseases remains unclear, even if many studies suggest a causal relationship between homocysteine-mediated processes like oxidative stress, NO-inactivation and endothelial deficiency and atherogenesis. Proposed mechanisms of action of homocysteine are discussed, and the question is addressed, whether effects that are attributed to homocysteine, are not rather the consequence of folate and vitamin B12-deficiency. Deficiency of these B-vitamins in parallel with moderate hyperhomocysteinemia is often found in patients with enhanced activation of the cellular immune system, like Alzheimer's disease, rheumatoid arthritis and also vascular diseases. In patients with these diseases an association between homocysteine metabolism, oxidative stress and immune activation exists. On the one hand proliferation of immunocompetent cells having an enhanced demand for B-vitamins leads to the accumulation of homocysteine. On the other hand macrophages stimulated by TH1-type cytokine interferon-gamma form reactive oxygen species (ROS), which oxidize antioxidants, lipoproteins and oxidation-sensitive B-vitamins. Thereby Th1-type immune response could contribute importantly to the development of hyperhomocysteinemia, and may also be a major determinant of disease progression. PMID:14965213

  11. Transfer of Maternal Immune Cells by Breastfeeding: Maternal Cytotoxic T Lymphocytes Present in Breast Milk Localize in the Peyer’s Patches of the Nursed Infant

    PubMed Central

    Tang, May; Zumba, Osvaldo; Mehta, Hetali; Toma, Annmarie; Sant’Angelo, Derek; Laouar, Yasmina

    2016-01-01

    Despite our knowledge of the protective role of antibodies passed to infants through breast milk, our understanding of immunity transfer via maternal leukocytes is still limited. To emulate the immunological interface between the mother and her infant while breast-feeding, we used murine pups fostered after birth onto MHC-matched and MHC-mismatched dams. Overall, data revealed that: 1) Survival of breast milk leukocytes in suckling infants is possible, but not significant after the foster-nursing ceases; 2) Most breast milk lymphocytes establish themselves in specific areas of the intestine termed Peyer’s patches (PPs); 3) While most leukocytes in the milk bolus were myeloid cells, the majority of breast milk leukocytes localized to PPs were T lymphocytes, and cytotoxic T cells (CTLs) in particular; 4) These CTLs exhibit high levels of the gut-homing molecules α4β7 and CCR9, but a reduced expression of the systemic homing marker CD62L; 5) Under the same activation conditions, transferred CD8 T cells through breast milk have a superior capacity to produce potent cytolytic and inflammatory mediators when compared to those generated by the breastfed infant. It is therefore possible that maternal CTLs found in breast milk are directed to the PPs to compensate for the immature adaptive immune system of the infant in order to protect it against constant oral infectious risks during the postnatal phase. PMID:27285085

  12. Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy

    PubMed Central

    Nishio, Hisanori; Takada, Hidetoshi; Sakai, Yasunari; Nanishi, Etsuro; Ochiai, Masayuki; Onimaru, Mitsuho; Chen, Si Jing; Matsui, Toshiro; Hara, Toshiro

    2016-01-01

    Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. We report that administration of FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice induced IUGR and IUFD. Mass spectrometry analysis revealed that maternally injected FK565 was distributed to the fetal tissues across placenta. In addition, maternal injection of FK565 induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. Nod1 was highly expressed in fetal vascular tissues, where significantly higher levels of CCL2 and IL-6 mRNAs were induced with maternal injection of FK565 than those in other tissues. Using Nod1-knockout mice, we verified that both maternal and fetal tissues were involved in the development of IUGR and IUFD. Furthermore, FK565 induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface. PMID:26880761

  13. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

    NASA Astrophysics Data System (ADS)

    van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

    2014-04-01

    The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

  14. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

    PubMed Central

    van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O’Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

    2016-01-01

    The impact of the nutritional status during foetal life in the overall health of adults has been recognised1. However dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs (SLOs) occurs during embryogenesis and is considered to be developmentally programmed2,3. SLO formation dependents on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells2,3,4,5. Here we show that foetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero pre-setting the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi differentiation was controlled by maternal retinoid intake and foetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, while RA receptors directly regulated the Rorc locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring. PMID:24670648

  15. Neonatal Immunization with Respiratory Syncytial Virus Glycoprotein Fragment Induces Protective Immunity in the Presence of Maternal Antibodies in Mice

    PubMed Central

    Noh, Youran; Shim, Byoung-Shik; Cheon, In Su; Rho, Semi; Kim, Hee Joo; Choi, Youngjoo; Kang, Chang-Yuil; Chang, Jun

    2013-01-01

    Abstract Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly worldwide. The significant morbidity and mortality associated with this infection underscores the urgent need for development of RSV vaccine. In this study, we first show that intranasal administration of RSV glycoprotein core fragment (Gcf) to neonatal mice can induce systemic humoral immune responses and protective immunity against RSV without causing lung eosinophilia, although antibody response was shifted to a Th2 response. Next, we examined whether the presence of maternal anti-RSV antibodies would affect the responsiveness and protection efficacy of Gcf in newborn mice, since infants can possess RSV-specific maternal antibodies due to frequent RSV re-infections to adults. Intranasal administration of Gcf induced antibody response and increased IFNγ secretion and protected mice against RSV challenge without severe lung eosinophilia, even in the presence of high levels of RSV-specific maternal antibodies. Thus, our findings suggest that Gcf may be an effective and safe RSV vaccine during the neonatal period. PMID:23869549

  16. Perceived Maternal Role Competence among the Mothers Attending Immunization Clinics of Dharan, Nepal

    PubMed Central

    Shrooti, Shah; Mangala, Shrestha; Nirmala, Pokharel; Devkumari, Shrestha; Dharanidhar, Baral

    2016-01-01

    Background: Being a mother is considered by many women as their most important role in life. Women’s perceptions of their abilities to manage the demands of parenting and the parenting skills they posses are reflected by perceived maternal role competence. The present study was carried out to assess the perceived maternal role competence and its associated factors among mothers. Methods: A descriptive cross-sectional research study was carried out on 290 mothers of infant in four immunization clinics of Dharan, Nepal. Data were collected using a standardized predesigned, pretested questionnaire (Parent sense of competence scale, Rosenberg’s self esteem scale, Maternity social support scale). The data were analyzed using descriptive and inferential statistics and multiple regression analysis at 0.05 level of significance. Results: The mean score of the perceived maternal role competence obtained by mothers was 64.34±7.90 and those of knowledge/skill and valuing/comfort subscale were 31±6.01 and 33±3.75, respectively. There was a significant association between perceived maternal role competence and factors as the age of the mother (P<0.001), educational status (P=0.015), occupation (P=0.001) and readiness for pregnancy (P=0.022). The study findings revealed a positive correlation between perceived maternal role competence and age at marriage (r=0.132, P=0.024), per capita income (r=0.118, P=0.045), self esteem (r=0.379, P<0.001), social support (r=0.272, P<0.001), and number of support persons (r=0.119, P=0.043). The results of the step wise multiple regression analysis revealed that the major predictor of perceived maternal role competence was self esteem. Conclusion: The factors associated with perceived maternal role competence were age, education, occupation, per capita income, self esteem, social support, and the number of support persons. PMID:27218107

  17. Maternal transfer of antibodies in vertebrates: trans-generational effects on offspring immunity

    PubMed Central

    Hasselquist, Dennis; Nilsson, Jan-Åke

    2008-01-01

    Maternal effects by which females provide their offspring with non-genetic factors such as hormones, nutrients and antibodies can have an important impact on offspring fitness. In vertebrates, maternal antibodies (matAb) are transferred from the mother, via the placenta, egg yolk or milk during lactation to offspring until they are 2 weeks (birds), 4–10 weeks (rodents) and 9 months (humans) old, respectively. matAb transfer can have direct effects on offspring growth rate in birds and rodents, probably by passively protecting the newborn from common pathogens before their endogenous immune system has matured. Indirect long-term effects of matAb transfer on the offspring's own immunity can be synergistic, if matAb act as antigen templates of the accumulated immunological experience of the mother and educate the newborn's immune system. However, it may also be suppressive if matAb reduce antigen presentation to the newborn resulting in antigen-specific blocking of offspring endogenous immunity. Our aim is to review the mechanisms and direct effects of matAb transfer in vertebrates with an emphasis on birds, outline a framework for research on the long-term effects of matAb on the endogenous immune system of the mature offspring and encourage ecological and evolutionary studies of matAb transfer in non-domesticated animals. PMID:18926976

  18. Trace Metals Affect Early Maternal Transfer of Immune Components in the Feral Pigeon.

    PubMed

    Chatelain, M; Gasparini, J; Haussy, C; Frantz, A

    2016-01-01

    Maternal early transfers of immune components influence eggs' hatching probability and nestlings' survival. They depend on females' own immunity and, because they are costly, on their physiological state. Therefore, trace metals, whether toxic and immunosuppressive (e.g., lead, cadmium, etc.) or necessary and immunostimulant (e.g., zinc, copper, iron, etc.), are likely to affect the amount of immune components transferred into the eggs. It may also vary with plumage eumelanin level, which is known to be linked to immunity, to transfer of antibodies, and to metal detoxification. In feral pigeons (Columba livia) injected with an antigen and experimentally exposed to lead and/or zinc (two highly abundant trace metals in urban areas), we measured specific antibody transfer and concentrations of two antimicrobial proteins (lysozyme and ovotransferrin) in eggs. As expected, lead had negative effects on specific antibody transfer, while zinc positively affected lysozyme egg concentrations. Moreover, eggs from lead-exposed females exhibited higher ovotransferrin concentrations; because it binds metal ions, ovotransferrin may enable egg detoxification and embryo protection. Finally, eggs' lysozyme concentrations increased with plumage darkness of females not exposed to zinc, while the relation was opposite among zinc-exposed females, suggesting that benefits and costs of plumage melanism depend on trace metal environmental levels. Overall, our study underlines the potential ecotoxicological effects of trace metals on maternal transfers of immune components and the role of plumage melanism in modulating these effects. PMID:27153130

  19. Maternal Immunization Earlier in Pregnancy Maximizes Antibody Transfer and Expected Infant Seropositivity Against Pertussis

    PubMed Central

    Eberhardt, Christiane S.; Blanchard-Rohner, Geraldine; Lemaître, Barbara; Boukrid, Meriem; Combescure, Christophe; Othenin-Girard, Véronique; Chilin, Antonina; Petre, Jean; de Tejada, Begoña Martinez; Siegrist, Claire-Anne

    2016-01-01

    Background. Maternal immunization against pertussis is currently recommended after the 26th gestational week (GW). Data on the optimal timing of maternal immunization are inconsistent. Methods. We conducted a prospective observational noninferiority study comparing the influence of second-trimester (GW 13–25) vs third-trimester (≥GW 26) tetanus-diphtheria-acellular pertussis (Tdap) immunization in pregnant women who delivered at term. Geometric mean concentrations (GMCs) of cord blood antibodies to recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) were assessed by enzyme-linked immunosorbent assay. The primary endpoint were GMCs and expected infant seropositivity rates, defined by birth anti-PT >30 enzyme-linked immunosorbent assay units (EU)/mL to confer seropositivity until 3 months of age. Results. We included 335 women (mean age, 31.0 ± 5.1 years; mean gestational age, 39.3 ± 1.3 GW) previously immunized with Tdap in the second (n = 122) or third (n = 213) trimester. Anti-PT and anti-FHA GMCs were higher following second- vs third-trimester immunization (PT: 57.1 EU/mL [95% confidence interval {CI}, 47.8–68.2] vs 31.1 EU/mL [95% CI, 25.7–37.7], P < .001; FHA: 284.4 EU/mL [95% CI, 241.3–335.2] vs 140.2 EU/mL [95% CI, 115.3–170.3], P < .001). The adjusted GMC ratios after second- vs third-trimester immunization differed significantly (PT: 1.9 [95% CI, 1.4–2.5]; FHA: 2.2 [95% CI, 1.7–3.0], P < .001). Expected infant seropositivity rates reached 80% vs 55% following second- vs third-trimester immunization (adjusted odds ratio, 3.7 [95% CI, 2.1–6.5], P < .001). Conclusions. Early second-trimester maternal Tdap immunization significantly increased neonatal antibodies. Recommending immunization from the second trimester onward would widen the immunization opportunity window and could improve seroprotection. PMID:26797213

  20. Maternal physical activity, birth weight and perinatal mortality.

    PubMed

    Briend, A

    1980-11-01

    As a result of the acquisition of upright posture, adaptation to muscular exercise seems to be unique in man. It involves a redistribution of the cardiac output mediated by the sympathetic system towards priority organs which apparently do not include the pregnant uterus. This could explain the poor tolerance of the human fetus to maternal exercise. The hypothesis is supported by the independence of a detrimental effect of work from the effect of maternal nutrition and by an influence of maternal posture in late pregnancy on its outcome. Possible relations between maternal activity before and during late pregnancy and perinatal mortality are discussed in the context of this hypothesis. PMID:7005626

  1. Decidual vascular endothelial cells promote maternal-fetal immune tolerance by inducing regulatory T cells through canonical Notch1 signaling.

    PubMed

    Yao, Yanyi; Song, Jieping; Wang, Weipeng; Liu, Nian

    2016-05-01

    Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro. Moreover, under in vitro Treg cell induction condition with agonistic antibodies and transforming growth factor (TGF)-β, DVECs promoted Treg cell differentiation from non-Treg conventional T cells. Consistent with the promotion of Treg cell maintenance and differentiation, Treg cell-associated gene expression such as TGF-β, Epstein-Barr-induced gene-3, CD39 and glucocorticoid-induced tumor necrosis factor receptor was also increased in the presence of DVECs. Further study revealed that DVECs expressed Notch ligands such as Jagged-1, Delta-like protein 1 (DLL-1) and DLL-4, while Treg cells expressed Notch1 on their surface. The effects of DVECs on Treg cells was inhibited by siRNA-induced knockdown of expression of Jagged-1 and DLL-1 in DVECs. Downregulation of Notch1 in Treg cells using lentiviral shRNA transduction decreased Foxp3 expression in Treg cells. Adoptive transfer of Notch1-deficient Treg cells increased abortion rate in a murine semiallogeneic pregnancy model. Taken together, our study suggests that maternal DVECs are able to maintain decidual Treg cell identity and promote Treg cell differentiation through activation of Notch1 signal pathway in Treg cells and subsequently inhibit the immune response against semiallogeneic fetuses and preventing spontaneous abortion. PMID:26714886

  2. HIV-associated chronic immune activation

    PubMed Central

    Paiardini, Mirko; Müller-Trutwin, Michaela

    2013-01-01

    Summary Systemic chronic immune activation is considered today as the driving force of CD4+ T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by antiretroviral therapy, with the extent of this residual immune activation being associated with CD4+ T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4+ T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation that have been observed to be characteristic for human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to ‘show AIDS the door’, and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives. PMID:23772616

  3. Dual Positive Regulation of Embryo Implantation by Endocrine and Immune Systems--Step-by-Step Maternal Recognition of the Developing Embryo.

    PubMed

    Fujiwara, Hiroshi; Araki, Yoshihiko; Imakawa, Kazuhiko; Saito, Shigeru; Daikoku, Takiko; Shigeta, Minoru; Kanzaki, Hideharu; Mori, Takahide

    2016-03-01

    In humans, HCG secreted from the implanting embryo stimulates progesterone production of the corpus luteum to maintain embryo implantation. Along with this endocrine system, current evidence suggests that the maternal immune system positively contributes to the embryo implantation. In mice, immune cells that have been sensitized with seminal fluid and then the developing embryo induce endometrial differentiation and promote embryo implantation. After hatching, HCG activates regulatory T and B cells through LH/HCG receptors and then stimulates uterine NK cells and monocytes through sugar chain receptors, to promote and maintain pregnancy. In accordance with the above, the intrauterine administration of HCG-treated PBMC was demonstrated to improve implantation rates in women with repeated implantation failures. These findings suggest that the maternal immune system undergoes functional changes by recognizing the developing embryos in a stepwise manner even from a pre-fertilization stage and facilitates embryo implantation in cooperation with the endocrine system. PMID:26755274

  4. The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders

    PubMed Central

    Marques, Andrea Horvath; O'Connor, Thomas G.; Roth, Christine; Susser, Ezra; Bjørke-Monsen, Anne-Lise

    2013-01-01

    The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions. PMID:23914151

  5. Toxicogenomic Profiles in Relation to Maternal Immunotoxic Exposure and Immune Functionality in Newborns

    PubMed Central

    Hochstenbach, Kevin

    2012-01-01

    A crucial period for the development of the immune system occurs in utero. This results in a high fetal vulnerability to immunotoxic exposure, and indeed, immunotoxic effects have been reported, demonstrating negative effects on immune-related health outcomes and immune functionality. Within the NewGeneris cohort BraMat, a subcohort of the Norwegian Mother and Child Cohort Study (MoBa), immunotoxicity was demonstrated for polychlorinated biphenyls and dioxins, showing associations between estimated maternal intake levels and reduced measles vaccination responses in the offspring at the age of 3. The present study aimed to investigate this link at the transcriptomic level within the same BraMat cohort. To this end, whole-genome gene expression in cord blood was investigated and found to be associated with maternal Food Frequency Questionnaires–derived exposure estimates and with vaccination responses in children at 3 years of age. Because the literature reports gender specificity in the innate, humoral, and cell-mediated responses to viral vaccines, separate analysis for males and females was conducted. Separate gene sets for male and female neonates were identified, comprising genes significantly correlating with both 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and polychlorinated biphenyls (PCB) exposure and with measles vaccination response. Noteworthy, genes correlating negatively with exposure in general show positive correlations with antibody levels and vice versa. For both sexes, these included immune-related genes, suggesting immunosuppressive effects of maternal exposure to TCDD and PCB at the transcriptomic level in neonates in relation to measles vaccination response 3 years later. PMID:22738990

  6. Immune Response Gene Profiles in the Term Placenta Depend Upon Maternal Muscle Mass

    PubMed Central

    O’Tierney, P. F.; Lewis, R. M.; McWeeney, S. K.; Hanson, M. A.; Inskip, H. M.; Morgan, T. K.; Barker, D. J.; Bagby, G.; Cooper, C.; Godfrey, K. M.

    2012-01-01

    Maternal thinness leads to metabolic challenges in the offspring, but it is unclear whether reduced maternal fat mass or muscle mass drives these metabolic changes. Recently, it has been shown that low maternal muscle mass—as measured by arm muscle area (AMA)—is associated with depressed nutrient transport to the fetus. To determine the role of maternal muscle mass on placental function, we analyzed the gene expression profiles of 30 human placentas over the range of AMA (25.2-90.8 cm2) from uncomplicated term pregnancies from the Southampton Women’s Survey cohort. Eighteen percent of the ∼60 genes that were highly expressed in less muscular women were related to immune system processes and the interferon-γ (IFNG) signaling pathway in particular. Those transcripts related to the IFNG pathway included IRF1, IFI27, IFI30, and GBP6. Placentas from women with low muscularity are, perhaps, more sensitive to the effects of inflammatory cytokines than those from more muscular women. PMID:22534332

  7. Innate immune activation in intestinal homeostasis.

    PubMed

    Harrison, Oliver J; Maloy, Kevin J

    2011-01-01

    Loss of intestinal immune regulation leading to aberrant immune responses to the commensal microbiota are believed to precipitate the chronic inflammation observed in the gastrointestinal tract of patients with inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Innate immune receptors that recognize conserved components derived from the microbiota are widely expressed by both epithelial cells and leucocytes of the gastrointestinal tract and play a key role in host protection from infectious pathogens; yet precisely how pathogenic and commensal microbes are distinguished is not understood. Furthermore, aberrant innate immune activation may also drive intestinal pathology, as patients with IBD exhibit extensive infiltration of innate immune cells to the inflamed intestine, and polymorphisms in many innate immunity genes influence susceptibility to IBD. Thus, a balanced interaction between the microbiota and innate immune activation is required to maintain a healthy mutualistic relationship between the microbiota and the host, which when disturbed can result in intestinal inflammation. PMID:21912101

  8. Uterine NK cells: active regulators at the maternal-fetal interface

    PubMed Central

    Moffett, Ashley; Colucci, Francesco

    2014-01-01

    Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation. PMID:24789879

  9. Maternal supplementation of seaweed-derived polysaccharides improves intestinal health and immune status of suckling piglets.

    PubMed

    Heim, G; O'Doherty, J V; O'Shea, C J; Doyle, D N; Egan, A M; Thornton, K; Sweeney, T

    2015-01-01

    The experiment investigated the effect of maternal dietary supplementation of seaweed-derived polysaccharides (SDP) (-SDP v. +SDP, n   20) from day 83 of gestation until weaning (day 28) on selected sow faeces and piglet digesta microbiota populations, piglet small-intestinal morphology, and intestinal nutrient transporter and inflammatory cytokine gene expression at birth, 48 h after birth and weaning. The effect of maternal dietary treatment on the piglet gene expression profile of inflammatory cytokines in the colon following a lipopolysaccharide (LPS) challenge was also investigated. Dietary SDP reduced sow faecal Enterobacteriaceae gene numbers at parturition. Small-intestinal morphology, nutrient transporter and cytokine gene expression in newborn piglets did not differ between maternal dietary treatments (P > 0·10). At 48 h after birth, sodium-glucose-linked transporter 1 gene expression was down-regulated in the ileum of piglets suckling the SDP-supplemented sows compared with those suckling the basal sows (P = 0·050). There was a SDP × LPS challenge interaction on IL-1 and IL-6 gene expression in the colon of piglets (P < 0·05). The gene expression of IL-1 and IL-6 was down-regulated in the LPS-challenged colon of piglets suckling the SDP sows compared with those suckling the basal sows (P < 0·05). However, there was no difference in IL-1 and IL-6 gene expression in the unchallenged colon between treatment groups. At weaning, piglets suckling the SDP-supplemented sows had increased villus height in the jejunum and ileum compared with those suckling the basal-fed sows (P < 0·05). In conclusion, maternal dietary SDP supplementation enhanced the immune response of suckling piglets and improved gut morphology, making them more immune competent to deal with post-weaning adversities. PMID:26495119

  10. Zygotic genome activation during the maternal-to-zygotic transition

    PubMed Central

    Lee, Miler T.; Bonneau, Ashley R.; Giraldez, Antonio J.

    2015-01-01

    Embryogenesis depends on a highly coordinated cascade of genetically encoded events. In animals, maternal factors contributed by the egg cytoplasm initially control development, while the zygotic nuclear genome is quiescent. Subsequently, the genome is activated, embryonic gene products are mobilized and maternal factors are cleared. This transfer of developmental control is called the maternal-to-zygotic transition (MZT). In this review, we discuss recent advances toward understanding the scope, timing and mechanisms that underlie zygotic genome activation at the MZT in animals. We describe high-throughput techniques to measure the embryonic transcriptome and explore how regulation of the cell cycle, chromatin and transcription factors together elicits specific patterns of embryonic gene expression. Finally, we discuss the interplay between zygotic transcription and maternal clearance, and show how these two activities combine to reprogram two terminally differentiated gametes into a totipotent embryo. PMID:25150012

  11. Immune activation generates corticosterone-mediated terminal reproductive investment in a wild bird

    PubMed Central

    Bowers, E. Keith; Bowden, Rachel M.; Sakaluk, Scott K.; Thompson, Charles F.

    2015-01-01

    Despite classical expectations of a trade-off between immune activity and reproduction, an emergent view suggests that individuals experiencing activation of their immune system actually increase reproductive effort and allocation to offspring as a form of terminal investment in response to reduced survival probability. However, the components and mechanisms of increased parental investment following immunostimulation are currently unknown. We hypothesize that increased glucocorticoid production following immunostimulation modulates the increase in reproductive effort that constitutes terminal investment. We activated the immune system of breeding female house wrens (Troglodytes aedon) with an immunogen and cross-fostered the eggs they subsequently produced to separate pre- and post-natal components of maternal investment. Cross-fostering revealed an increase in both pre- and post-natal allocation from immunostimulated females, which was confirmed by quantification of egg constituents and maternal provisioning behavior. The increase in maternal provisioning was mediated, at least in part, by increased corticosterone in these females. Offspring immune responsiveness was also enhanced through transgenerational immune priming via the egg. Thus, our results indicate that maternal immunostimulation induces transgenerational effects on offspring through both pre- and post-natal parental effects, and support an important role for corticosterone in mediating parental investment. PMID:25996862

  12. Sexual orientation, fraternal birth order, and the maternal immune hypothesis: a review.

    PubMed

    Bogaert, Anthony F; Skorska, Malvina

    2011-04-01

    In 1996, psychologists Ray Blanchard and Anthony Bogaert found evidence that gay men have a greater number of older brothers than do heterosexual men. This "fraternal birth order" (FBO) effect has been replicated numerous times, including in non-Western samples. More recently, strong evidence has been found that the FBO effect is of prenatal origin. Although there is no direct support for the exact prenatal mechanism, the most plausible explanation may be immunological in origin, i.e., a mother develops an immune reaction against a substance important in male fetal development during pregnancy, and that this immune effect becomes increasingly likely with each male gestation. This immune effect is hypothesized to cause an alteration in (some) later born males' prenatal brain development. The target of the immune response may be molecules (i.e., Y-linked proteins) on the surface of male fetal brain cells, including in sites of the anterior hypothalamus, which has been linked to sexual orientation in other research. Antibodies might bind to these molecules and thus alter their role in typical sexual differentiation, leading some later born males to be attracted to men as opposed to women. Here we review evidence in favor of this hypothesis, including recent research showing that mothers of boys develop an immune response to one Y-linked protein (i.e., H-Y antigen; SMCY) important in male fetal development, and that this immune effect becomes increasingly likely with each additional boy to which a mother gives birth. We also discuss other Y-linked proteins that may be relevant if this hypothesis is correct. Finally, we discuss issues in testing the maternal immune hypothesis of FBO. PMID:21315103

  13. Translocation of bacteria from the gut to the eggs triggers maternal transgenerational immune priming in Tribolium castaneum

    PubMed Central

    Knorr, Eileen; Schmidtberg, Henrike; Arslan, Derya; Bingsohn, Linda; Vilcinskas, Andreas

    2015-01-01

    Invertebrates can be primed to enhance their protection against pathogens they have encountered before. This enhanced immunity can be passed maternally or paternally to the offspring and is known as transgenerational immune priming. We challenged larvae of the red flour beetle Tribolium castaneum by feeding them on diets supplemented with Escherichia coli, Micrococcus luteus or Pseudomonas entomophila, thus mimicking natural exposure to pathogens. The oral uptake of bacteria induced immunity-related genes in the offspring, but did not affect the methylation status of the egg DNA. However, we observed the translocation of bacteria or bacterial fragments from the gut to the developing eggs via the female reproductive system. Such translocating microbial elicitors are postulated to trigger bacterial strain-specific immune responses in the offspring and provide an alternative mechanistic explanation for maternal transgenerational immune priming in coleopteran insects. PMID:26701756

  14. Translocation of bacteria from the gut to the eggs triggers maternal transgenerational immune priming in Tribolium castaneum.

    PubMed

    Knorr, Eileen; Schmidtberg, Henrike; Arslan, Derya; Bingsohn, Linda; Vilcinskas, Andreas

    2015-12-01

    Invertebrates can be primed to enhance their protection against pathogens they have encountered before. This enhanced immunity can be passed maternally or paternally to the offspring and is known as transgenerational immune priming. We challenged larvae of the red flour beetle Tribolium castaneum by feeding them on diets supplemented with Escherichia coli, Micrococcus luteus or Pseudomonas entomophila, thus mimicking natural exposure to pathogens. The oral uptake of bacteria induced immunity-related genes in the offspring, but did not affect the methylation status of the egg DNA. However, we observed the translocation of bacteria or bacterial fragments from the gut to the developing eggs via the female reproductive system. Such translocating microbial elicitors are postulated to trigger bacterial strain-specific immune responses in the offspring and provide an alternative mechanistic explanation for maternal transgenerational immune priming in coleopteran insects. PMID:26701756

  15. Heritable variation in maternally derived yolk androgens, thyroid hormones and immune factors.

    PubMed

    Ruuskanen, S; Gienapp, P; Groothuis, T G G; Schaper, S V; Darras, V M; Pereira, C; de Vries, B; Visser, M E

    2016-09-01

    Maternal reproductive investment can critically influence offspring phenotype, and thus these maternal effects are expected to be under strong natural selection. Knowledge on the extent of heritable variation in the physiological mechanisms underlying maternal effects is however limited. In birds, resource allocation to eggs is a key mechanism for mothers to affect their offspring and different components of the egg may or may not be independently adjusted. We studied the heritability of egg components and their genetic and phenotypic covariation in great tits (Parus major), using captive-bred full siblings of wild origin. Egg mass, testosterone (T) and androstenedione (A4) hormone concentrations showed moderate heritability, in agreement with earlier findings. Interestingly, yolk triiodothyronine hormone (T3), but not its precursor, thyroxine hormone (T4), concentration was heritable. An immune factor, albumen lysozyme, showed moderate heritability, but yolk immunoglobulins (IgY) did not. The genetic correlation estimates were moderate but statistically nonsignificant; a trend for a positive genetic correlation was found between A4 and egg mass, T and lysozyme and IgY and lysozyme, respectively. Interestingly, phenotypic correlations were found only between A4 and T, and T4 and T3, respectively. Given that these egg components are associated with fitness-related traits in the offspring (and mother), and that we show that some components are heritable, it opens the possibility that natural selection may shape the rate and direction of phenotypic change via egg composition. PMID:27381323

  16. Maternal exercise during pregnancy promotes physical activity in adult offspring.

    PubMed

    Eclarinal, Jesse D; Zhu, Shaoyu; Baker, Maria S; Piyarathna, Danthasinghe B; Coarfa, Cristian; Fiorotto, Marta L; Waterland, Robert A

    2016-07-01

    Previous rodent studies have shown that maternal voluntary exercise during pregnancy leads to metabolic changes in adult offspring. We set out to test whether maternal voluntary exercise during pregnancy also induces persistent changes in voluntary physical activity in the offspring. Adult C57BL/6J female mice were randomly assigned to be caged with an unlocked (U) or locked (L) running wheel before and during pregnancy. Maternal running behavior was monitored during pregnancy, and body weight, body composition, food intake, energy expenditure, total cage activity, and running wheel activity were measured in the offspring at various ages. U offspring were slightly heavier at birth, but no group differences in body weight or composition were observed at later ages (when mice were caged without access to running wheels). Consistent with our hypothesis, U offspring were more physically active as adults. This effect was observed earlier in female offspring (at sexual maturation). Remarkably, at 300 d of age, U females achieved greater fat loss in response to a 3-wk voluntary exercise program. Our findings show for the first time that maternal physical activity during pregnancy affects the offspring's lifelong propensity for physical activity and may have important implications for combating the worldwide epidemic of physical inactivity and obesity.-Eclarinal, J. D., Zhu, S., Baker, M. S., Piyarathna, D. B., Coarfa, C., Fiorotto, M. L., Waterland, R. A. Maternal exercise during pregnancy promotes physical activity in adult offspring. PMID:27033262

  17. Antibody response and maternal immunity upon boosting PRRSV-immune sows with experimental farm-specific and commercial PRRSV vaccines.

    PubMed

    Geldhof, Marc F; Van Breedam, Wander; De Jong, Ellen; Lopez Rodriguez, Alfonso; Karniychuk, Uladzimir U; Vanhee, Merijn; Van Doorsselaere, Jan; Maes, Dominiek; Nauwynck, Hans J

    2013-12-27

    attenuated EU-type vaccine in immune sows at 60 days of gestation. The impact of this vaccination on maternal immunity and on the PRRSV infection pattern in piglets during their first weeks of life was evaluated. Upon vaccination with the farm-specific inactivated vaccine, a significant increase in farm-specific virus-neutralizing antibodies was detected in all sows. Virus-neutralizing antibodies were also transferred to the piglets via colostrum and were detectable in the serum of these animals until 5 weeks after parturition. In contrast, not all sows vaccinated with the commercial attenuated vaccine showed an increase in farm-specific virus-neutralizing antibodies and the piglets of this group generally had lower virus-neutralizing antibody titers. Interestingly, the number of viremic animals (i.e. animals that have infectious virus in their bloodstream) was significantly lower among piglets of both vaccinated groups than among piglets of mock-vaccinated sows and this at least until 9 weeks after parturition. The results of this study indicate that inactivated farm-specific PRRSV vaccines and commercial attenuated vaccines can be useful tools to boost PRRSV-specific (humoral) immunity in sows and reduce viremia in weaned piglets. PMID:24041768

  18. Maternal determinants of complete child immunization among children aged 12-23 months in a southern district of Nigeria.

    PubMed

    Fatiregun, Akinola Ayoola; Okoro, Anselm O

    2012-01-17

    This study was conducted to identify determinants of complete immunization status among children aged 12-23 months in a southern district of Nigeria. The World Health Organization cluster survey was used to evaluate immunization coverage of infants. Mothers of 525 children selected by the two-stage sampling method and interviewed using an adapted questionnaire responded. Completion of the immunization schedule was verified by an immunization card or by reported history indicating that the child had received full doses of four of the antigens included in the Nigeria routine immunization schedule. Multivariate logistic regression was used to identify factors associated with completion of immunization. Only 32.4% of children had completed the immunization schedule. Determinants of complete immunization status included a maternal age less than 30 years (AOR=2.26, 95% CI:1.27-4.03), availability of an immunization card at first contact (AOR=7.72, 95% CI:4.43-13.44), fewer than three children (AOR=2.22, 95% CI:11.1-4.42), completion of post secondary education (AOR=2.34, 95% CI:1.12-4.47) and maternal unemployment (AOR=1.71, 95% CI:1.01-2.89). Identifying mothers whose children are at risk of not completing the immunization schedule and educating them is an important strategy to improve antigen coverage and prevent early childhood deaths from diseases like tuberculosis, poliomyelitis, tetanus, diphtheria, pertussis and measles. PMID:22137878

  19. Regulation of maternal transcript destabilization during egg activation in Drosophila.

    PubMed Central

    Tadros, Wael; Houston, Simon A; Bashirullah, Arash; Cooperstock, Ramona L; Semotok, Jennifer L; Reed, Bruce H; Lipshitz, Howard D

    2003-01-01

    In animals, the transfer of developmental control from maternal RNAs and proteins to zygotically derived products occurs at the midblastula transition. This is accompanied by the destabilization of a subset of maternal transcripts. In Drosophila, maternal transcript destabilization occurs in the absence of fertilization and requires specific cis-acting instability elements. We show here that egg activation is necessary and sufficient to trigger transcript destabilization. We have identified 13 maternal-effect lethal loci that, when mutated, result in failure of maternal transcript degradation. All mutants identified are defective in one or more additional processes associated with egg activation. These include vitelline membrane reorganization, cortical microtubule depolymerization, translation of maternal mRNA, completion of meiosis, and chromosome condensation (the S-to-M transition) after meiosis. The least pleiotropic class of transcript destabilization mutants consists of three genes: pan gu, plutonium, and giant nuclei. These three genes regulate the S-to-M transition at the end of meiosis and are thought to be required for the maintenance of cyclin-dependent kinase (CDK) activity during this cell cycle transition. Consistent with a possible functional connection between this S-to-M transition and transcript destabilization, we show that in vitro-activated eggs, which exhibit aberrant postmeiotic chromosome condensation, fail to initiate transcript degradation. Several genetic tests exclude the possibility that reduction of CDK/cyclin complex activity per se is responsible for the failure to trigger transcript destabilization in these mutants. We propose that the trigger for transcript destabilization occurs coincidently with the S-to-M transition at the end of meiosis and that pan gu, plutonium, and giant nuclei regulate maternal transcript destabilization independent of their role in cell cycle regulation. PMID:12871909

  20. Fetal and maternal immune responses to methylmercury exposure: a cross-sectional study.

    PubMed

    Nyland, Jennifer F; Wang, Susie B; Shirley, Devon L; Santos, Elisabeth O; Ventura, Ana Maria; de Souza, Jose M; Silbergeld, Ellen K

    2011-05-01

    Methylmercury (MeHg) is a ubiquitous environmental contaminant with known neurodevelopmental effects. In humans, prenatal exposures primarily occur through maternal consumption of contaminated fish. In this study, we evaluated the association between prenatal exposure to MeHg and titers of total immunoglobulins (Ig) and specific autoantibodies in both mothers and fetuses by analyzing maternal and cord blood serum samples. We examined multiple immunoglobulin isotypes to determine if these biomarkers could inform as to fetal or maternal responses since IgG but not IgM can cross the placenta. Finally, we evaluated serum cytokine levels to further characterize the immune response to mercury exposure. The study was conducted using a subset of serum samples (N=61 pairs) collected from individuals enrolled in a population surveillance of MeHg exposures in the Brazilian Amazon during 2000/2001. Serum titers of antinuclear and antinucleolar autoantibodies were measured by indirect immunofluorescence. Serum immunoglobulins were measured by enzyme-linked immunosorbent assay (ELISA) and BioPlex multiplex assay. Serum cytokines were measured by BioPlex multiplex assay. In this population, the geometric mean mercury level was within the 95th percentile for US populations of women of childbearing age but the upper level of the range was significantly higher. Fetal blood mercury levels were higher (1.35 times) than those in their mothers, but highly correlated (correlation coefficient [r]=0.71; 95% CI: 0.54, 0.89). Total IgG (r=0.40; 95% CI: 0.19, 0.62) and antinuclear autoantibody (odds ratio [OR]=1.05; 95% CI: 1.02, 1.08) levels in paired maternal and fetal samples were also associated; in contrast, other immunoglobulin (IgM, IgE, and IgA) levels were not associated between pairs. Total IgG levels were significantly correlated with both maternal (r=0.60; 95% CI: 0.25, 0.96) and cord blood mercury levels (r=0.61; 95% CI: 0.25, 0.97), but individual isotypes were not. Serum

  1. Effect of maternal exposure to ozone on reproductive outcome and immune, inflammatory, and allergic responses in the offspring

    EPA Science Inventory

    There is growing concern that exposure to air pollutants during pregnancy affects health outcomes in the offspring due to alterations in the development of immune and other homeostatic processes. To assess the risks of maternal inhalation exposure to ozone (O3), timed pregnant BA...

  2. Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and pre-eclampsia.

    PubMed

    Hsu, Peter; Nanan, Ralph Kay Heinrich

    2014-01-01

    Maternal immune tolerance of the fetus is indispensable for a healthy pregnancy outcome. Nowhere is this immune tolerance more important than at the fetal-maternal interface - the decidua, the site of implantation, and placentation. Indeed, many lines of evidence suggest an immunological origin to the common pregnancy-related disorder, pre-eclampsia. Within the innate immune system, decidual NK cells and antigen presenting cells (including dendritic cells and macrophages) make up a large proportion of the decidual leukocyte population, and are thought to modulate vascular remodeling and trophoblast invasion. On the other hand, within the adaptive immune system, Foxp3(+) regulatory T cells are crucial for ensuring immune tolerance toward the semi-allogeneic fetus. Additionally, another population of CD4(+)HLA-G(+) suppressor T cells has also been identified as a potential player in the maintenance of immune tolerance. More recently, studies are beginning to unravel the potential interactions between the innate and the adaptive immune system within the decidua, that are required to maintain a healthy pregnancy. In this review, we discuss the recent advances exploring the complex crosstalk between the innate and the adaptive immune system during human pregnancy. PMID:24734032

  3. Immune response in mice to ingested soya protein: antibody production, oral tolerance and maternal transfer.

    PubMed

    Christensen, Hanne R; Brix, Susanne; Frøkiaer, Hanne

    2004-05-01

    While allergic reactions to soya are increasingly investigated, the normal immune response to ingested soya is scarcely described. In the present study, we wanted to characterise the soya-specific immune response in healthy mice ingesting soya protein. Mice fed a soya-containing diet (F0) and mice of the first (F1) and second (F2) offspring generation bred on a soya protein-free diet were used either directly or were transferred between the soya-containing and soya protein-free diet during pregnancy or neonatal life. The mice were compared as to levels of naturally occurring specific antibodies analysed by ELISA, and to the presence of oral tolerance detected as a suppressed antibody and cell-proliferation response upon immunisation with soya protein. F0 mice generated soya-specific antibodies, while oral tolerance to the same soya proteins was also clearly induced. When F0 dams were transferred to soya protein-free feed before mating, the F1 and F2 offspring generations showed no significantly different response, indicating that soya-specific immune components were not maternally transmitted. However, the ingestion of dietary soya protein by F1 mice during late pregnancy and lactation caused a lasting antibody response in the offspring, but in this case in the absence of oral tolerance. This indicates that, under certain conditions, factors involved in spontaneous antibody production can be transmitted from mother to offspring. Understanding the immune response to soya protein ingested under healthy conditions is important in the assessment of adverse effects of soya protein and in the use of animal allergy models. The present results add to this understanding. PMID:15137924

  4. Protection of Mice against Shiga Toxin 2 (Stx2)-Associated Damage by Maternal Immunization with a Brucella Lumazine Synthase-Stx2 B Subunit Chimera

    PubMed Central

    Mejias, María Pilar; Cabrera, Gabriel; Fernández-Brando, Romina Jimena; Baschkier, Ariela; Ghersi, Giselle; Abrey-Recalde, Maria Jimena; Miliwebsky, Elizabeth; Meiss, Roberto; Goldbaum, Fernando; Zylberman, Vanesa; Rivas, Marta

    2014-01-01

    Hemolytic-uremic syndrome (HUS) is defined as the triad of anemia, thrombocytopenia, and acute kidney injury. Enterohemorrhagic Shiga toxin (Stx)-producing Escherichia coli (EHEC), which causes a prodromal hemorrhagic enteritis, remains the most common etiology of the typical or epidemic form of HUS. Because no licensed vaccine or effective therapy is presently available for human use, we recently developed a novel immunogen based on the B subunit of Shiga toxin 2 (Stx2B) and the enzyme lumazine synthase from Brucella spp. (BLS) (BLS-Stx2B). The aim of this study was to analyze maternal immunization with BLS-Stx2B as a possible approach for transferring anti-Stx2 protection to the offspring. BALB/c female mice were immunized with BLS-Stx2B before mating. Both dams and pups presented comparable titers of anti-Stx2B antibodies in sera and fecal extracts. Moreover, pups were totally protected against a lethal dose of systemic Stx2 injection up to 2 to 3 months postpartum. In addition, pups were resistant to an oral challenge with an Stx2-producing EHEC strain at weaning and did not develop any symptomatology associated with Stx2 toxicity. Fostering experiments demonstrated that anti-Stx2B neutralizing IgG antibodies were transmitted through breast-feeding. Pups that survived the EHEC infection due to maternally transferred immunity prolonged an active and specific immune response that protected them against a subsequent challenge with intravenous Stx2. Our study shows that maternal immunization with BLS-Stx2B was very effective at promoting the transfer of specific antibodies, and suggests that preexposure of adult females to this immunogen could protect their offspring during the early phase of life. PMID:24421050

  5. Rapid assessment of maternal activity among rural Indian mothers (Pune Maternal Nutrition Study)

    PubMed Central

    Kanade, AN; Rao, S; Yajnik, CS; Margetts, BM; Fall, CHD

    2012-01-01

    Objective To develop an activity questionnaire for objective and rapid assessment of maternal habitual physical activity with the aim of describing its relationship with birth size. Design Prospective observational study. Setting Six villages near Pune, Maharashtra, India. Subjects Seven hundred and ninety-seven rural Indian mothers were studied after excluding abortions and termination of pregnancies, foetal anomalies, etc. Method Principal components analysis (PCA) was used to identify a few leading questions from an elaborate questionnaire involving 36 questions related to 14 typical maternal activities. Results On the basis of high loading (>0.8), PCA identified three activities, i.e. farming, fetching water and washing clothes. Questions and sub-questions related to these activities only were considered for defining an activity score for rapid assessment. Validation of this new activity score, with the score based on the elaborate questionnaire, showed 70% sensitivity as well as specificity. New activity scores showed strong inverse relationships similar to those observed using the elaborate questionnaire, at early as well as late gestation, with neonatal head circumference (P = 0.001 and 0.055) and mid-arm circumference (P = 0.02 and 0.03). Conclusions Simple questionnaires, based on leading activities identified by PCA, can be as informative as longer and detailed questionnaires. This method has potential for adaptation, especially in rural communities in developing countries. PMID:16236188

  6. Is Infant Immunity Actively Suppressed or Immature?

    PubMed Central

    Gervassi, Ana L; Horton, Helen

    2014-01-01

    Almost 7 million children under the age 5 die each year, and most of these deaths are attributable to vaccine-preventable infections. Young infants respond poorly to infections and vaccines. In particular, dendritic cells secrete less IL-12 and IL-18, CD8pos T cells and NK cells have defective cytolysis and cytokine production, and CD4pos T cell responses tend to bias towards a Th2 phenotype and promotion of regulatory T cells (Tregs). The basis for these differences is not well understood and may be in part explained by epigenetic differences, as well as immaturity of the infant’s immune system. Here we present a third possibility, which involves active suppression by immune regulatory cells and place in context the immune suppressive pathways of mesenchymal stromal cells (MSC), myeloid-derived suppressor cells (MDSC), CD5pos B cells, and Tregs. The immune pathways that these immune regulatory cells inhibit are similar to those that are defective in the infant. Therefore, the immune deficiencies seen in infants could be explained, in part, by active suppressive cells, indicating potential new avenues for intervention. PMID:25429207

  7. The role of the maternal immune system in the regulation of human birthweight.

    PubMed

    Moffett, Ashley; Hiby, Susan E; Sharkey, Andrew M

    2015-03-01

    Human birthweight is subject to stabilizing selection. Large babies are at risk of obstetric complications such as obstructed labour, which endangers both mother and child. Small babies are also at risk with reduced survival. Fetal growth requires remodelling of maternal spiral arteries to provide an adequate maternal blood supply to the placenta. This arterial transformation is achieved by placental trophoblast cells, which invade into the uterine wall. Under-invasion is associated with fetal growth restriction; but if invasion is excessive large babies can result. A growing body of evidence suggests that this process is controlled by interactions between killer-cell immunoglobulin-like receptors (KIRs) expressed on maternal uterine natural killer cells (uNK) and their corresponding human leukocyte antigen-C (HLA-C) ligands on invading trophoblast. Mothers with the KIR AA genotype and a fetus with a paternal HLA-C2 allele tend to have small babies, because this combination inhibits cytokine secretion by uNK. Mothers with the activating KIR2DS1 gene and an HLA-C2 fetus are more likely to have large babies. When KIR2DS1 binds to HLA-C2 this increases secretion of cytokines that enhance trophoblast invasion. We conclude that specific combinations of the highly polymorphic gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birthweight between two extremes. PMID:25602075

  8. The role of the maternal immune system in the regulation of human birthweight

    PubMed Central

    Moffett, Ashley; Hiby, Susan E.; Sharkey, Andrew M.

    2015-01-01

    Human birthweight is subject to stabilizing selection. Large babies are at risk of obstetric complications such as obstructed labour, which endangers both mother and child. Small babies are also at risk with reduced survival. Fetal growth requires remodelling of maternal spiral arteries to provide an adequate maternal blood supply to the placenta. This arterial transformation is achieved by placental trophoblast cells, which invade into the uterine wall. Under-invasion is associated with fetal growth restriction; but if invasion is excessive large babies can result. A growing body of evidence suggests that this process is controlled by interactions between killer-cell immunoglobulin-like receptors (KIRs) expressed on maternal uterine natural killer cells (uNK) and their corresponding human leukocyte antigen-C (HLA-C) ligands on invading trophoblast. Mothers with the KIR AA genotype and a fetus with a paternal HLA-C2 allele tend to have small babies, because this combination inhibits cytokine secretion by uNK. Mothers with the activating KIR2DS1 gene and an HLA-C2 fetus are more likely to have large babies. When KIR2DS1 binds to HLA-C2 this increases secretion of cytokines that enhance trophoblast invasion. We conclude that specific combinations of the highly polymorphic gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birthweight between two extremes. PMID:25602075

  9. Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants

    PubMed Central

    Chilengi, Roma; Simuyandi, Michelo; Beach, Lauren; Mwila, Katayi; Becker-Dreps, Sylvia; Emperador, Devy M.; Velasquez, Daniel E.; Bosomprah, Samuel; Jiang, Baoming

    2016-01-01

    Introduction Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1). Methods 420 mother-child pairs were recruited at infant age 6–12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. Results Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68–0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). Conclusion Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and

  10. Activation of maternal centrosomes in unfertilized sea urchin eggs

    NASA Technical Reports Server (NTRS)

    Schatten, H.; Walter, M.; Biessmann, H.; Schatten, G.

    1992-01-01

    Centrosomes are undetectable in unfertilized sea urchin eggs, and normally the sperm introduces the cell's microtubule-organizing center (MTOC) at fertilization. However, artificial activation or parthenogenesis triggers microtubule assembly in the unfertilized egg, and this study explores the reappearance and behavior of the maternal centrosome. During activation with A23187 or ammonia, microtubules appear first at the cortex; centrosomal antigen is detected diffusely throughout the entire cytoplasm. Later, the centrosome becomes more distinct and organizes a radial microtubule shell, and eventually a compact centrosome at the egg center organizes a monaster. In these activated eggs, centrosomes undergo cycles of compaction and decompaction in synchrony with the chromatin, which also undergoes cycles of condensation and decondensation. Parthenogenetic activation with heavy water (50% D2O) or the microtubule-stabilizing drug taxol (10 microM) induces numerous centrosomal foci in the unfertilized sea urchin egg. Within 15 min after incubation in D2O, numerous fine centrosomal foci are detected, and they organize a connected network of numerous asters which fill the entire egg. Taxol induces over 100 centrosomal foci by 15 min after treatment, which organize a corresponding number of asters. The centrosomal material in either D2O- or taxol-treated eggs aggregates with time to form fewer but denser foci, resulting in fewer and larger asters. Fertilization of eggs pretreated with either D2O or taxol shows that the paternal centrosome is dominant over the maternal centrosome. The centrosomal material gradually becomes associated with the enlarged sperm aster. These experiments demonstrate that maternal centrosomal material is present in the unfertilized egg, likely as dispersed undetectable material, which can be activated without paternal contributions. At fertilization, paternal centrosomes become dominant over the maternal centrosomal material.

  11. The HLA-G cycle provides for both NK tolerance and immunity at the maternal-fetal interface.

    PubMed

    Tilburgs, Tamara; Evans, J Henry; Crespo, Ângela C; Strominger, Jack L

    2015-10-27

    The interaction of noncytotoxic decidual natural killer cells (dNK) and extravillous trophoblasts (EVT) at the maternal-fetal interface was studied. Confocal microscopy revealed that many dNK interact with a single large EVT. Filamentous projections from EVT enriched in HLA-G were shown to contact dNK, and may represent the initial stage of synapse formation. As isolated, 2.5% of dNK contained surface HLA-G. However, surface HLA-G-negative dNK contained internalized HLA-G. Activation of dNK resulted in the disappearance of internalized HLA-G in parallel with restoration of cytotoxicity. Surface HLA-G was reacquired by incubation with EVT. This HLA-G cycle of trogocytosis, endocytosis, degradation, and finally reacquisition provides a transient and localized acquisition of new functional properties by dNK upon interaction with EVT. Interruption of the cycle by activation of dNK by cytokines and/or viral products serves to ensure the NK control of virus infection at the interface, and is illustrated here by the response of dNK to human cytomegalo virus (HCMV)-infected decidual stromal cells. Thus, the HLA-G cycle in dNK can provide both for NK tolerance and antiviral immunity. PMID:26460007

  12. Bacterial RNAs activate innate immunity in Arabidopsis.

    PubMed

    Lee, Boyoung; Park, Yong-Soon; Lee, Soohyun; Song, Geun Cheol; Ryu, Choong-Min

    2016-01-01

    The common molecular patterns of microbes play a critical role in the regulation of plant innate immunity. However, little is known about the role of nucleic acids in this process in plants. We pre-infiltrated Arabidopsis leaves with total RNAs from Pseudomonas syringae pv. tomato DC3000 (Pto DC3000) and subsequently inoculated these plants with the same bacterial cells. Total Pto DC3000 RNAs pre-infiltrated into Arabidopsis leaves elicited plant immune responses against Pto DC3000. However, sheared RNAs and RNase A application failed to induce immunity, suggesting that intact bacterial RNAs function in plant innate immunity. This notion was supported by the positive regulation of superoxide anion levels, callose deposition, two mitogen-activated protein kinases and defense-related genes observed in bacterial RNA-pre-treated leaves. Intriguingly, the Pto DC3000 population was not compromised in known pattern recognition receptor mutants for chitin, flagellin and elongation factor-Tu (EF-Tu). Plant defense-related mutant analyses further revealed that bacterial RNA-elicited innate immunity was normally required for salicylic and jasmonic acid signaling. Notably, among total RNAs, the abundant bacterial RNA species 16S and 23S ribosomal RNAs were the major determinants of this response. Our findings provide evidence that bacterial RNA serves as a microbe-associated molecular pattern in plants. PMID:26499893

  13. Waning of maternal immunity and the impact of diseases: the example of myxomatosis in natural rabbit populations.

    PubMed

    Fouchet, D; Marchandeau, S; Langlais, M; Pontier, D

    2006-09-01

    Myxomatosis is a leporipoxvirus that infects the european rabbit, inducing a high mortality rate. Observations lead us to hypothesize that a rabbit carrying maternal antibodies (or having recovered) can be infected (or re-infected) upon being exposed (or re-exposed) to the virus. Infection will lead to mild disease, boosting host immune protection. Using a modelling approach we show that this phenomenon may lead to a difference of impact of myxomatosis according to its transmission rate. Young are exposed when they still carry maternal antibodies and develop a mild disease in high transmission populations. Our results show that the impact of myxomatosis is generally higher in epidemic situations compared to populations where the virus circulates all the year. As a consequence, waning of acquired immunity and the continuous supply of newborn along the year may reduce the impact of the disease. PMID:16580697

  14. Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity.

    PubMed

    Vinketova, Kameliya; Mourdjeva, Milena; Oreshkova, Tsvetelina

    2016-01-01

    The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described. PMID:27239344

  15. Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity

    PubMed Central

    Vinketova, Kameliya; Mourdjeva, Milena

    2016-01-01

    The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described. PMID:27239344

  16. Effects of inadequate maternal dietary protein:carbohydrate ratios during pregnancy on offspring immunity in pigs

    PubMed Central

    2012-01-01

    Background Inadequate nutrition in utero may retard foetal growth and alter physiological development of offspring. This study investigated the effects of low and high protein diets fed to primiparous German Landrace sows throughout pregnancy on the immune function of their offspring at different ages. Sows were fed diets with adequate (AP, 12.1%; n = 13), low (LP, 6.5%; n = 15), or high (HP, 30%; n = 14) protein content, made isoenergetic by varying carbohydrate levels. Cortisol, total protein and immunoglobulin (IgG, IgM, IgA) concentrations were measured in the blood of sows over the course of pregnancy. Cortisol, total protein, immunoglobulins, lymphocyte proliferation, immune cell counts, and cytokines were assessed in the blood of offspring at baseline and under challenging conditions (weaning; lipopolysaccharide (LPS) administration). Results In sows, the LP diet increased cortisol (P < 0.05) and decreased protein levels (P < 0.01) at the end of pregnancy. Immunoglobulin concentrations were decreased in LP (IgA) and HP piglets (IgG, IgM and IgA) on the first day of life (P < 0.05), whereas the number of lymphocytes and mitogen-induced lymphocyte proliferation of the piglets were unaffected by the maternal diet. Mortality during the suckling period was higher in LP piglets compared with AP and HP offspring (P < 0.01). Furthermore, LP piglets showed an elevated cortisol response to weaning, and in HP piglets, the CD4+ cell percentage and the CD4+/CD8+ ratio increased after weaning (P < 0.05). The lipopolysaccharide-induced rise of IL-6 was higher in LP (P = 0.09) and HP (P < 0.01) compared with AP piglets, and LP piglets displayed higher IL-10 levels than AP piglets (P < 0.05). Conclusions Our results indicate that both low and high protein:carbohydrate ratios in the diet of pregnant sows can induce short-term as well as long-lasting effects on immune competence in piglets that may have serious consequences for host

  17. Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

    PubMed Central

    Ibi, Daisuke; Yamada, Kiyofumi

    2015-01-01

    Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders. PMID:26633355

  18. Active immunization against renin in normotensive marmoset

    SciTech Connect

    Michel, J.B.; Guettier, C.; Philippe, M.; Galen, F.X.; Corvol, P.; Menard, J.

    1987-06-01

    Primate renins (human and monkey) are very similar. We used pure human renin to immunize marmosets (Callithrix jacchus) and thereby produce a chronic blockade of the renin-angiotensinogen reaction. After a control period of 2 months, five male marmosets, on their usual sodium-poor diet, were immunized against pure human renin by three subcutneous injections of 30 ..mu..g each, with complete and then incomplete Freund's adjuvant. Three marmosets were injected with adjuvant only and served as controls. Blood sampling and blood pressure measurements were performed weekly. After the third injection, the five marmosets immunized against renin developed a high titer of renin antibodies (50% binding of /sup 125/I-labeled human renin at a dilution of greater than or equal to 1:10,000). The antibodies inhibited the enzymatic activity of both marmoset and human renins. At the same time, systolic blood pressure decreased significantly. Plasma renin enzyme activity was undetectable in the animals. Plasma aldosterone decreased significantly. After 1-4 months with low blood pressure, a normal urinary output, and a normal plasma creatinine, the five marmosets became sick and died within one month. At autopsy an immunological renal disease, characterize by the presence of immunoglobulin and macrophage infiltration colocalized with renin, was found. No immunoglobulin was detectable in extrarenal vessels or in other organs. These experiments demonstrate that, in this primate, a chronic blockade of the renin-angiotensin system can be achieved by active immunization against homologous renin, but this blockade is associated with the development of an autoimmune disease localized in the kidney.

  19. Systemic Immune Activation Profiles of HIV-1 Subtype C-Infected Children and Their Mothers

    PubMed Central

    Makhubele, Tinyiko G.; Steel, Helen C.; Anderson, Ronald; van Dyk, Gisela; Theron, Annette J.; Rossouw, Theresa M.

    2016-01-01

    Little is known about immune activation profiles of children infected with HIV-1 subtype C. The current study compared levels of selected circulating biomarkers of immune activation in HIV-1 subtype C-infected untreated mothers and their children with those of healthy controls. Multiplex bead array, ELISA, and immunonephelometric procedures were used to measure soluble CD14 (sCD14), beta-2 microglobulin (β2M), CRP, MIG, IP-10, and transforming growth factor beta 1 (TGF-β1). Levels of all 6 biomarkers were significantly elevated in the HIV-infected mothers and, with the exception of MIG, in their children (P < 0.01–P < 0.0001). The effects of antiretroviral therapy (ART) and maternal smoking on these biomarkers were also assessed. With the exception of TGF-β1, which was unchanged in the children 12 months after therapy, initiation of ART was accompanied by decreases in the other biomarkers. Regression analysis revealed that although most biomarkers were apparently unaffected by smoking, exposure of children to maternal smoking was associated with a significant increase in IP-10. These findings demonstrate that biomarkers of immune activation are elevated in HIV-infected children pre-ART and decline, with the exception of TGF-β1, after therapy. Although preliminary, elevation of IP-10 in smoke-exposed infants is consistent with a higher level of immune activation in this group. PMID:27019552

  20. Estimation of immunization providers' activities cost, medication cost, and immunization dose errors cost in Iraq.

    PubMed

    Al-lela, Omer Qutaiba B; Bahari, Mohd Baidi; Al-abbassi, Mustafa G; Salih, Muhannad R M; Basher, Amena Y

    2012-06-01

    The immunization status of children is improved by interventions that increase community demand for compulsory and non-compulsory vaccines, one of the most important interventions related to immunization providers. The aim of this study is to evaluate the activities of immunization providers in terms of activities time and cost, to calculate the immunization doses cost, and to determine the immunization dose errors cost. Time-motion and cost analysis study design was used. Five public health clinics in Mosul-Iraq participated in the study. Fifty (50) vaccine doses were required to estimate activities time and cost. Micro-costing method was used; time and cost data were collected for each immunization-related activity performed by the clinic staff. A stopwatch was used to measure the duration of activity interactions between the parents and clinic staff. The immunization service cost was calculated by multiplying the average salary/min by activity time per minute. 528 immunization cards of Iraqi children were scanned to determine the number and the cost of immunization doses errors (extraimmunization doses and invalid doses). The average time for child registration was 6.7 min per each immunization dose, and the physician spent more than 10 min per dose. Nurses needed more than 5 min to complete child vaccination. The total cost of immunization activities was 1.67 US$ per each immunization dose. Measles vaccine (fifth dose) has a lower price (0.42 US$) than all other immunization doses. The cost of a total of 288 invalid doses was 744.55 US$ and the cost of a total of 195 extra immunization doses was 503.85 US$. The time spent on physicians' activities was longer than that spent on registrars' and nurses' activities. Physician total cost was higher than registrar cost and nurse cost. The total immunization cost will increase by about 13.3% owing to dose errors. PMID:22521848

  1. Maternal immunization with vaccines containing recombinant NetB toxin partially protects progeny chickens from necrotic enteritis

    PubMed Central

    2013-01-01

    Avian necrotic enteritis is a major economic and welfare issue throughout the global poultry industry and is caused by isolates of Clostridium perfringens that produce NetB toxin. Previously we have shown that birds directly vaccinated with inactivated C. perfringens type A culture supernatant (toxoid) combined with recombinant NetB (rNetB) protein were significantly protected from homologous and heterologous challenge. In the present study the protective effect of maternal immunization was examined. Broiler breeder hens were injected subcutaneously with genetically toxoided rNetB(S254L) alone, C. perfringens type A toxoid and toxoid combined with rNetB(S254L). Vaccination resulted in a strong serum immunoglobulin Y response to NetB in hens immunized with rNetB(S254L) formulations. Anti-NetB antibodies were transferred to the eggs and on into the hatched progeny. Subclinical necrotic enteritis was induced experimentally in the progeny and the occurrence of specific necrotic enteritis lesions evaluated. Birds derived from hens immunized with rNetB(S254L) combined with toxoid and challenged with a homologous strain (EHE-NE18) at either 14 or 21 days post-hatch had significantly lower levels of disease compared to birds from adjuvant only vaccinated hens. In addition, birds from hens immunized with rNetB(S254L) alone were significantly protected when challenged at 14 days post-hatch. These results demonstrate that maternal immunization with a NetB-enhanced toxoid vaccine is a promising method for the control of necrotic enteritis in young broiler chickens. PMID:24219318

  2. Maternal age effects on myometrial expression of contractile proteins, uterine gene expression, and contractile activity during labor in the rat

    PubMed Central

    Elmes, Matthew; Szyszka, Alexandra; Pauliat, Caroline; Clifford, Bethan; Daniel, Zoe; Cheng, Zhangrui; Wathes, Claire; McMullen, Sarah

    2015-01-01

    Advanced maternal age of first time pregnant mothers is associated with prolonged and dysfunctional labor and significant risk of emergency cesarean section. We investigated the influence of maternal age on myometrial contractility, expression of contractile associated proteins (CAPs), and global gene expression in the parturient uterus. Female Wistar rats either 8 (YOUNG n = 10) or 24 (OLDER n = 10) weeks old were fed laboratory chow, mated, and killed during parturition. Myometrial strips were dissected to determine contractile activity, cholesterol (CHOL) and triglycerides (TAG) content, protein expression of connexin-43 (GJA1), prostaglandin-endoperoxide synthase 2 (PTGS2), and caveolin 1 (CAV-1). Maternal plasma concentrations of prostaglandins PGE2, PGF2α, and progesterone were determined by RIA. Global gene expression in uterine samples was compared using Affymetrix Genechip Gene 2.0 ST arrays and Ingenuity Pathway analysis (IPA). Spontaneous contractility in myometrium exhibited by YOUNG rats was threefold greater than OLDER animals (P < 0.027) but maternal age had no significant effect on myometrial CAP expression, lipid profiles, or pregnancy-related hormones. OLDER myometrium increased contractile activity in response to PGF2α, phenylephrine, and carbachol, a response absent in YOUNG rats (all P < 0.002). Microarray analysis identified that maternal age affected expression of genes related to immune and inflammatory responses, lipid transport and metabolism, steroid metabolism, tissue remodeling, and smooth muscle contraction. In conclusion YOUNG laboring rat myometrium seems primed to contract maximally, whereas activity is blunted in OLDER animals and requires stimulation to meet contractile potential. Further work investigating maternal age effects on myometrial function is required with focus on lipid metabolism and inflammatory pathways. PMID:25876907

  3. Protein palmitoylation activate zygotic gene expression during the maternal-to-zygotic transition.

    PubMed

    Du, Zhaoxia; Chen, Xueran; Li, Xian; He, Kun; Ji, Shufang; Shi, Wei; Hao, Aijun

    2016-06-24

    Upon fertilization, maternal factors direct development and trigger zygotic genome activation at the maternal-to-zygotic transition (MZT). However, the factors that activate the zygotic program in vertebrates are not well defined. Here, we found that protein palmitoylation played an important role in acquiring transcriptional competency and orchestrating the clearance of the maternal program in zebrafish. After inhibition of protein palmitoylation, zebrafish embryos developed normally before the Mid-Blastula Transition (MBT); however, they did not initiate epiboly. Moreover, our results showed that protein palmitoylation is required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression. PMID:27235108

  4. Predicting future trends in the burden of pertussis in the 21st century: implications for infant pertussis and the success of maternal immunization.

    PubMed

    van den Biggelaar, Anita H J; Poolman, Jan T

    2016-01-01

    Support is growing for maternal immunization using acellular pertussis (aP) vaccines to prevent severe pertussis disease and deaths among very young, unvaccinated infants. Vaccine effectiveness of maternal immunization is 91% in preventing laboratory-confirmed pertussis in infants aged <3 months. To date, most mothers were primed in childhood with whole-cell pertussis vaccines. Soon, the generation of aP-primed individuals will become the new mothers-to-be. The shorter duration of protection afforded by aP vaccines, which is more pronounced with repeated aP boosters, may lead to increased pertussis circulation among aP-primed parents. Maternal Tdap immunization in aP-primed mothers-to-be may become less effective. Additional measures to protect young infants may eventually be needed, along with new vaccines that induce higher quality and more durable responses. PMID:26559122

  5. Maternal work and children's diet, activity, and obesity.

    PubMed

    Datar, Ashlesha; Nicosia, Nancy; Shier, Victoria

    2014-04-01

    Mothers' work hours are likely to affect their time allocation towards activities related to children's diet, activity and well-being. For example, mothers who work more may be more reliant on processed foods, foods prepared away from home and school meal programs for their children's meals. A greater number of work hours may also lead to more unsupervised time for children that may, in turn, allow for an increase in unhealthy behaviors among their children such as snacking and sedentary activities such as TV watching. Using data on a national cohort of children, we examine the relationship between mothers' average weekly work hours during their children's school years on children's dietary and activity behaviors, BMI and obesity in 5th and 8th grade. Our results are consistent with findings from the literature that maternal work hours are positively associated with children's BMI and obesity especially among children with higher socioeconomic status. Unlike previous papers, our detailed data on children's behaviors allow us to speak directly to affected behaviors that may contribute to the increased BMI. We show that children whose mothers work more consume more unhealthy foods (e.g. soda, fast food) and less healthy foods (e.g. fruits, vegetables, milk) and watch more television. Although they report being slightly more physically active, likely due to organized physical activities, the BMI and obesity results suggest that the deterioration in diet and increase in sedentary behaviors dominate. PMID:24491828

  6. Maternal Work and Children’s Diet, Activity, and Obesity

    PubMed Central

    Datar, Ashlesha; Nicosia, Nancy; Shier, Victoria

    2014-01-01

    Mothers’ work hours are likely to affect their time allocation towards activities related to children’s diet, activity and well-being. For example, mothers who work more may be more reliant on processed foods, foods prepared away from home and school meal programs for their children’s meals. A greater number of work hours may also lead to more unsupervised time for children that may, in turn, allow for an increase in unhealthy behaviors among their children such as snacking and sedentary activities such as TV watching. Using data on a national cohort of children, we examine the relationship between mothers’ average weekly work hours during their children’s school years on children’s dietary and activity behaviors, BMI and obesity in 5th and 8th grade. Our results are consistent with findings from the literature that maternal work hours are positively associated with children’s BMI and obesity especially among children with higher socioeconomic status. Unlike previous papers, our detailed data on children’s behaviors allow us to speak directly to affected behaviors that may contribute to the increased BMI. We show that children whose mothers work more consume more unhealthy foods (e.g. soda, fast food) and less healthy foods (e.g. fruits, vegetables, milk) and watch more television. Although they report being slightly more physically active, likely due to organized physical activities, the BMI and obesity results suggest that the deterioration in diet and increase in sedentary behaviors dominate. PMID:24491828

  7. Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice

    PubMed Central

    Kieckbusch, Jens; Balmas, Elisa; Hawkes, Delia A.; Colucci, Francesco

    2015-01-01

    Summary Maternal immune cells are an integral part of reproduction, but how they might cause pregnancy complications remains elusive. Macrophages and their dual function in inflammation and tissue repair are thought to play key yet undefined roles. Altered perinatal growth underpins adult morbidity, and natural killer (NK) cells may sustain fetal growth by establishing the placental blood supply. Using a mouse model of genetic inactivation of PI3K p110δ, a key intracellular signaling molecule in leukocytes, we show that p110δ regulates macrophage dynamics and NK-cell-mediated arterial remodeling. The uterus of dams with inactive p110δ had decreased IFN-γ and MHC class IIlow macrophages but enhanced IL-6. Poor vascular remodeling and a pro-inflammatory uterine milieu resulted in fetal death or growth retardation. Our results provide one mechanism that explains how imbalanced adaptations of maternal innate immune cells to gestation affect offspring well-being with consequence perinatally and possibly into adulthood. PMID:26711346

  8. Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice.

    PubMed

    Kieckbusch, Jens; Balmas, Elisa; Hawkes, Delia A; Colucci, Francesco

    2015-12-29

    Maternal immune cells are an integral part of reproduction, but how they might cause pregnancy complications remains elusive. Macrophages and their dual function in inflammation and tissue repair are thought to play key yet undefined roles. Altered perinatal growth underpins adult morbidity, and natural killer (NK) cells may sustain fetal growth by establishing the placental blood supply. Using a mouse model of genetic inactivation of PI3K p110δ, a key intracellular signaling molecule in leukocytes, we show that p110δ regulates macrophage dynamics and NK-cell-mediated arterial remodeling. The uterus of dams with inactive p110δ had decreased IFN-γ and MHC class II(low) macrophages but enhanced IL-6. Poor vascular remodeling and a pro-inflammatory uterine milieu resulted in fetal death or growth retardation. Our results provide one mechanism that explains how imbalanced adaptations of maternal innate immune cells to gestation affect offspring well-being with consequence perinatally and possibly into adulthood. PMID:26711346

  9. Knowledge, attitudes, beliefs, and behaviors of pregnant women approached to participate in a Tdap maternal immunization randomized, controlled trial

    PubMed Central

    MacDougall, Donna M.; Halperin, Beth A.; Langley, Joanne M.; McNeil, Shelly A.; MacKinnon-Cameron, Donna; Li, Li; Halperin, Scott A.

    2016-01-01

    ABSTRACT Immunization with pertussis vaccine during pregnancy is recommended in a number of countries to prevent newborn deaths from whooping cough. In some jurisdictions, vaccine uptake during pregnancy is low. We undertook a survey of the knowledge, attitudes, beliefs, and behaviors of pregnant women who had been approached to participate in a randomized, controlled trial of tetanus-diphtheria-acellular pertussis (Tdap) vaccine during pregnancy. A total of 346 women completed the survey. Knowledge about pertussis and pertussis vaccine was generally low; the mean number of correct answers was 10.65 out of 19 questions. Attitudes toward maternal immunization were generally favorable; 51.7%–94.7% of women had positive responses to 10 attitudinal statements. Substantial uncertainty was shown in responses to a number of the attitudinal statements related to vaccination during pregnancy; 22.3%–45.7% neither agreed nor disagreed with the statements. Importantly, 89% of women reported that they would get immunized with pertussis vaccine during pregnancy if their physician recommended it. We conclude that a national recommendation to be immunized with pertussis vaccine during pregnancy supported by their physicians' recommendation would be well received by Canadian women. PMID:27176822

  10. Knowledge, attitudes, beliefs, and behaviors of pregnant women approached to participate in a Tdap maternal immunization randomized, controlled trial.

    PubMed

    MacDougall, Donna M; Halperin, Beth A; Langley, Joanne M; McNeil, Shelly A; MacKinnon-Cameron, Donna; Li, Li; Halperin, Scott A

    2016-04-01

    Immunization with pertussis vaccine during pregnancy is recommended in a number of countries to prevent newborn deaths from whooping cough. In some jurisdictions, vaccine uptake during pregnancy is low. We undertook a survey of the knowledge, attitudes, beliefs, and behaviors of pregnant women who had been approached to participate in a randomized, controlled trial of tetanus-diphtheria-acellular pertussis (Tdap) vaccine during pregnancy. A total of 346 women completed the survey. Knowledge about pertussis and pertussis vaccine was generally low; the mean number of correct answers was 10.65 out of 19 questions. Attitudes toward maternal immunization were generally favorable; 51.7%-94.7% of women had positive responses to 10 attitudinal statements. Substantial uncertainty was shown in responses to a number of the attitudinal statements related to vaccination during pregnancy; 22.3%-45.7% neither agreed nor disagreed with the statements. Importantly, 89% of women reported that they would get immunized with pertussis vaccine during pregnancy if their physician recommended it. We conclude that a national recommendation to be immunized with pertussis vaccine during pregnancy supported by their physicians' recommendation would be well received by Canadian women. PMID:27176822

  11. Randomized controlled trial to improve childhood immunization adherence in rural Pakistan: redesigned immunization card and maternal education

    PubMed Central

    Usman, Hussain R.; Rahbar, Mohammad H.; Kristensen, Sibylle; Vermund, Sten H.; Kirby, Russell S.; Habib, Faiza; Chamot, Eric

    2013-01-01

    SUMMARY OBJECTIVE A substantial dropout from the first dose of diphtheria-tetanus-pertussis (DTP1) to the 3rd dose of DTP (DTP3) immunization has been recorded in Pakistan. We conducted a randomized controlled trial to assess the effects of providing substantially redesigned immunization card, center-based education, or both interventions together on DTP3 completion at six rural Expanded Programme on Immunization (EPI) centers in Pakistan. METHODS Mother-child units were enrolled at DTP1 and randomized to four study groups: redesigned card, center-based education, combined intervention, and standard care. Each child was followed-up for 90 days to record the dates of DTP2 and DTP3 visits. The study outcome was DTP3 completion by the end of follow-up period in each study group. RESULTS We enrolled 378 mother-child units in redesigned card group, 376 in center-based education group, 374 in combined intervention group, and 378 in standard care group. By the end of follow-up, 39% of children in standard care group completed DTP3. Compared to this, a significantly higher proportion of children completed DTP3 in redesigned card group (66%) (crude Risk Ratio [RR] = 1.7; 95% CI = 1.5, 2.0), center-based education group (61%) (RR = 1.5; 95% CI = 1.3, 1.8), and combined intervention group (67%) (RR = 1.7; 95% CI = 1.4, 2.0). CONCLUSIONS Improved immunization card alone, education to mothers alone, or both together were all effective in increasing follow-up immunization visits. The study underscores the potential of study interventions’ public health impact and necessitates their evaluation for complete EPI schedule at a large scale in the EPI system. PMID:21159080

  12. Cross-fostering to prevent maternal cell transfer did not prevent vaccine-associated enhanced respiratory disease that occurred following heterologous influenza challenge of pigs vaccinated in presence of maternal immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Whole-inactivated virus (WIV) vaccines for influenza A virus (IAV) provide limited cross-protection to diverse antigenic strains that are circulating or may emerge in a population. Maternal vaccination is used to protect neonatal animals from disease through passive transfer of immunity. It is desir...

  13. Maternal exposure to fish oil primes offspring to harbor intestinal pathobionts associated with altered immune cell balance.

    PubMed

    Gibson, D L; Gill, S K; Brown, K; Tasnim, N; Ghosh, S; Innis, S; Jacobson, K

    2015-01-01

    Our previous studies revealed that offspring from rat dams fed fish oil (at 8% and 18% energy), developed impaired intestinal barriers sensitizing the colon to exacerbated injury later in life. To discern the mechanism, we hypothesized that in utero exposure to fish oil, rich in n-3 polyunsaturated fatty acid (PUFA), caused abnormal intestinal reparative responses to mucosal injury through differences in intestinal microbiota and the presence of naïve immune cells. To identify such mechanisms, gut microbes and naïve immune cells were compared between rat pups born to dams fed either n-6 PUFA, n-3 PUFA or breeder chow. Maternal exposure to either of the PUFA rich diets altered the development of the intestinal microbiota with an overall reduction in microbial density. Using qPCR, we found that each type of PUFA differentially altered the major gut phyla; fish oil increased Bacteroidetes and safflower oil increased Firmicutes. Both PUFA diets reduced microbes known to dominate the infant gut like Enterobacteriaceae and Bifidobacteria spp. when compared to the chow group. Uniquely, maternal fish oil diets resulted in offspring showing blooms of opportunistic pathogens like Bilophila wadsworthia, Enterococcus faecium and Bacteroides fragilis in their gut microbiota. As well, fish oil groups showed a reduction in colonic CD8+ T cells, CD4+ Foxp3+ T cells and arginase+ M2 macrophages. In conclusion, fish oil supplementation in pharmacological excess, at 18% by energy as shown in this study, provides an example where excess dosing in utero can prime offspring to harbor intestinal pathobionts and alter immune cell homeostasis. PMID:25559197

  14. The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette–Guérin immunization

    PubMed Central

    Mawa, Patrice A.; Nkurunungi, Gyaviira; Egesa, Moses; Webb, Emily L.; Smith, Steven G.; Kizindo, Robert; Akello, Mirriam; Lule, Swaib A.; Muwanga, Moses; Dockrell, Hazel M.; Cose, Stephen; Elliott, Alison M.

    2015-01-01

    Bacille Calmette–Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml−1 [3300–11 050] in cord blood) and six weeks (0.00 ng ml−1 [0–288]). Frequencies of PPD-specific IFN-γ-expressing CD4+T cells increased at one week and declined between one and six weeks (p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4+T cells increased between one and six weeks (p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4+T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses (p = 0.002) and after adjusting for confounders (mean difference, 95% CI −0.041% (−0.082, −0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCG immunization. These findings are being explored further in a larger study. PMID:25964450

  15. Immune Activation and HIV Persistence: Considerations for Novel Therapeutic Interventions

    PubMed Central

    Hatano, Hiroyu

    2014-01-01

    Purpose of review One of the potential barriers to current HIV cure strategies is the persistence of elevated levels of immune activation despite otherwise effective antiretroviral therapy (ART). The purpose of this review is to examine the relationship between immune activation and HIV persistence, and to review novel therapeutic interventions that are currently being pursued to target immune activation in treated HIV disease. Recent findings Multiple groups have consistently observed that elevated levels of inflammation, immune activation, and immune dysfunction persist in ART-treated individuals, despite successful suppression of plasma viremia. Increased immune activation may lead to viral persistence through multiple mechanisms. Several novel interventions aimed at decreasing persistent immune activation are being pursued and include studies aimed at decreasing low-level viral replication, approaches aimed at decreasing microbial translocation, interventions to treat co-infections, and therapies that directly target immune activation. Summary There appears to be a clear and consistent relationship between immune activation and viral persistence in treated HIV disease. Whether this relationship is causal or mediated through other mechanisms is still unknown. Small-scale, pathogenesis-oriented interventional studies are necessary to further evaluate this relationship and the effect of potential interventions. PMID:23454864

  16. Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies.

    PubMed

    Giovanoli, Sandra; Weber-Stadlbauer, Ulrike; Schedlowski, Manfred; Meyer, Urs; Engler, Harald

    2016-07-01

    Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1β levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. PMID:26408796

  17. [Modifications of the maternal immune response associated to pregnancy (author's transl)].

    PubMed

    Soubiran, P

    1979-01-01

    The author reviews the literature on the immune status of pregnant women. No major alteration of the immune response was observed. If any, the modifications are not important and involve the synthesis of immunoglobulins, the presence of circulating immune complexes, some sub-populations of mononuclear cells and the in vitro lymphocyte response to T dependent antigens. Phagocytosis, the number of B and T cells and mitogen lymphocyte response are normal. Studies on the immuno-suppressive effect of both pregnant women sera and serum substances (hormones, pregnancy associated or specific proteins, carcino-embryonic antigens) are reported. Discrepancies are observed between conclusions drawn by various authors: they relate to the efficiency of the measurement and to the observed effect. The contradictory results obtained with alpha-foetoprotein provide an illustration of the critical analysis of these studies. Finally, the in vivo immune status of pregnant women is reported as observed in cutaneous tests, transplantations and auto-immune diseases. The most relevant observations are: a defect of the expression of delayed hypersensitivity reaction, a facilitating effect of pregnancy in kidney transplantation similar to that obtained after transfusion and an inconstant and mild defect of graft immunity. Therefore, pregnancy produces a specific immune status about which tests presently available give few relevant results, similar to those obtained in some cancers. PMID:88974

  18. Exposure to Maternal Distress in Childhood and Cortisol Activity in Young Adulthood

    ERIC Educational Resources Information Center

    Mahrer, Nicole E.; Luecken, Linda J.; Wolchik, Sharlene A.; Tein, Jenn-Yun; Sandler, Irwin N.

    2014-01-01

    Dysregulated cortisol is a risk factor for poor health outcomes. Children of distressed mothers exhibit dysregulated cortisol, yet it is unclear whether maternal distress predicts cortisol activity in later developmental stages. This longitudinal study examined the prospective relation between maternal distress during late childhood (9-12 years)…

  19. The Effect of Maternal Teaching Talk on Children's Emergent Literacy as a Function of Type of Activity and Maternal Education Level

    ERIC Educational Resources Information Center

    Korat, Ofra

    2009-01-01

    This study examined the extent to which maternal education affects mothers' teaching talk level as a function of activity (book reading vs. looking at a family photo album), and the contribution of maternal teaching talk level during these activities to 88 five- to six-year old children's emergent literacy. Videotaped mother-child interactions…

  20. Maternal and paternal alcohol use: Effects on the immune system of the offspring

    SciTech Connect

    Gottesfeld, Z.; Abel, E.L. Wayne State Univ., Detroit, MI )

    1991-01-01

    There is no single mechanism which can account for such a complex biological phenomenon as immune regulation, nor is it clear how alcohol teratogenicity exerts its multiple adversive effects, including lasting immune deficits. Much of the research aimed at unravelling effects of pre- or early postnatal alcohol exposure on the organism's defense mechanisms and long-term health risks has been phenomenological. A better understanding of mechanisms which underlie alcohol effects on immune competency will require integrated studies of the neuro-immuno-endocrine networks.

  1. Light and immune systems: activation of immunological activities

    NASA Astrophysics Data System (ADS)

    Huang, Zheng; Liu, Hong; Chen, Wei R.

    2006-02-01

    Light has been used to treat diseases for hundreds of years. Convenient and powerful light sources such as lasers make photomedicine a major branch in diseases treatment and detection. Originally, light was often used for local treatment, using photomechanical, photochemical, photothermal reactions and photomodulation as the major mechanisms. More and more investigators have become interested in the systemic effects of light, particularly in its effects on immune systems. Much work has been done to activate and/or enhance the host immune system to combat cancer, either using light as a direct tool or as an adjuvant method. Light has long been used for assisting disease detection and diagnosis. Advances in light technology have made photo-diagnostics ever more precise spatially and temporally. Many techniques facilitate observation of bio-molecule interactions and other biological processes at the cellular level, hence providing opportunities to detect and monitor immune activities. This manuscript will review recent photo-immunological research in treatment of cancer. The recent development of combination therapies involving lasers will be presented. Specifically, the results of cancer treatment using laser photothermal interaction, either with or without additional immunological stimulation will be discussed. The immunological effects of photodynamic therapy (PDT), and of its combination with immunotherapy in cancer treatment will also be discussed. Much interest has been recently concentrated in the immunological responses after laser treatment. Such responses at cellular and molecular levels will be discussed. The effect of these treatment modalities on the distant metastases also showed promise of light induced antitumor immunity. The combination therapy and induced immunological responses appear to be the key for long-term control of tumors.

  2. Viral competition and maternal immunity influence the clinical disease caused by very virulent infectious bursal disease virus.

    PubMed

    Jackwood, Daral J

    2011-09-01

    The very virulent form of infectious bursal disease virus (vvIBDV) causes an immunosuppressive disease that is further characterized by the rapid onset of morbidity and high mortality in susceptible chickens. In 2009, vvIBDV was first reported in California, U. S. A., and since that time only a few cases of acute infectious bursal disease attributed to vvIBDV have been recognized in California. In other countries where vvIBDV has become established, it rapidly spreads to most poultry-producing regions. Two factors that may be involved in limiting the spread or reducing the severity of the clinical disease caused by vvIBDV in the U. S. A. are maternal immunity and competition with endemic variant strains of the virus. In this study, the ability of vvIBDV to infect and cause disease in maternally immune layer chickens was examined at weekly intervals over a 5-wk period during which their neutralizing maternal antibodies waned. Birds inoculated with vvIBDV at 2, 3, and 4 wk of age seemed healthy throughout the duration of the experiment, but macroscopic and microscopic lesions were observed in their bursa tissues. A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay also confirmed the presence of vvIBDV RNA in their bursa tissues, indicating this virus was infecting the birds even at 2 wk of age when neutralizing maternal antibodies to infectious bursal disease virus were still relatively high (> 2000 geometric mean antibody titer). No mortality was observed in any birds when inoculated at 2, 3, or 4 wk of age; however, inoculation at 5 and 6 wk of age resulted in 10% and 20% mortality, respectively. Three experiments on the competition between vvIBDV and the two variant viruses T1 and FF6 were conducted. In all three experiments, specific-pathogen-free (SPF) birds that were inoculated with only the vvIBDV became acutely moribund, and except for Experiment 1 (62% mortality) all succumbed to the infection within 4 days of being exposed. When the

  3. Maternal and fetal immune response patterns in heifers experimentally infected with Neospora caninum in the second trimester of pregnancy- A descriptive study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fetal and maternal immune responses 3, 6 and 9 weeks post infection (wpi) were investigated in cows experimentally infected with Neospora caninum on day 110 of gestation. Descriptive analysis showed that the fetuses had lower percentages of spleen T cell subpopulations (CD3+, CD4+ and CD8+) at 6 wpi...

  4. Maternal and foetal immune responses of cattle following an experimental challenge with Neospora caninum at day 70 of gestation

    PubMed Central

    2012-01-01

    The immune responses of pregnant cattle and their foetuses were examined following inoculation on day 70 of gestation either intravenously (iv) (group 1) or subcutaneously (sc) (group 2) with live NC1 strain tachyzoites or with Vero cells (control) (group 3). Peripheral blood mononuclear cell (PBMC) responses to Neospora antigen and foetal viability were assessed throughout the experiment. Two animals from each group were sacrificed at 14, 28, 42 and 56 days post inoculation (pi). At post mortem, maternal lymph nodes, spleen and PBMC and when possible foetal spleen, thymus and PBMC samples were collected for analysis. Inoculation with NC1 (iv and sc) lead to foetal deaths in all group 1 dams (6/6) and in 3/6 group 2 dams from day 28pi; statistically significant (p ≤ 0.05) increases in cell-mediated immune (CMI) responses including antigen-specific cell proliferation and IFN-γ production as well as increased levels of IL-4, IL-10 and IL-12 were observed in challenged dams compared to the group 3 animals. Lymph node samples from the group 2 animals carrying live foetuses showed greater levels of cellular proliferation as well as significantly (p ≤ 0.05) higher levels of IFN-γ compared to the dams in group 2 carrying dead foetuses. Foetal spleen, thymus and PBMC samples demonstrated cellular proliferation as well as IFN-γ, IL-4, IL-10 and IL-12 production following mitogenic stimulation with Con A from day 14pi (day 84 gestation) onwards. This study shows that the generation of robust peripheral and local maternal CMI responses (lymphoproliferation, IFN-γ) may inhibit the vertical transmission of the parasite. PMID:22536795

  5. Do Maternal Knowledge and Attitudes towards Childhood Immunizations in Rural Uganda Correlate with Complete Childhood Vaccination?

    PubMed Central

    Vonasek, Bryan J.; Bajunirwe, Francis; Jacobson, Laura E.; Twesigye, Leonidas; Dahm, James; Grant, Monica J.; Sethi, Ajay K.; Conway, James H.

    2016-01-01

    Improving childhood vaccination coverage and timeliness is a key health policy objective in many developing countries such as Uganda. Of the many factors known to influence uptake of childhood immunizations in under resourced settings, parents’ understanding and perception of childhood immunizations has largely been overlooked. The aims of this study were to survey mothers’ knowledge and attitudes towards childhood immunizations and then determine if these variables correlate with the timely vaccination coverage of their children. From September to December 2013, we conducted a cross-sectional survey of 1,000 parous women in rural Sheema district in southwest Uganda. The survey collected socio-demographic data and knowledge and attitudes towards childhood immunizations. For the women with at least one child between the age of one month and five years who also had a vaccination card available for the child (N = 302), the vaccination status of this child was assessed. 88% of these children received age-appropriate, on-time immunizations. 93.5% of the women were able to state that childhood immunizations protect children from diseases. The women not able to point this out were significantly more likely to have an under-vaccinated child (PR 1.354: 95% CI 1.018–1.802). When asked why vaccination rates may be low in their community, the two most common responses were “fearful of side effects” and “ignorance/disinterest/laziness” (44% each). The factors influencing caregivers’ demand for childhood immunizations vary widely between, and also within, developing countries. Research that elucidates local knowledge and attitudes, like this study, allows for decisions and policy pertaining to vaccination programs to be more effective at improving child vaccination rates. PMID:26918890

  6. Do Maternal Knowledge and Attitudes towards Childhood Immunizations in Rural Uganda Correlate with Complete Childhood Vaccination?

    PubMed

    Vonasek, Bryan J; Bajunirwe, Francis; Jacobson, Laura E; Twesigye, Leonidas; Dahm, James; Grant, Monica J; Sethi, Ajay K; Conway, James H

    2016-01-01

    Improving childhood vaccination coverage and timeliness is a key health policy objective in many developing countries such as Uganda. Of the many factors known to influence uptake of childhood immunizations in under resourced settings, parents' understanding and perception of childhood immunizations has largely been overlooked. The aims of this study were to survey mothers' knowledge and attitudes towards childhood immunizations and then determine if these variables correlate with the timely vaccination coverage of their children. From September to December 2013, we conducted a cross-sectional survey of 1,000 parous women in rural Sheema district in southwest Uganda. The survey collected socio-demographic data and knowledge and attitudes towards childhood immunizations. For the women with at least one child between the age of one month and five years who also had a vaccination card available for the child (N = 302), the vaccination status of this child was assessed. 88% of these children received age-appropriate, on-time immunizations. 93.5% of the women were able to state that childhood immunizations protect children from diseases. The women not able to point this out were significantly more likely to have an under-vaccinated child (PR 1.354: 95% CI 1.018-1.802). When asked why vaccination rates may be low in their community, the two most common responses were "fearful of side effects" and "ignorance/disinterest/laziness" (44% each). The factors influencing caregivers' demand for childhood immunizations vary widely between, and also within, developing countries. Research that elucidates local knowledge and attitudes, like this study, allows for decisions and policy pertaining to vaccination programs to be more effective at improving child vaccination rates. PMID:26918890

  7. Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission.

    PubMed

    Giugliano, Silvia; Petroff, Margaret G; Warren, Bryce D; Jasti, Susmita; Linscheid, Caitlin; Ward, Ashley; Kramer, Anita; Dobrinskikh, Evgenia; Sheiko, Melissa A; Gale, Michael; Golden-Mason, Lucy; Winn, Virginia D; Rosen, Hugo R

    2015-10-15

    Hepatitis C virus (HCV) is the world's most common blood-borne viral infection for which there is no vaccine. The rates of vertical transmission range between 3 and 6% with odds 90% higher in the presence of HIV coinfection. Prevention of vertical transmission is not possible because of lack of an approved therapy for use in pregnancy or an effective vaccine. Recently, HCV has been identified as an independent risk factor for preterm delivery, perinatal mortality, and other complications. In this study, we characterized the immune responses that contribute to the control of viral infection at the maternal-fetal interface (MFI) in the early gestational stages. In this study, we show that primary human trophoblast cells and an extravillous trophoblast cell line (HTR8), from first and second trimester of pregnancy, express receptors relevant for HCV binding/entry and are permissive for HCV uptake. We found that HCV-RNA sensing by human trophoblast cells induces robust upregulation of type I/III IFNs and secretion of multiple chemokines that elicit recruitment and activation of decidual NK cells. Furthermore, we observed that HCV-RNA transfection induces a proapoptotic response within HTR8 that could affect the morphology of the placenta. To our knowledge, for the first time, we demonstrate that HCV-RNA sensing by human trophoblast cells elicits a strong antiviral response that alters the recruitment and activation of innate immune cells at the MFI. This work provides a paradigm shift in our understanding of HCV-specific immunity at the MFI as well as novel insights into mechanisms that limit vertical transmission but may paradoxically lead to virus-related pregnancy complications. PMID:26342030

  8. Immunizations.

    PubMed

    Sanford, Christopher A; Jong, Elaine C

    2016-03-01

    Vaccinations are a cornerstone of the pretravel consultation. The pretravel provider should assess a traveler's past medical history, planned itinerary, activities, mode of travel, and duration of stay and make appropriate vaccine recommendations. Given that domestic vaccine-preventable illnesses are more common in international travelers than are exotic or low-income nation-associated vaccine-preventable illnesses, clinicians should first ensure that travelers are current regarding routine immunizations. Additional immunizations may be indicated in some travelers. Familiarity with geographic distribution and seasonality of infectious diseases is essential. Clinicians should be cognizant of which vaccines are live, as there exist contraindications for live vaccines. PMID:26900111

  9. Passive transfer of maternal immunity in the dromedary (Camelus dromedarius), involvement of heavy chain antibodies.

    PubMed

    Salhi, Imed; Bessalah, Salma; Mbarek, Sonia Ben; Chniter, Mohamed; Seddik, Mabrouk-Mouldi; Khorchani, Touhami; Hammadi, Mohamed

    2015-03-01

    In many mammalian species, newborns are agammaglobulinemic; thus, colostrum and milk are the main sources of early protective antibodies. These antibodies are produced in the mother's serum and transferred to mammalian glands a few days before parturition. Here, we have studied the transfer of immunity from a she-camel immunized with human serum albumin (HSA) to her calf via colostrum and milk. Our results show that HSA-specific antibodies are produced in the mother's serum and are subsequently transferred to her colostrum. These specific antibodies are then transferred by suckling to the calf. The calf serum did not contain HSA-reactive antibodies at parturition and before the first feed, after suckling, a rise in reactivity was observed peaking at 24 h postpartum. The involvement of heavy chain antibodies (HCAbs) in the process of immunity transfer was also examined, and it was found that they were also transferred from the colostrum to the calf serum like conventional antibodies. PMID:25547806

  10. Chimeric Newcastle Disease Virus Protects Chickens against Avian Influenza in the Presence of Maternally Derived NDV Immunity

    PubMed Central

    Steglich, Constanze; Grund, Christian; Ramp, Kristina; Breithaupt, Angele; Höper, Dirk; Keil, Günther; Veits, Jutta; Ziller, Mario; Granzow, Harald; Mettenleiter, Thomas C.; Römer-Oberdörfer, Angela

    2013-01-01

    Newcastle disease virus (NDV), an avian paramyxovirus type 1, is a promising vector for expression of heterologous proteins from a variety of unrelated viruses including highly pathogenic avian influenza virus (HPAIV). However, pre-existing NDV antibodies may impair vector virus replication, resulting in an inefficient immune response against the foreign antigen. A chimeric NDV-based vector with functional surface glycoproteins unrelated to NDV could overcome this problem. Therefore, an NDV vector was constructed which carries the fusion (F) and hemagglutinin-neuraminidase (HN) proteins of avian paramyxovirus type 8 (APMV-8) instead of the corresponding NDV proteins in an NDV backbone derived from the lentogenic NDV Clone 30 and a gene expressing HPAIV H5 inserted between the F and HN genes. After successful virus rescue by reverse genetics, the resulting chNDVFHN PMV8H5 was characterized in vitro and in vivo. Expression and virion incorporation of the heterologous proteins was verified by Western blot and electron microscopy. Replication of the newly generated recombinant virus was comparable to parental NDV in embryonated chicken eggs. Immunization with chNDVFHN PMV8H5 stimulated full protection against lethal HPAIV infection in chickens without as well as with maternally derived NDV antibodies. Thus, tailored NDV vector vaccines can be provided for use in the presence or absence of routine NDV vaccination. PMID:24023747

  11. Adolescent voluntary exercise attenuated hippocampal innate immunity responses and depressive-like behaviors following maternal separation stress in male rats.

    PubMed

    Sadeghi, Mahsa; Peeri, Maghsoud; Hosseini, Mir-Jamal

    2016-09-01

    Early life stressful events have detrimental effects on the brain and behavior, which are associated with the development of depression. Immune-inflammatory responses have been reported to contribute in the pathophysiology of depression. Many studies have reported on the beneficial effects of exercise against stress. However, underlying mechanisms through which exercise exerts its effects were poorly studied. Therefore, it applied maternal separation (MS), as a valid animal model of early-life adversity, in rats from postnatal day (PND) 2 to 14 for 180min per day. At PND 28, male Wistar albino rats were subjected to 5 experimental groups; 1) controls 2) MS rats 3) MS rats treated with fluoxetine 5mg/kg to PND 60, 4) MS rats that were subjected to voluntary running wheel (RW) exercise and 5) MS rats that were subjected to mandatory treadmill (TM) exercise until adulthood. At PND 60, depressive-like behaviors were assessed by using forced swimming test (FST), splash test, and sucrose preference test (SPT). Our results revealed that depressive-like behaviors following MS stress were associated with an increase in expression of toll-like receptor 4 (Tlr-4) and its main signaling protein, Myd88, in the hippocampal formation. Also, we found that voluntary (and not mandatory) physical exercise during adolescence is protected against depressant effects of early-life stress at least partly through mitigating the innate immune responses in the hippocampus. PMID:27184238

  12. Immune-Based Approaches to the Prevention of Mother-to-child-Transmission of HIV-1: Active and Passive Immunization

    PubMed Central

    Lohman-Payne, Barb; Slyker, Jennifer; Rowland-Jones, Sarah L.

    2010-01-01

    Synopsis Despite more than two decades of research, an effective vaccine that can prevent HIV-1 infection in populations exposed to the virus remains elusive. In the pursuit of an HIV-1 vaccine, does prevention of exposure to maternal HIV-1 in utero, at birth or in early life through breast-milk require special consideration? In this article we will review what is known about the immune mechanisms of susceptibility and resistance to mother-to-child transmission (MTCT) of HIV-1 and will summarise studies that have used passive or active immunisation strategies to interrupt -MTCT of HIV-1. We will also describe potentially modifiable infectious co-factors that may enhance transmission and/or disease progression (especially in the developing world). Ultimately an effective prophylactic vaccine against HIV-1 infection will need to be deployed as part of the Extended Programme of Immunisation (EPI) recommended by the World Health Organisation (WHO) for use in developing countries, so it is important to understand how the infant immune system responds to HIV-1 antigens, both in natural infection and presented by candidate vaccines. PMID:21078451

  13. TGF-β Activation and Function in Immunity

    PubMed Central

    Travis, Mark A.; Sheppard, Dean

    2014-01-01

    The cytokine TGF-β plays an integral role in regulating immune responses. TGF-β has pleiotropic effects on adaptive immunity, especially in the regulation of effector and regulatory CD4+ T cell responses. Many immune and nonimmune cells can produce TGF-β, but it is always produced as an inactive complex that must be activated to exert functional effects. Thus, activation of latent TGF-β provides a crucial layer of regulation that controls TGF-β function. In this review, we highlight some of the important functional roles for TGF-β in immunity, focusing on its context-specific roles in either dampening or promoting T cell responses. We also describe how activation of TGF-β controls its function in the immune system, with a focus on the key roles for members of the integrin family in this process. PMID:24313777

  14. Commentary on “Maternal immunization: Clinical experiences, challenges, and opportunities in vaccine acceptance”

    PubMed Central

    Bradley, Sarah L.; Ehrenthal, Deborah B.

    2014-01-01

    Abstract Immunization during pregnancy is an important and effective public health strategy. Obstetrician-gynecologists should start thinking of themselves as vaccinators and develop systems approaches to facilitate vaccination for women both during and outside of pregnancy. The importance of a strong provider recommendation is key. PMID:25483475

  15. Development of maternal and foetal immune responses in cattle following experimental challenge with Neospora caninum at day 210 of gestation

    PubMed Central

    2013-01-01

    This study examined the immunological responses of pregnant cattle and their foetuses following an experimental challenge with live Neospora caninum tachyzoites at day 210 of gestation. Animals were bled prior to and weekly throughout the experiment and sacrificed at 14, 28, 42 and 56 days post inoculation (dpi). At post mortem examination, samples of lymph nodes and spleen were collected from both dam and foetus for immunological analysis. Subcutaneous (sc) inoculation over the left prefemoral (LPF) lymph node of pregnant cattle at day 210 of gestation, led to the vertical transmission of parasites by 14 dpi, however no foetal deaths were observed in the infected animals. Foetuses from infected dams mounted Neospora-specific humoral and cell-mediated immune (CMI) responses by 14 dpi. These responses involved anti-Neospora IgG, antigen-specific lymphocyte proliferation, and the production of the cytokines IFN–γ, interleukin (IL)-4 and IL-10. There was also evidence of innate immunity during the response against Neospora from infected dams, with statistically significant (p < 0.05) increases in mean expression of toll like receptors (TLR)-2 on 56 dpi in maternal spleen, LPF, right prefemoral (RPF), left uterine (LUL) and right uterine (RUL) lymph nodes and TLR-9 in retropharyngeal (RLN), LPF and RPF lymph nodes from 28 dpi. Statistically significant (p < 0.05) increases in mean TLR-9 were detected in spleen samples from foetuses of infected dams, compared to the foetuses from control animals. Our results show that vertical transmission of the parasite occurred in all infected dams, with their foetuses showing effective Neospora-specific cell mediated, humoral and innate immune responses. PMID:24090114

  16. The influence of culture on maternal soothing behaviours and infant pain expression in the immunization context

    PubMed Central

    Vinall, Jillian; Pillai Riddell, Rebecca; Greenberg, Saul

    2011-01-01

    OBJECTIVE: To investigate how maternal culture (ie, individualist versus collectivist) influences soothing techniques and infant distress. METHODS: Archival data were analyzed using a subsample of 80 mother-infant dyads selected from a larger database of infant pain expression. RESULTS: Mothers belonging to the individualist group used more affection behaviours when attempting to regulate their infants’ distress. No differences were observed in mothers’ touching, holding, rocking, vocalizing, caregiving or distracting their infants. Mothers’ culture did not appear to be related to the level of distress expressed by their infants. CONCLUSIONS: These results suggest that the similarities in soothing and infant pain expression between individualist and collectivist cultures are more prominent than their differences. PMID:22059192

  17. Breastfeeding, Brain Activation to Own Infant Cry, and Maternal Sensitivity

    ERIC Educational Resources Information Center

    Kim, Pilyoung; Feldman, Ruth; Mayes, Linda C.; Eicher, Virginia; Thompson, Nancy; Leckman, James F.; Swain, James E.

    2011-01-01

    Background: Research points to the importance of breastfeeding for promoting close mother-infant contact and social-emotional development. Recent functional magnetic resonance imaging (fMRI) studies have identified brain regions related to maternal behaviors. However, little research has addressed the neurobiological mechanisms underlying the…

  18. Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes.

    PubMed

    Tilburgs, Tamara; Crespo, Ângela C; van der Zwan, Anita; Rybalov, Basya; Raj, Towfique; Stranger, Barbara; Gardner, Lucy; Moffett, Ashley; Strominger, Jack L

    2015-06-01

    Invading human leukocyte antigen-G+ (HLA-G+) extravillous trophoblasts (EVT) are rare cells that are believed to play a key role in the prevention of a maternal immune attack on foreign fetal tissues. Here highly purified HLA-G+ EVT and HLA-G- villous trophoblasts (VT) were isolated. Culture on fibronectin that EVT encounter on invading the uterus increased HLA-G, EGF-Receptor-2, and LIF-Receptor expression on EVT, presumably representing a further differentiation state. Microarray and functional gene set enrichment analysis revealed a striking immune-activating potential for EVT that was absent in VT. Cocultures of HLA-G+ EVT with sample matched decidual natural killer cells (dNK), macrophages, and CD4+ and CD8+ T cells were established. Interaction of EVT with CD4+ T cells resulted in increased numbers of CD4+CD25(HI)FOXP3+CD45RA+ resting regulatory T cells (Treg) and increased the expression level of the Treg-specific transcription factor FOXP3 in these cells. However, EVT did not enhance cytokine secretion in dNK, whereas stimulation of dNK with mitogens or classical natural killer targets confirmed the distinct cytokine secretion profiles of dNK and peripheral blood NK cells (pNK). EVT are specialized cells involved in maternal-fetal tolerance, the properties of which are not imitated by HLA-G-expressing surrogate cell lines. PMID:26015573

  19. Impact of maternal physical activity on fetal breathing and body movement--A review.

    PubMed

    Sussman, Dafna; Lye, Stephen J; Wells, Greg D

    2016-03-01

    Fetal movements, which include body and breathing movement, are important indicators of fetal well-being and nervous system development. These have been shown to be affected by intrauterine conditions. While maternal physical activity does induce a change in intrauterine conditions and physiology, its impact on fetal movements is still unclear. This paper will provide a brief review of the literature and outline the current knowledge with regards to the effects of maternal exercise on fetal body and breathing movements. PMID:26811196

  20. Active immunization by a dengue virus-induced cytokine.

    PubMed Central

    Chaturvedi, U C; Mukerjee, R; Dhawan, R

    1994-01-01

    Dengue type 2 virus (DV)-induced cytotoxic factor (CF) is capable of reproducing various pathological lesions in mice that are seen in human dengue. The present study was undertaken to investigate the protective effect of active immunization of mice with CF. Mice were immunized with 5 microgram of CF and prevention of CF-induced increase in capillary permeability and damage to the blood-brain barrier were studied at weekly intervals, up to 48 weeks, by challenging with 3 microgram of CF. Maximum protection against increase in capillary permeability and damage to the blood-brain barrier was observed in week 4 after immunization. A breakthrough in the protection occurred with higher doses of CF in a dose-dependent manner. Challenge with a lethal intracerebral (i.c.) dose of DV showed significantly prolonged mean survival time and delayed onset of symptoms of sickness in the immunized mice compared with the normal mice, but the titre of the virus in the brain was similar in the two groups. On i.p. challenge with the virus the protection against damage to the blood-brain barrier was 86 +/- 7% at week 4 and 17 +/- 4% at week 26 after immunization. Sera obtained from the immunized mice showed the presence of CF-specific antibodies by ELISA, Western blot, and by neutralization of the cytotoxic activity of CF in vitro. The present study describes successful prevention of a cytokine-induced pathology by specific active immunization. PMID:8187327

  1. [Bone marrow stromal damage mediated by immune response activity].

    PubMed

    Vojinović, J; Kamenov, B; Najman, S; Branković, Lj; Dimitrijević, H

    1994-01-01

    The aim of this work was to estimate influence of activated immune response on hematopoiesis in vitro, using the experimental model of BCG immunized BALB/c mice and in patients with chronic immunoactivation: long-lasting infections, autoimmunity or malignancy. We correlated changes in long term bone marrow cultures (Dexter) and NBT reduction with appearance of anemia in patients and experimental model of immunization by BCG. Increased spontaneous NBT reduction pointed out role of macrophage activation in bone marrow stroma damage. Long-term bone marrow cultures showed reduced number of hematopoietic cells, with predomination of fibroblasts and loss of fat cells. This results correlated with anemia and leucocytosis with stimulated myelopoiesis in peripheral blood. Activation of immune response, or acting of any agent that directly changes extracellular matrix and cellularity of bone marrow, may result in microenviroment bone marrow damage that modify hematopoiesis. PMID:18173180

  2. Antepartum Screening for Maternal Infection and Immune Status: Is it Time to Broaden Our Routine?

    PubMed

    Poliquin, Vanessa; Yudin, Mark H; Murphy, Kellie E; Okun, Nan

    2015-12-01

    Maternal infections with PVB19, HCV, CMV, and HIV during the antepartum period are important health problems for which the technological capacities for screening and diagnosis during the antepartum period are available. Each of these viruses requires individual consideration for inclusion in screening and for the method of screening during the antepartum period. The availability of efficacious treatments for HCV and CMV, with demonstrable benefits to the mother or fetus, is required before antepartum screening for these infections can be justified. Screening for parvovirus B19 presents a greater concern because it meets most of the features of a screening test (Wilson’s criteria) endorsed by the WHO. There is insufficient evidence to argue strongly for implementation of antepartum PVB19 screening, but the available evidence indicates a need for large studies of potential effectiveness and costs of routine PVB19 screening, either for all pregnant woman or for those at high risk of exposure to PVB19. While the technology to screen for HCV, PVB19, and CMV certainly exists, there must be careful consideration of the downstream implications of routine screening at the level of the individual patient, the general population, and other health care resources, including laboratory infrastructure, before recommending that these infections be screened for routinely in the antepartum period. A strategy for national adoption of an opt-out screening strategy for HIV should be considered. PMID:26637086

  3. Gut hormones: emerging role in immune activation and inflammation.

    PubMed

    Khan, W I; Ghia, J E

    2010-07-01

    Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders. PMID:20408856

  4. Prenatal immune activation alters hippocampal place cell firing characteristics in adult animals.

    PubMed

    Wolff, Amy R; Bilkey, David K

    2015-08-01

    Prenatal maternal immune activation (MIA) is a risk factor for several developmental neuropsychiatric disorders, including autism, bipolar disorder and schizophrenia. Adults with these disorders display alterations in memory function that may result from changes in the structure and function of the hippocampus. In the present study we use an animal model to investigate the effect that a transient prenatal maternal immune activation episode has on the spatially-modulated firing activity of hippocampal neurons in adult animals. MIA was induced in pregnant rat dams with a single injection of the synthetic cytokine inducer polyinosinic:polycytidylic acid (poly I:C) on gestational day 15. Control dams were given a saline equivalent. Firing activity and local field potentials (LFPs) were recorded from the CA1 region of the adult male offspring of these dams as they moved freely in an open arena. Most neurons displayed characteristic spatially-modulated 'place cell' firing activity and while there was no between-group difference in mean firing rate between groups, place cells had smaller place fields in MIA-exposed animals when compared to control-group cells. Cells recorded in MIA-group animals also displayed an altered firing-phase synchrony relationship to simultaneously recorded LFPs. When the floor of the arena was rotated, the place fields of MIA-group cells were more likely to shift in the same direction as the floor rotation, suggesting that local cues may have been more salient for these animals. In contrast, place fields in control group cells were more likely to shift firing position to novel spatial locations suggesting an altered response to contextual cues. These findings show that a single MIA intervention is sufficient to change several important characteristics of hippocampal place cell activity in adult offspring. These changes could contribute to the memory dysfunction that is associated with MIA, by altering the encoding of spatial context and by

  5. Enhancing Cancer Immunotherapy Via Activation of Innate Immunity

    PubMed Central

    Goldberg, Jacob L.; Sondel, Paul M.

    2015-01-01

    Given recent technological advances and advances in our understanding of cancer, immunotherapy of cancer is being used with clear clinical benefit. The immunosuppression accompanying cancer itself, as well as with current cancer treatment with radiation or chemotherapy, impairs adaptive immune effectors to a greater extent than innate effector cells. In addition to being less suppressed, innate immune cells are capable of being enhanced via immune-stimulatory regimens. Most strategies being investigated to promote innate immune responses against cancer do not require complex, patient-specific, ex-vivo cellular or molecular creation of therapeutic agents; thus they can, generally, be used as “off the shelf” therapeutics that could be administered by most cancer clinics. Successful applications of innate immunotherapy in the clinic have effectively targeted components of the innate immune response. Preclinical data demonstrate how initiation of innate immune responses can lead to subsequent adaptive long-term cancer immunity. We hypothesize that integration of innate immune activation strategies into combination therapies for cancer treatment will lead to more effective and long term clinical benefit. PMID:26320061

  6. The synergistic effect of density stress during the maternal period and adulthood on immune traits of root vole (Microtus oeconomus) individuals-a field experiment.

    PubMed

    Du, Shou-Yang; Cao, Yi-Fan; Nie, Xu-Heng; Wu, Yan; Bian, Jiang-Hui

    2016-06-01

    The literature reveals that stress in early life or adulthood can influence immune function. As most studies on this are from the laboratory, there is a need for replicated studies in wild animals. This study aims to examine the effects of density stress during the maternal period and adulthood on immune traits of root vole (Microtus oeconomus) individuals. Four replicated high- and low-density parental populations were established, from which we obtained offspring and assigned each into four enclosures, two for each of the two density treatments used in establishing parental populations. The F1 offspring fecal corticosterone metabolite response to acute immobilization stress, anti-keyhole limpet hemocyanin immunoglobulin G (anti-KLH IgG) level, phytohemagglutinin (PHA)-delayed hypersensitivity and hematology at the end of the first breeding season, and prevalence and intensity of coccidial infection throughout the two breeding seasons, were tested. Density-induced maternally stressed offspring had delayed responses to acute immobilization stress. Density-stressed offspring as adults had reduced anti-KLH IgG levels and PHA responses, and the effects further deteriorated in maternally stressed offspring, leading to higher coccidial infection in the first breeding season than in the second. No correlations were found between immune traits or coccidial infection and survival over winter. These findings indicated that the combined density stresses during the maternal period and adulthood exhibited negative synergistic effects on immune traits. The synergistic effects lead to higher coccidial infection; however, this consequently reduced the risk of subsequent infection. The increased coccidial infection mediated by the synergistic effects may have an adaptive value in the context of the environment. PMID:26373286

  7. Activation and Regulation of DNA-Driven Immune Responses

    PubMed Central

    2015-01-01

    SUMMARY The innate immune system provides early defense against infections and also plays a key role in monitoring alterations of homeostasis in the body. DNA is highly immunostimulatory, and recent advances in this field have led to the identification of the innate immune sensors responsible for the recognition of DNA as well as the downstream pathways that are activated. Moreover, information on how cells regulate DNA-driven immune responses to avoid excessive inflammation is now emerging. Finally, several reports have demonstrated how defects in DNA sensing, signaling, and regulation are associated with susceptibility to infections or inflammatory diseases in humans and model organisms. In this review, the current literature on DNA-stimulated innate immune activation is discussed, and important new questions facing this field are proposed. PMID:25926682

  8. Activation of the reward system boosts innate and adaptive immunity.

    PubMed

    Ben-Shaanan, Tamar L; Azulay-Debby, Hilla; Dubovik, Tania; Starosvetsky, Elina; Korin, Ben; Schiller, Maya; Green, Nathaniel L; Admon, Yasmin; Hakim, Fahed; Shen-Orr, Shai S; Rolls, Asya

    2016-08-01

    Positive expectations contribute to the clinical benefits of the placebo effect. Such positive expectations are mediated by the brain's reward system; however, it remains unknown whether and how reward system activation affects the body's physiology and, specifically, immunity. Here we show that activation of the ventral tegmental area (VTA), a key component of the reward system, strengthens immunological host defense. We used 'designer receptors exclusively activated by designer drugs' (DREADDs) to directly activate dopaminergic neurons in the mouse VTA and characterized the subsequent immune response after exposure to bacteria (Escherichia coli), using time-of-flight mass cytometry (CyTOF) and functional assays. We found an increase in innate and adaptive immune responses that were manifested by enhanced antibacterial activity of monocytes and macrophages, reduced in vivo bacterial load and a heightened T cell response in the mouse model of delayed-type hypersensitivity. By chemically ablating the sympathetic nervous system (SNS), we showed that the reward system's effects on immunity are, at least partly, mediated by the SNS. Thus, our findings establish a causal relationship between the activity of the VTA and the immune response to bacterial infection. PMID:27376577

  9. HLA-G in human early pregnancy: control of uterine immune cell activation and likely vascular remodeling.

    PubMed

    Le Bouteiller, Philippe

    2015-01-01

    Despite a number of controversies, the functional importance of human leukocyte antigen G (HLA-G) in early human pregnancy is now sustained by a large amount of sound data. Membrane-bound and soluble HLA-G isoforms, either as β2-microglobulin-free or -associated as monomers or dimers, are expressed by different trophoblast subpopulations, the only fetal-derived cells that are directly in contact with maternal cells (maternal-fetal interfaces). Trophoblast HLA-G is the specific ligand of multiple cellular receptors present in maternal immune and non-immune cells, including CD8, leukocyte immunoglobulin-like receptor (LILR) B1, LILRB2, killer cell immunoglobulin-like receptor (KIR) 2DL4, and possibly CD160. Trophoblast HLA-G specific engagement of these cellular receptors triggers either inhibitory or activating signals in decidual CD8 + T cells, CD4 + T cells, natural killer (NK) cells, macrophages, dendritic cells, or endothelial cells. Such HLA-G-receptor specific interactions first contribute to limit potentially harmful maternal anti-paternal immune response by impairment of decidual NK cell cytotoxicity, inhibition of CD4 + and CD8 + T-cell and B-cell proliferation, and induction of apoptosis of activated CD8 + T cells. Second, these HLA-G specific interactions contribute to stimulate placental development through secretion of angiogenic factors by decidual NK cells and macrophages, and to provide a protective effect for the outcome of pregnancy by the secretion of interleukin (IL)-4 by decidual trophoblast antigen-specific CD4 + T cells. PMID:25163504

  10. Mucosal priming of newborn mice with S. Typhi Ty21a expressing anthrax protective antigen (PA) followed by parenteral PA-boost induces B and T cell-mediated immunity that protects against infection bypassing maternal antibodies.

    PubMed

    Ramirez, Karina; Ditamo, Yanina; Galen, James E; Baillie, Les W J; Pasetti, Marcela F

    2010-08-23

    The currently licensed anthrax vaccine has several limitations and its efficacy has been proven only in adults. Effective immunization of newborns and infants requires adequate stimulation of their immune system, which is competent but not fully activated. We explored the use of the licensed live attenuated S. Typhi vaccine strain Ty21a expressing Bacillus anthracis protective antigen [Ty21a(PA)] followed PA-alum as a strategy for immunizing the pediatric population. Newborn mice primed with a single dose of Ty21a(PA) exhibited high frequencies of mucosal IgA-secreting B cells and IFN-gamma-secreting T cells during the neonatal period, none of which was detected in newborns immunized with a single dose of PA-alum. Priming with Ty21a(PA) followed by PA-boost resulted in high levels of PA-specific IgG, toxin neutralizing and opsonophagocytic antibodies and increased frequency of bone marrow IgG plasma cells and memory B cells compared with repeated immunization with PA-alum alone. Robust B and T cell responses developed even in the presence of maternal antibodies. The prime-boost protected against systemic and respiratory infection. Mucosal priming with a safe and effective S. Typhi-based anthrax vaccine followed by PA-boost could serve as a practical and effective prophylactic approach to prevent anthrax early in life. PMID:20619377

  11. Maternal immunization in Argentina: A storyline from the prospective of a middle income country.

    PubMed

    Vizzotti, C; Neyro, S; Katz, N; Juárez, M V; Perez Carrega, M E; Aquino, A; Kaski Fullone, F

    2015-11-25

    The importance of vaccination during pregnancy lies not only in directly protecting vaccinated women, but also by indirectly protecting small infants during the first few months of life. Vaccination against the flu and whooping cough is a priority within the comprehensive care strategy for pregnant women and small infants in Argentina, in the context of transitioning from child vaccination to family vaccination. In 2011, the flu vaccine was included in the National Immunization Schedule (NIS) as mandatory and free of charge, with the aim of decreasing complications and death due to influenza in the at-risk population in Argentina. The national vaccination coverage attained in pregnant women in the past 4 years (2011-2014) has been satisfactory; 88% coverage was attained in the year this program was introduced to the schedule. In the following years, coverage was maintained at greater than 95%. In February 2012, Argentina became the first country in Latin America to have universal vaccination strategy for pregnant women against whooping cough. This recommendation was implemented throughout the country by vaccination with the diphtheria toxoid, tetanus toxoid, and acellular pertussis (Tdap) vaccine starting at 20 weeks of pregnancy, with the aim of decreasing morbimortality due to whooping cough in infants under 6 months of age. The vaccine was incorporated into the NIS in 2014. More than 1,200,000 doses were applied in this period. Both vaccines showed a suitable safety profile and no serious events were reported. Argentina is an example of a middle-income country that has been able to implement a successful strategy for primary prevention through vaccines, making it a health policy. PMID:26277071

  12. Limited evidence for trans-generational effects of maternal dietary supplementation with ω-3 fatty acids on immunity in broiler chickens.

    PubMed

    Koppenol, Astrid; Delezie, Evelyne; Parmentier, Henk K; Buyse, Johan; Everaert, Nadia

    2015-02-01

    The aim of the present study was to investigate whether the immune response of broiler chickens is modulated by including different omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the maternal diet. Broiler breeder hens (n = 120 birds per group) were fed one of four diets, differing in the ratios of n-6:n-3 PUFAs and eicosapentaenoic acid (EPA):docosahexaenoic acid (DHA). At 28 weeks of age, the eggs produced were incubated to obtain 720 chicks (n = 180 per group). All broiler chicks were fed a control diet and were vaccinated against Newcastle disease virus (NDV). Blood samples were taken at different time points after immunisation with human serum albumin (HuSA) in Freund's adjuvant to determine the acute phase response, antibody response and cytokine production. Addition of EPA to the maternal diet was associated with greater ovotransferrin concentrations post-immunisation, compared to other groups. Altering the ratios of n-6:n-3 PUFA or EPA:DHA in the maternal diet did not affect the offspring in terms of production of caeruloplasmin, α1-acid glycoprotein, interleukin (IL)-1β, IL-6, IL-12 or tumour necrosis factor (TNF)-α. Dietary manipulation of the maternal diet did not influence the specific antibody response to HuSA or NDV, nor did it alter the levels of natural antibody binding to keyhole limpet haemocyanin in the offspring. Thus, maternal supplementation with n-3 PUFAs played a minor role in perinatal programming of the immune response of broiler chickens. PMID:25576140

  13. An imbalance between innate and adaptive immune cells at the maternal-fetal interface occurs prior to endotoxin-induced preterm birth.

    PubMed

    Arenas-Hernandez, Marcia; Romero, Roberto; St Louis, Derek; Hassan, Sonia S; Kaye, Emily B; Gomez-Lopez, Nardhy

    2016-07-01

    Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal-fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4+ regulatory T cells (Tregs) in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of IL10, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4+ T cells at the maternal-fetal interface. However, it causes an imbalance between Tregs (CD4+ and CD8+), effector CD8+ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II+ neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal-fetal interface. PMID:25849119

  14. Maternal nutrition influences angiogenesis in the placenta through peroxisome proliferator activated receptors: A novel hypothesis.

    PubMed

    Meher, Akshaya; Sundrani, Deepali; Joshi, Sadhana

    2015-10-01

    Placental angiogenesis is critical to maintain adequate blood flow during gestation, and any alterations in this process can result in an adverse pregnancy. Growing evidence indicates that suboptimal maternal nutrition can alter placental development. Although the underlying mechanisms are not clear, maternal nutrition likely influences the expression of genes involved in placental development through regulation of various transcription factors such as peroxisome proliferator-activated receptors (PPARs), which can be activated by ligands including long-chain polyunsaturated fatty acids. Indeed, several studies demonstrated a role for PPAR in implantation, trophoblast differentiation, and angiogenesis. Alterations in maternal nutrition during pregnancy can affect the expression of PPARs via epigenetic mechanisms or through homocysteine, which is known to compete for PPARs. This review discusses the role of maternal nutrition-particularly micronutrients like folate, vitamin B12 , and omega-3 fatty acids-in modulating the activity of PPARs during placentation and angiogenesis, which affects placental and fetal growth. Additional animal and human studies need to be undertaken to elucidate the molecular mechanisms through which maternal nutrition regulates PPARs, specifically to determine whether PPARs affect placental angiogenesis directly through angiogenic factors or indirectly by modulating trophoblast differentiation. PMID:26099847

  15. BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample

    PubMed Central

    Moser, Dominik A.; Paoloni-Giacobino, Ariane; Stenz, Ludwig; Adouan, Wafae; Manini, Aurélia; Suardi, Francesca; Cordero, Maria I.; Vital, Marylene; Sancho Rossignol, Ana; Rusconi-Serpa, Sandra; Ansermet, François; Dayer, Alexandre G.; Schechter, Daniel S.

    2015-01-01

    It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children—including their own—was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk

  16. BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample.

    PubMed

    Moser, Dominik A; Paoloni-Giacobino, Ariane; Stenz, Ludwig; Adouan, Wafae; Manini, Aurélia; Suardi, Francesca; Cordero, Maria I; Vital, Marylene; Sancho Rossignol, Ana; Rusconi-Serpa, Sandra; Ansermet, François; Dayer, Alexandre G; Schechter, Daniel S

    2015-01-01

    It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children-including their own-was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk for

  17. The immune system as a regulator of thyroid hormone activity.

    PubMed

    Klein, John R

    2006-03-01

    It has been known for decades that the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In contrast, far less is known about the extent to which the immune system collaborates in the regulation of endocrine activity. This is particularly true for immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis. Although thyroid-stimulating hormone (TSH) can be produced by many types of extra-pituitary cells--including T cells, B cells, splenic dendritic cells, bone marrow hematopoietic cells, intestinal epithelial cells, and lymphocytes--the functional significance of those TSH pathways remains elusive and historically has been largely ignored from a research perspective. There is now, however, evidence linking cells of the immune system to the regulation of thyroid hormone activity in normal physiological conditions as well as during times of immunological stress. Although the mechanisms behind this are poorly understood, they appear to reflect a process of local intrathyroidal synthesis of TSH mediated by a population of bone marrow cells that traffic to the thyroid. This hitherto undescribed cell population has the potential to microregulate thyroid hormone secretion leading to critical alterations in metabolic activity independent of pituitary TSH output, and it has expansive implications for understanding mechanisms by which the immune system may act to modulate neuroendocrine function during times of host stress. In this article, the basic underpinnings of the hematopoietic-thyroid connection are described, and a model is presented in which the immune system participates in the regulation of thyroid hormone activity during acute infection. PMID:16514168

  18. Obligate symbionts activate immune system development in the tsetse fly

    PubMed Central

    Weiss, Brian L.; Maltz, Michele; Aksoy, Serap

    2012-01-01

    Many insects rely on the presence of symbiotic bacteria for proper immune system function. However, the molecular mechanisms that underlie this phenomenon are poorly understood. Adult tsetse flies (Glossina spp.) house 3 symbiotic bacteria that are vertically transmitted from mother to offspring during this insect's unique viviparous mode of reproduction. Larval tsetse that undergo intrauterine development in the absence of their obligate mutualist, Wigglesworthia, exhibit a compromised immune system during adulthood. In this study we characterize the immune phenotype of tsetse that develop in the absence of all of their endogenous symbiotic microbes. Aposymbiotic tsetse (GmmApo) present a severely compromised immune system that is characterized by the absence of phagocytic hemocytes and atypical expression of immunity-related genes. Correspondingly, these flies quickly succumb to infection with normally non-pathogenic E. coli. The susceptible phenotype exhibited by GmmApo adults can be reversed when they receive hemocytes transplanted from wild-type donor flies prior to infection. Furthermore, the process of immune system development can be restored in intrauterine GmmApo larvae when their moms are fed a diet supplemented with Wigglesworthia cell extracts. Our finding that molecular components of Wigglesworthia exhibit immunostimulatory activity within tsetse is representative of a novel evolutionary adaptation that steadfastly links an obligate symbiont with it's host. PMID:22368278

  19. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against things like measles, ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  20. Immunizations

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immunizations KidsHealth > For Teens > Immunizations Print A A A ... That Shot? en español Las vacunas Why Are Vaccinations Important? Measles, mumps, and whooping cough may seem ...

  1. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  2. Electroporation enhances immune responses and protection induced by a bovine viral diarrhea virus DNA vaccine in newborn calves with maternal antibodies.

    PubMed

    van Drunen Littel-van den Hurk, Sylvia; Lawman, Zoe; Wilson, Don; Luxembourg, Alain; Ellefsen, Barry; van den Hurk, Jan V; Hannaman, Drew

    2010-09-01

    Bovine viral diarrhea virus (BVDV) is one of the major pathogens in cattle. In this study, newborn calves with maternal antibodies were vaccinated with a BVDV DNA vaccine, either by conventional intramuscular (IM) injection or with the TriGrid™ Delivery System for IM delivery (TDS-IM). The calves vaccinated with the TDS-IM developed more rapidly and effectively BVDV-specific humoral and cell-mediated immune responses in the presence of maternal antibodies. Overall, the immune responses induced by delivery with the TDS-IM remained stronger than those elicited by conventional IM injection of the BVDV DNA vaccine. Accordingly, electroporation-mediated delivery of the BVDV DNA vaccine resulted in close to complete protection from clinical signs of disease, while conventional IM administration did not fully prevent morbidity and mortality following challenge with BVDV-2. These results demonstrate the TDS-IM to be effective as a delivery system for a BVDV DNA vaccine in newborn calves in the presence of maternal antibodies, which supports the potential of electroporation as a delivery method for prophylactic DNA vaccines. PMID:20670907

  3. Epidemic spreading and immunization in node-activity networks

    NASA Astrophysics Data System (ADS)

    Wu, Qingchu; Chen, Shufang

    2015-09-01

    In this paper, we study the epidemic spreading in node-activity networks, where an individual participates in social networks with a certain rate h. There are two cases for h: the state-independent case and the state-dependent case. We investigate the epidemic threshold as a function of h compared to the static network. Our results suggest the epidemic threshold cannot be exactly predicted by using the analysis approach in the static network. In addition, we further propose a local information-based immunization protocol on node-activity networks. Simulation analysis shows that the immunization can not only eliminate the infectious disease, but also change the epidemic threshold via increasing the immunization parameter.

  4. Maternal inflammation during late pregnancy is lower in physically active compared to inactive obese women

    PubMed Central

    Tinius, Rachel A.; Cahill, Alison G.; Strand, Eric A.; Todd Cade, W.

    2016-01-01

    Purpose The primary purpose of this study was to compare maternal plasma inflammation between physically active and inactive obese women during late pregnancy. The secondary purpose was to examine the relationships between maternal plasma inflammation and lipid metabolism and maternal and neonatal metabolic health in these women. Methods A cross-sectional, observational study design was performed in 16 obese-inactive ((OBI) age: 25.0 ± 4.8 years, pre-pregnancy BMI: 36.3 ± 4.3kg/m2, body fat percentage in late gestation: 37.7 ± 3.5%) and 16 obese-active ((OBA) age: 28.9 ± 4.8 years, pre-pregnancy BMI: 34.0±3.7kg/m2, body fat in late gestation: 36.6 ± 3.8%) women during the third trimester of pregnancy. Maternal plasma inflammation (C -reactive protein (CRP)) and insulin resistance (Homeostatic Model Assessment-Insulin Resistance (HOMA-IR)) were measured at rest. Plasma lipid concentration and metabolism (lipid oxidation and lipolysis) were measured at rest, during a 30-minute bout of low-intensity (40% VO2peak) exercise, and during a resting recovery period using indirect calorimetry. Umbilical cord blood was collected for measurement of neonatal plasma insulin resistance, inflammation, and lipid concentration. Neonatal body composition was measured via air displacement plethysmography. Results Maternal plasma CRP concentration was significantly higher in OBI compared to OBA women (9.1 ± 4.0 mg/L versus 6.3 ±2.5mg/L, p=0.02). Maternal plasma CRP concentration was significantly associated with maternal lipolysis (r=0.43, p=0.02), baseline lipid oxidation rate (r=0.39, p=0.03), and baseline plasma free fatty acid concentration (r=0.36, p=0.04). Conclusions Maternal physical activity may reduce inflammation during pregnancy in obese women. Maternal lipid metabolism is related to systemic inflammation. PMID:26799789

  5. Maternal inflammation during late pregnancy is lower in physically active compared with inactive obese women.

    PubMed

    Tinius, Rachel A; Cahill, Alison G; Strand, Eric A; Cade, W Todd

    2016-02-01

    The primary purpose of this study was to compare maternal plasma inflammation between physically active and inactive obese women during late pregnancy. The secondary purpose was to examine the relationships between maternal plasma inflammation and lipid metabolism and maternal and neonatal metabolic health in these women. A cross-sectional, observational study design was performed in 16 obese-inactive (OBI; means ± SD; age, 25.0 ± 4.8 years; prepregnancy body mass index (BMI), 36.3 ± 4.3 kg/m(2); body fat percentage in late gestation, 37.7% ± 3.5%) and 16 obese-active (OBA; age, 28.9 ± 4.8 years; prepregnancy BMI, 34.0 ± 3.7 kg/m(2); body fat in late gestation, 36.6% ± 3.8%) women during the third trimester of pregnancy. Maternal plasma inflammation (C -reactive protein (CRP)) and insulin resistance (Homeostatic Model Assessment-Insulin Resistance) were measured at rest. Plasma lipid concentration and metabolism (lipid oxidation and lipolysis) were measured at rest, during a 30-min bout of low-intensity (40% peak oxygen uptake) exercise, and during a resting recovery period using indirect calorimetry. Umbilical cord blood was collected for measurement of neonatal plasma insulin resistance, inflammation, and lipid concentration. Neonatal body composition was measured via air displacement plethysmography. Maternal plasma CRP concentration was significantly higher in OBI compared with OBA women (9.1 ± 4.0 mg/L vs. 6.3 ± 2.5 mg/L, p = 0.02). Maternal plasma CRP concentration was significantly associated with maternal lipolysis (r = 0.43, p = 0.02), baseline lipid oxidation rate (r = 0.39, p = 0.03), and baseline plasma free fatty acid concentration (r = 0.36, p = 0.04). In conclusion, maternal physical activity may reduce inflammation during pregnancy in obese women. Maternal lipid metabolism is related to systemic inflammation. PMID:26799789

  6. Pathogen-Secreted Proteases Activate a Novel Plant Immune Pathway

    PubMed Central

    Cheng, Zhenyu; Li, Jian-Feng; Niu, Yajie; Zhang, Xue-Cheng; Woody, Owen Z.; Xiong, Yan; Djonović, Slavica; Millet, Yves; Bush, Jenifer; McConkey, Brendan J.; Sheen, Jen; Ausubel, Frederick M.

    2015-01-01

    Mitogen-Activated Protein Kinase (MAPK) cascades play central roles in innate immune signaling networks in plants and animals1,2. In plants, however, the molecular mechanisms of how signal perception is transduced to MAPK activation remain elusive1. We report that pathogen-secreted proteases activate a previously unknown signaling pathway in Arabidopsis thaliana involving the Gα, Gβ and Gγ subunits of heterotrimeric G-protein complexes, which function upstream of a MAPK cascade. In this pathway, Receptor for Activated C Kinase 1 (RACK1) functions as a novel scaffold that binds to the Gβ subunit as well as to all three tiers of the MAPK cascade, thereby linking upstream G protein signaling to downstream activation of a MAPK cascade. The protease-G protein-RACK1-MAPK cascade modules identified in these studies are distinct from previously described plant immune signaling pathways such as the one elicited by bacterial flagellin, in which G proteins function downstream of or in parallel to a MAPK cascade without the involvement of the RACK1 scaffolding protein. The discovery of the novel protease-mediated immune signaling pathway described here was facilitated by the use of the broad host range, opportunistic bacterial pathogen Pseudomonas aeruginosa. The ability of P. aeruginosa to infect both plants and animals makes it an excellent model to identify novel types of immunoregulatory strategies that account for its niche adaptation to diverse host tissues and immune systems. PMID:25731164

  7. Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.

    PubMed

    Frascoli, Michela; Jeanty, Cerine; Fleck, Shannon; Moradi, Patriss W; Keating, Sheila; Mattis, Aras N; Tang, Qizhi; MacKenzie, Tippi C

    2016-06-15

    The development of the fetal immune system during pregnancy is a well-orchestrated process with important consequences for fetal and neonatal health, but prenatal factors that affect immune activation are poorly understood. We hypothesized that chronic fetal inflammation may lead to alterations in development of the fetal immune system. To test this hypothesis, we examined neonates with gastroschisis, a congenital abdominal wall defect that leads to exposure of the fetal intestines to amniotic fluid, with resultant intestinal inflammation. We determined that patients with gastroschisis show high systemic levels of inflammatory cytokines and chemokines such as eotaxin, as well as earlier activation of CD4(+) and CD8(+) effector and memory T cells in the cord blood compared with controls. Additionally, increased numbers of T cells and eosinophils infiltrate the serosa and mucosa of the inflamed intestines. Using a mouse model of gastroschisis, we observed higher numbers of eosinophils and both type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), specifically in the portion of organs exposed to the amniotic fluid. Given the role of IL-5 produced by ILC2 in regulating eosinophil development and survival, we determined that maternal or fetal administration of the anti-IL-5 neutralizing Ab, or a depleting Ab against ILCs, can both effectively reduce intestinal eosinophilia. Thus, a congenital anomaly causing chronic inflammation can alter the composition of circulating and tissue-resident fetal immune cells. Given the high rate of prenatal and neonatal complications in these patients, such changes have clinical significance and might become targets for fetal therapy. PMID:27183609

  8. Right Frontoinsular Cortex and Subcortical Activity to Infant Cry Is Associated with Maternal Mental State Talk

    PubMed Central

    Phillips, Mary L.; Swain, James E.; Moses-Kolko, Eydie L.

    2015-01-01

    The study objective was to examine neural correlates of a specific component of human caregiving: maternal mental state talk, reflecting a mother's proclivity to attribute mental states and intentionality to her infant. Using a potent, ecologically relevant stimulus of infant cry during fMRI, we tested hypotheses that postpartum neural response to the cry of “own” versus a standard “other” infant in the right frontoinsular cortex (RFIC) and subcortical limbic network would be associated with independent observations of maternal mental state talk. The sample comprised 76 urban-living, low socioeconomic mothers (82% African American) and their 4-month-old infants. Before the fMRI scan, mothers were filmed in face-to-face interaction with their infant, and maternal behaviors were coded by trained researchers unaware of all other information about the participants. The results showed higher functional activity in the RFIC to own versus other infant cry at the group level. In addition, RFIC and bilateral subcortical neural activity (e.g., thalamus, amygdala, hippocampus, putamen) was associated positively with maternal mental state talk but not with more global aspects of observed caregiving. These findings held when accounting for perceptual and contextual covariates, such as maternal felt distress, urge to help, depression severity, and recognition of own infant cry. Our results highlight the need to focus on specific components of caregiving to advance understanding of the maternal brain. Future work will examine the predictive utility of this neural marker for mother–child function. SIGNIFICANCE STATEMENT The current study advances extant literature examining the neural underpinning of early parenting behavior. The findings highlight the special functional importance of the right frontoinsular cortex–thalamic–limbic network in a mother's proclivity to engage in mental state talk with her preverbal infant, a circumscribed aspect of maternal caregiving

  9. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    PubMed Central

    Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

    2013-01-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. PMID:24202450

  10. Photodynamic therapy for cancer and activation of immune response

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Huang, Ying-Ying; Hamblin, Michael R.

    2010-02-01

    Anti-tumor immunity is stimulated after PDT for cancer due to the acute inflammatory response, exposure and presentation of tumor-specific antigens, and induction of heat-shock proteins and other danger signals. Nevertheless effective, powerful tumor-specific immune response in both animal models and also in patients treated with PDT for cancer, is the exception rather than the rule. Research in our laboratory and also in others is geared towards identifying reasons for this sub-optimal immune response and discovering ways of maximizing it. Reasons why the immune response after PDT is less than optimal include the fact that tumor-antigens are considered to be self-like and poorly immunogenic, the tumor-mediated induction of CD4+CD25+foxP3+ regulatory T-cells (T-regs), that are able to inhibit both the priming and the effector phases of the cytotoxic CD8 T-cell anti-tumor response and the defects in dendritic cell maturation, activation and antigen-presentation that may also occur. Alternatively-activated macrophages (M2) have also been implicated. Strategies to overcome these immune escape mechanisms employed by different tumors include combination regimens using PDT and immunostimulating treatments such as products obtained from pathogenic microorganisms against which mammals have evolved recognition systems such as PAMPs and toll-like receptors (TLR). This paper will cover the use of CpG oligonucleotides (a TLR9 agonist found in bacterial DNA) to reverse dendritic cell dysfunction and methods to remove the immune suppressor effects of T-regs that are under active study.

  11. Frequency of Maternal Touch Predicts Resting Activity and Connectivity of the Developing Social Brain.

    PubMed

    Brauer, Jens; Xiao, Yaqiong; Poulain, Tanja; Friederici, Angela D; Schirmer, Annett

    2016-08-01

    Previous behavioral research points to a positive relationship between maternal touch and early social development. Here, we explored the brain correlates of this relationship. The frequency of maternal touch was recorded for 43 five-year-old children during a 10 min standardized play session. Additionally, all children completed a resting-state functional magnetic resonance imaging session. Investigating the default mode network revealed a positive relation between the frequency of maternal touch and activity in the right posterior superior temporal sulcus (pSTS) extending into the temporo-parietal junction. Using this effect as a seed in a functional connectivity analysis identified a network including extended bilateral regions along the temporal lobe, bilateral frontal cortex, and left insula. Compared with children with low maternal touch, children with high maternal touch showed additional connectivity with the right dorso-medial prefrontal cortex. Together these results support the notion that childhood tactile experiences shape the developing "social brain" with a particular emphasis on a network involved in mentalizing. PMID:27230216

  12. Frequency of Maternal Touch Predicts Resting Activity and Connectivity of the Developing Social Brain

    PubMed Central

    Brauer, Jens; Xiao, Yaqiong; Poulain, Tanja; Friederici, Angela D.; Schirmer, Annett

    2016-01-01

    Previous behavioral research points to a positive relationship between maternal touch and early social development. Here, we explored the brain correlates of this relationship. The frequency of maternal touch was recorded for 43 five-year-old children during a 10 min standardized play session. Additionally, all children completed a resting-state functional magnetic resonance imaging session. Investigating the default mode network revealed a positive relation between the frequency of maternal touch and activity in the right posterior superior temporal sulcus (pSTS) extending into the temporo-parietal junction. Using this effect as a seed in a functional connectivity analysis identified a network including extended bilateral regions along the temporal lobe, bilateral frontal cortex, and left insula. Compared with children with low maternal touch, children with high maternal touch showed additional connectivity with the right dorso-medial prefrontal cortex. Together these results support the notion that childhood tactile experiences shape the developing “social brain” with a particular emphasis on a network involved in mentalizing. PMID:27230216

  13. The Effects of Morning Naps, Car Trips, and Maternal Separation on Adrenocortical Activity in Human Infants.

    ERIC Educational Resources Information Center

    Larson, Mary C.; And Others

    1991-01-01

    Three studies examined adrenocortical activity in infants. Morning naps were associated with decreases in salivary cortisol. Riding for 40 minutes in a car lowered salivary cortisol concentrations. Thirty minutes of maternal separation in the laboratory resulted in higher salivary cortisol concentrations than did 30 minutes of play with the mother…

  14. Platelet-Activating Factor-Receptor and Tumor Immunity

    PubMed Central

    Sahu, Ravi P; Konger, Raymond L.; Travers, Jeffrey B.

    2016-01-01

    First described in 1972 by Benveniste and colleagues, platelet-activating factor (PAF) remains one of the potent phospholipid known to date. The role of PAF produced enzymatically in mediating diverse biological and pathophysiological processes including inflammatory and allergic diseases and cancers in response to various stimuli has been extensively studied. However, little is known about the role of non-enzymatically-generated PAF-like lipids produced in response to pro-oxidative stressors, particularly in modulating the host immune responses to tumor immunity, which is the focus of this review.

  15. Photodynamic effect on specific antitumor immune activity

    NASA Astrophysics Data System (ADS)

    Vonarx-Coinsmann, Veronique; Foultier, Marie-Therese; Morlet, Laurent; de Brito, Leonor X.; Patrice, Thierry

    1995-03-01

    In this study the effect of PDT on the antitumoral specific immunologic response was evaluated. We compared the specific cytolytic activity (CLA) by a chromium release assay of primed mouse spleen T lymphocytes sensitized against syngeneic mastocytoma P511 cells. P511 cells, or lymphocytes, or both cells were treated or not with photofrin and/or light (514 nm). Photofrin II alone (1 (mu) g/ml, 2 hours) reduced CLA 59% when P511 were treated. Photofrin II (1 (mu) g/ml) followed by light (25 Joules/sq cm) also reduced CLA 35%. Photofrin II alone (0.5 (mu) g/ml, 2 hours) reduced CLA 8% when only lymphocytes were treated. And Photofrin II (0.5 (mu) g/ml) followed by light (25 Joules/sq cm) also reduced CLA 45%. When both cells were treated with Photofrin II alone or followed by light (25 Joules/sq cm) the CLA was also reduced respectively 19, 41%.

  16. Nucleosides Accelerate Inflammatory Osteolysis, Acting as Distinct Innate Immune Activators

    PubMed Central

    Pan, George; Zheng, Rui; Yang, Pingar; Li, Yao; Clancy, John P.; Liu, Jianzhong; Feng, Xu; Garber, David A; Spearman, Paul; McDonald, Jay M

    2015-01-01

    The innate immune system and its components play an important role in the pathogenesis of inflammatory bone destruction. Blockade of inflammatory cytokines does not completely arrest bone erosion, suggesting that other mediators also may be involved in osteolysis. Previously we showed that nucleosides promote osteoclastogenesis and bone-resorption activity in the presence of receptor activator for nuclear factor κB ligand (RANKL) in vitro. The studies described here further demonstrate that selected nucleosides and nucleoside analogues accelerate bone destruction in mice immunized with collagen II alone (CII) but also further enhance bone erosion in mice immunized by collagen II plus complete Freund's adjuvant (CII + CFA). Abundant osteoclasts are accumulated in destructive joints. These data indicate that nucleosides act as innate immune activators distinct from CFA, synergistically accelerating osteoclast formation and inflammatory osteolysis. The potential roles of the surface triggering receptor expressed on myeloid cells (TREM) and the intracellular inflammasome in nucleoside-enhanced osteoclastogenesis have been studied. These observations provide new insight into the pathogenesis and underlying mechanism of bone destruction in inflammatory autoimmune osteoarthritis. PMID:21472777

  17. The uses and results of active tetanus immunization

    PubMed Central

    Scheibel, Inga

    1955-01-01

    Both in animal experiments and in the course of two world wars active immunization has proved a safe method of protection against tetanus, and a method superior to passive serum prophylaxis. The three types of vaccine—plain, combined, and precipitated or adsorbed—all have their advantages and disadvantages, and the choice between them must be left to individual national health authorities. They should, however, be administered in two or three doses to confer basic immunity. What amount of circulating antitoxin is necessary to give full protection has not been accurately determined, but it is clear that one recall dose should be given about a year after the first injections as part of the routine course of injections. This seems enough to provide a long-lasting immunity, but a dose of vaccine should also be given at the time of injury. General immunization of the population is not practicable, but children, who are among the groups most at risk, can be immunized relatively simply by combined diphtheria and tetanus vaccine; in many countries, indeed, this is being done on an ever-increasing scale. PMID:13270078

  18. Immune Activation Reduces Sperm Quality in the Great Tit

    PubMed Central

    Losdat, Sylvain; Richner, Heinz; Blount, Jonathan D.; Helfenstein, Fabrice

    2011-01-01

    Mounting an immune response against pathogens incurs costs to organisms by its effects on important life-history traits, such as reproductive investment and survival. As shown recently, immune activation produces large amounts of reactive species and is suggested to induce oxidative stress. Sperm are highly susceptible to oxidative stress, which can negatively impact sperm function and ultimately male fertilizing efficiency. Here we address the question as to whether mounting an immune response affects sperm quality through the damaging effects of oxidative stress. It has been demonstrated recently in birds that carotenoid-based ornaments can be reliable signals of a male's ability to protect sperm from oxidative damage. In a full-factorial design, we immune-challenged great tit males while simultaneously increasing their vitamin E availability, and assessed the effect on sperm quality and oxidative damage. We conducted this experiment in a natural population and tested the males' response to the experimental treatment in relation to their carotenoid-based breast coloration, a condition-dependent trait. Immune activation induced a steeper decline in sperm swimming velocity, thus highlighting the potential costs of an induced immune response on sperm competitive ability and fertilizing efficiency. We found sperm oxidative damage to be negatively correlated with sperm swimming velocity. However, blood resistance to a free-radical attack (a measure of somatic antioxidant capacity) as well as plasma and sperm levels of oxidative damage (lipid peroxidation) remained unaffected, thus suggesting that the observed effect did not arise through oxidative stress. Towards the end of their breeding cycle, swimming velocity of sperm of more intensely colored males was higher, which has important implications for the evolution of mate choice and multiple mating in females because females may accrue both direct and indirect benefits by mating with males having better quality sperm

  19. Maternal high-fat diet acts as a stressor increasing maternal glucocorticoids' signaling to the fetus and disrupting maternal behavior and brain activation in C57BL/6J mice.

    PubMed

    Bellisario, Veronica; Panetta, Pamela; Balsevich, Georgia; Baumann, Valentin; Noble, June; Raggi, Carla; Nathan, Olivia; Berry, Alessandra; Seckl, Jonathan; Schmidt, Mathias; Holmes, Megan; Cirulli, Francesca

    2015-10-01

    Maternal diet during pregnancy can impact maternal behavior as well as the intrauterine environment, playing a critical role in programming offspring's physiology. In a preliminary study, we found a strong association between high-fat diet (HFD) during pregnancy and increased cannibalistic episodes and dams' mortality during late pregnancy and parturition. Based upon these data, we hypothesized that HFD during pregnancy could negatively affect neuroendocrine and metabolic regulations occurring during the final stages of pregnancy, thereby disrupting maternal behavior. To test this hypothesis, female C57BL/6J mice were fed HFD or control diet for 11 weeks until three days before the expected delivery date. Basal corticosterone plasma levels and brain levels of c-Fos were measured both before and after delivery, in addition to leptin levels in the adipose tissue. Dam's emotional behavior and social anxiety, in addition to locomotor activity were assessed before parturition. Data show that HFD led to aberrant maternal behavior, dams being characterized by behaviors related to aggression toward an unfamiliar social stimulus in the social avoidance test, in addition to decreased locomotor activity. Neural activity in HFD dams was reduced in the olfactory bulbs, a crucial brain region for social and olfactory recognition hence essential for maternal behavior. Furthermore, HFD feeding resulted in increased circulating levels of maternal corticosterone and decreased levels of leptin. In addition, the activity of the protective 11β-dehydrogenase-2 (11β-HSD-2) barrier in the placenta was decreased together with 11β-dehydrogenase-1 (11β-HSD-1) gene expression. Overall, these data suggest that HFD acts as a stressful challenge during pregnancy, impairing the neuroendocrine system and the neural activity of brain regions involved in the processing of relevant olfactory stimuli, with negative consequences on maternal physiology and behavior. PMID:26143538

  20. Piglets with maternally derived antibodies from sows immunized with rAdV-SFV-E2 were completely protected against lethal CSFV challenge.

    PubMed

    Xia, Shui-Li; Du, Mingliang; Lei, Jian-Lin; Liu, Yan; Wang, Yimin; Ji, Shengwei; Xiang, Guang-Tao; Li, Lian-Feng; Cong, Xin; Luo, Yuzi; Shao, Lina; Qiu, Hua-Ji; Sun, Yuan

    2016-07-15

    Classical swine fever (CSF) is an economically important infectious disease of pigs caused by Classical swine fever virus (CSFV). To facilitate the eradication of CSF in endemic areas, a marker vaccine enabling differentiation of infected from vaccinated animals (DIVA) is urgently needed. Previously, we have demonstrated that the DIVA vaccine rAdV-SFV-E2, an adenovirus-vectored Semliki Forest virus replicon expressing the E2 glycoprotein of CSFV, induces complete protection from lethal CSFV challenge. The aim of this study was to investigate whether maternally derived antibodies (MDAs) from sows immunized with rAdV-SFV-E2 can effectively protect piglets against lethal CSFV challenge. Three groups of five-week-old piglets (n=4), with or without MDAs, were challenged with the highly virulent CSFV Shimen strain. Clinical signs, CSFV-specific antibodies, viremia and pathological and histopathological changes were monitored. The results showed that the piglets with MDAs from the sow immunized with rAdV-SFV-E2 were protected clinically, virologically and pathologically, while the piglets with undetectable MDAs from the rAdV-SFV-E2-immunized sow were partially protected (2/4 survival), in contrast with the piglets from the non-vaccinated sow, which displayed CSF-typical clinical signs, viremia, deaths (4/4) and pathological/histopathological lesions. These results indicate that MDAs from the sow immunized with rAdV-SFV-E2 are able to confer full passive immunity to newborn piglets. PMID:27283854

  1. Effects of experimentally-induced maternal hypothyroidism on crucial offspring rat brain enzyme activities.

    PubMed

    Koromilas, Christos; Liapi, Charis; Zarros, Apostolos; Stolakis, Vasileios; Tsagianni, Anastasia; Skandali, Nikolina; Al-Humadi, Hussam; Tsakiris, Stylianos

    2014-06-01

    Hypothyroidism is known to exert significant structural and functional changes to the developing central nervous system, and can lead to the establishment of serious mental retardation and neurological problems. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil-induced experimental hypothyroidism on crucial brain enzyme activities of Wistar rat offspring, at two time-points of their lives: at birth (day-1) and at 21 days of age (end of lactation). Under all studied experimental conditions, offspring brain acetylcholinesterase (AChE) activity was found to be significantly decreased due to maternal hypothyroidism, in contrast to the two studied adenosinetriphosphatase (Na(+),K(+)-ATPase and Mg(2+)-ATPase) activities that were only found to be significantly altered right after birth (increased and decreased, respectively, following an exposure to gestational maternal hypothyroidism) and were restored to control levels by the end of lactation. As our findings regarding the pattern of effects that maternal hypothyroidism has on the above-mentioned crucial offspring brain enzyme activities are compared to those reported in the literature, several differences are revealed that could be attributed to both the mode of the experimental simulation approach followed as well as to the time-frames examined. These findings could provide the basis for a debate on the need of a more consistent experimental approach to hypothyroidism during neurodevelopment as well as for a further evaluation of the herein presented and discussed neurochemical (and, ultimately, neurodevelopmental) effects of experimentally-induced maternal hypothyroidism, in a brain region-specific manner. PMID:24632022

  2. Coordination of maternal directives with preschoolers' behavior: influence of maternal coordination training on dyadic activity and child compliance.

    PubMed

    Strand, Paul S

    2002-03-01

    Investigated the impact of a specific intervention on child cooperation. The intervention was designed to increase maternal coordination with child behavior. Mothers assigned to the experimental condition were instructed on how to modulate the specificity of directives to their preschooler as a function of the child's moment-to-moment behavior. Mothers assigned to the control condition received no such training. Degree of maternal coordination was then assessed. Child compliance during a pick-up task was also assessed. Compared to controls, experimental mothers had significantly higher scores on several measures of maternal coordination and experimental children were significantly more compliant. The relation between parental coordination and child socialization is discussed. PMID:11845652

  3. Biophysical Aspects of T Lymphocyte Activation at the Immune Synapse

    PubMed Central

    Hivroz, Claire; Saitakis, Michael

    2016-01-01

    T lymphocyte activation is a pivotal step of the adaptive immune response. It requires the recognition by T-cell receptors (TCR) of peptides presented in the context of major histocompatibility complex molecules (pMHC) present at the surface of antigen-presenting cells (APCs). T lymphocyte activation also involves engagement of costimulatory receptors and adhesion molecules recognizing ligands on the APC. Integration of these different signals requires the formation of a specialized dynamic structure: the immune synapse. While the biochemical and molecular aspects of this cell–cell communication have been extensively studied, its mechanical features have only recently been addressed. Yet, the immune synapse is also the place of exchange of mechanical signals. Receptors engaged on the T lymphocyte surface are submitted to many tensile and traction forces. These forces are generated by various phenomena: membrane undulation/protrusion/retraction, cell mobility or spreading, and dynamic remodeling of the actomyosin cytoskeleton inside the T lymphocyte. Moreover, the TCR can both induce force development, following triggering, and sense and convert forces into biochemical signals, as a bona fide mechanotransducer. Other costimulatory molecules, such as LFA-1, engaged during immune synapse formation, also display these features. Moreover, T lymphocytes themselves are mechanosensitive, since substrate stiffness can modulate their response. In this review, we will summarize recent studies from a biophysical perspective to explain how mechanical cues can affect T lymphocyte activation. We will particularly discuss how forces are generated during immune synapse formation; how these forces affect various aspects of T lymphocyte biology; and what are the key features of T lymphocyte response to stiffness. PMID:26913033

  4. High physical activity in young children suggests positive effects by altering autoantigen-induced immune activity.

    PubMed

    Carlsson, E; Ludvigsson, J; Huus, K; Faresjö, M

    2016-04-01

    Physical activity in children is associated with several positive health outcomes such as decreased cardiovascular risk factors, improved lung function, enhanced motor skill development, healthier body composition, and also improved defense against inflammatory diseases. We examined how high physical activity vs a sedentary lifestyle in young children influences the immune response with focus on autoimmunity. Peripheral blood mononuclear cells, collected from 55 5-year-old children with either high physical activity (n = 14), average physical activity (n = 27), or low physical activity (n = 14), from the All Babies In Southeast Sweden (ABIS) cohort, were stimulated with antigens (tetanus toxoid and beta-lactoglobulin) and autoantigens (GAD65 , insulin, HSP60, and IA-2). Immune markers (cytokines and chemokines), C-peptide and proinsulin were analyzed. Children with high physical activity showed decreased immune activity toward the autoantigens GAD65 (IL-5, P < 0.05), HSP60 and IA-2 (IL-10, P < 0.05) and also low spontaneous pro-inflammatory immune activity (IL-6, IL-13, IFN-γ, TNF-α, and CCL2 (P < 0.05)) compared with children with an average or low physical activity. High physical activity in young children seems to have positive effects on the immune system by altering autoantigen-induced immune activity. PMID:25892449

  5. Development of an active boring bar for increased chatter immunity

    SciTech Connect

    Redmond, J.; Barney, P.; Smith, D.

    1997-03-01

    The development and initial evaluation of a prototype boring bar featuring active vibration control for increased chatter immunity is described. The significance of active damping both normal and tangential to the workpiece surface is evaluated, indicating the need for two axis control to ensure adequate performance over expected variations in tool mounting procedures. The prototype tool features a commercially available boring bar modified to accommodate four PZT stack actuators for two axis bending control. Measured closed-loop dynamics are combined with a computer model of the boring process to simulate increased metal removal rate and improved workpiece surface finish through active control.

  6. Immune Activation in the Liver by Nucleic Acids

    PubMed Central

    Sun, Qian; Wang, Qingde; Scott, Melanie J.; Billiar, Timothy R.

    2016-01-01

    Abstract Viral infection in the liver, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, is a major health problem worldwide, especially in developing countries. The infection triggers a pro-inflammatory response in patients that is crucial for host defense. Recent studies have identified multiple transmembrane and cytosolic receptors that recognize pathogen-derived nucleic acids, and these receptors are essential for driving immune activation in the liver. In addition to sensing DNA/RNA from pathogens, these intracellular receptors can be activated by nucleic acids of host origin in response to sterile injuries. In this review, we discuss the expanding roles of these receptors in both immune and nonimmune cells in the liver. PMID:27350945

  7. Maternal obesity is associated with a reduction in placental taurine transporter activity

    PubMed Central

    Ditchfield, A M; Desforges, M; Mills, T A; Glazier, J D; Wareing, M; Mynett, K; Sibley, C P; Greenwood, S L

    2015-01-01

    Background/Objectives: Maternal obesity increases the risk of poor pregnancy outcome including stillbirth, pre-eclampsia, fetal growth restriction and fetal overgrowth. These pregnancy complications are associated with dysfunctional syncytiotrophoblast, the transporting epithelium of the human placenta. Taurine, a β-amino acid with antioxidant and cytoprotective properties, has a role in syncytiotrophoblast development and function and is required for fetal growth and organ development. Taurine is conditionally essential in pregnancy and fetal tissues depend on uptake of taurine from maternal blood. We tested the hypothesis that taurine uptake into placental syncytiotrophoblast by the taurine transporter protein (TauT) is lower in obese women (body mass index (BMI)⩾30 kg m−2) than in women of ideal weight (BMI 18.5–24.9 kg m−2) and explored potential regulatory factors. Subjects/Methods: Placentas were collected from term (37–42-week gestation), uncomplicated, singleton pregnancies from women with BMI 19–49 kg m−2. TauT activity was measured as the Na+-dependent uptake of 3H-taurine into placental villous fragments. TauT expression in membrane-enriched placental samples was investigated by western blot. In vitro studies using placental villous explants examined whether leptin or IL-6, adipokines/cytokines that are elevated in maternal obesity, regulates TauT activity. Results: Placental TauT activity was significantly lower in obese women (BMI⩾30) than women of ideal weight (P<0.03) and inversely related to maternal BMI (19–49 kg m−2; P<0.05; n=61). There was no difference in TauT expression between placentas of ideal weight and obese class III (BMI⩾40) subjects. Long-term exposure (48 h) of placental villous explants to leptin or IL-6 did not affect TauT activity. Conclusions: Placental TauT activity at term is negatively related to maternal BMI. We propose that the reduction in placental TauT activity in maternal obesity

  8. Radiation exposure induces inflammasome pathway activation in immune cells.

    PubMed

    Stoecklein, Veit M; Osuka, Akinori; Ishikawa, Shizu; Lederer, Madeline R; Wanke-Jellinek, Lorenz; Lederer, James A

    2015-02-01

    Radiation exposure induces cell and tissue damage, causing local and systemic inflammatory responses. Because the inflammasome pathway is triggered by cell death and danger-associated molecular patterns, we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase-1 detection in cells. Time course analysis showed the appearance of cleaved caspase-1 in cells by day 1 and sustained expression until day 7 after radiation. Also, cells showing inflammasome activation coexpressed the cell surface apoptosis marker annexin V. The role of caspase-1 as a trigger for hematopoietic cell losses after radiation was studied in caspase-1(-/-) mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase-1(-/-) mice than in control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase-1 activation in cells. Finally, we demonstrate that radiation-induced caspase-1 activation occurs by a Nod-like receptor family protein 3-independent mechanism because radiation-exposed Nlrp3(-/-) mice showed caspase-1 activation profiles that were indistinguishable from those of wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation. PMID:25539818

  9. Maternal vaccination: moving the science forward

    PubMed Central

    Faucette, Azure N.; Unger, Benjamin L.; Gonik, Bernard; Chen, Kang

    2015-01-01

    BACKGROUND Infections remain one of the leading causes of morbidity in pregnant women and newborns, with vaccine-preventable infections contributing significantly to the burden of disease. In the past decade, maternal vaccination has emerged as a promising public health strategy to prevent and combat maternal, fetal and neonatal infections. Despite a number of universally recommended maternal vaccines, the development and evaluation of safe and effective maternal vaccines and their wide acceptance are hampered by the lack of thorough understanding of the efficacy and safety in the pregnant women and the offspring. METHODS An outline was synthesized based on the current status and major gaps in the knowledge of maternal vaccination. A systematic literature search in PUBMED was undertaken using the key words in each section title of the outline to retrieve articles relevant to pregnancy. Articles cited were selected based on relevance and quality. On the basis of the reviewed information, a perspective on the future directions of maternal vaccination research was formulated. RESULTS Maternal vaccination can generate active immune protection in the mother and elicit systemic immunoglobulin G (IgG) and mucosal IgG, IgA and IgM responses to confer neonatal protection. The maternal immune system undergoes significant modulation during pregnancy, which influences responsiveness to vaccines. Significant gaps exist in our knowledge of the efficacy and safety of maternal vaccines, and no maternal vaccines against a large number of old and emerging pathogens are available. Public acceptance of maternal vaccination has been low. CONCLUSIONS To tackle the scientific challenges of maternal vaccination and to provide the public with informed vaccination choices, scientists and clinicians in different disciplines must work closely and have a mechanistic understanding of the systemic, reproductive and mammary mucosal immune responses to vaccines. The use of animal models should be

  10. Prenatal immune challenge in rats: altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC.

    PubMed

    Vorhees, Charles V; Graham, Devon L; Braun, Amanda A; Schaefer, Tori L; Skelton, Matthew R; Richtand, Neil M; Williams, Michael T

    2012-08-01

    Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction). PMID:22473973

  11. Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to Poly IC

    PubMed Central

    Vorhees, Charles V.; Graham, Devon L.; Braun, Amanda A.; Schaefer, Tori L.; Skelton, Matthew R.; Richtand, Neil M.; Williams, Michael T.

    2012-01-01

    Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero-maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, acoustic startle, or latent inhibition deficits reported in Poly IC-treated rats, but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction). PMID:22473973

  12. Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant's immune system early in life.

    PubMed

    Richard, Caroline; Lewis, Erin D; Field, Catherine J

    2016-05-01

    Long-chain polyunsaturated fatty acids (LCPUFA), especially the balance between arachidonic (AA) and docosahexaenoic (DHA) acids are known to have important immunomodulatory roles during the postnatal period when the immune system is rapidly developing. AA and DHA are required in infant formula in many countries but are optional in North America. The rationale for adding these LCPUFA to full-term formula is based on their presence in breast milk and randomized controlled studies that suggest improved cognitive function in preterm infants, but results are more variable in full-term infants. Recently, the European Food Safety Authority has proposed, based on a lack of functional evidence, that AA is not required in infant formula for full-term infants during the first year of life but DHA should remain mandatory. The purpose of this review is to review the evidence from epidemiological and intervention studies regarding the essentiality of AA and DHA in the postnatal infant and maternal diet (breast-feeding) for the immune system development early in life. Although studies support the essentiality of DHA for the immune system development, more research is needed to rule out the essentiality of AA. Nevertheless, intervention studies have demonstrated improvement in many markers of immune function in infants fed formula supplemented with AA and DHA compared with unsupplemented formula, which appears to consistently result in beneficial health outcomes including reduction in the risk of developing allergic and atopic disease early in life. PMID:27138971

  13. Candesartan ameliorates impaired fear extinction induced by innate immune activation.

    PubMed

    Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

    2016-02-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. PMID:26520214

  14. Inflammation, immune activation, and cardiovascular disease in HIV.

    PubMed

    Nou, Eric; Lo, Janet; Grinspoon, Steven K

    2016-06-19

    Cardiovascular disease is one of the leading causes of morbidity and mortality in people living with HIV. Several epidemiological studies have shown an increased risk of myocardial infarction and stroke compared to uninfected controls. Although traditional risk factors contribute to this increased risk of cardiovascular disease, HIV-specific mechanisms likely also play a role. Systemic inflammation has been linked to cardiovascular disease in several populations suffering from chronic inflammation, including people living with HIV. Although antiretroviral therapy reduces immune activation, levels of inflammatory markers remain elevated compared to uninfected controls. The causes of this sustained immune response are likely multifactorial and incompletely understood. In this review, we summarize the evidence describing the relationship between inflammation and cardiovascular disease and discuss potential anti-inflammatory treatment options for cardiometabolic disease in people living with HIV. PMID:27058351

  15. Inactivation Or Inhibition Of Neuronal Activity In The Medial Prefrontal Cortex Largely Reduces Pup Retrieval And Grouping in Maternal Rats

    PubMed Central

    Febo, Marcelo; Felix-Ortiz, Ada C.; Johnson, Tehya R.

    2010-01-01

    Previous research suggests that the maternal medial prefrontal cortex (mPFC) may play a role in maternal care and that cocaine sensitization before pregnancy can affect neuronal activity within this region. The present work was carried out to test whether the mPFC does actually play a role in the expression of maternal behaviors in the rats and to understand what specific behaviors this cortical area may modulate. In the first experiment, tetrodotoxin (TTX) was used to chemically inactivate the mPFC during tests for maternal behavior latencies. Lactating rats were tested on postpartum day 7–9. The results of this first experiment indicate that there is a large effect of TTX-induced inactivation on retrieval behavior latencies. TTX nearly abolished the expression of maternal retrieval of pups without significantly impairing locomotor activity. In the second experiment, GABA-mediated inhibition was used to test maternal behavior latencies and durations of maternal and other behaviors in postpartum dams. In agreement with experiment 1, it was observed that dams capable of retrieving are rendered incapable by inhibition in the mPFC. GABA-mediated inhibition in the mPFC largely reduced retrieval without altering other indices of maternal care and non-specific behavior such as ambulation time, self-grooming, and inactivity. Moreover, in both experiments dams were able to establish contact with pups within seconds. The overall results indicate that the mPFC may play an active role in modulating maternal care, particularly retrieval behavior. External factors that affect the function of the frontal cortical site may result in significant impairments in maternal goal-directed behavior as reported in our earlier work. PMID:20156425

  16. Maternal exposure to endocrine-active substances and breastfeeding.

    PubMed

    Dorea, Jose G

    2006-07-01

    Women pass on low levels of hazardous environmental contaminants and naturally occurring substances during pregnancy and nursing. In addition to estrogenic activity, these substances exhibit antiestrogenic, antiandrogenic, and androgenic actions, and because they can affect thyroid metabolism, they are described as endocrine-active substances (EAS). Specific topics related to EAS metabolism by mothers, fetuses, and infants are discussed. There is strong evidence that the assumed risk of EAS in early human development is exacerbated by interrupting neonatal priming provided by breastfeeding. The benefits of breastfeeding are fundamental to attenuate possible EAS effects on infants due to long-term intrauterine exposure. Breastfeeding is a guarantor of health benefits, whereas its alternative (infant formula) is a predictor of some health limitations. Mothers concerned with exposure to environmental contaminants should be advised of the proven benefits of breastfeeding and the possible health limitations of formula feeding. PMID:16799917

  17. Inflammatory and Immune Activation in Intestinal Myofibroblasts Is Developmentally Regulated.

    PubMed

    Zawahir, Sharmila; Li, Guanghui; Banerjee, Aditi; Shiu, Jessica; Blanchard, Thomas G; Okogbule-Wonodi, Adora C

    2015-08-01

    We previously demonstrated that intestinal myofibroblasts from immature tissue produce excessive IL-8 in response to Escherichia coli lipopolysaccharide (LPS) compared to cells from mature tissue. However, it is unknown whether other cytokines and TLR agonists contribute to this developmentally regulated response. The aim of this study was to further characterize differences in inflammatory signaling in human primary intestinal fibroblasts from fetal (FIF) and infant (IIF) tissue and examine their potential to activate the adaptive immune response in vitro. Cytokine profiles of LPS-stimulated FIF and IIF were assessed by cytokine profile array. IL-8, IL-6, and IL-10 production in response to TLR2, TLR2/6, TLR4, and TLR5 agonists was determined by quantitative ELISA. The potential of activated myofibroblasts to activate adaptive immunity was determined by measuring surface class II MHC expression using flow cytometry. LPS-stimulated FIF produced a distinct proinflammatory cytokine profile consisting of MCP-1, GRO-alpha, IL-6, and IL-8 expression. FIF produced significant IL-8 and IL-6 in response to TLR4 agonist. IIF produced significant levels of IL-8 and IL-6 in the presence of TLR5 and TLR2 agonists. IFN-γ-treated FIF expressed greater HLA-DR levels compared to unstimulated controls and IFN-γ- and LPS-treated IIF. Activated FIF produce a more diverse inflammatory cytokine profile and greater levels of IL-8 and IL-6 in response to TLR4 stimulation compared to IIF. FIF express class II MHC proteins associated with activation of the adaptive immune response. These data suggest that FIF may contribute to bacterial-associated gut inflammation in the immature intestine. PMID:26101946

  18. Inflammatory and Immune Activation in Intestinal Myofibroblasts Is Developmentally Regulated

    PubMed Central

    Zawahir, Sharmila; Li, Guanghui; Banerjee, Aditi; Shiu, Jessica; Blanchard, Thomas G.

    2015-01-01

    We previously demonstrated that intestinal myofibroblasts from immature tissue produce excessive IL-8 in response to Escherichia coli lipopolysaccharide (LPS) compared to cells from mature tissue. However, it is unknown whether other cytokines and TLR agonists contribute to this developmentally regulated response. The aim of this study was to further characterize differences in inflammatory signaling in human primary intestinal fibroblasts from fetal (FIF) and infant (IIF) tissue and examine their potential to activate the adaptive immune response in vitro. Cytokine profiles of LPS-stimulated FIF and IIF were assessed by cytokine profile array. IL-8, IL-6, and IL-10 production in response to TLR2, TLR2/6, TLR4, and TLR5 agonists was determined by quantitative ELISA. The potential of activated myofibroblasts to activate adaptive immunity was determined by measuring surface class II MHC expression using flow cytometry. LPS-stimulated FIF produced a distinct proinflammatory cytokine profile consisting of MCP-1, GRO-alpha, IL-6, and IL-8 expression. FIF produced significant IL-8 and IL-6 in response to TLR4 agonist. IIF produced significant levels of IL-8 and IL-6 in the presence of TLR5 and TLR2 agonists. IFN-γ-treated FIF expressed greater HLA-DR levels compared to unstimulated controls and IFN-γ- and LPS-treated IIF. Activated FIF produce a more diverse inflammatory cytokine profile and greater levels of IL-8 and IL-6 in response to TLR4 stimulation compared to IIF. FIF express class II MHC proteins associated with activation of the adaptive immune response. These data suggest that FIF may contribute to bacterial-associated gut inflammation in the immature intestine. PMID:26101946

  19. Does Severe Maternal Morbidity Affect Female Sexual Activity and Function? Evidence from a Brazilian Cohort Study

    PubMed Central

    Andreucci, Carla B.; Cecatti, José G.; Pacagnella, Rodolfo C.; Silveira, Carla; Parpinelli, Mary A.; Ferreira, Elton C.; Angelini, Carina R.; Santos, Juliana P.; Zanardi, Dulce M.; Bussadori, Jamile C.; Cecchino, Gustavo N.; Souza, Renato T.; Sousa, Maria H.; Costa, Maria L.

    2015-01-01

    Objective to assess Female Sexual Function Index (FSFI) scores and delay to resume sexual activity associated with a previous severe maternal morbidity. Method This was a multidimensional retrospective cohort study. Women who gave birth at a Brazilian tertiary maternity between 2008 and 2012 were included, with data extraction from the hospital information system. Those with potentially life-threatening conditions and maternal near miss episodes (severe maternal morbidity) were considered the exposed group. The control group was a random sample of women who had had uncomplicated pregnancy. Female sexual function was evaluated through FSFI questionnaire, and general and reproductive aspects were addressed through specific questions. Statistical analyses were performed using Mann-Whitney and Pearson´s Chi-square for bivariate analyses. Logistic regression was used to identify variables independently associated with lower FSFI scores. Results 638 women were included (315 at exposed and 323 at not exposed groups). The majority of women were under 30 years-old in the control group and between 30 and 46 years-old in the exposed group (p = 0.003). Women who experienced severe maternal morbidity (SMM) had statistically significant differences regarding cesarean section (82.4% versus 47.1% among deliveries without complications, p<0.001), and some previous pathological conditions. FSFI mean scores were similar among groups ranging from 24.39 to 24.42. It took longer for exposed women to resume sexual activity after index pregnancy (mean 84 days after SMM and 65 days for control group, p = 0.01). Multiple analyses showed no significant association of FSFI below cut-off value with any predictor. Conclusion FSFI scores were not different in both groups. However, they were lower than expected. SMM delayed resumption of sexual activity after delivery, beyond postpartum period. However, the proportion of women in both groups having sex at 3 months after delivery was similar

  20. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity

    PubMed Central

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  1. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity.

    PubMed

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin; Henriques-Normark, Birgitta; Olliver, Marie

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  2. Effect of Maternal Schistosoma mansoni Infection and Praziquantel Treatment During Pregnancy on Schistosoma mansoni Infection and Immune Responsiveness among Offspring at Age Five Years

    PubMed Central

    Tweyongyere, Robert; Naniima, Peter; Mawa, Patrice A.; Jones, Frances M.; Webb, Emily L.; Cose, Stephen; Dunne, David W.; Elliott, Alison M.

    2013-01-01

    Introduction Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years. Methods In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years. Results Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not. Conclusion We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood

  3. Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis

    PubMed Central

    George, Parakkal Jovvian; Kumar, Nathella Pavan; Sridhar, Rathinam; Hanna, Luke E.; Nair, Dina; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. PMID:25375117

  4. Maternal caffeine exposure alters neuromotor development and hippocampus acetylcholinesterase activity in rat offspring.

    PubMed

    Souza, Ana Claudia; Souza, Andressa; Medeiros, Liciane Fernandes; De Oliveira, Carla; Scarabelot, Vanessa Leal; Da Silva, Rosane Souza; Bogo, Mauricio Reis; Capiotti, Katiucia Marques; Kist, Luiza Wilges; Bonan, Carla D; Caumo, Wolnei; Torres, Iraci L S

    2015-01-21

    The objective of this study was to evaluate the effects of maternal caffeine intake on the neuromotor development of rat offspring and on acetylcholine degradation and acetylcholinesterase (AChE) expression in the hippocampus of 14-day-old infant rats. Rat dams were treated with caffeine (0.3g/L) throughout gestation and lactation until the pups were 14 days old. The pups were divided into three groups: (1) control, (2) caffeine, and (3) washout caffeine. The washout group received a caffeine solution until the seventh postnatal day (P7). Righting reflex (RR) and negative geotaxis (NG) were assessed to evaluate postural parameters as an index of neuromotor reflexes. An open-field (OF) test was conducted to assess locomotor and exploratory activities as well as anxiety-like behaviors. Caffeine treatment increased both RR and NG latency times. In the OF test, the caffeine group had fewer outer crossings and reduced locomotion compared to control, while the washout group showed increased inner crossings in relation to the other groups and fewer rearings only in comparison to the control group. We found decreased AChE activity in the caffeine group compared to the other groups, with no alteration in AChE transcriptional regulation. Chronic maternal exposure to caffeine promotes important alterations in neuromotor development. These results highlight the ability of maternal caffeine intake to interfere with cholinergic neurotransmission during brain development. PMID:25451122

  5. Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition.

    PubMed

    Li, Xiao-Yong; Harrison, Melissa M; Villalta, Jacqueline E; Kaplan, Tommy; Eisen, Michael B

    2014-01-01

    We describe the genome-wide distributions and temporal dynamics of nucleosomes and post-translational histone modifications throughout the maternal-to-zygotic transition in embryos of Drosophila melanogaster. At mitotic cycle 8, when few zygotic genes are being transcribed, embryonic chromatin is in a relatively simple state: there are few nucleosome free regions, undetectable levels of the histone methylation marks characteristic of mature chromatin, and low levels of histone acetylation at a relatively small number of loci. Histone acetylation increases by cycle 12, but it is not until cycle 14 that nucleosome free regions and domains of histone methylation become widespread. Early histone acetylation is strongly associated with regions that we have previously shown to be bound in early embryos by the maternally deposited transcription factor Zelda, suggesting that Zelda triggers a cascade of events, including the accumulation of specific histone modifications, that plays a role in the subsequent activation of these sequences. PMID:25313869

  6. sIgZ exhibited maternal transmission in embryonic development and played a prominent role in mucosal immune response of Megalabrama amblycephala.

    PubMed

    Xia, Hu; Liu, Wanjing; Wu, Kang; Wang, Weimin; Zhang, Xuezhen

    2016-07-01

    IgZ is considered to be the last immunoglobulin discovered in vertebrate species. In this study, the structure of secreted form of blunt snout bream (Megalabrama amblycephala) IgZ (sIgZ) heavy chain gene is VH-Cζ1-Cζ2-Cζ3-Cζ4, in which Cζ4 provides the specificity to the IgZ isotype. The deduced amino acid sequence of sIgZ shows highest similarity with that of Ctenopharyngodon idella (79%). The ontogeny of sIgZ gene expression showed a V-shape change pattern: decreased initially from unfertilized egg stage to 16-cell embryos and increased significantly from blastula stage, which exhibited maternal transmission effects. Compared with the juvenile fish, sIgZ mRNA level was higher in head kidney, spleen, trunk kidney, liver, intestine and gill of adult fish. In both juvenile and adult fish, sIgZ mRNA was detected in intestine and gill. Aeromonas hydrophila challenge experiment showed that sIgZ transcription significantly increased in skin, gill and intestine, indicating a prominent mucosal immune response. The results of Western blot also verified the protein alterations of sIgZ in mucosal organs in M. amblycephal. Our studies indicate a prominent role of IgZ in mucosa-associated lymphoid tissue immunity and further support the specialized role of IgZ in teleost mucosal immune responses. PMID:27044330

  7. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  8. Maternal coordination of the daily rhythm of malate dehydrogenase activity in testes from young rats: effect of maternal sympathetic denervation of the pineal gland and administration of melatonin.

    PubMed

    Vermouth, N T; Carriazo, C S; Gallará, R V; Carpentieri, A R; Bellavía, S L

    1995-02-01

    Chronic sympathetic denervation of the pineal gland by bilateral removal of the superior cervical ganglia (SCG) was performed on female rats 30 days before impregnation. The offspring, maintained in the dark from birth, had disruption of the malate dehydrogenase circadian rhythm in the testes at 25 days of age. A daily injection of melatonin (1 mg/kg s.c. at 10:00 or 18:00 h) to denervated mothers from the 14th day of pregnancy up to the 10th day postpartum produced one daily phase in the enzyme activity of tests in the offspring. Entrainment of daily enzyme activity also was obtained when the hormone was administered orally to the pups during the postnatal period or when pups were reared by intact (not denervated) foster mothers. The results indicate the involvement of the maternal pineal gland in the maternal transfer of photoperiodic information necessary for the coordination of the circadian system in young rats. PMID:7750160

  9. The Effects of Maternal Natural (RRR Alpha-Tocopherol Acetate) or Synthetic (All-Rac Alpha-Tocopherol Acetate) Vitamin E Supplementation on Suckling Calf Performance, Colostrum IgG, and Immune Function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to determine the effects of maternally supplemented natural- or synthetic-source vitamin E on suckling calf performance and immune response. In a two-year study, 152 two- and three-year old spring-calving Angus-cross beef cows were blocked by age, BW, and BCS into on...

  10. Path to impact: A report from the Bill and Melinda Gates Foundation convening on maternal immunization in resource-limited settings; Berlin - January 29-30, 2015.

    PubMed

    Sobanjo-Ter Meulen, Ajoke; Abramson, Jon; Mason, Elizabeth; Rees, Helen; Schwalbe, Nina; Bergquist, Sharon; Klugman, Keith P

    2015-11-25

    Global initiatives such as the Millennium Development Goals have led to major improvements in the health of women and children, and significant reductions in childhood mortality. Worldwide, maternal mortality has decreased by 45% and under-five mortality has fallen by over 50% over the past two decades [1]. However, improvements have not been achieved evenly across all ages; since 1990, under-five mortality has declined by ∼5% annually, but the average decrease in neonatal mortality is only ∼3% per year. Against this background, the Bill and Melinda Gates Foundation (BMGF) convened a meeting in Berlin on January 29-30, 2015 of global health stakeholders, representing funders, academia, regulatory agencies, non-governmental organizations, vaccine manufacturers, and Ministries of Health from Africa and Asia. The topic of discussion was the potential of maternal immunization (MI) to achieve further improvements in under-five morbidity and mortality rates in children, and particularly neonates and young infants, through targeting infectious diseases that are not preventable by other interventions in these age groups. The meeting focused on effective and appropriately priced MI vaccines against influenza, pertussis, and tetanus, as well as against respiratory syncytial virus, and the group B Streptococcus, for which no licensed vaccines currently exist. The primary goals of the BMGF 2015 convening were to bring together the global stakeholders in vaccine development, policy and delivery together with the Maternal, Newborn and Child Health (MNCH) community, to get recognition that MI is a strategy shared between these groups and so encourage increased collaboration, and obtain alignment on the next steps toward achieving a significant health impact through implementation of a MI program. PMID:26314626

  11. Microglia mechanics: immune activation alters traction forces and durotaxis

    PubMed Central

    Bollmann, Lars; Koser, David E.; Shahapure, Rajesh; Gautier, Hélène O. B.; Holzapfel, Gerhard A.; Scarcelli, Giuliano; Gather, Malte C.; Ulbricht, Elke; Franze, Kristian

    2015-01-01

    Microglial cells are key players in the primary immune response of the central nervous system. They are highly active and motile cells that chemically and mechanically interact with their environment. While the impact of chemical signaling on microglia function has been studied in much detail, the current understanding of mechanical signaling is very limited. When cultured on compliant substrates, primary microglial cells adapted their spread area, morphology, and actin cytoskeleton to the stiffness of their environment. Traction force microscopy revealed that forces exerted by microglia increase with substrate stiffness until reaching a plateau at a shear modulus of ~5 kPa. When cultured on substrates incorporating stiffness gradients, microglia preferentially migrated toward stiffer regions, a process termed durotaxis. Lipopolysaccharide-induced immune-activation of microglia led to changes in traction forces, increased migration velocities and an amplification of durotaxis. We finally developed a mathematical model connecting traction forces with the durotactic behavior of migrating microglial cells. Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies. Stiffness gradients in tissue surrounding neural implants such as electrodes, for example, could mechanically attract microglial cells, thus facilitating foreign body reactions detrimental to electrode functioning. PMID:26441534

  12. Active immunization therapies for Parkinson's disease and multiple system atrophy.

    PubMed

    Schneeberger, Achim; Tierney, Lanay; Mandler, Markus

    2016-02-01

    Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs. PMID:26260853

  13. Activation of cellular immune response in acute pancreatitis.

    PubMed Central

    Mora, A; Pérez-Mateo, M; Viedma, J A; Carballo, F; Sánchez-Payá, J; Liras, G

    1997-01-01

    BACKGROUND: Inflammatory mediators have recently been implicated as potential markers of severity in acute pancreatitis. AIMS: To determine the value of neopterin and polymorphonuclear (PMN) elastase as markers of activation of cellular immunity and as early predictors of disease severity. PATIENTS: Fifty two non-consecutive patients classified according to their clinical outcome into mild (n = 26) and severe pancreatitis (n = 26). METHODS: Neopterin in serum and the PMN elastase/A1PI complex in plasma were measured during the first three days of hospital stay. RESULTS: Within three days after the onset of acute pancreatitis, PMN elastase was significantly higher in the severe pancreatitis group. Patients with severe disease also showed significantly higher values of neopterin on days 1 and 2 but not on day 3 compared with patients with mild disease. There was a significant correlation between PMN elastase and neopterin values on days 1 and 2. PMN elastase on day 1 predicted disease severity with a sensitivity of 76.7% and a specificity of 91.6%. Neopterin did not surpass PMN elastase in the probability of predicting disease severity. CONCLUSIONS: These data show that activation of cellular immunity is implicated in the pathogenesis of acute pancreatitis and may be a main contributory factor to disease severity. Neopterin was not superior to PMN elastase in the prediction of severity. PMID:9245935

  14. Divergent immune responses and disease outcomes in piglets immunized with inactivated and attenuated H3N2 swine influenza vaccines in the presence of maternally-derived antibodies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vaccine-associated enhanced respiratory disease (VAERD) can occur in pigs immunized with whole-inactivated influenza virus (WIV) vaccine and subsequently infected with an antigenically divergent virus of the same HA subtype. Live-attenuated influenza virus (LAIV) vaccines administered intranasally h...

  15. Sex-dependent changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of maternal deprivation and adolescent cocaine exposure.

    PubMed

    Llorente-Berzal, Alvaro; Assis, María A; Rubino, Tiziana; Zamberletti, Erica; Marco, Eva M; Parolaro, Daniela; Ambrosio, Emilio; Viveros, María-Paz

    2013-08-01

    Early life stress has been associated with several psychiatric disorders, including drug addiction. Actually, maternal deprivation (MD) alters the endocannabinoid system, which participates in motivation and reward for drugs, including cocaine. At youth, the rate of cocaine abuse is alarmingly increasing. Herein, we have investigated the consequences of MD and/or adolescent cocaine exposure in brain CB1Rs and CB2Rs in immune tissues. Control and maternally deprived (24h on postnatal day, pnd, 9) male and female Wistar rats were administered cocaine (8mg/kg/day) or saline during adolescence (pnd 28-42). At adulthood, [(3)H]-CP-55,940 autoradiographic binding was employed for the analysis of CB1R density and CP-55,940-stimulated [(35)S]-GTPgammaS binding for CB1R functionality; CB2R expression was analyzed by Western blotting. Sex differences in CB1R expression and functionality were found, and MD induced important and enduring sex-dependent changes. In addition, the plastic changes induced by adolescent cocaine administration in brain CB1Rs were differentially influenced by early life events. MD increased spleen CB2R expression while adolescent cocaine administration attenuated this effect; cocaine exposure also diminished CB2R expression in bone marrow. Present findings provide evidence for changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of early life stress and adolescent cocaine exposure, and indicate functional interactions between both treatments, which in many regions differ between males and females. PMID:23680694

  16. Cellular Immune Activation in Cerebrospinal Fluid From Ugandans With Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome

    PubMed Central

    Meya, David B.; Okurut, Samuel; Zziwa, Godfrey; Rolfes, Melissa A.; Kelsey, Melander; Cose, Steve; Joloba, Moses; Naluyima, Prossy; Palmer, Brent E.; Kambugu, Andrew; Mayanja-Kizza, Harriet; Bohjanen, Paul R.; Eller, Michael A.; Wahl, Sharon M.; Boulware, David R.; Manabe, Yuka C.; Janoff, Edward N.

    2015-01-01

    Background. Human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is characterized by high fungal burden and limited leukocyte trafficking to cerebrospinal fluid (CSF). The immunopathogenesis of CM immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy at the site of infection is poorly understood. Methods. We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). Results. At diagnosis, highly activated CD8+ T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4+ T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood. Conclusions. After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4+ T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS. PMID:25492918

  17. Innate immunity and monocyte-macrophage activation in atherosclerosis

    PubMed Central

    2011-01-01

    Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review. PMID:21526997

  18. The effect of maternal immunization on female oxidative status, yolk antioxidants and offspring survival in a songbird.

    PubMed

    Casasole, G; Costantini, D; Cichoń, M; Rutkowska, J

    2016-04-01

    Immune defense involves inflammatory reactions in which immune cells produce reactive oxygen species (ROS) to fight pathogens. ROS may however cause damage to the host if they are not balanced by antioxidant defenses. Therefore, one should expect individuals undergoing an immune reaction to use antioxidants to prevent oxidative stress. Antioxidants are vital compounds that provide important protection against oxidative damage of embryos and newly hatched chicks. Thus, during egg laying a female that contracted an infection may face a trade-off between the allocation of antioxidants into self-maintenance and into her offspring via the eggs. In our study we investigated whether immunized females face this trade-off and consequently modify the antioxidant allocation into the eggs and whether this allocation affects offspring performance. We injected female zebra finches (Taeniopygia guttata) with lipopolysaccharide prior to egg laying while some females were left unimmunized. We removed the second egg of each clutch, while we allowed the other eggs to hatch. We assessed oxidative stress in females 24h after immunization, yolk antioxidant capacity of the second egg of the clutch and survival success of the offspring until adulthood. Compared to controls, immunized females had higher oxidative damage, but similar plasma non-enzymatic antioxidant levels. The treatment did not affect yolk antioxidants, clutch size, laying date and offspring survival. However, we found a positive correlation between yolk antioxidant capacity and offspring survival, irrespective of the treatment. Our study suggests that our immune challenge may not have changed female strategy of antioxidant allocation between self-maintenance and offspring survival. PMID:26812206

  19. Metabolic signals and innate immune activation in obesity and exercise.

    PubMed

    Ringseis, Robert; Eder, Klaus; Mooren, Frank C; Krüger, Karsten

    2015-01-01

    The combination of a sedentary lifestyle and excess energy intake has led to an increased prevalence of obesity which constitutes a major risk factor for several co-morbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system. Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IκBα kinase/nuclear factor-κB (IKK/NF- κB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD-like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling. Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing obesity- induced chronic inflammation. This review summarizes current knowledge of the cellular recognition mechanisms for FFAs, the inflammatory signaling pathways triggered by excess FFAs in obesity and the counteractive effects of both acute and chronic exercise on obesity-induced activation of inflammatory signaling pathways. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its comorbidities. PMID:25825956

  20. Protein Translation Activity: A New Measure of Host Immune Cell Activation.

    PubMed

    Seedhom, Mina O; Hickman, Heather D; Wei, Jiajie; David, Alexandre; Yewdell, Jonathan W

    2016-08-15

    We describe the in vivo ribopuromycylation (RPM) method, which uses a puromycin-specific Ab to fluorescently label ribosome-bound puromycylated nascent chains, enabling measurement of translational activity via immunohistochemistry or flow cytometry. Tissue staining provides a unique view of virus-induced activation of adaptive, innate, and stromal immune cells. RPM flow precisely quantitates virus-induced activation of lymphocytes and innate immune cells, and it provides a unique measure of immune cell deactivation and quiescence. Using RPM we find that high endothelial cells in draining lymph nodes rapidly increase translation in the first day of vaccinia virus infection. We also find a population of constitutively activated splenic T cells in naive mice and further that most bone marrow T cells activate 3 d after vaccinia virus infection. Bone marrow T cell activation is nonspecific, IL-12-dependent, and induces innate memory T cell phenotypic markers. Thus, RPM measures translational activity to uniquely identify cell populations that participate in the immune response to pathogens, other foreign substances, and autoantigens. PMID:27385780

  1. Does Infection-Induced Immune Activation Contribute to Dementia?

    PubMed Central

    Barichello, Tatiana; Generoso, Jaqueline S; Goularte, Jessica A; Collodel, Allan; Pitcher, Meagan R; Simões, Lutiana R; Quevedo, João; Dal-Pizzol, Felipe

    2015-01-01

    The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen-associated molecular patterns (PAMP) and they are identified by pattern-recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of αβ-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders. PMID:26425389

  2. Lessons in community health activism: the maternity care coalition, 1970-1990.

    PubMed

    Maldonado, Linda

    2014-01-01

    This study employed historical methodologies to explore the means through which the Maternity Care Coalition used grassroots activism to dismantle the power structures and other obstacles that contributed to high infant mortality rates in Philadelphia's health districts 5 and 6 during the 1980s. Infant mortality within the black community has been a persistent phenomenon in the United States. Refusing to accept poverty as a major determinant of infant mortality within marginalized populations of women, activists during the 1980s harnessed momentum from a postcivil rights context and sought alternative methods toward change and improvement of infant mortality rates. PMID:24892861

  3. GITR Activation Positively Regulates Immune Responses against Toxoplasma gondii

    PubMed Central

    Costa, Frederico R. C.; Mota, Caroline M.; Santiago, Fernanda M.; Silva, Murilo V.; Ferreira, Marcela D.; Fonseca, Denise M.; Silva, João S.; Mineo, José R.; Mineo, Tiago W. P.

    2016-01-01

    Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals. Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells. However, the precise role of this receptor in the context of T. gondii infection remains elusive. Therefore, the current study investigated the role of GITR activation in the immunoregulation mechanisms induced during the experimental infection of mice with T. gondii. Our data show that T. gondii infection slightly upregulates GITR expression in Treg cells and B cells, but the most robust increment in expression was observed in macrophages and dendritic cells. Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1. Several in vivo and in vitro analysis were performed to identify the cellular mechanisms involved in GITR activation upon infection, however no clear alterations were detected in the phenotype/function of macrophages, Tregs and B cells under treatment with DTA-1. Therefore, GITR appears as a potential target for intervention during infection by the parasite Toxoplasma gondii, even though further studies are still necessary to better characterize the immune response triggered by GITR activation during T. gondii infection. PMID:27027302

  4. IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.

    PubMed

    Paquin-Proulx, Dominic; Santos, Bianca A N; Carvalho, Karina I; Toledo-Barros, Myrthes; Barreto de Oliveira, Ana Karolina; Kokron, Cristina M; Kalil, Jorge; Moll, Markus; Kallas, Esper G; Sandberg, Johan K

    2013-01-01

    Common variable immunodeficiency (CVID) is characterized by defective B cell function, impaired antibody production, and increased susceptibility to bacterial infections. Here, we addressed the hypothesis that poor antibody-mediated immune control of infections may result in substantial perturbations in the T cell compartment. Newly diagnosed CVID patients were sampled before, and 6-12 months after, initiation of intravenous immunoglobulin (IVIg) therapy. Treatment-naïve CVID patients displayed suppressed CD4 T cell counts and myeloid dendritic cell (mDC) levels, as well as high levels of immune activation in CD8 T cells, CD4 T cells, and invariant natural killer T (iNKT) cells. Expression of co-stimulatory receptors CD80 and CD83 was elevated in mDCs and correlated with T cell activation. Levels of both FoxP3+ T regulatory (Treg) cells and iNKT cells were low, whereas soluble CD14 (sCD14), indicative of monocyte activation, was elevated. Importantly, immune reconstitution treatment with IVIg partially restored the CD4 T cell and mDC compartments. Treatment furthermore reduced the levels of CD8 T cell activation and mDC activation, whereas levels of Treg cells and iNKT cells remained low. Thus, primary deficiency in humoral immunity with impaired control of microbial infections is associated with significant pathological changes in cell-mediated immunity. Furthermore, therapeutic enhancement of humoral immunity with IVIg infusions alleviates several of these defects, indicating a relationship between poor antibody-mediated immune control of infections and the occurrence of abnormalities in the T cell and mDC compartments. These findings help our understanding of the immunopathogenesis of primary immunodeficiency, as well as acquired immunodeficiency caused by HIV-1 infection. PMID:24130688

  5. Maternal and fetal immune response patterns in heifers experimentally infected with Neospora caninum in the second trimester of pregnancy--a descriptive study.

    PubMed

    Almería, S; Serrano-Pérez, B; Darwich, L; Araujo, R N; Lopez-Gatius, F; Dubey, J P; Gasbarre, L C

    2014-08-29

    Fetal and maternal immune responses 3, 6 and 9 weeks post infection (wpi) were investigated in cows experimentally infected with Neospora caninum on day 110 of gestation. Descriptive analysis showed that the fetuses had lower percentages of spleen T cell subpopulations (CD3+, CD4+ and CD8+) at 6 wpi compared to 3 wpi and/or 9 wpi, with the lowest percentages observed in a dead fetus found upon euthanasia at that time. Increased expression of most cytokines over levels recorded at 3 and 9 wpi were found in fetuses that were alive at 6 wpi. Up-regulated Th1, Th2 and Treg expression was also observed at 6 wpi in the spleen and in the lymph nodes draining the placenta of the cows. At the placental level, while most cytokines were down-regulated from 6 wpi, up-regulation of IL-4 expression was observed at 6 wpi in the caruncle. Our results suggest that the immune response at 6 wpi was crucial for fetal survival in this model of bovine neosporosis. PMID:24880649

  6. INVOLVEMENT OF PEPTIDOGLYCAN RECOGNITION PROTEIN L6 IN ACTIVATION OF IMMUNE DEFICIENCY PATHWAY IN THE IMMUNE RESPONSIVE SILKWORM CELLS.

    PubMed

    Tanaka, Hiromitsu; Sagisaka, Aki

    2016-06-01

    The immune deficiency (Imd) signaling pathway is activated by Gram-negative bacteria for producing antimicrobial peptides (AMPs). In Drosophila melanogaster, the activation of this pathway is initiated by the recognition of Gram-negative bacteria by peptidoglycan (PGN) recognition proteins (PGRPs), PGRP-LC and PGRP-LE. In this study, we found that the Imd pathway is involved in enhancing the promoter activity of AMP gene in response to Gram-negative bacteria or diaminopimelic (DAP) type PGNs derived from Gram-negative bacteria in an immune responsive silkworm cell line, Bm-NIAS-aff3. Using gene knockdown experiments, we further demonstrated that silkworm PGRP L6 (BmPGRP-L6) is involved in the activation of E. coli or E. coli-PGN mediated AMP promoter activation. Domain analysis revealed that BmPGRP-L6 contained a conserved PGRP domain, transmembrane domain, and RIP homotypic interaction motif like motif but lacked signal peptide sequences. BmPGRP-L6 overexpression enhances AMP promoter activity through the Imd pathway. BmPGRP-L6 binds to DAP-type PGNs, although it also binds to lysine-type PGNs that activate another immune signal pathway, the Toll pathway in Drosophila. These results indicate that BmPGRP-L6 is a key PGRP for activating the Imd pathway in immune responsive silkworm cells. PMID:26991439

  7. Association between maternal education and objectively measured physical activity and sedentary time in adolescents

    PubMed Central

    Sherar, Lauren B; Griffin, Tom P; Ekelund, Ulf; Cooper, Ashley R; Esliger, Dale W; van Sluijs, Esther M F; Bo Andersen, Lars; Cardon, Greet; Davey, Rachel; Froberg, Karsten; Hallal, Pedro C; Janz, Kathleen F; Kordas, Katarzyna; Kriemler, Susi; Pate, Russell R; Puder, Jardena J; Sardinha, Luis B; Timperio, Anna F; Page, Angie S

    2016-01-01

    Background Investigating socioeconomic variation in physical activity (PA) and sedentary time is important as it may represent a pathway by which socioeconomic position (SEP) leads to ill health. Findings on the association between children's SEP and objectively assessed PA and/or sedentary time are mixed, and few studies have included international samples. Objective Examine the associations between maternal education and adolescent's objectively assessed PA and sedentary time. Methods This is an observational study of 12 770 adolescents (10–18 years) pooled from 10 studies from Europe, Australia, Brazil and the USA. Original PA data were collected between 1997 and 2009. The associations between maternal education and accelerometer variables were examined using robust multivariable regression, adjusted for a priori confounders (ie, body mass index, monitor wear time, season, age and sex) and regression coefficients combined across studies using random effects meta-analyses. Analyses were conducted in March 2014. Results Adolescents of university educated mothers spent more time sedentary (9.5 min/day, p=0.005) and less time in light activity (10 min/day, p<0.001) compared with adolescents of high school educated mothers. Pooled analysis across two studies from Brazil and Portugal (analysed separately because of the different coding of maternal education) showed that children of higher educated mothers (tertiary vs primary/secondary) spent less time in moderate to vigorous PA (MVPA) (6.6 min/day, p=0.001) and in light PA (39.2 min/day: p<0.001), and more time sedentary (45.9 min/day, p<0.001). Conclusions Across a number of international samples, adolescents of mothers with lower education may not be at a disadvantage in terms of overall objectively measured PA. PMID:26802168

  8. The effect of a maternal dietary yeast cell wall supplement during gestation on cow performance and calf growth and immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to determine if feeding of yeast cell wall (YCW) to pregnant cows influences cow performance as well as postnatal calf growth and immunity. Multiparous cows were grouped by predicted calving date into groups of control (C; n=24) and supplemented (Y; n=24) cows. The Y ...

  9. Prenatal immune activation in mice blocks the effects of environmental enrichment on exploratory behavior and microglia density.

    PubMed

    Buschert, Jens; Sakalem, Marna E; Saffari, Roja; Hohoff, Christa; Rothermundt, Matthias; Arolt, Volker; Zhang, Weiqi; Ambrée, Oliver

    2016-06-01

    Adverse environmental factors including prenatal maternal infection are capable of inducing long-lasting behavioral and neural alterations which can enhance the risk to develop schizophrenia. It is so far not clear whether supportive postnatal environments are able to modify such prenatally-induced alterations. In rodent models, environmental enrichment influences behavior and cognition, for instance by affecting endocrinologic, immunologic, and neuroplastic parameters. The current study was designed to elucidate the influence of postnatal environmental enrichment on schizophrenia-like behavioral alterations induced by prenatal polyI:C immune stimulation at gestational day 9 in mice. Adult offspring were tested for amphetamine-induced locomotion, social interaction, and problem-solving behavior as well as expression of dopamine D1 and D2 receptors and associated molecules, microglia density and adult neurogenesis. Prenatal polyI:C treatment resulted in increased dopamine sensitivity and dopamine D2 receptor expression in adult offspring which was not reversed by environmental enrichment. Prenatal immune activation prevented the effects of environmental enrichment which increased exploratory behavior and microglia density in NaCl treated mice. Problem-solving behavior as well as the number of immature neurons was affected by neither prenatal immune stimulation nor postnatal environmental enrichment. The behavioral and neural alterations that persist into adulthood could not generally be modified by environmental enrichment. This might be due to early neurodevelopmental disturbances which could not be rescued or compensated for at a later developmental stage. PMID:26776071

  10. Maternally-derived antibodies (MDAs) impair piglets' humoral and cellular immune responses to vaccination against porcine reproductive and respiratory syndrome (PRRS).

    PubMed

    Fablet, C; Renson, P; Eono, F; Mahé, S; Eveno, E; Le Dimna, M; Normand, V; Lebret, A; Rose, N; Bourry, O

    2016-08-30

    The influence of maternally-derived antibodies (MDAs) on the post-vaccination humoral and cellular immune responses in piglets vaccinated against PRRS was studied. The piglets came from a vaccinated breeding herd. Thirty piglets with a low (A-) or high level (A+) of PRRSV-neutralizing MDAs were vaccinated (V+) with a modified live vaccine at 3 weeks of age. Blood samples were collected before vaccination and then at 2, 4, 8 and 14 weeks post-vaccination (WPV). The samples were analysed to detect the vaccine viraemia (RT-PCR) and quantify the post-vaccination humoral (ELISA and virus neutralisation test) and cellular (ELISPOT IFNγ) immune responses. PRRSV vaccine strain was detected in 60%, 64%, 36% and 0% of A-V+ piglets 2, 4, 8 and 14 WPV respectively. No virus was detected in A+V+ piglets during the first four WPV but 32% and 6% of A+V+ piglets were PCR-positive at 8 and 14 WPV. Eighty-five percent of A-V+ piglets and 0% of A+V+ piglets seroconverted (ELISA) between 2 and 4 WPV. Neutralising antibodies appeared 4 WPV in the A-V+ piglets and 14 WPV in the A+V+ piglets. The number of PRRSV-specific IFNγ-secreting cells was significantly higher in A-V+ piglets at 2 and 4 WPV than in A+V+ piglets. These results show that MDAs can affect both post-vaccination humoral and cellular immune responses in piglets. Further studies are required to assess the impact of MDAs on vaccine efficacy following a PRRSV challenge and its ability to reduce viral transmission. PMID:27527780

  11. The immune pathogenesis of immune reconstitution inflammatory syndrome associated with highly active antiretroviral therapy in AIDS.

    PubMed

    Zheng, Yuhuang; Zhou, Huaying; He, Yan; Chen, Zi; He, Bo; He, Mei

    2014-12-01

    The present study investigated the immunological pathogenesis of immune reconstitution inflammatory syndrome (IRIS) in acquired immunodeficiency syndrome (AIDS) patients undergoing highly active antiretroviral therapy (HAART). A total of 238 patients with AIDS who received initial HAART were included in this prospective cohort study. Blood samples were collected immediately, at baseline, at week 12, and at week 24 after initial HAART and at the onset of IRIS. Lymphocyte subsets, Th1 and Th2 cytokines, and interleukin (IL)-7 levels were measured by flow cytometry or ELISA. Among the 238 patients with AIDS who received HAART, 47 patients developed IRIS. The percentages of CD4(+) and CD8(+) naive, memory, and activated cells exhibited no significant differences between AIDS patients with and without IRIS 24 weeks after initial HAART. The percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells was lower in IRIS patients than in non-IRIS patients before HAART, 12 weeks after HAART, 24 weeks after HAART, and at the onset of IRIS. IL-2 and interferon (IFN)-γ levels were significantly higher at week 4 and at the onset of IRIS in IRIS patients than in non-IRIS patients. In contrast, IL-4 and IL-10 levels were significantly lower at week 4 and at the onset of IRIS in IRIS patients than in non-IRIS patients. Plasma IL-7 decreased gradually with the progression of HAART. The level of IL-7 was higher in IRIS patients than in non-IRIS patients at all follow-up time points. An imbalance of Th1/Th2 cytokines, a consistently low CD(+)CD25(+)Fox3(+) percentage, and a high IL-7 level may be crucial in the pathogenesis of IRIS in AIDS patients who had received HAART. PMID:25131160

  12. Effect of maternal anti-HPA-1a antibodies and polyclonal IVIG on the activation status of vascular endothelial cells

    PubMed Central

    RADDER, C M; BEEKHUIZEN, H; KANHAI, H H H; BRAND, A

    2004-01-01

    Maternal anti-HPA-1a antibodies can cause severe fetal and neonatal alloimmune thrombocytopenia (FNAIT), complicated by intracranial haemorrhage (ICH). Antenatal treatment with maternal intravenous immunoglobulin (IVIG) seems to protect against ICH even when thrombocytopenia persists. The aim of this study was to investigate if anti-HPA-1a antibodies and IVIG potentially affect vascular endothelial cells (ECs) in order to identify susceptibility for ICH. Human umbilical cord endothelial cells (HUVEC) were incubated with anti-HPA-1a antibodies with or without polyclonal IVIG and evaluated for EC activation. Maternal sera with anti-HPA-1a antibodies affected neither the EC expression of intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and tissue factor (TF) nor the release of van Willebrand factor (vWF) or interleukin (IL)-8 nor the integrity of ECs. Maternal sera obtained after IVIG treatment and polyclonal IVIG decrease constitutive and cytokine-induced ICAM-1 and VCAM-1 expression on ECs. The results show that maternal anti-HPA-1a antibodies cause no activation or damage of ECs in this model. The clinical relevance of the de-activating properties of IVIG on EC activation with respect to ICH deserves further investigation. PMID:15196265

  13. Mechanisms and pathways of innate immune activation and regulation in health and cancer

    PubMed Central

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2015-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer. PMID:25625930

  14. Muscles provide protection during microbial infection by activating innate immune response pathways in Drosophila and zebrafish

    PubMed Central

    Chatterjee, Arunita; Roy, Debasish; Patnaik, Esha

    2016-01-01

    ABSTRACT Muscle contraction brings about movement and locomotion in animals. However, muscles have also been implicated in several atypical physiological processes including immune response. The role of muscles in immunity and the mechanism involved has not yet been deciphered. In this paper, using Drosophila indirect flight muscles (IFMs) as a model, we show that muscles are immune-responsive tissues. Flies with defective IFMs are incapable of mounting a potent humoral immune response. Upon immune challenge, the IFMs produce anti-microbial peptides (AMPs) through the activation of canonical signaling pathways, and these IFM-synthesized AMPs are essential for survival upon infection. The trunk muscles of zebrafish, a vertebrate model system, also possess the capacity to mount an immune response against bacterial infections, thus establishing that immune responsiveness of muscles is evolutionarily conserved. Our results suggest that physiologically fit muscles might boost the innate immune response of an individual. PMID:27101844

  15. Mechanisms and pathways of innate immune activation and regulation in health and cancer.

    PubMed

    Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

    2014-01-01

    Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer. PMID:25625930

  16. Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats.

    PubMed

    Györffy, Balázs A; Gulyássy, Péter; Gellén, Barbara; Völgyi, Katalin; Madarasi, Dóra; Kis, Viktor; Ozohanics, Olivér; Papp, Ildikó; Kovács, Péter; Lubec, Gert; Dobolyi, Árpád; Kardos, József; Drahos, László; Juhász, Gábor; Kékesi, Katalin A

    2016-08-01

    An increasing number of studies have revealed associations between pre- and perinatal immune activation and the development of schizophrenia and autism spectrum disorders (ASDs). Accordingly, neuroimmune crosstalk has a considerably large impact on brain development during early ontogenesis. While a plethora of heterogeneous abnormalities have already been described in established maternal immune activation (MIA) rodent and primate animal models, which highly correlate to those found in human diseases, the underlying molecular background remains obscure. In the current study, we describe the long-term effects of MIA on the neocortical pre- and postsynaptic proteome of adolescent rat offspring in detail. Molecular differences were revealed in sub-synaptic fractions, which were first thoroughly characterized using independent methods. The widespread proteomic examination of cortical samples from offspring exposed to maternal lipopolysaccharide administration at embryonic day 13.5 was conducted via combinations of different gel-based proteomic techniques and tandem mass spectrometry. Our experimentally validated proteomic data revealed more pre- than postsynaptic protein level changes in the offspring. The results propose the relevance of altered synaptic vesicle recycling, cytoskeletal structure and energy metabolism in the presynaptic region in addition to alterations in vesicle trafficking, the cytoskeleton and signal transduction in the postsynaptic compartment in MIA offspring. Differing levels of the prominent signaling regulator molecule calcium/calmodulin-dependent protein kinase II in the postsynapse was validated and identified specifically in the prefrontal cortex. Finally, several potential common molecular regulators of these altered proteins, which are already known to be implicated in schizophrenia and ASD, were identified and assessed. In summary, unexpectedly widespread changes in the synaptic molecular machinery in MIA rats were demonstrated which

  17. Supplementary polio immunization activities and prior use of routine immunization services in non-polio-endemic sub-Saharan Africa

    PubMed Central

    Frimpong, Jemima A; Abdelwahab, Jalaa; Asuming, Patrick; Touré, Hamadassalia; Awoonor-Williams, John Koku; Abachie, Thomas; Guidetti, Flavia

    2012-01-01

    Abstract Objective To determine participation in polio supplementary immunization activities (SIAs) in sub-Saharan Africa among users and non-users of routine immunization services and among users who were compliant or non-compliant with the routine oral poliovirus vaccine (OPV) immunization schedule. Methods Data were obtained from household-based surveys in non-polio-endemic sub-Saharan African countries. Routine immunization service users were children (aged < 5 years) who had ever had a health card containing their vaccination history; non-users were children who had never had a health card. Users were considered compliant with the OPV routine immunization schedule if, by the SIA date, their health card reflected receipt of required OPV doses. Logistic regression measured associations between SIA participation and use of both routine immunization services and compliance with routine OPV among users. Findings Data from 21 SIAs conducted between 1999 and 2010 in 15 different countries met inclusion criteria. Overall SIA participation ranged from 70.2% to 96.1%. It was consistently lower among infants than among children aged 1–4 years. In adjusted analyses, participation among routine immunization services users was > 85% in 12 SIAs but non-user participation was > 85% in only 5 SIAs. In 18 SIAs, participation was greater among users (P < 0.01 in 16, 0.05 in 1 and < 0.10 in 1) than non-users. In 14 SIAs, adjusted analyses revealed lower participation among non-compliant users than among compliant users (P < 0.01 in 10, < 0.05 in 2 and < 0.10 in 2). Conclusion Large percentages of children participated in SIAs. Prior use of routine immunization services and compliance with the routine OPV schedule showed a strong positive association with SIA participation. PMID:22807595

  18. Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation

    PubMed Central

    Pandiyan, Pushpa; Younes, Souheil-Antoine; Ribeiro, Susan Pereira; Talla, Aarthi; McDonald, David; Bhaskaran, Natarajan; Levine, Alan D.; Weinberg, Aaron; Sekaly, Rafick P.

    2016-01-01

    Residual mucosal inflammation along with chronic systemic immune activation is an important feature in individuals infected with human immunodeficiency virus (HIV), and has been linked to a wide range of co-morbidities, including malignancy, opportunistic infections, immunopathology, and cardiovascular complications. Although combined antiretroviral therapy (cART) can reduce plasma viral loads to undetectable levels, reservoirs of virus persist, and increased mortality is associated with immune dysbiosis in mucosal lymphoid tissues. Immune-based therapies are pursued with the goal of improving CD4+ T-cell restoration, as well as reducing chronic immune activation in cART-treated patients. However, the majority of research on immune activation has been derived from analysis of circulating T cells. How immune cell alterations in mucosal tissues contribute to HIV immune dysregulation and the associated risk of non-infectious chronic complications is less studied. Given the significant differences between mucosal T cells and circulating T cells, and the immediate interactions of mucosal T cells with the microbiome, more attention should be devoted to mucosal immune cells and their contribution to systemic immune activation in HIV-infected individuals. Here, we will focus on mucosal immune cells with a specific emphasis on CD4+ T lymphocytes, such as T helper 17 cells and CD4+Foxp3+ regulatory T cells (Tregs), which play crucial roles in maintaining mucosal barrier integrity and preventing inflammation, respectively. We hypothesize that pro-inflammatory milieu in cART-treated patients with immune activation significantly contributes to enhanced loss of Th17 cells and increased frequency of dysregulated Tregs in the mucosa, which in turn may exacerbate immune dysfunction in HIV-infected patients. We also present initial evidence to support this hypothesis. A better comprehension of how pro-inflammatory milieu impacts these two types of cells in the mucosa will shed light

  19. Immune-suppressive activity of punicalagin via inhibition of NFAT activation

    SciTech Connect

    Lee, Sang-Ik; Kim, Byoung-Soo; Kim, Kyoung-Shin; Lee, Samkeun; Shin, Kwang-Soo; Lim, Jong-Soon

    2008-07-11

    Since T cell activation is central to the development of autoimmune diseases, we screened a natural product library comprising 1400 samples of medicinal herbal extracts, to identify compounds that suppress T cell activity. Punicalagin (PCG) isolated from the fruit of Punica granatum was identified as a potent immune suppressant, based on its inhibitory action on the activation of the nuclear factor of activated T cells (NFAT). PCG downregulated the mRNA and soluble protein expression of interleukin-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppressed mixed leukocytes reaction (MLR) without exhibiting cytotoxicity to the cells. In vivo, the PCG treatment inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice and decreased CD3+ T cell infiltration of the inflamed tissue. These results suggest that PCG could be a potential candidate for the therapeutics of various immune pathologies.

  20. Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation.

    PubMed

    Inglis, Fiona M; Lee, Kim M; Chiu, Kevin B; Purcell, Olivia M; Didier, Peter J; Russell-Lodrigue, Kasi; Weaver, Scott C; Roy, Chad J; MacLean, Andrew G

    2016-04-01

    Chikungunya, "that which bends up" in the Makonde dialect, is an emerging global health threat, with increasing incidence of neurological complications. Until 2013, Chikungunya infection had been largely restricted to East Africa and the Indian Ocean, with cases within the USA reported to be from foreign travel. However, in 2014, over 1 million suspected cases were reported in the Americas, and a recently infected human could serve as an unwitting reservoir for the virus resulting in an epidemic in the continental USA. Chikungunya infection is increasingly being associated with neurological sequelae. In this study, we sought to understand the role of astrocytes in the neuropathogenesis of Chikungunya infection. Even after virus has been cleared form the circulation, astrocytes were activated with regard to TLR2 expression. In addition, white matter astrocytes were hypertrophic, with increased arbor volume in gray matter astrocytes. Combined, these would alter the number and distribution of synapses that each astrocyte would be capable of forming. These results provide the first evidence that Chikungunya infection induces morphometric and innate immune activation of astrocytes in vivo. Perturbed glia-neuron signaling could be a major driving factor in the development of Chikungunya-associated neuropathology. PMID:26419894

  1. Immune activation by combination human lymphokine-activated killer and dendritic cell therapy

    PubMed Central

    West, E J; Scott, K J; Jennings, V A; Melcher, A A

    2011-01-01

    Background: Optimal cellular immunotherapy for cancer should ideally harness both the innate and adaptive arms of the immune response. Lymphokine-activated killer cells (LAKs) can trigger early innate killing of tumour targets, whereas long-term adaptive-specific tumour control requires priming of CD8+ cytotoxic lymphocytes (CTLs) following acquisition of tumour-associated antigens (TAAs) by antigen-presenting cells such as dendritic cells (DCs). As DCs stimulate both innate and adaptive effectors, combination cell therapy using LAKs and DCs has the potential to maximise anti-tumour immune priming. Methods: Reciprocal activation between human clinical grade LAKs and DCs on co-culture, and its immune consequences, was monitored by cell phenotype, cytokine release and priming of both innate and adaptive cytotoxicity against melanoma targets. Results: Co-culture of DCs and LAKs led to phenotypic activation of natural killer (NK) cells within the LAK population, which was associated with increased production of inflammatory cytokines and enhanced innate cytotoxicity against tumour cell targets. The LAKs reciprocally matured DCs, and the combination of LAKs and DCs, on addition of melanoma cells, supported priming of specific anti-tumour CTLs better than DCs alone. Conclusion: Clinical-grade LAKs/DCs represents a practical, effective combination cell immunotherapy for stimulation of both innate and adaptive anti-tumour immunity in cancer patients. PMID:21847125

  2. An ECG simulator for generating maternal-foetal activity mixtures on abdominal ECG recordings.

    PubMed

    Behar, Joachim; Andreotti, Fernando; Zaunseder, Sebastian; Li, Qiao; Oster, Julien; Clifford, Gari D

    2014-08-01

    Accurate foetal electrocardiogram (FECG) morphology extraction from non-invasive sensors remains an open problem. This is partly due to the paucity of available public databases. Even when gold standard information (i.e derived from the scalp electrode) is present, the collection of FECG can be problematic, particularly during stressful or clinically important events.In order to address this problem we have introduced an FECG simulator based on earlier work on foetal and adult ECG modelling. The open source foetal ECG synthetic simulator, fecgsyn, is able to generate maternal-foetal ECG mixtures with realistic amplitudes, morphology, beat-to-beat variability, heart rate changes and noise. Positional (rotation and translation-related) movements in the foetal and maternal heart due to respiration, foetal activity and uterine contractions were also added to the simulator.The simulator was used to generate some of the signals that were part of the 2013 PhysioNet Computing in Cardiology Challenge dataset and has been posted on Physionet.org (together with scripts to generate realistic scenarios) under an open source license. The toolbox enables further research in the field and provides part of a standard for industry and regulatory testing of rare pathological scenarios. PMID:25071094

  3. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation.

    PubMed

    Xiong, Shiqiu; Sharkey, Andrew M; Kennedy, Philippa R; Gardner, Lucy; Farrell, Lydia E; Chazara, Olympe; Bauer, Julien; Hiby, Susan E; Colucci, Francesco; Moffett, Ashley

    2013-10-01

    Reduced trophoblast invasion and vascular conversion in decidua are thought to be the primary defect of common pregnancy disorders including preeclampsia and fetal growth restriction. Genetic studies suggest these conditions are linked to combinations of polymorphic killer cell Ig-like receptor (KIR) genes expressed by maternal decidual NK cells (dNK) and HLA-C genes expressed by fetal trophoblast. Inhibitory KIR2DL1 and activating KIR2DS1 both bind HLA-C2, but confer increased risk or protection from pregnancy disorders, respectively. The mechanisms underlying these genetic associations with opposing outcomes are unknown. We show that KIR2DS1 is highly expressed in dNK, stimulating strong activation of KIR2DS1+ dNK. We used microarrays to identify additional responses triggered by binding of KIR2DS1 or KIR2DL1 to HLA-C2 and found different responses in dNK coexpressing KIR2DS1 with KIR2DL1 compared with dNK only expressing KIR2DL1. Activation of KIR2DS1+ dNK by HLA-C2 stimulated production of soluble products including GM-CSF, detected by intracellular FACS and ELISA. We demonstrated that GM-CSF enhanced migration of primary trophoblast and JEG-3 trophoblast cells in vitro. These findings provide a molecular mechanism explaining how recognition of HLA class I molecules on fetal trophoblast by an activating KIR on maternal dNK may be beneficial for placentation. PMID:24091323

  4. Striatal but not frontal cortical up-regulation of the epidermal growth factor receptor in rats exposed to immune activation in utero and cannabinoid treatment in adolescence.

    PubMed

    Idrizi, Rejhan; Malcolm, Peter; Weickert, Cynthia Shannon; Zavitsanou, Katerina; Suresh Sundram

    2016-06-30

    In utero maternal immune activation (MIA) and cannabinoid exposure during adolescence constitute environmental risk factors for schizophrenia. We investigated these risk factors alone and in combination ("two-hit") on epidermal growth factor receptor (EGFR) and neuregulin-1 receptor (ErbB4) levels in the rat brain. EGFR but not ErbB4 receptor protein levels were significantly increased in the nucleus accumbens and striatum of "two-hit" rats only, with no changes seen at the mRNA level. These findings support region specific EGF-system dysregulation as a plausible mechanism in this animal model of schizophrenia pathogenesis. PMID:27138815

  5. Physical activity and maternal-fetal circulation measured by Doppler ultrasound

    PubMed Central

    Nguyen, Nghia C.; Evenson, Kelly R.; Savitz, David A.; Chu, Haitao; Thorp, John M.; Daniels, Julie L.

    2012-01-01

    Objective To examine the association of physical activity on maternal-fetal circulation measured by uterine and umbilical artery Doppler flow velocimetry waveforms. Study Design Participants included 781 pregnant women with Doppler ultrasounds of the uterine and umbilical artery and who self-reported past week physical activity. Linear and generalized estimating equation regression models were used to examine these associations. Results Moderate-to-vigorous total and recreational activity were associated with higher uterine artery pulsatility index (PI) and an increased risk of uterine artery notching as compared to reporting no total or recreational physical activity, respectively. Moderate-to-vigorous work activity was associated with lower uterine artery PI and a reduced risk of uterine artery notching as compared to no work activity. No associations were identified with the umbilical circulation measured by the resistance index. Conclusion In this epidemiologic study, recreational and work activity were associated with opposite effects on uterine artery PI and uterine artery notching, though associations were modest in magnitude. PMID:22678142

  6. Immune activation affects chemical sexual ornaments of male Iberian wall lizards

    NASA Astrophysics Data System (ADS)

    López, Pilar; Gabirot, Marianne; Martín, José

    2009-01-01

    Many animals use chemical signals in sexual selection, but it is not clear how these sexual traits might have evolved to signal honestly male condition. It is possible that there is a trade-off between maintaining the immune system and the elaboration of ornaments. We experimentally challenged the immune system of male Iberian wall lizards, Podarcis hispanica, with a bacterial antigen (lipopolysaccharide), without pathogenic effects, to explore whether the immune activation affected chemical ornaments. Immune activation resulted in decreased proportions of a major chemical in femoral secretions (cholesta-5,7-dien-3-ol = provitamin D3) known to be selected in scent of males by females and which active form (vitamin D) has a variety of important effects on immune system function. This result suggests the existence of a potential trade-off between physiological regulation of the immune system and the allocation of essential nutrients (vitamins) to sexual chemical ornaments in male lizards.

  7. The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function.

    PubMed

    Hoeijmakers, Lianne; Lucassen, Paul J; Korosi, Aniko

    2014-01-01

    Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity. PMID:25620909

  8. The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function

    PubMed Central

    Hoeijmakers, Lianne; Lucassen, Paul J.; Korosi, Aniko

    2015-01-01

    Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity. PMID:25620909

  9. The Split Virus Influenza Vaccine rapidly activates immune cells through Fcγ receptors.

    PubMed

    O'Gorman, William E; Huang, Huang; Wei, Yu-Ling; Davis, Kara L; Leipold, Michael D; Bendall, Sean C; Kidd, Brian A; Dekker, Cornelia L; Maecker, Holden T; Chien, Yueh-Hsiu; Davis, Mark M

    2014-10-14

    Seasonal influenza vaccination is one of the most common medical procedures and yet the extent to which it activates the immune system beyond inducing antibody production is not well understood. In the United States, the most prevalent formulations of the vaccine consist of degraded or "split" viral particles distributed without any adjuvants. Based on previous reports we sought to determine whether the split influenza vaccine activates innate immune receptors-specifically Toll-like receptors. High-dimensional proteomic profiling of human whole-blood using Cytometry by Time-of-Flight (CyTOF) was used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response ex vivo. This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature quite distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a serum factor was necessary for vaccine-dependent immune activation. We found this serum factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza virus "splitting" inactivates any potential adjuvants endogenous to influenza, such as RNA, but in previously exposed individuals can elicit a potent immune response by facilitating the rapid formation of immune complexes. PMID:25203448

  10. The Split Virus Influenza Vaccine rapidly activates immune cells through Fcγ Receptors

    PubMed Central

    O’Gorman, William E.; Huang, Huang; Wei, Yu-Ling; Davis, Kara L.; Leipold, Michael D.; Bendall, Sean C.; Kidd, Brian A.; Dekker, Cornelia L.; Maecker, Holden T.; Chien, Yueh-Hsiu; Davis, Mark M.

    2014-01-01

    Seasonal influenza vaccination is one of the most common medical procedures and yet the extent to which it activates the immune system beyond inducing antibody production is not well understood. In the United States, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles distributed without any adjuvants. Based on previous reports we sought to determine whether the split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. High-dimensional proteomic profiling of human whole-blood using Cytometry by Time-of-Flight (CyTOF) was used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response ex vivo. This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature quite distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a serum factor was necessary for vaccine-dependent immune activation. We found this serum factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza virus “splitting” inactivates any potential adjuvants endogenous to influenza, such as RNA, but in previously exposed individuals can elicit a potent immune response by facilitating the rapid formation of immune complexes. PMID:25203448

  11. Unveiling Unexpected Immune Activities Induced by Your Pneumococcal Vaccine

    PubMed Central

    Hurwitz, Julia L.

    2016-01-01

    ABSTRACT In modern-day vaccine design, a good pneumococcal capsular polysaccharide vaccine is measured by its ability to induce opsonic antibodies. These antibodies label bacteria for phagocytosis by neutrophils and thereby overcome the capsule’s barrier function. Doyle and Pirofski have raised a serious challenge to the current paradigm by describing anti-capsular antibodies that are highly protective but nonopsonic [C.R. Doyle and L. Pirofski, mBio 7(1):e02260-15, 2016, doi:10.1128/mBio.02260-15]. In fact, some functions are not related to neutrophils or phagocytosis at all. An increased awareness of these activities is critical not only for accurate comparisons of vaccine candidates but also for improvements in vaccination outcomes in settings of neutropenia. When vaccine developers select a single gatekeeper assay (e.g., an opsonophagocytic assay for bacteria or a neutralization assay for viruses), promising vaccine candidates may be missed. Doyle and Pirofski stress that multiple functions, not just one, should be investigated to enhance discovery of antibody mechanisms and to best assess vaccine-induced correlates of immune protection. PMID:26908576

  12. Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation.

    PubMed

    Shaabani, Namir; Khairnar, Vishal; Duhan, Vikas; Zhou, Fan; Tur, Rita Ferrer; Häussinger, Dieter; Recher, Mike; Tumanov, Alexei V; Hardt, Cornelia; Pinschewer, Daniel; Christen, Urs; Lang, Philipp A; Honke, Nadine; Lang, Karl S

    2016-02-01

    The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8(+) T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell-derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8(+) T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system. PMID:26553386

  13. Experimental verification and molecular basis of active immunization against fungal pathogens in termites.

    PubMed

    Liu, Long; Li, Ganghua; Sun, Pengdong; Lei, Chaoliang; Huang, Qiuying

    2015-01-01

    Termites are constantly exposed to many pathogens when they nest and forage in the field, so they employ various immune strategies to defend against pathogenic infections. Here, we demonstrate that the subterranean termite Reticulitermes chinensis employs active immunization to defend against the entomopathogen Metarhizium anisopliae. Our results showed that allogrooming frequency increased significantly between fungus-treated termites and their nestmates. Through active social contact, previously healthy nestmates only received small numbers of conidia from fungus-treated individuals. These nestmates experienced low-level fungal infections, resulting in low mortality and apparently improved antifungal defences. Moreover, infected nestmates promoted the activity of two antioxidant enzymes (SOD and CAT) and upregulated the expression of three immune genes (phenoloxidase, transferrin, and termicin). We found 20 differentially expressed proteins associated with active immunization in R. chinensis through iTRAQ proteomics, including 12 stress response proteins, six immune signalling proteins, and two immune effector molecules. Subsequently, two significantly upregulated (60S ribosomal protein L23 and isocitrate dehydrogenase) and three significantly downregulated (glutathione S-transferase D1, cuticle protein 19, and ubiquitin conjugating enzyme) candidate immune proteins were validated by MRM assays. These findings suggest that active immunization in termites may be regulated by different immune proteins. PMID:26458743

  14. Experimental verification and molecular basis of active immunization against fungal pathogens in termites

    PubMed Central

    Liu, Long; Li, Ganghua; Sun, Pengdong; Lei, Chaoliang; Huang, Qiuying

    2015-01-01

    Termites are constantly exposed to many pathogens when they nest and forage in the field, so they employ various immune strategies to defend against pathogenic infections. Here, we demonstrate that the subterranean termite Reticulitermes chinensis employs active immunization to defend against the entomopathogen Metarhizium anisopliae. Our results showed that allogrooming frequency increased significantly between fungus-treated termites and their nestmates. Through active social contact, previously healthy nestmates only received small numbers of conidia from fungus-treated individuals. These nestmates experienced low-level fungal infections, resulting in low mortality and apparently improved antifungal defences. Moreover, infected nestmates promoted the activity of two antioxidant enzymes (SOD and CAT) and upregulated the expression of three immune genes (phenoloxidase, transferrin, and termicin). We found 20 differentially expressed proteins associated with active immunization in R. chinensis through iTRAQ proteomics, including 12 stress response proteins, six immune signalling proteins, and two immune effector molecules. Subsequently, two significantly upregulated (60S ribosomal protein L23 and isocitrate dehydrogenase) and three significantly downregulated (glutathione S-transferase D1, cuticle protein 19, and ubiquitin conjugating enzyme) candidate immune proteins were validated by MRM assays. These findings suggest that active immunization in termites may be regulated by different immune proteins. PMID:26458743

  15. Endocrine factors modulating immune responses in pregnancy.

    PubMed

    Schumacher, Anne; Costa, Serban-Dan; Zenclussen, Ana Claudia

    2014-01-01

    How the semi-allogeneic fetus is tolerated by the maternal immune system remains a fascinating phenomenon. Despite extensive research activity in this field, the mechanisms underlying fetal tolerance are still not well understood. However, there are growing evidences that immune-immune interactions as well as immune-endocrine interactions build up a complex network of immune regulation that ensures fetal survival within the maternal uterus. In the present review, we aim to summarize emerging research data from our and other laboratories on immune modulating properties of pregnancy hormones with a special focus on progesterone, estradiol, and human chorionic gonadotropin. These pregnancy hormones are critically involved in the successful establishment, maintenance, and termination of pregnancy. They suppress detrimental maternal alloresponses while promoting tolerance pathways. This includes the reduction of the antigen-presenting capacity of dendritic cells (DCs), monocytes, and macrophages as well as the blockage of natural killer cells, T and B cells. Pregnancy hormones also support the proliferation of pregnancy supporting uterine killer cells, retain tolerogenic DCs, and efficiently induce regulatory T (Treg) cells. Furthermore, they are involved in the recruitment of mast cells and Treg cells into the fetal-maternal interface contributing to a local accumulation of pregnancy-protective cells. These findings highlight the importance of endocrine factors for the tolerance induction during pregnancy and encourage further research in the field. PMID:24847324

  16. The danger is growing! A new paradigm for immune system activation and peripheral tolerance.

    PubMed

    Bewick, Sharon; Yang, Ruoting; Zhang, Mingjun

    2009-01-01

    Successful immune defense is a complex balancing act. In order to protect a host against invasion by harmful pathogens, an immune response must be rapid and vigorous, and must eliminate foreign invaders before their populations grow beyond control. That same immune response, however, must be selective enough to recognize and ignore commensal bacteria, environmental antigens and host tissue itself. How the immune system makes the crucial decision whether or not to attack a particular antigen has been a long-standing question central to the study of immunology. Here we show that the structure of the signaling network between regulatory T-cells and type 17 helper T-cells allows the immune system to selectively attack pathogens based on whether or not the pathogens represent a growing, and thus dangerous population. We term this mechanism for immune system activation the 'Growth Detection Paradigm', because it offers an entirely new explanation for immune system regulation and peripheral tolerance. PMID:19956616

  17. Increased BOLD Activation to Predator Stressor in Subiculum and Midbrain of Amphetamine-Sensitized Maternal Rats

    PubMed Central

    Febo, Marcelo; Pira, Ashley S.

    2011-01-01

    Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5 μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1 mg/kg, i.p. X 3 days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized, but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. PMID:21134359

  18. Increased BOLD activation to predator stressor in subiculum and midbrain of amphetamine-sensitized maternal rats.

    PubMed

    Febo, Marcelo; Pira, Ashley S

    2011-03-25

    Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1mg/kg, i.p. ×3days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. PMID:21134359

  19. Placental cadmium as an additional noninvasive bioindicator of active maternal tobacco smoking.

    PubMed

    Piasek, Martina; Jurasović, Jasna; Sekovanić, Ankica; Brajenović, Nataša; Brčić Karačonji, Irena; Mikolić, Anja; Grgec, Antonija Sulimanec; Stasenko, Sandra

    2016-01-01

    Tobacco smoke (TS) is a mixture of chemicals that is known to exert carcinogenic and endocrine-disrupting effects, as well as adverse effects on various systems. In TS nicotine is the major alkaloid and cadmium (Cd) the most abundant metal ion. The aim of this investigation was to assess exposure to Cd attributed to TS in healthy postpartum subjects (mean age 28 years) after term vaginal delivery in a clinical hospital by determining metal levels in maternal blood, placenta, and cord blood in relation to nicotine in maternal hair (12-cm-long samples). Two study groups were compared based upon self-reporting data: smokers (n = 32; continual cigarette smoking 3 months before and 9 months during pregnancy) and nonsmokers (n = 54; including passive smokers whose parameters did not differ from unexposed nonsmokers). In smokers compared to nonsmokers maternal hair nicotine concentrations increased approximately sevenfold, while Cd levels rose fourfold in maternal blood and up to twofold in placenta. Significant positive correlations were noted between maternal hair nicotine and placental Cd, maternal hair nicotine and maternal blood Cd, and placental Cd and maternal blood Cd. Levels of cord blood Cd were low in both study groups (<0.1 ng/ml). Data indicate that Cd in placenta may serve as a noninvasive bioindicator in addition to commonly used noninvasive hair nicotine in maternal TS assessment, especially in cases where unavailable or inappropriate (short or chemically treated) hair samples occur. PMID:27210017

  20. Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity.

    PubMed

    Glastras, Sarah J; Chen, Hui; McGrath, Rachel T; Zaky, Amgad A; Gill, Anthony J; Pollock, Carol A; Saad, Sonia

    2016-01-01

    Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring. PMID:27004609

  1. Effect of GLP-1 Receptor Activation on Offspring Kidney Health in a Rat Model of Maternal Obesity

    PubMed Central

    Glastras, Sarah J.; Chen, Hui; McGrath, Rachel T.; Zaky, Amgad A.; Gill, Anthony J.; Pollock, Carol A.; Saad, Sonia

    2016-01-01

    Maternal obesity is associated with an increased risk of chronic disease in offspring, including type 2 diabetes (T2D). Exendin-4 (Exd-4) activates the glucagon like peptide-1 (GLP-1) receptor thereby decreasing serum glucose levels and body weight. In addition, Exd-4 has been shown to reduce renal and cardiac complications in experimental models of T2D. We hypothesized that treatment with Exd-4 would ameliorate the detrimental effects of maternal and diet-induced obesity on renal characteristics in offspring. Female Sprague-Dawley rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and lactation, and their offspring were weaned to normal or HFD. The offspring were randomized to Exd-4 or placebo from weaning and their kidneys harvested at Week 9. We found that the kidneys of offspring from obese mothers, regardless of postnatal diet, had significantly increased markers of inflammation, oxidative stress and fibrosis. Exd-4 ameliorated the negative renal effects of maternal obesity and in particular, reduced renal inflammation, oxidative stress and fibrosis. In conclusion, maternal obesity has persisting effects on renal structure in the offspring. GLP-1 analogues are potentially useful for protecting against the deleterious effects of maternal obesity on renal physiology in offspring. PMID:27004609

  2. A Dyadic Approach to Understanding the Relationship of Maternal Knowledge of Youths' Activities to Youths' Problem Behavior among Rural Adolescents

    ERIC Educational Resources Information Center

    Lippold, Melissa A.; Greenberg, Mark T.; Feinberg, Mark E.

    2011-01-01

    Most studies that explore parental knowledge of youths' activities utilize parents' and youths' reports separately. Using a sample of 938 rural early adolescents (53% female; 84% White), we explore congruence between mothers' and youths' perceptions of maternal knowledge and its association with youth problem behaviors (delinquency, substance use,…

  3. Maternal High-Fat Feeding Increases Placental Lipoprotein Lipase Activity by Reducing SIRT1 Expression in Mice.

    PubMed

    Qiao, Liping; Guo, Zhuyu; Bosco, Chris; Guidotti, Stefano; Wang, Yunfeng; Wang, Mingyong; Parast, Mana; Schaack, Jerome; Hay, William W; Moore, Thomas R; Shao, Jianhua

    2015-09-01

    This study investigated how maternal overnutrition and obesity regulate expression and activation of proteins that facilitate lipid transport in the placenta. To create a maternal overnutrition and obesity model, primiparous C57BL/6 mice were fed a high-fat (HF) diet throughout gestation. Fetuses from HF-fed dams had significantly increased serum levels of free fatty acid and body fat. Despite no significant difference in placental weight, lipoprotein lipase (LPL) protein levels and activity were remarkably elevated in placentas from HF-fed dams. Increased triglyceride content and mRNA levels of CD36, VLDLr, FABP3, FABPpm, and GPAT2 and -3 were also found in placentas from HF-fed dams. Although both peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein-α protein levels were significantly increased in placentas of the HF group, only PPARγ exhibited a stimulative effect on LPL expression in cultured JEG-3 human trophoblasts. Maternal HF feeding remarkably decreased SIRT1 expression in placentas. Through use of an SIRT1 activator and inhibitor and cultured trophoblasts, an inhibitory effect of SIRT1 on LPL expression was demonstrated. We also found that SIRT1 suppresses PPARγ expression in trophoblasts. Most importantly, inhibition of PPARγ abolished the SIRT1-mediated regulatory effect on LPL expression. Together, these results indicate that maternal overnutrition induces LPL expression in trophoblasts by reducing the inhibitory effect of SIRT1 on PPARγ. PMID:25948680

  4. Predicting Adolescents' Organized Activity Involvement: The Role of Maternal Depression History, Family Relationship Quality, and Adolescent Cognitions

    ERIC Educational Resources Information Center

    Bohnert, Amy M.; Martin, Nina C.; Garber, Judy

    2007-01-01

    Although the potential benefits of organized activity involvement during high school have been documented, little is known about what familial and individual characteristics are associated with higher levels of participation. Using structural equation modeling, this longitudinal study examined the extent to which maternal depression history (i.e.,…

  5. Innate Immune Activation Enhances HIV Acquisition in Women, Diminishing the Effectiveness of Tenofovir Microbicide Gel

    PubMed Central

    Naranbhai, Vivek; Abdool Karim, Salim S.; Altfeld, Marcus; Samsunder, Natasha; Durgiah, Raveshni; Sibeko, Sengeziwe; Abdool Karim, Quarraisha; Carr, William H.

    2012-01-01

    The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides. PMID:22829639

  6. Comparison of humoral and cellular immune responses to a pentavalent modified live virus vaccine in three age groups of calves with maternal antibodies, before and after BVDV type 2 challenge.

    PubMed

    Platt, Ratree; Widel, Philip W; Kesl, Lyle D; Roth, James A

    2009-07-16

    The aim of this study was to evaluate the ability of a pentavalent (BVDV types 1 and 2, BHV-1, BRSV, and PI-3) modified live virus (MLV) vaccine given to 1-2-, 4-5-, and 7-8-week-old calves with maternal antibodies to induce humoral and cellular immune responses and protect calves from virulent BVDV type 2. Eight calves in each age group were vaccinated and four served as controls. All calves were challenged intranasally with BVDV type 2, 12 weeks after vaccination. SVN titers to all five viruses declined in all groups after vaccination (except 4-5-week-old calves to BVDV type 1). After challenge, the SVN titers for both types of BVDV showed anamnestic responses in calves vaccinated at 4-5 and 7-8 weeks, but not at 1-2 weeks of age. In all groups, T cell subsets responded specifically to BVDV types 1 and 2 but not to BHV-1, BRSV, or PI-3 after vaccination by increasing their expression of activation markers (CD25, IFN-gamma and IL-4). All vaccinated calves were significantly protected from BVDV type 2 challenge. PMID:19446589

  7. Nutritionally Mediated Programming of the Developing Immune System12

    PubMed Central

    Palmer, Amanda C.

    2011-01-01

    A growing body of evidence highlights the importance of a mother’s nutrition from preconception through lactation in programming the emerging organ systems and homeostatic pathways of her offspring. The developing immune system may be particularly vulnerable. Indeed, examples of nutrition-mediated immune programming can be found in the literature on intra-uterine growth retardation, maternal micronutrient deficiencies, and infant feeding. Current models of immune ontogeny depict a “layered” expansion of increasingly complex defenses, which may be permanently altered by maternal malnutrition. One programming mechanism involves activation of the maternal hypothalamic-pituitary-adrenal axis in response to nutritional stress. Fetal or neonatal exposure to elevated stress hormones is linked in animal studies to permanent changes in neuroendocrine-immune interactions, with diverse manifestations such as an attenuated inflammatory response or reduced resistance to tumor colonization. Maternal malnutrition may also have a direct influence, as evidenced by nutrient-driven epigenetic changes to developing T regulatory cells and subsequent risk of allergy or asthma. A 3rd programming pathway involves placental or breast milk transfer of maternal immune factors with immunomodulatory functions (e.g. cytokines). Maternal malnutrition can directly affect transfer mechanisms or influence the quality or quantity of transferred factors. The public health implications of nutrition-mediated immune programming are of particular importance in the developing world, where prevalent maternal undernutrition is coupled with persistent infectious challenges. However, early alterations to the immune system, resulting from either nutritional deficiencies or excesses, have broad relevance for immune-mediated diseases, such as asthma, and chronic inflammatory conditions like cardiovascular disease. PMID:22332080

  8. Suppression of Adaptive Immune Cell Activation Does Not Alter Innate Immune Adipose Inflammation or Insulin Resistance in Obesity

    PubMed Central

    Subramanian, Manikandan; Ozcan, Lale; Ghorpade, Devram Sampat; Ferrante, Anthony W.; Tabas, Ira

    2015-01-01

    Obesity-induced inflammation in visceral adipose tissue (VAT) is a major contributor to insulin resistance and type 2 diabetes. Whereas innate immune cells, notably macrophages, contribute to visceral adipose tissue (VAT) inflammation and insulin resistance, the role of adaptive immunity is less well defined. To address this critical gap, we used a model in which endogenous activation of T cells was suppressed in obese mice by blocking MyD88-mediated maturation of CD11c+ antigen-presenting cells. VAT CD11c+ cells from Cd11cCre+Myd88fl/fl vs. control Myd88fl/fl mice were defective in activating T cells in vitro, and VAT T and B cell activation was markedly reduced in Cd11cCre+Myd88fl/fl obese mice. However, neither macrophage-mediated VAT inflammation nor systemic inflammation were altered in Cd11cCre+Myd88fl/fl mice, thereby enabling a focused analysis on adaptive immunity. Unexpectedly, fasting blood glucose, plasma insulin, and the glucose response to glucose and insulin were completely unaltered in Cd11cCre+Myd88fl/fl vs. control obese mice. Thus, CD11c+ cells activate VAT T and B cells in obese mice, but suppression of this process does not have a discernible effect on macrophage-mediated VAT inflammation or systemic glucose homeostasis. PMID:26317499

  9. Effect of the South African asinine-94 strain of equine arteritis virus (EAV) in pregnant donkey mares and duration of maternal immunity in foals.

    PubMed

    Paweska, J T

    1997-06-01

    Clinical, virological and serological responses were investigated in five pregnant donkey mares after experimental exposure to the South African asinine-94 strain of equine arteritis virus (EAV), and the duration of maternal immunity to EAV was studied in their foals. In four intranasally inoculated mares, fever with maximum rectal temperatures of 39.1-40.7 degrees C was recorded 2-11 d after challenge. All the inoculated mares developed mild depression, and a serous ocular and nasal discharge; in three mares mild conjuctivitis was observed. The virus was recovered from the nasopharynx and from buffy-coat samples of all the mares 3-10 d, and 2-18 d post inoculation (p.i.), respectively. Seroconversion to EAV was detected on days 8-10 p.i. Peak serum-virus-neutralizing antibody titres of log10 1.8-2.4, and IgG ELISA OD values of 0.85-2.15 were recorded 2-3 weeks p.i. The in-contact (p.c.) control mare developed fever on days 15-19 post exposure, and showed mild clinical signs of equine viral arteritis similar to those observed in the inoculated mares. Seroconversion to EAV was detected in the p.c. mare on day 20 post exposure, and virus was isolated from nasal swabs and blood samples collected at the time of the febrile response and 1-3 d afterwards. None of the mares aborted. After they had given normal birth 45-128 d p.i. or after p.c. exposure, no virus could be isolated from their placentas. The concentration of EAV-neutralizing antibody in colostrum was two to eight times higher than in serum samples collected at the time of parturition. All the foals born to infected mares were clinically normal at the time of birth and throughout the subsequent 1-2 months of observation. No EAV was recovered from the buffy-coat fraction of blood samples collected at birth nor from those collected on days 1, 2 and 7 after birth. Also, no virus-serum-neutralizing or IgG ELISA antibody to EAV was detected in sera collected immediately after birth before the foals started nursing

  10. Office of Maternal and Child Health Active Projects FY 1989. An Annotated Listing.

    ERIC Educational Resources Information Center

    National Center for Education in Maternal and Child Health, Washington, DC.

    An annotated listing is presented of projects offering maternal and child health care services. These projects, referred to as special projects of regional and national significance (SPRANS), are supported by the Office of Maternal and Child Health of the Department of Health and Human Services. The first section provides information on services…

  11. Decidual soluble factors, through modulation of dendritic cells functions, determine the immune response patterns at the feto-maternal interface.

    PubMed

    Ahmadabad, Hasan Namdar; Salehnia, Mojdeh; Saito, Shigeru; Moazzeni, Seyed Mohammad

    2016-04-01

    Dendritic cells (DCs) can acquire immunogenic or tolerogenic properties depending on intrinsic and tissue environmental factors. We aimed to determine the immunomodulatory effects of decidual soluble factors from abortion- and non-abortion-prone mice on DC functions. The decidual cell supernatants (DS) were obtained from abortion-prone and non-abortion-prone mice. Splenic DCs were treated with DS and conalbumin (as an antigen) and injected into the palms of the mice. After five days, regional lymph node cells were collected and cultured in the presence and absence of conalbumin. The proliferation of lymphocyte cells, the frequency of regulatory T cells (Tregs), and the production of IL-4 and IFN-γ were measured by [(3)H]thymidine incorporation, flow cytometry, and ELISA respectively. Our results indicated that DS from both abortion- and non-abortion-prone mice decreased the ability of DCs to induce lymphocyte proliferation and IFN-γ production, while enhanced their capacity to induce Tregs compared with non-treated DCs. Another important finding was that the immunosuppressive effects of DS from abortion-prone mice on DCs for inducing proliferative responses, developing Tregs, and producing IFN-γ by primed lymphocytes was less than DS from non-abortion-prone mice. We also found that only DS from non-abortion-prone mice could enhance the capacity of DCs to induce IL-4 production by primed lymphocytes. It can be concluded that decidua-secreted factors, by altering DC functions, can determine the pattern of immune responses at the fetomaternal interface and, subsequently, pregnancy outcome. PMID:26852388

  12. Immune-enhancing activity of extracellular polysaccharides isolated from Rhizopus nigricans.

    PubMed

    Yu, Zhidan; Kong, Mengli; Zhang, Pengying; Sun, Qingjie; Chen, Kaoshan

    2016-09-01

    Extracellular polysaccharides (EPS1-1) was extracted from fermentation liquor of Rhizopus nigricans and evaluated its immune-enhancing activities in vitro and in vivo. Results suggested that the proliferation of lymphocyte was stimulated after treated with EPS1-1. Moreover, the activities of macrophages were enhanced by increasing the activities of phagocytosis and acid phosphatase, the production of NO and the mRNA levels of IL-2, TNF-α and iNOS. Furthermore, EPS1-1 could significantly boost the immunity of normal and immunosuppressed mice, which included the increase of loaded swimming time, footpad swelling, organ index and the secretion of IL-2 and TNF-α in serum, thus suggesting that EPS1-1 could improve the body immunity through cellular immunity and humoral immunity. These findings provided further insights into the potential use of EPS1-1 as immunopotentiator or new function food. PMID:27185145

  13. Integrative analysis of breast cancer reveals prognostic haematopoietic activity and patient-specific immune response profiles

    PubMed Central

    Varn, Frederick S.; Andrews, Erik H.; Mullins, David W.; Cheng, Chao

    2016-01-01

    Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these programmes function in the context of cancer can provide valuable insights into host immune response, cancer severity and potential therapy response. Here we present a method that uses the transcriptomes of over 200 murine haematopoietic cells, to infer the lineage-specific haematopoietic activity present in human breast tumours. Correlating this activity with patient survival and tumour purity reveals that the transcriptional programmes of many cell types influence patient prognosis and are found in environments of high lymphocytic infiltration. Collectively, these results allow for a detailed and personalized assessment of the patient immune response to a tumour. When combined with routinely collected patient biopsy genomic data, this method can enable a richer understanding of the complex interplay between the host immune system and cancer. PMID:26725977

  14. Integrative analysis of breast cancer reveals prognostic haematopoietic activity and patient-specific immune response profiles.

    PubMed

    Varn, Frederick S; Andrews, Erik H; Mullins, David W; Cheng, Chao

    2016-01-01

    Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these programmes function in the context of cancer can provide valuable insights into host immune response, cancer severity and potential therapy response. Here we present a method that uses the transcriptomes of over 200 murine haematopoietic cells, to infer the lineage-specific haematopoietic activity present in human breast tumours. Correlating this activity with patient survival and tumour purity reveals that the transcriptional programmes of many cell types influence patient prognosis and are found in environments of high lymphocytic infiltration. Collectively, these results allow for a detailed and personalized assessment of the patient immune response to a tumour. When combined with routinely collected patient biopsy genomic data, this method can enable a richer understanding of the complex interplay between the host immune system and cancer. PMID:26725977

  15. Maternal Eating and Physical Activity Strategies and their Relation with Children's Nutritional Status1

    PubMed Central

    Flores-Peña, Yolanda; Ortiz-Félix, Rosario Edith; Cárdenas-Villarreal, Velia Margarita; Ávila-Alpirez, Hermelinda; Alba-Alba, Corina Mariela; Hernández-Carranco, Roandy Gaspar

    2014-01-01

    Objectives to describe the maternal eating and physical activity strategies (monitoring, discipline, control, limits and reinforcement) [MEES]; to determine the relation between MEES and the child's nutritional status [body mass index (BMI) and body fat percentage (BFP)]; to verify whether the MEES differ according to the child's nutritional status. Method participants were 558 mothers and children (3 to 11 years of age) who studied at public schools. The Parental Strategies for Eating and Activity Scale (PEAS) was applied and the child's weight, height and BFP were measured. For analysis purposes, descriptive statistics were obtained, using multiple linear regression and the Kruskal-Wallis test. Results the highest mean score was found for reinforcement (62.72) and the lowest for control (50.07). Discipline, control and limits explained 12% of the BMI, while discipline and control explained 6% of the BFP. Greater control is found for obese children (χ2=38.36, p=0.001) and greater reinforcement for underweight children (χ2=7.19, p<0.05). Conclusions the mothers exert greater control (pressure to eat) over obese children and greater recognition (congratulating due to healthy eating) in underweight children. Modifications in parental strategies are recommended with a view to strengthening healthy eating and physical activity habits. PMID:26107837

  16. Mild maternal iron deficiency anemia induces DPOAE suppression and cochlear hair cell apoptosis by caspase activation in young guinea pigs.

    PubMed

    Yu, Fei; Hao, Shuai; Zhao, Yue; Ren, Yahao; Yang, Jun; Sun, Xiance; Chen, Jie

    2014-01-01

    Iron deficiency (ID) anemia (IDA) alters auditory neural normal development in the mammalian cochlea. Previous results suggest that mild maternal IDA during pregnancy and lactation altered the hearing and nervous system development of the young offspring, but the mechanisms underlying the association are incompletely understood. The objective of this study was to evaluate the role of apoptosis in the development of sensory hair cells following mild maternal IDA during pregnancy and lactation. We established a maternal anemia model in female guinea pigs by using a mild iron deficient diet. The offspring were weaned on postnatal day (PND) 9 and then was given the iron sufficient diet. Maternal blood samples were collected on gestational day (GD) 21, GD 42, GD 63 and PND 9, serum level of iron (SI) or hemoglobin (Hb) was measured. Blood samples of pups were collected on PND 9 for SI measurement. On PND 24, pups were examined the distortion product otoacoustic emission (DPOAE) task, and then the cochleae were harvested for assessment of apoptosis by immunohistochemistry of cysteine-aspartic acid proteases 3/9 (caspase-3/9) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, and by double immunofluorescence for the colocalization of TUNEL and caspase-3. Blood samples of pups were collected on PND 24 for SI and Hb measurements. Here we show that mild maternal IDA during pregnancy and lactation resulted in hearing impairment, decreased hair cell number, caspase-3/9 activation and increased apoptotic cell number of young guinea pigs. These results indicate a key role for apoptosis in inhibition of hair cell development, caused by mild maternal IDA during pregnancy and lactation. PMID:24378594

  17. Immune activity elevates energy expenditure of house sparrows: a link between direct and indirect costs?

    PubMed Central

    Martin, Lynn B; Scheuerlein, Alex; Wikelski, Martin

    2003-01-01

    The activation of an immune response is beneficial for organisms but may also have costs that affect fitness. Documented immune costs include those associated with acquisition of special nutrients, as well as immunopathology or autoimmunity. Here, we test whether an experimental induction of the immune system with a non-pathological stimulant can elevate energy turnover in passerine birds. We injected phytohaemagglutinin (PHA), a commonly used mitogen that activates the cell-mediated immune response, into the wing web of house sparrows, Passer domesticus. We then examined energetic costs resulting from this immune activity and related those costs to other physiological activities. We found that PHA injection significantly elevated resting metabolic rate (RMR) of challenged sparrows relative to saline controls. We calculated the total cost of this immune activity to be ca. 4.20 kJ per day (29% RMR), which is equivalent to the cost of production of half of an egg (8.23 kJ egg(-1)) in this species. We suggest that immune activity in wild passerines increases energy expenditure, which in turn may influence important life-history characteristics such as clutch size, timing of breeding or the scheduling of moult. PMID:12590753

  18. Gender differences in the immune system activities of sea urchin Paracentrotus lividus.

    PubMed

    Arizza, Vincenzo; Vazzana, Mirella; Schillaci, Domenico; Russo, Debora; Giaramita, Francesca Tiziana; Parrinello, Nicolò

    2013-03-01

    In the immune system of vertebrates, gender-specific differences in individual immune competence are well known. In general, females possess more powerful immune response than males. In invertebrates, the situation is much less clear. For this purpose we have chosen to study the immune response of the two sexes of the echinoderm Paracentrotus lividus in pre- and post-spawning phases. The coelomic fluid from the echinoderms contains several coelomocyte types and molecules involved in innate immune defenses. In this article we report that the degree of immune responses in the P. lividus differs according to sex in both pre- and post-spawning phases. We found in all tests that females were more active than males. The results indicate that females possess a significant higher number of immunocytes consisting of phagocytes and uncolored spherulocytes. Since the immunological activity is mainly based on immunocytes, it was not surprising that females possessed the highest values of cytotoxicity and hemolysis activity and showed a greater ability to uptake neutral red and phagocyte yeasts cells, while the average number of ingested particles per active phagocyte was not significantly different. Furthermore, agglutinating activity was more evident in the coelomocyte lysate and coelomic fluid of females than in those of males. Finally we found that the acidic extract of female gonads possessed greater antimicrobial activity than that of male gonads. These results make it very likely that gender differences in the immune response are not restricted to vertebrates; rather, they are a general evolutionary phenomenon. PMID:23220062

  19. Effect of maternal deprivation on N-acetyltransferase activity rhythm in blinded rat pups.

    PubMed

    Katoh, Y; Takeuchi, Y; Yamazaki, K; Takahashi, K

    1998-02-15

    It has been reported that the rhythms of infant rats synchronize with the mother's rhythm until the light-dark cycle comes and has strong effects on their endogenous clocks. We found that periodic maternal deprivation (PMD) was able to cause a phase shift of serotonin N-acetyltransferase (NAT) in neonatal blinded rat pups. PMD in which contact with the mother was allowed for only 4 h caused a phase shift of NAT rhythm, irrespective of the timing of contact with the mother in a day. Acute single mother deprivation caused an excess of NAT activity for more hours than usual and contact with the mother prevented such an excessive response. Mother deprivation may act as a cold stress, since artificial warming of pups gave the same results as contact with the mother. When the pups were artificially warmed by a heater during a 1-week deprivation period, a flat 24-h pattern of NAT was observed. The mechanism causing a phase shift of NAT activity rhythm of rat pups may be complicated. PMID:9523895

  20. Effects of Feeding Bt Maize to Sows during Gestation and Lactation on Maternal and Offspring Immunity and Fate of Transgenic Material

    PubMed Central

    Buzoianu, Stefan G.; Walsh, Maria C.; Rea, Mary C.; O'Donovan, Orla; Gelencsér, Eva; Ujhelyi, Gabriella; Szabó, Erika; Nagy, Andras; Ross, R. Paul; Gardiner, Gillian E.; Lawlor, Peadar G.

    2012-01-01

    Background We aimed to determine the effect of feeding transgenic maize to sows during gestation and lactation on maternal and offspring immunity and to assess the fate of transgenic material. Methodology/Principal Findings On the day of insemination, sows were assigned to one of two treatments (n = 12/treatment); 1) non-Bt control maize diet or 2) Bt-MON810 maize diet, which were fed for ∼143 days throughout gestation and lactation. Immune function was assessed by leukocyte phenotyping, haematology and Cry1Ab-specific antibody presence in blood on days 0, 28 and 110 of gestation and at the end of lactation. Peripheral-blood mononuclear cell cytokine production was investigated on days 28 and 110 of gestation. Haematological analysis was performed on offspring at birth (n = 12/treatment). Presence of the cry1Ab transgene was assessed in sows' blood and faeces on day 110 of gestation and in blood and tissues of offspring at birth. Cry1Ab protein presence was assessed in sows' blood during gestation and lactation and in tissues of offspring at birth. Blood monocyte count and percentage were higher (P<0.05), while granulocyte percentage was lower (P<0.05) in Bt maize-fed sows on day 110 of gestation. Leukocyte count and granulocyte count and percentage were lower (P<0.05), while lymphocyte percentage was higher (P<0.05) in offspring of Bt maize-fed sows. Bt maize-fed sows had a lower percentage of monocytes on day 28 of lactation and of CD4+CD8+ lymphocytes on day 110 of gestation, day 28 of lactation and overall (P<0.05). Cytokine production was similar between treatments. Transgenic material or Cry1Ab-specific antibodies were not detected in sows or offspring. Conclusions/Significance Treatment differences observed following feeding of Bt maize to sows did not indicate inflammation or allergy and are unlikely to be of major importance. These results provide additional data for Bt maize safety assessment. PMID:23091650

  1. CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection.

    PubMed

    Côme, Christophe; Cvrljevic, Anna; Khan, Mohd Moin; Treise, Irina; Adler, Thure; Aguilar-Pimentel, Juan Antonio; Au-Yeung, Byron; Sittig, Eleonora; Laajala, Teemu Daniel; Chen, Yiling; Oeder, Sebastian; Calzada-Wack, Julia; Horsch, Marion; Aittokallio, Tero; Busch, Dirk H; Ollert, Markus W; Neff, Frauke; Beckers, Johannes; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabě de Angelis, Martin; Chen, Zhi; Lahesmaa, Riitta; Westermarck, Jukka

    2016-01-01

    The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2AHOZ) present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2AHOZ mice display an impaired adaptive immune response that is combined with decreased frequency of both CD4+ T-cells and CD8+ effector T-cells. Importantly, the cell autonomous effect of CIP2A deficiency for T-cell activation was confirmed. Induction of CIP2A expression during T-cell activation was dependent on Zap70 activity. Thus, we reveal CIP2A as a hitherto unrecognized mediator of T-cell activation during adaptive immune response. These results also reveal CIP2AHOZ as a possible novel mouse model for studying the role of PP2A activity in immune regulation. On the other hand, the results also indicate that CIP2A targeting cancer therapies would not cause serious immunological side-effects. PMID:27100879

  2. CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection

    PubMed Central

    Cvrljevic, Anna; Khan, Mohd Moin; Treise, Irina; Adler, Thure; Aguilar-Pimentel, Juan Antonio; Au-Yeung, Byron; Sittig, Eleonora; Laajala, Teemu Daniel; Chen, Yiling; Oeder, Sebastian; Calzada-Wack, Julia; Horsch, Marion; Aittokallio, Tero; Busch, Dirk H.; Ollert, Markus W.; Neff, Frauke; Beckers, Johannes; Gailus-Durner, Valerie; Fuchs, Helmut; de Angelis, Martin Hrabě; Chen, Zhi; Lahesmaa, Riitta; Westermarck, Jukka

    2016-01-01

    The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2AHOZ) present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2AHOZ mice display an impaired adaptive immune response that is combined with decreased frequency of both CD4+ T-cells and CD8+ effector T-cells. Importantly, the cell autonomous effect of CIP2A deficiency for T-cell activation was confirmed. Induction of CIP2A expression during T-cell activation was dependent on Zap70 activity. Thus, we reveal CIP2A as a hitherto unrecognized mediator of T-cell activation during adaptive immune response. These results also reveal CIP2AHOZ as a possible novel mouse model for studying the role of PP2A activity in immune regulation. On the other hand, the results also indicate that CIP2A targeting cancer therapies would not cause serious immunological side-effects. PMID:27100879

  3. Innate immune system activation by viral RNA: How to predict it?

    PubMed

    Kondili, M; Roux, M; Vabret, N; Bailly-Bechet, M

    2016-01-15

    The immune system is able to identify foreign pathogens via different pathways. In the case of viral infection, recognition of the viral RNA is a crucial step, and many efforts have been made to understand which features of viral RNA are detected by the immune system. The biased viral RNA composition, measured as host-virus nucleotidic divergence, or CpG enrichment, has been proposed as salient signal. Peculiar structural features of these RNA could also be related to the immune system activation. Here, we gather multiple datasets and proceed to a meta-analysis to uncover the best predictors of immune system activation by viral RNA. "A" nucleotide content and Minimum Folding Energy are good predictors, and are more easily generalized than more complex indicators suggested previously. As RNA composition and structure are highly correlated, we suggest further experiments on synthetic sequences to identify the viral RNA sensing mechanisms by immune system receptors. PMID:26650692

  4. Maternal recasts and activity variations: a comparison of mother-child dyads involving children with and without SLI.

    PubMed

    Rezzonico, Stefano; de Weck, Geneviève; Salazar Orvig, Anne; da Silva Genest, Christine; Rahmati, Somayeh

    2014-04-01

    This study investigated maternal recast and the children's responses comparing dyads made up of a mother and a child with typical language development (TD) or a child with specific language impairment (SLI). More specifically, this article deals with the influence of the type of activity being carried out on the number and types of maternal recasts. A sample of 17 French-speaking children with SLI (age 5 to 7 years) matched with 17 TD same-age peers was observed in interaction with their mother during four different activities (joint reading, symbolic play, question guessing game and clue guessing game). The results showed that group and activity had an impact on the number and type of recasts. Mothers of children with SLI offered more recasts than mothers of TD children. The former preferred phonological recasts whereas the latter preferred lexical ones. Moreover, recasts were more frequently used in joint reading than in other activities. Regarding the children's responses, no significant difference was observed between the two groups. Children with SLI took up the maternal proposition more frequently after a lexical recast than after a recast of another type. The findings provide evidence for considering the features of the activities in clinical settings. PMID:23819678

  5. Maternal and paternal parenting practices and their influence on children's adiposity, screen-time, diet and physical activity.

    PubMed

    Lloyd, Adam B; Lubans, David R; Plotnikoff, Ronald C; Collins, Clare E; Morgan, Philip J

    2014-08-01

    The primary aim of this study was to examine a range of potential behavioral and maternal/paternal correlates of adiposity in children. Secondary aims were to examine (a) correlates of screen-time, diet and physical activity and (b) if there were differences in maternal and paternal physical activity- and dietary-related parenting practices. Cross-sectional analysis was conducted using 70 families with children (59% boys (41/70), mean age 8.4 (±2.4) years). Parenting practices were measured using the Parenting Strategies for Eating and Activity Scale. Children's outcomes included: 7-day pedometry (physical activity), screen-time, percent energy from core foods (Food frequency questionnaire) and BMI z-score. Multiple regression models were generated to examine the associations between maternal and paternal parenting practices and children's variables. In the regression analyses, fathers' BMI (p < .01) and mothers' control (p < .001) were significantly associated with child weight status. Fathers' reinforcement (p < .01) was significantly associated with child physical activity. For screen-time, mothers' monitoring (p < .001) and child characteristics [age (p = .01), sex (p = .01), BMI z-score (p = .03)] were significant predictors. Mothers' parenting practices [limit setting (p = .01), reinforcement (p = .02)] and child screen-time (p = .02) were significantly associated with intake of core foods. Despite some similarities within families, three out of five parenting constructs were significantly different between mothers and fathers. Mothers and fathers have different parental influences on their children's weight status and lifestyle behaviors and both should be included in lifestyle interventions targeting children. A focus on maternal parenting specifically relating to screen-time and diet, and father's physical activity parenting and weight status may support their children in developing more healthy behaviors. PMID:24751915

  6. From Wasting to Obesity: The Contribution of Nutritional Status to Immune Activation in HIV Infection.

    PubMed

    Koethe, John R; Heimburger, Douglas C; PrayGod, George; Filteau, Suzanne

    2016-10-01

    The impact of human immunodeficiency virus (HIV) infection on innate and adaptive immune activation occurs in the context of host factors, which serve to augment or dampen the physiologic response to the virus. Independent of HIV infection, nutritional status, particularly body composition, affects innate immune activation through a variety of conditions, including reduced mucosal barrier defenses and microbiome dysbiosis in malnutrition and the proinflammatory contribution of adipocytes and stromal vascular cells in obesity. Similarly, T-cell activation, proliferation, and cytokine expression are reduced in the setting of malnutrition and increased in obesity, potentially due to adipokine regulatory mechanisms restraining energy-avid adaptive immunity in times of starvation and exerting a paradoxical effect in overnutrition. The response to HIV infection is situated within these complex interactions between host nutritional health and immunologic function, which contribute to the varied phenotypes of immune activation among HIV-infected patients across a spectrum from malnutrition to obesity. PMID:27625434

  7. Activism: working to reduce maternal mortality through civil society and health professional alliances in sub-Saharan Africa.

    PubMed

    Ray, Sunanda; Madzimbamuto, Farai; Fonn, Sharon

    2012-06-01

    Partnerships between civil society groups campaigning for reproductive and human rights, health professionals and others could contribute more to the strengthening of health systems needed to bring about declines in maternal deaths in Africa. The success of the HIV treatment literacy model developed by the Treatment Action Campaign in South Africa provides useful lessons for activism on maternal mortality, especially the combination of a right-to-health approach with learning and capacity building, community networking, popular mobilisation and legal action. This paper provides examples of these from South Africa, Botswana, Kenya and Uganda. Confidential enquiries into maternal deaths can be powerful instruments for change if pressure to act on their recommendations is brought to bear. Shadow reports presented during UN human rights country assessments can be used in a similar way. Public protests and demonstrations over avoidable deaths have succeeded in drawing attention to under-resourced services, shortages of supplies, including blood for transfusion, poor morale among staff, and lack of training and supervision. Activists could play a bigger role in holding health services, governments, and policy-makers accountable for poor maternity services, developing user-friendly information materials for women and their families, and motivating appropriate human resources strategies. Training and support for patients' groups, in how to use health facility complaints procedures is also a valuable strategy. PMID:22789081

  8. Immune complexes that contain HIV antigens activate peripheral blood T cells.

    PubMed

    Korolevskaya, L B; Shmagel, K V; Saidakova, E V; Shmagel, N G; Chereshnev, V A

    2016-07-01

    Uninfected donor T cells were treated in vitro by model immune complexes that contained either HIV or hepatitis C virus (HCV) antigens. Unlike HCV antigen-containing complexes, the immune complexes that contained HIV antigens have been shown to activate peripheral blood T cells of uninfected donors under in vitro conditions. Both the antiviral antibodies and HIV antigen were involved in the activation process. The unique properties of the immune complexes formed by HIV antigens and antiviral antibodies are believed to result from the virus-specific antibody properties and molecular conformation of the antigen-antibody complex. PMID:27595830

  9. Moving forward with strengthening routine immunization delivery as part of measles and rubella elimination activities.

    PubMed

    Fields, Rebecca; Dabbagh, Alya; Jain, Manish; Sagar, Karan Singh

    2013-04-18

    The Global Vaccine Action Plan includes a goal of meeting global and regional measles and rubella elimination targets, noting that such efforts should not operate in silos but be coordinated with other immunization efforts. Similarly, the Global Measles and Rubella Strategic Plan for 2012-2020 emphasizes the need for integrated approaches to achieve and maintain very high levels of population immunity using both routine immunization and supplemental immunization activities (SIAs). The strategic plan also includes routine vaccination coverage targets, highlighting the critical role of strong routine immunization systems as a cornerstone for sustainable measles control/elimination efforts. It encourages exploiting the resources and visibility of SIAs to strengthen routine immunization, thereby reducing the frequency with which SIAs are needed. Documented examples of doing so include training health workers, procuring cold chain equipment, and improving injection safety and adverse events management. However, the concept has been put into practice only to a limited extent and missed opportunities persist regarding this aspect of SIA planning and execution. This paper draws on recent studies of the interaction between measles activities and health systems as well as country experiences in using SIAs to strengthen routine immunization. It identifies obstacles and enabling factors to doing so and proposes options for systematically strengthening routine immunization as part of a best practice SIA. PMID:23598472

  10. Dermatophytes Activate Skin Keratinocytes via Mitogen-Activated Protein Kinase Signaling and Induce Immune Responses

    PubMed Central

    Achterman, Rebecca R.; Moyes, David L.; Thavaraj, Selvam; Smith, Adam R.; Blair, Kris M.

    2015-01-01

    Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte, Trichophyton equinum. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with Microsporum gypseum inducing the greatest level of damage and cytokine release. Using T. equinum as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected. T. equinum also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of T. equinum to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation. PMID:25667269

  11. Adolescent adrenocortical activity and adiposity: differences by sex and exposure to early maternal depression.

    PubMed

    Ruttle, Paula L; Klein, Marjorie H; Slattery, Marcia J; Kalin, Ned H; Armstrong, Jeffrey M; Essex, Marilyn J

    2014-09-01

    Prior research has linked either basal cortisol levels or stress-induced cortisol responses to adiposity; however, it remains to be determined whether these distinct cortisol measures exert joint or independent effects. Further, it is unclear how they interact with individual and environmental characteristics to predict adiposity. The present study aims to address whether morning cortisol levels and cortisol responses to a psychosocial stressor independently and/or interactively influence body mass index (BMI) in 218 adolescents (117 female) participating in a longitudinal community study, and whether associations are moderated by sex and exposure to early maternal depression. Reports of maternal depressive symptoms were obtained in infancy and preschool. Salivary cortisol measures included a longitudinal morning cortisol measure comprising sampling points across ages 11, 13, 15, and 18 and measures of stress-induced cortisol responses assessed via the Trier Social Stress Test (TSST) at age 18. Lower morning cortisol and higher TSST cortisol reactivity independently predicted higher age 18 BMI. Morning cortisol also interacted with sex and exposure to early maternal depression to predict BMI. Specifically, girls exposed to lower levels of early maternal depression displayed a strong negative morning cortisol-BMI association, and girls exposed to higher levels of maternal depression demonstrated a weaker negative association. Among boys, those exposed to lower levels of maternal depression displayed no association, while those exposed to higher levels of maternal depression displayed a negative morning cortisol-BMI association. Results point to the independent, additive effects of morning and reactive cortisol in the prediction of BMI and suggest that exposure to early maternal depression may exert sexually dimorphic effects on normative cortisol-BMI associations. PMID:25001956

  12. Adolescent Adrenocortical Activity and Adiposity: Differences by Sex and Exposure to Early Maternal Depression

    PubMed Central

    Ruttle, Paula L.; Klein, Marjorie H.; Slattery, Marcia J.; Kalin, Ned H.; Armstrong, Jeffrey M.; Essex, Marilyn J.

    2014-01-01

    Summary Prior research has linked either basal cortisol levels or stress-induced cortisol responses to adiposity; however, it remains to be determined whether these distinct cortisol measures exert joint or independent effects. Further, it is unclear how they interact with individual and environmental characteristics to predict adiposity. The present study aims to address whether morning cortisol levels and cortisol responses to a psychosocial stressor independently and/or interactively influence body mass index (BMI) in 218 adolescents (117 female) participating in a longitudinal community study, and whether associations are moderated by sex and exposure to early maternal depression. Reports of maternal depressive symptoms were obtained in infancy and preschool. Salivary cortisol measures included a longitudinal morning cortisol measure comprising sampling points across ages 11, 13, 15, and 18 and measures of stress-induced cortisol responses assessed via the Trier Social Stress Test (TSST) at age 18. Lower morning cortisol and higher TSST cortisol reactivity independently predicted higher age 18 BMI. Morning cortisol also interacted with sex and exposure to early maternal depression to predict BMI. Specifically, girls exposed to lower levels of early maternal depression displayed a strong negative morning cortisol-BMI association, and girls exposed to higher levels of maternal depression demonstrated a weaker negative association. Among boys, those exposed to lower levels of maternal depression displayed no association, while those exposed to higher levels of maternal depression displayed a negative morning cortisol-BMI association. Results point to the independent, additive effects of morning and reactive cortisol in the prediction of BMI and suggest that exposure to early maternal depression may exert sexually dimorphic effects on normative cortisol-BMI associations. PMID:25001956

  13. Screening of Immune-Active Lactic Acid Bacteria

    PubMed Central

    Hwang, E-Nam; Kang, Sang-Mo; Kim, Mi-Jung

    2015-01-01

    The purpose of this study was to investigate the effect of lactic acid bacteria (LAB) cell wall extract on the proliferation and cytokine production of immune cells to select suitable probiotics for space food. Ten strains of LAB (Lactobacillus bulgaricus, L. paracasei, L. casei, L. acidophilus, L. plantarum, L. delbruekii, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, and Pedicoccus pentosaceus) were sub-cultured and further cultured for 3 d to reach 7-10 Log colony-forming units (CFU)/mL prior to cell wall extractions. All LAB cell wall extracts failed to inhibit the proliferation of BALB/c mouse splenocytes or mesenteric lymphocytes. Most LAB cell wall extracts except those of L. plantarum and L. delbrueckii induced the proliferation of both immune cells at tested concentrations. In addition, the production of TH1 cytokine (IFN-γ) rather than that of TH2 cytokine (IL-4) was enhanced by LAB cell wall extracts. Of ten LAB extracts, four (from L. acidophilus, L. bulgaricus, L. casei, and S. thermophiles) promoted both cell proliferating and TH1 cytokine production. These results suggested that these LAB could be used as probiotics to maintain immunity and homeostasis for astronauts in extreme space environment and for general people in normal life. PMID:26761877

  14. Screening of Immune-Active Lactic Acid Bacteria.

    PubMed

    Hwang, E-Nam; Kang, Sang-Mo; Kim, Mi-Jung; Lee, Ju-Woon

    2015-01-01

    The purpose of this study was to investigate the effect of lactic acid bacteria (LAB) cell wall extract on the proliferation and cytokine production of immune cells to select suitable probiotics for space food. Ten strains of LAB (Lactobacillus bulgaricus, L. paracasei, L. casei, L. acidophilus, L. plantarum, L. delbruekii, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, and Pedicoccus pentosaceus) were sub-cultured and further cultured for 3 d to reach 7-10 Log colony-forming units (CFU)/mL prior to cell wall extractions. All LAB cell wall extracts failed to inhibit the proliferation of BALB/c mouse splenocytes or mesenteric lymphocytes. Most LAB cell wall extracts except those of L. plantarum and L. delbrueckii induced the proliferation of both immune cells at tested concentrations. In addition, the production of TH1 cytokine (IFN-γ) rather than that of TH2 cytokine (IL-4) was enhanced by LAB cell wall extracts. Of ten LAB extracts, four (from L. acidophilus, L. bulgaricus, L. casei, and S. thermophiles) promoted both cell proliferating and TH1 cytokine production. These results suggested that these LAB could be used as probiotics to maintain immunity and homeostasis for astronauts in extreme space environment and for general people in normal life. PMID:26761877

  15. Immune and hormonal activity in adults suffering from depression.

    PubMed

    Nunes, S O V; Reiche, E M V; Morimoto, H K; Matsuo, T; Itano, E N; Xavier, E C D; Yamashita, C M; Vieira, V R; Menoli, A V; Silva, S S; Costa, F B; Reiche, F V; Silva, F L V; Kaminami, M S

    2002-05-01

    An association between depression and altered immune and hormonal systems has been suggested by the results of many studies. In the present study we carried out immune and hormonal measurements in 40 non-medicated, ambulatory adult patients with depression determined by CID-10 criteria and compared with 34 healthy nondepressed subjects. The severity of the condition was determined with the Hamilton Depression Rating Scale. Of 40 depressed patients, 31 had very severe and 9 severe or moderate depression, 29 (72.5%) were females and 11 (27.5%) were males (2.6:1 ratio). The results revealed a significant reduction of albumin and elevation of alpha-1, alpha-2 and beta-globulins, and soluble IL-2 receptor in patients with depression compared to the values obtained for nondepressed subjects (P<0.05). The decrease lymphocyte proliferation in response to a mitogen was significantly lower in severely or moderately depressed patients when compared to control (P<0.05). These data confirm the immunological disturbance of acute phase proteins and cellular immune response in patients with depression. Other results may be explained by a variety of interacting factors such as number of patients, age, sex, and the nature, severity and/or duration of depression. Thus, the data obtained should be interpreted with caution and the precise clinical relevance of these findings requires further investigation. PMID:12011944

  16. Lactic acid bacteria activating innate immunity improve survival in bacterial infection model of silkworm.

    PubMed

    Nishida, Satoshi; Ono, Yasuo; Sekimizu, Kazuhisa

    2016-02-01

    Lactic acid bacteria (LAB) have been thought to be helpful for human heath in the gut as probiotics. It recently was noted that activity of LAB stimulating immune systems is important. Innate immune systems are conserved in mammals and insects. Silkworm has innate immunity in response to microbes. Microbe-associated molecular pattern (ex. peptidoglycan and β-glucan) induces a muscle contraction of silkworm larva. In this study, we established an efficient method to isolate lactic acid bacteria derived from natural products. We selected a highly active LAB to activate the innate immunity in silkworm by using the silkworm muscle contraction assay, as well. The assay revealed that Lactococcus lactis 11/19-B1 was highly active on the stimulation of the innate immunity in silkworm. L. lactis 11/19-B1 solely fermented milk with casamino acid and glucose. This strain would be a starter strain to make yogurt. Compared to commercially available yogurt LAB, L. lactis 11/19-B1 has higher activity on silkworm contraction. Silkworm normally ingested an artificial diet mixed with L. lactis 11/19-B1 or a yogurt fermented with L. lactis 11/19-B1. Interestingly, silkworms that ingested the LAB showed tolerance against the pathogenicity of Pseudomonas aeruginosa. These data suggest that Lactococcus lactis 11/19-B1 would be expected to be useful for making yogurt and probiotics to activate innate immunity. PMID:26971556

  17. Lipopolysaccharide Induces Immune Activation and SIV Replication in Rhesus Macaques of Chinese Origin

    PubMed Central

    Bao, Rong; Zhuang, Ke; Liu, Jinbiao; Wu, Jianguo; Li, Jieliang; Wang, Xu; Ho, Wen-Zhe

    2014-01-01

    Background Chronic immune activation is a hallmark of progressive HIV infection and a key determinant of immunodeficiency in HIV-infected individuals. Bacterial lipopolysaccharide (LPS) in the circulation has been implicated as a key factor in HIV infection-related systemic immune activation. We thus investigate the impact of LPS on systemic immune activation in simian immunodeficiency virus (SIV)-infected rhesus macaques of Chinese origin. Methods The animals were inoculated intravenously with SIVmac239. The levels of plasma viral load and host inflammatory cytokines in PBMC were measured by real-time RT-PCR. CD4/CD8 ratio and systemic immune activation markers were examined by flow cytometric analysis of PBMCs. White blood cell and neutrophil counts and C Reactive Protein levels were determined using biochemistry analyzer. The plasma levels of LPS were determined by Tachypleus Amebocyte Lysate (TAL) test. Results The animals inoculated with SIVmac239 became infected as evidenced by the increased plasma levels of SIV RNA and decreased CD4/CD8 ratio. LPS administration of SIV-infected animals induced a transient increase of plasma SIV RNA and immune activation, which was indicated by the elevated expression of the inflammatory cytokines and CD4+HLA-DR+ T cells in PBMCs. Conclusions These data support the concept that LPS is a driving factor in systemic immune activation of HIV disease. PMID:24918575

  18. Sexually dimorphic effects of neonatal immune system activation with lipopolysaccharide on the behavioural response to a homotypic adult immune challenge.

    PubMed

    Tenk, Christine M; Kavaliers, Martin; Ossenkopp, Klaus-Peter

    2008-01-01

    Research has shown that acute immune activation during the early postnatal period with the Gram-negative endotoxin, lipopolysaccharide (LPS), alters a variety of physiological and behavioural processes in the adult animal. For example, neonatal LPS exposure affects disease susceptibility later in life, though these effects appear to be modulated by time of exposure, sex, and immune stimulus. The current study examined sex differences in the effect of neonatal LPS treatment on the locomotor activity response to adult LPS administration. Male and female Long-Evans rats were treated systemically with either LPS (50 microg/kg) or saline (0.9%) on postnatal days 3 and 5. Later in adulthood (postnatal day 92), all animals were subjected to an adult LPS challenge and were injected (i.p.) with 200 microg/kg LPS. Two hours after injection, animals were placed in a non-novel open-field and locomotor activity was assessed for 30 min. Body weights were determined both at the time of injection and 24h later to examine LPS-induced weight loss. Adult males treated neonatally with LPS exhibited significantly less horizontal and vertical activity in response to the LPS challenge relative to males treated neonatally with saline. This effect was not observed in females. Thus, the current study provides important evidence of sexual dimorphism in the long-term effects of neonatal LPS exposure on the responses to an adult homotypic immune challenge in rats. These findings have potential clinical significance given that neonatal exposure to pathogens is a fairly common occurrence and Gram-negative bacteria are a common cause of neonatal bacterial infections. PMID:18280690

  19. Evidence that FcRn mediates the transplacental passage of maternal IgE in the form of IgG anti-IgE/IgE immune complexes

    PubMed Central

    Bundhoo, Arvin; Paveglio, Sara; Rafti, Ektor; Dhongade, Ashish; Blumberg, Richard S.; Matson, Adam P.

    2015-01-01

    Background The mechanism(s) responsible for acquisition of maternal antibody isotypes other than IgG are not fully understood. This uncertainty is a major reason underlying the continued controversy regarding whether cord blood (CB) IgE originates in the mother or fetus. Objective To investigate the capacity of maternal IgE to be transported across the placenta in the form of IgG anti-IgE/IgE immune complexes (ICs) and to determine the role of the neonatal Fc receptor (FcRn) in mediating this process. Methods Maternal and CB serum concentrations of IgE, IgG anti-IgE, and IgG anti-IgE/IgE ICs were determined in a cohort of allergic and non-allergic mother/infant dyads. Madin-Darby Canine Kidney (MDCK) cells stably transfected with human FcRn were used to study the binding and transcytosis of IgE in the form of IgG anti-IgE/IgE ICs. Results Maternal and CB serum concentrations of IgG anti-IgE/IgE ICs were highly correlated, regardless of maternal allergic status. IgG anti-IgE/IgE ICs generated in vitro bound strongly to FcRn-expressing MDCK cells and were transcytosed in an FcRn-dependent manner. Conversely, monomeric IgE did not bind to FcRn and was not transcytosed. IgE was detected in solutions of transcytosed IgG anti-IgE/IgE ICs, even though essentially all the IgE remained in complex form. Similarly, the majority of IgE in CB sera was found to be complexed to IgG. Conclusions and Clinical Relevance These data indicate that human FcRn facilitates the transepithelial transport of IgE in the form of IgG anti-IgE/IgE ICs. They also strongly suggest that the majority of IgE in CB sera is the result of FcRn-mediated transcytosis of maternal-derived IgG anti-IgE/IgE ICs. These findings challenge the widespread perception that maternal IgE does not cross the placenta. Measuring maternal or CB levels of IgG anti-IgE/IgE ICs may be a more accurate predictor of allergic risk. PMID:25652137

  20. Persistent Immune Activation in CVID and the Role of IVIg in Its Suppression.

    PubMed

    Paquin-Proulx, Dominic; Sandberg, Johan K

    2014-01-01

    Common variable immunodeficiency (CVID) is one of the most common and clinically important primary immune deficiencies. CVID patients have poor humoral immunity, resulting in recurrent infections of the gastrointestinal and upper respiratory tracts, as well as increased incidence of some forms of cancers and autoimmune diseases. The treatment for CVID is IgG replacement, often given as intravenous immunoglobulins (IVIg). IVIg consists of monomeric IgG purified from pooled plasma from healthy donors and is used to treat an increasing number of conditions including autoimmune diseases. In the case of CVID, IVIg has mainly been seen as reconstitution therapy, providing patients with pathogen-specific antibodies. Recent evidence shows that IVIg has diverse effects on the immune system of CVID patients, and one important component is that IVIg alleviates the state of chronic immune activation. In this review, we will discuss causes and consequences of persistent immune activation in CVID, possible underlying mechanisms for how IVIg treatment reduces immune activation, and implications for our understanding of primary as well as acquired immune deficiencies. PMID:25566250

  1. Targeting KIT on innate immune cells to enhance the antitumor activity of checkpoint inhibitors.

    PubMed

    Stahl, Maximilian; Gedrich, Richard; Peck, Ronald; LaVallee, Theresa; Eder, Joseph Paul

    2016-06-01

    Innate immune cells such as mast cells and myeloid-derived suppressor cells are key components of the tumor microenvironment. Recent evidence indicates that levels of myeloid-derived suppressor cells in melanoma patients are associated with poor survival to checkpoint inhibitors. This suggests that targeting both the innate and adaptive suppressive components of the immune system will maximize clinical benefit and elicit more durable responses in cancer patients. Preclinical data suggest that targeting signaling by the receptor tyrosine kinase KIT, particularly on mast cells, may modulate innate immune cell numbers and activity in tumors. Here, we review data highlighting the importance of the KIT signaling in regulating antitumor immune responses and the potential benefit of combining selective KIT inhibitors with immune checkpoint inhibitors. PMID:27349976

  2. Immune Activation Efficacy of Indolicidin Is Enhanced upon Conjugation with Carbon Nanotubes and Gold Nanoparticles

    PubMed Central

    Banerjee, Arka; Aich, Palok

    2015-01-01

    Antibiotic resistance is concern of today's world. Search for alternative molecules, for treatment and immune stimulation, remains at the forefront. One such group of biomolecules with promise, along the line of immune stimulation or therapy, is host defense peptide (HDP). These molecules, however, are required at a higher dose to be effective which leads to high cost. To alleviate such problems, an aid can be used to achieve similar efficacy but at a smaller effective dose of the immune stimulant. We hypothesised that by conjugating HDPs with carbon nanotubes and/or gold nanoparticles, it would be possible to stimulate a protective immune response in host system at a lower dosage of HDP. In this report, we characterized, using biophysical methodologies, conjugation of Indolicidin, as a representative of HDP. We further established efficacy of peptide-nanomaterial conjugates in activating innate immunity and protecting against pathogen infection in vitro at a significantly small dose. PMID:25876153

  3. Immune activation efficacy of indolicidin is enhanced upon conjugation with carbon nanotubes and gold nanoparticles.

    PubMed

    Sur, Abhinav; Pradhan, Biswaranjan; Banerjee, Arka; Aich, Palok

    2015-01-01

    Antibiotic resistance is concern of today's world. Search for alternative molecules, for treatment and immune stimulation, remains at the forefront. One such group of biomolecules with promise, along the line of immune stimulation or therapy, is host defense peptide (HDP). These molecules, however, are required at a higher dose to be effective which leads to high cost. To alleviate such problems, an aid can be used to achieve similar efficacy but at a smaller effective dose of the immune stimulant. We hypothesised that by conjugating HDPs with carbon nanotubes and/or gold nanoparticles, it would be possible to stimulate a protective immune response in host system at a lower dosage of HDP. In this report, we characterized, using biophysical methodologies, conjugation of Indolicidin, as a representative of HDP. We further established efficacy of peptide-nanomaterial conjugates in activating innate immunity and protecting against pathogen infection in vitro at a significantly small dose. PMID:25876153

  4. Maternal microchimerism

    PubMed Central

    Ye, Jody; Vives-Pi, Marta; Gillespie, Kathleen M

    2014-01-01

    Increased levels of non-inherited maternal HLA alleles have been detected in the periphery of children with type 1 diabetes and an increased frequency of maternal cells have been identified in type 1 diabetes pancreas. It is now clear that the phenotype of these cells is pancreatic,1 supporting the hypothesis that maternal cells in human pancreas are derived from multipotent maternal progenitors. Here we hypothesize how increased levels of maternal cells could play a role in islet autoimmunity. PMID:25093746

  5. Surfactant protein D induces immune quiescence and apoptosis of mitogen-activated peripheral blood mononuclear cells.

    PubMed

    Pandit, Hrishikesh; Thakur, Gargi; Koippallil Gopalakrishnan, Aghila Rani; Dodagatta-Marri, Eswari; Patil, Anushree; Kishore, Uday; Madan, Taruna

    2016-02-01

    Surfactant protein D (SP-D) is an integral molecule of the innate immunity secreted by epithelial cells lining the mucosal surfaces. The C-type lectin domain of SP-D performs pattern recognition functions while it binds to putative receptors on immune cells to modify cellular functions. Activation of immune cells and increased serum SP-D is observed in a range of patho-physiological conditions including infections. We speculated if SP-D can modulate systemic immune response via direct interaction with activated PBMCs. In this study, we examined interaction of a recombinant fragment of human SP-D (rhSP-D) on PHA-activated PBMCs. We report a significant downregulation of activation receptors such as TLR2, TLR4, CD11c and CD69 upon rhSP-D treatment. rhSP-D inhibited production of Th1 (TNF-α and IFN-γ) and Th17 (IL-17A) cytokines along with IL-6. Interestingly, levels of IL-2, Th2 (IL-4) and regulatory (IL-10 and TGF-β) cytokines remained unaltered. Analysis of co-stimulatory CD28 and co-inhibitory CTLA4 receptors along with their ligands CD80 and CD86 revealed a selective up-regulation of CTLA4 in the lymphocyte subset. rhSP-D induced apoptosis in the activated but not in non-activated lymphocytes. Blockade of CTLA4 inhibited rhSP-D mediated apoptosis of activated lymphocytes, confirming involvement of CTLA4. We conclude that SP-D restores immune homeostasis. It regulates expression of immunomodulatory receptors and cytokines, which is followed by induction of apoptosis in activated lymphocytes. These findings suggest a critical role of SP-D in immune surveillance against activated immune cells. PMID:26563748

  6. Lgt Processing Is an Essential Step in Streptococcus suis Lipoprotein Mediated Innate Immune Activation

    PubMed Central

    Wichgers Schreur, Paul J.; Rebel, Johanna M. J.; Smits, Mari A.; van Putten, Jos P. M.; Smith, Hilde E.

    2011-01-01

    Background Streptococcus suis causes invasive infections in pigs and occasionally in humans. The host innate immune system plays a major role in counteracting S. suis infections. The main components of S. suis able to activate the innate immune system likely include cell wall constituents that may be released during growth or after cell wall integrity loss, however characterization of these components is still limited. Methology/Principal Findings A concentrated very potent innate immunity activating supernatant of penicillin-treated S. suis was SDS-PAGE fractionated and tested for porcine peripheral blood mononucleated cell (PBMC) stimulating activity using cytokine gene transcript analysis. More than half of the 24 tested fractions increased IL-1β and IL-8 cytokine gene transcript levels in porcine PBMCs. Mass spectrometry of the active fractions indicated 24 proteins including 9 lipoproteins. Genetic inactivation of a putative prolipoprotein diacylglyceryl transferase (Lgt) gene resulted in deficient lipoprotein synthesis as evidenced by palmitate labeling. The Lgt mutant showed strongly reduced activation of porcine PBMCs, indicating that lipoproteins are dominant porcine PBMC activating molecules of S. suis. Conclusion/Significance This study for the first time identifies and characterizes lipoproteins of S. suis as major activators of the innate immune system of the pig. In addition, we provide evidence that Lgt processing of lipoproteins is required for lipoprotein mediated innate immune activation. PMID:21811583

  7. Persistently Active Microbial Molecules Prolong Innate Immune Tolerance In Vivo

    PubMed Central

    Lu, Mingfang; Varley, Alan W.; Munford, Robert S.

    2013-01-01

    Measures that bolster the resolution phase of infectious diseases may offer new opportunities for improving outcome. Here we show that inactivation of microbial lipopolysaccharides (LPS) can be required for animals to recover from the innate immune tolerance that follows exposure to Gram-negative bacteria. When wildtype mice are exposed to small parenteral doses of LPS or Gram-negative bacteria, their macrophages become reprogrammed (tolerant) for a few days before they resume normal function. Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months; during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality. We show here that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells' in vivo environment, where naïve cells can acquire LPS via cell-cell contact or from the extracellular fluid. The findings provide strong evidence that inactivation of a stimulatory microbial molecule can be required for animals to regain immune homeostasis following parenteral exposure to bacteria. Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases. PMID:23675296

  8. Microbiota activation and regulation of innate and adaptive immunity

    PubMed Central

    Alexander, Katie L.; Targan, Stephan R.; Elson, Charles O.

    2014-01-01

    Summary The human host has co-evolved with the collective of bacteria species, termed microbiota, in a complex fashion that affects both innate and adaptive immunity. Differential regulation of regulatory T-cell and effector T-cell responses are a direct result of specific microbial species present within the gut, and this relationship is subject is dysregulation during inflammation and disease. The microbiota varies widely between individuals and has a profound effect on how one reacts to various environmental stimuli, particularly if a person is genetically predisposed to an immune-mediated inflammatory disorder such as inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Approximately half of all CD patients have elevated antibodies to CBir1, a microbiota flagellin common to mice and humans, demonstrating flagellins as immunodominant antigens in the intestines. This review focuses on the use of flagellins as probes to study microbiota specific responses in the context of health and disease as well as probes of innate and adaptive responses employed by the host to deal with the overwhelming bacterial presence of the microbiota. PMID:24942691

  9. Methods to Evaluate the Antitumor Activity of Immune Checkpoint Inhibitors in Preclinical Studies.

    PubMed

    Allard, Bertrand; Allard, David; Stagg, John

    2016-01-01

    Immune checkpoint inhibitors (ICI) are a new class of drugs characterized by their ability to enhance antitumor immune responses through the blockade of critical cell surface receptors involved in the maintenance of peripheral tolerance. The recent approval of ICI targeting CTLA-4 or PD-1 for the treatment of cancer constitutes a major breakthrough in the field of oncology and demonstrates the potential of immune-mediated therapies in achieving durable cancer remissions. The identification of new immune regulatory pathways that could be targeted to reactivate or boost antitumor immunity is now a very active field of research. In this context, the use of syngeneic mouse models and immune monitoring techniques are the cornerstone of proof-of-concept studies. In this chapter, we describe the general methodology to evaluate antitumor activity of ICI in immunocompetent mice. We outline protocols to reliably establish tumors in mice and generate lung metastasis through tail vein injections with the aim of testing the efficacy of ICI. We also present methods to analyze the composition of the tumor immune-infiltrate by multicolor flow cytometry. PMID:27581021

  10. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation

    PubMed Central

    Wong, Carmen P.; Rinaldi, Nicole A.; Ho, Emily

    2015-01-01

    Scope Zinc deficiency results in immune dysfunction and promotes systemic inflammation. The objective of this study was to examine the effects of zinc deficiency on cellular immune activation and epigenetic mechanisms that promote inflammation. This work is potentially relevant to the aging population given that age-related immune defects, including chronic inflammation, coincide with declining zinc status. Methods and results An in vitro cell culture system and the aged mouse model were used to characterize immune activation and DNA methylation profiles that may contribute to the enhanced proinflammatory response mediated by zinc deficiency. Zinc deficiency up-regulated cell activation markers ICAM1, MHC class II, and CD86 in THP1 cells, that coincided with increased IL1β and IL6 responses following LPS stimulation. A decreased zinc status in aged mice was similarly associated with increased ICAM1 and IL6 gene expression. Reduced IL6 promoter methylation was observed in zinc deficient THP1 cells, as well as in aged mice and human lymphoblastoid cell lines derived from aged individuals. Conclusion Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Our results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation. PMID:25656040

  11. Spatiotemporal Regulation of Hsp90–Ligand Complex Leads to Immune Activation

    PubMed Central

    Tamura, Yasuaki; Yoneda, Akihiro; Takei, Norio; Sawada, Kaori

    2016-01-01

    Although heat shock proteins (HSPs) primarily play a pivotal role in the maintenance of cellular homeostasis while reducing extracellular as well as intracellular stresses, their role in immunologically relevant scenarios, including activation of innate immunity as danger signals, antitumor immunity, and autoimmune diseases, is now gaining much attention. The most prominent feature of HSPs is that they function both in their own and as an HSP–ligand complex. We here show as a unique feature of extracellular HSPs that they target chaperoned molecules into a particular endosomal compartment of dendritic cells, thereby inducing innate and adaptive immune responses via spatiotemporal regulation. PMID:27252703

  12. TRPV4-Mediated Detection of Hyposmotic Stress by Skin Keratinocytes Activates Developmental Immunity.

    PubMed

    Galindo-Villegas, Jorge; Montalban-Arques, Ana; Liarte, Sergio; de Oliveira, Sofia; Pardo-Pastor, Carlos; Rubio-Moscardo, Fanny; Meseguer, José; Valverde, Miguel A; Mulero, Victoriano

    2016-01-15

    As an organism is exposed to pathogens during very early development, specific defense mechanisms must take effect. In this study, we used a germ-free zebrafish embryo model to show that osmotic stress regulates the activation of immunity and host protection in newly hatched embryos. Mechanistically, skin keratinocytes were responsible for both sensing the hyposmolarity of the aquatic environment and mediating immune effector mechanisms. This occurred through a transient potential receptor vanilloid 4/Ca(2+)/TGF-β-activated kinase 1/NF-κB signaling pathway. Surprisingly, the genes encoding antimicrobial effectors, which do not have the potential to cause tissue damage, are constitutively expressed during development, independently of both commensal microbes and osmotic stress. Our results reveal that osmotic stress is associated with the induction of developmental immunity in the absence of tissue damage and point out to the embryo skin as the first organ with full capacities to mount an innate immune response. PMID:26673139

  13. Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy.

    PubMed

    Xiong, Zhengming; Ampudia-Mesias, Elisabet; Shaver, Rob; Horbinski, Craig M; Moertel, Christopher L; Olin, Michael R

    2016-09-01

    There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy. PMID:27485078

  14. Fetal and maternal cardiac responses to physical activity and exercise during pregnancy.

    PubMed

    May, Linda E; Allen, John J B; Gustafson, Kathleen M

    2016-03-01

    Since the 1970s, researchers have studied the influence of exercise during pregnancy on offspring heart development. With the knowledge and current evidence of fetal programming effects, research has demonstrated that exercise is safe and beneficial for mother, fetus, and neonate. Predominantly, research has focused on maternal and fetal cardiac adaptations related to aerobic exercise during pregnancy; less is known regarding the effects of resistance or combination (aerobic and resistance) training during pregnancy. Ongoing research is focusing on fetal responses to different intensity, duration and modes of maternal exercise throughout pregnancy. This article will summarize our current state of knowledge regarding the influence of exercise intensity, duration, and modes during pregnancy on maternal and fetal cardiac responses. PMID:26805461

  15. Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation

    PubMed Central

    Deloch, Lisa; Derer, Anja; Hartmann, Josefin; Frey, Benjamin; Fietkau, Rainer; Gaipl, Udo S.

    2016-01-01

    Even though there is extensive research carried out in radiation oncology, most of the clinical studies focus on the effects of radiation on the local tumor tissue and deal with normal tissue side effects. The influence of dose fractionation and timing particularly with regard to immune activation is not satisfactorily investigated so far. This review, therefore, summarizes current knowledge on concepts of modern radiotherapy (RT) and evaluates the potential of RT for immune activation. Focus is set on radiation-induced forms of tumor cell death and consecutively the immunogenicity of the tumor cells. The so-called non-targeted, abscopal effects can contribute to anti-tumor responses in a specific and systemic manner and possess the ability to target relapsing tumor cells as well as metastases. The impact of distinct RT concepts on immune activation is outlined and pre-clinical evidence and clinical observations on RT-induced immunity will be discussed. Knowledge on the radiosensitivity of immune cells as well as clinical evidence for enhanced immunity after RT will be considered. While stereotactic ablative body radiotherapy seem to have a beneficial outcome over classical RT fractionation in pre-clinical animal models, in vitro model systems suggest an advantage for classical fractionated RT for immune activation. Furthermore, the optimal approach may differ based on the tumor site and/or genetic signature. These facts highlight that clinical trials are urgently needed to identify whether high-dose RT is superior to induce anti-tumor immune responses compared to classical fractionated RT and in particular how the outcome is when RT is combined with immunotherapy in selected tumor entities. PMID:27379203

  16. Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin

    PubMed Central

    Li, Wei; Yang, Jingyi; Zhang, Ejuan; Zhong, Maohua; Xiao, Yang; Yu, Jie; Zhou, Dihan; Cao, Yuan; Yang, Yi; Li, Yaoming; Yan, Huimin

    2016-01-01

    Bacterial flagellin is a unique pathogen-associated molecular pattern (PAMP), which can be recognized by surface localized Toll-like receptor 5 (TLR5) and the cytosolic NOD-like receptor (NLR) protein 4 (NLRC4) receptors. Activation of the TLR5 and/or NLRC4 signaling pathways by flagellin and the resulting immune responses play important roles in anti-bacterial immunity. However, it remains unclear how the dual activities of flagellin that activate the TLR5 and/or NLRC4 signaling pathways orchestrate the immune responses. In this study, we assessed the effects of flagellin and its mutants lacking the ability to activate TLR5 and NLRC4 alone or in combination on the adaptive immune responses against flagellin. Flagellin that was unable to activate NLRC4 induced a significantly higher antibody response than did wild-type flagellin. The increased antibody response could be eliminated when macrophages were depleted in vivo. The activation of NLRC4 by flagellin downregulated the flagellin-induced and TLR5-mediated immune responses against flagellin. PMID:25914934

  17. Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition

    PubMed Central

    Lee, Miler T.; Bonneau, Ashley R.; Takacs, Carter M.; Bazzini, Ariel A.; DiVito, Kate R.; Fleming, Elizabeth S.; Giraldez, Antonio J.

    2014-01-01

    Summary Upon fertilization, maternal factors direct development and trigger zygotic genome activation (ZGA) at the maternal-to-zygotic transition (MZT). In zebrafish, ZGA is required for gastrulation and clearance of maternal mRNAs, which is in part regulated by the conserved microRNA miR-430. However, the factors that activate the zygotic program in vertebrates are unknown. Here, we show that Nanog, Pou5f1 and SoxB1 regulate zygotic gene activation in zebrafish. We identified several hundred genes directly activated by maternal factors, constituting the first wave of zygotic transcription. Ribosome profiling revealed that nanog, sox19b and pou5f1 are the most highly translated transcription factors pre-MZT. Combined loss of these factors resulted in developmental arrest prior to gastrulation and a failure to activate >75% of zygotic genes, including miR-430. Our results demonstrate that maternal Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression. PMID:24056933

  18. Effects of spaceflight on levels and activity of immune cells

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald; Berry, Wallace D.; Mandel, Adrian D.; Konstantinova, Irena V.; Taylor, Gerald R.

    1990-01-01

    Experiments were carried out on cells from rats that had been flown on Soviet Biosputnik Cosmos 1887 to explore the effects of speceflight on immune responses. Rat bone marrow cells were examined for their response to colony stimulating factor-M. Rat spleen and bone marrow cells were stained with antibodies directed against cell surface antigenic markers. The results of the studies indicate that bone marrow cells from flown rats showed a decreased response to colony stimulating factor. There was a higher percentage of spleen cells from flown rats staining positively for pan-T-cell, suppressor-T-cell, and interleukin-2 receptor cell surface antigens. A small increase in the percentage of cells staining positively for helper-T-cell antigens was also noted. In addition, a higher percentage of cells that appeared to be part of the myelogenous population of bone marrow cells from flown rats stained positively for surface immunoglobulin.

  19. Effects of Stress on Commensal Microbes and Immune System Activity.

    PubMed

    Gur, Tamar L; Bailey, Michael T

    2016-01-01

    The body harbors a vast array of microbes that are collectively known as the microbiota. Increasing attention is being paid to the role of the gut microbiota in the health of the host. Gut microbial communities are relatively resistant to change, though alterations in homeostasis can also significantly change gut microbial community structure. An important factor that has been demonstrated to alter the composition of the gut microbiota is exposure to psychological stressors. And, evidence indicates that the commensal microbiota are involved in stressor-induced immunomodulation. This chapter will discuss the impact of psychosocial stress on immunity, and present evidence that stressor-induced alterations in the composition of gut microbial communities contributes to stressor-induced immunomodulation and neurobiological sequelae. Finally, the role of the microbiota in the perinatal time period will be explored, and an integrative hypothesis of the role of the microbiome in health and stress response will be proposed. PMID:26589225

  20. Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression12

    PubMed Central

    Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J

    2014-01-01

    Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an ∼20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses. PMID:24563621

  1. The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective.

    PubMed

    Chikka, Madhusudana Rao; Anbalagan, Charumathi; Dvorak, Katherine; Dombeck, Kyle; Prahlad, Veena

    2016-08-30

    Immunological mediators that originate outside the nervous system can affect neuronal health. However, their roles in neurodegeneration remain largely unknown. Here, we show that the p38MAPK-mediated immune pathway activated in intestinal cells of Caenorhabditis elegans upon mitochondrial dysfunction protects neurons in a cell-non-autonomous fashion. Specifically, mitochondrial complex I dysfunction induced by rotenone activates the p38MAPK/CREB/ATF-7-dependent innate immune response pathway in intestinal cells of C. elegans. Activation of p38MAPK in the gut is neuroprotective. Enhancing the p38MAPK-mediated immune pathway in intestinal cells alone suppresses rotenone-induced dopaminergic neuron loss, while downregulating it in the intestine exacerbates neurodegeneration. The p38MAPK/ATF-7 immune pathway modulates autophagy and requires autophagy and the PTEN-induced putative kinase PINK-1 for conferring neuroprotection. Thus, mitochondrial damage induces the clearance of mitochondria by the immune pathway, protecting the organism from the toxic effects of mitochondrial dysfunction. We propose that mitochondria are subject to constant surveillance by innate immune mechanisms. PMID:27545884

  2. RAC1 activation drives pathologic interactions between the epidermis and immune cells.

    PubMed

    Winge, Mårten C G; Ohyama, Bungo; Dey, Clara N; Boxer, Lisa M; Li, Wei; Ehsani-Chimeh, Nazanin; Truong, Allison K; Wu, Diane; Armstrong, April W; Makino, Teruhiko; Davidson, Matthew; Starcevic, Daniela; Kislat, Andreas; Nguyen, Ngon T; Hashimoto, Takashi; Homey, Bernard; Khavari, Paul A; Bradley, Maria; Waterman, Elizabeth A; Marinkovich, M Peter

    2016-07-01

    Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions. PMID:27294528

  3. Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity.

    PubMed

    Painter, Meghan M; Morrison, James H; Zoecklein, Laurie J; Rinkoski, Tommy A; Watzlawik, Jens O; Papke, Louisa M; Warrington, Arthur E; Bieber, Allan J; Matchett, William E; Turkowski, Kari L; Poeschla, Eric M; Rodriguez, Moses

    2015-12-01

    For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection. PMID:26633895

  4. Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity

    PubMed Central

    Painter, Meghan M.; Morrison, James H.; Zoecklein, Laurie J.; Rinkoski, Tommy A.; Watzlawik, Jens O.; Papke, Louisa M.; Warrington, Arthur E.; Bieber, Allan J.; Matchett, William E.; Turkowski, Kari L.; Poeschla, Eric M.; Rodriguez, Moses

    2015-01-01

    For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection. PMID:26633895

  5. Attenuation of Cocaine-Induced Locomotor Activity in Male and Female Mice by Active Immunization

    PubMed Central

    Kosten, Therese A.; Shen, Xiaoyun Y.; Kinsey, Berma M.; Kosten, Thomas R.; Orson, Frank M.

    2014-01-01

    Background and objectives Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Methods Male and female BALB/c mice were vaccinated (n=44) or served as non-vaccinated controls (n=34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7-wk and plasma obtained at 8-wk to assess antibody levels. Results High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. Discussion and conclusions The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Scientific significance Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction. PMID:25251469

  6. Maternal and Child Health Bureau Active Projects FY 1991: An Annotated Listing.

    ERIC Educational Resources Information Center

    National Center for Education in Maternal and Child Health, Washington, DC.

    This annotated listing provides brief descriptions of the 591 projects funded during 1991 by federal set-aside funds of the Maternal and Child Health (MCH) Services Block Grant and identified as special projects of regional and national significance (SPRANS). Preliminary information includes an introduction, an organization chart of the Maternal…

  7. Learning Innovative Maternal Instinct: Activity Designing Semantic Factors of Alcohol Modification in Rural Communities of Thailand

    ERIC Educational Resources Information Center

    Yodmongkol, Pitipong; Jaimung, Thunyaporn; Chakpitak, Nopasit; Sureephong, Pradorn

    2014-01-01

    At present, Thailand is confronting a serious problem of alcohol drinking behavior which needs to be solved urgently. This research aimed to identify the semantic factors on alcohol drinking behavior and to use maternal instinct driving for housewives as village health volunteers in rural communities, Thailand. Two methods were implemented as the…

  8. A Strategy for the Evaluation of Activities to Reduce Maternal Mortality in Developing Countries.

    ERIC Educational Resources Information Center

    Ward, Victoria M.; And Others

    1994-01-01

    An evaluation strategy in which a set of process indicators is applied to programs to reduce maternal mortality in developing countries is presented. The four-stage strategy is illustrated for three interventions: (1) providing safe abortion services; (2) increasing knowledge of obstetric complications; and (3) improving medical care quality. (SLD)

  9. Maternal Diet-Induced Obesity Alters Mitochondrial Activity and Redox Status in Mouse Oocytes and Zygotes

    PubMed Central

    Igosheva, Natalia; Abramov, Andrey Y.; Poston, Lucilla; Eckert, Judith J.; Fleming, Tom P.; Duchen, Michael R.; McConnell, Josie

    2010-01-01

    The negative impact of obesity on reproductive success is well documented but the stages at which development of the conceptus is compromised and the mechanisms responsible for the developmental failure still remain unclear. Recent findings suggest that mitochondria may be a contributing factor. However to date no studies have directly addressed the consequences of maternal obesity on mitochondria in early embryogenesis. Using an established murine model of maternal diet induced obesity and a live cell dynamic fluorescence imaging techniques coupled with molecular biology we have investigated the underlying mechanisms of obesity-induced reduced fertility. Our study is the first to show that maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and zygotes. Specifically, maternal diet-induced obesity in mice led to an increase in mitochondrial potential, mitochondrial DNA content and biogenesis. Generation of reactive oxygen species (ROS) was raised while glutathione was depleted and the redox state became more oxidised, suggestive of oxidative stress. These altered mitochondrial properties were associated with significant developmental impairment as shown by the increased number of obese mothers who failed to support blastocyst formation compared to lean dams. We propose that compromised oocyte and early embryo mitochondrial metabolism, resulting from excessive nutrient exposure prior to and during conception, may underlie poor reproductive outcomes frequently reported in obese women. PMID:20404917

  10. Increased activity correlates with reduced ability to mount immune defenses to endotoxin in zebra finches.

    PubMed

    Lopes, Patricia C; Springthorpe, Dwight; Bentley, George E

    2014-10-01

    When suffering from infection, animals experience behavioral and physiological alterations that potentiate the immune system's ability to fight pathogens. The behavioral component of this response, termed "sickness behavior," is characterized by an overall reduction in physical activity. A growing number of reports demonstrate substantial flexibility in these sickness behaviors, which can be partially overcome in response to mates, intruders and parental duties. Since it is hypothesized that adopting sickness behaviors frees energetic resources for mounting an immune response, we tested whether diminished immune responses coincided with reduced sickness behaviors by housing male zebra finches (Taeniopygia guttata) in social conditions that alter their behavioral response to an endotoxin. To facilitate our data collection, we developed and built a miniaturized sensor capable of detecting changes in dorsoventral acceleration and categorizing them as different behaviors when attached to the finches. We found that the immune defenses (quantified as haptoglobin-like activity, ability to change body temperature and bacterial killing capacity) increased as a function of increased time spent resting. The findings indicate that when animals are sick attenuation of sickness behaviors may exact costs, such as reduced immune function. The extent of these costs depends on how relevant the affected components of immunity are for fighting a specific infection. PMID:24888267

  11. CRF-R1 activation in the anterior-dorsal BNST induces maternal neglect in lactating rats via an HPA axis-independent central mechanism

    PubMed Central

    Klampfl, Stefanie M.; Brunton, Paula J.; Bayerl, Doris S.; Bosch, Oliver J.

    2016-01-01

    Adequate maternal behavior in rats requires minimal corticotropin-releasing factor receptor (CRF-R) activation in the medial-posterior bed nucleus of the stria terminalis (mpBNST). Based on the architectural heterogeneity of the BNST and its distinct inter-neural connectivity, we tested whether CRF-R manipulation in another functional part, the anterior-dorsal BNST (adBNST), differentially modulates maternal behavior. We demonstrate that in the adBNST, activation of CRF-R1 reduced arched back nursing (ABN) and nursing, whereas activation of CRF-R2 resulted in an initial reduction in nursing but significantly increased the incidence of ABN 5 h after the treatment. Following stressor exposure, which is detrimental to maternal care, ABN tended to be protected by CRF-R1 blockade. Maternal motivation, maternal aggression, and anxiety were unaffected by any manipulation. Furthermore, under basal and stress conditions, activation of adBNST CRF-R1 increased plasma ACTH and corticosterone concentrations, whereas stimulation of adBNST CRF-R2 increased basal plasma ACTH and corticosterone concentrations, but blocked the stress-induced increase in plasma corticosterone secretion. Moreover, both the CRF-R1 and -R2 antagonists prevented the stress-induced increase in plasma corticosterone secretion. Importantly, elevated levels of circulating corticosterone induced by intra-adBNST administration of CRF-R1 or -R2 agonist did not impact maternal care. Finally, Crf mRNA expression in the adBNST was increased during lactation; however, Crfr1 mRNA expression was similar between lactating and virgin rats. In conclusion, maternal care is impaired by adBNST CRF-R1 activation, and this appears to be the result of a central action, rather than an effect of elevated circulating levels of CORT. These data provide new insights into potential causes of disturbed maternal behavior postpartum. PMID:26630389

  12. Vaginal Immunization to Elicit Primary T-Cell Activation and Dissemination

    PubMed Central

    Pettini, Elena; Prota, Gennaro; Ciabattini, Annalisa; Boianelli, Alessandro; Fiorino, Fabio; Pozzi, Gianni; Vicino, Antonio; Medaglini, Donata

    2013-01-01

    Primary T-cell activation at mucosal sites is of utmost importance for the development of vaccination strategies. T-cell priming after vaginal immunization, with ovalbumin and CpG oligodeoxynucleotide adjuvant as model vaccine formulation, was studied in vivo in hormone-synchronized mice and compared to the one induced by the nasal route. Twenty-four hours after both vaginal or nasal immunization, antigen-loaded dendritic cells were detected within the respective draining lymph nodes. Vaginal immunization elicited a strong recruitment of antigen-specific CD4+ T cells into draining lymph nodes that was more rapid than the one observed following nasal immunization. T-cell clonal expansion was first detected in iliac lymph nodes, draining the genital tract, and proliferated T cells disseminated towards distal lymph nodes and spleen similarly to what observed following nasal immunization. T cells were indeed activated by the antigen encounter and acquired homing molecules essential to disseminate towards distal lymphoid organs as confirmed by the modulation of CD45RB, CD69, CD44 and CD62L marker expression. A multi-type Galton Watson branching process, previously used for in vitro analysis of T-cell proliferation, was applied to model in vivo CFSE proliferation data in draining lymph nodes 57 hours following immunization, in order to calculate the probabilistic decision of a cell to enter in division, rest in quiescence or migrate/die. The modelling analysis indicated that the probability of a cell to proliferate was higher following vaginal than nasal immunization. All together these data show that vaginal immunization, despite the absence of an organized mucosal associated inductive site in the genital tract, is very efficient in priming antigen-specific CD4+ T cells and inducing their dissemination from draining lymph nodes towards distal lymphoid organs. PMID:24349003

  13. In vitro activation of rat neutrophils and alveolar macrophages with IgA and IgG immune complexes. Implications for immune complex-induced lung injury.

    PubMed Central

    Warren, J. S.; Kunkel, S. L.; Johnson, K. J.; Ward, P. A.

    1987-01-01

    In the rat, both IgG and IgA immune complexes induce oxygen radical mediated lung injury that is partially complement-dependent. In vivo studies have suggested that the chief sources of oxygen radicals in IgG and IgA immune complex-induced lung injury are neutrophils and tissue macrophages, respectively. The current studies have been designed to provide additional insights into these two models of tissue injury. Preformed monoclonal IgG and IgA immune complexes stimulated dose-dependent O2-. and H2O2 production by alveolar macrophages. In contrast, neutrophils exhibited O2-. production and lysosomal enzyme secretion in response to IgG immune complexes, but not in response to IgA complexes. There is evidence that C5a significantly amplifies these responses. Purified human C5a enhanced the O2-. responses of neutrophils activated with IgG immune complexes and alveolar macrophages activated with either IgG or IgA immune complexes. Addition of C5a alone to neutrophils or alveolar macrophages had no direct stimulatory effect as measured by O2-. production. The observation that O2-. responses of immune complex-activated alveolar macrophages can be significantly enhanced by the presence of C5a and that C5a can also enhance O-2. responses of IgG immune complex-stimulated neutrophils suggests a potential amplification mechanism through which complement may participate in both IgG and IgA immune complex-induced lung injury. The present data corroborate in vivo studies which suggest that IgG immune complex lung injury is primarily neutrophil-mediated, whereas IgA complex lung injury is predominantly macrophage-mediated. PMID:2827492

  14. Nerve growth factor: a neurotrophin with activity on cells of the immune system.

    PubMed

    Aloe, L; Simone, M D; Properzi, F

    Numerous studies published in the last two decades provide evidence that nerve growth factor (NGF), a polypeptide originally discovered because of its neurotrophic activity, acts on a variety of cells of the immune system, including mast cells, eosinophils, and B and T lymphocytes. NGF has been shown to increase during inflammatory responses, autoimmune disorders, parasitic infections, and allergic diseases. Moreover, stress, which is characterized also by activation of a variety of immune cells, causes a significant increase in basal plasma NGF levels. Recently published studies reveal that hematopoietic progenitor cells seem to be able to produce and/or respond to NGF. We report these data and discuss the hypothesis of the possible implication of NGF on the functional activities of immune cells. PMID:10383121

  15. Maternal and newborn outcomes in Pakistan compared to other low and middle income countries in the Global Network’s Maternal Newborn Health Registry: an active, community-based, pregnancy surveillance mechanism

    PubMed Central

    2015-01-01

    Background Despite global improvements in maternal and newborn health (MNH), maternal, fetal and newborn mortality rates in Pakistan remain stagnant. Using data from the Global Network’s Maternal Newborn Health Registry (MNHR) the objective of this study is to compare the rates of maternal mortality, stillbirth and newborn mortality and levels of putative risk factors between the Pakistani site and those in other countries. Methods Using data collected through a multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in communities in discrete geographical areas in seven sites across six countries including Pakistan, India, Kenya, Zambia, Guatemala and Argentina from 2010 to 2013, the study compared MNH outcomes and risk factors. The MNHR captures more than 60,000 deliveries annually across all sites with over 10,000 of them in Thatta, Pakistan. Results The Pakistan site had a maternal mortality ratio almost three times that of the other sites (313/100,000 vs 116/100,000). Stillbirth (56.5 vs 22.9/1000 births), neonatal mortality (50.0 vs 20.7/1000 livebirths) and perinatal mortality rates (95.2/1000 vs 39.0/1000 births) in Thatta, Pakistan were more than twice those of the other sites. The Pakistani site is the only one in the Global Network where maternal mortality increased (from 231/100,000 to 353/100,000) over the study period and fetal and neonatal outcomes remained stagnant. The Pakistan site lags behind other sites in maternal education, high parity, and appropriate antenatal and postnatal care. However, facility delivery and skilled birth attendance rates were less prominently different between the Pakistani site and other sites, with the exception of India. The difference in the fetal and neonatal outcomes between the Pakistani site and the other sites was most pronounced amongst normal birth weight babies. Conclusions The increase in maternal mortality and the stagnation of fetal and neonatal outcomes from 2010 to

  16. A Novel Polysaccharide in Insects Activates the Innate Immune System in Mouse Macrophage RAW264 Cells

    PubMed Central

    Ohta, Takashi; Ido, Atsushi; Kusano, Kie; Miura, Chiemi; Miura, Takeshi

    2014-01-01

    A novel water-soluble polysaccharide was identified in the pupae of the melon fly (Bactrocera cucurbitae) as a molecule that activates the mammalian innate immune response. We attempted to purify this innate immune activator using nitric oxide (NO) production in mouse RAW264 macrophages as an indicator of immunostimulatory activity. A novel acidic polysaccharide was identified, which we named “dipterose”, with a molecular weight of 1.01×106 and comprising nine monosaccharides. Dipterose was synthesized in the melon fly itself at the pupal stage. The NO-producing activity of dipterose was approximately equal to that of lipopolysaccharide, a potent immunostimulator. Inhibition of Toll-like receptor 4 (TLR4) led to the suppression of NO production by dipterose. Furthermore, dipterose induced the expression of proinflammatory cytokines and interferon β (IFNβ) and promoted the activation of nuclear factor kappa B (NF-κB) in macrophages, indicating that it stimulates the induction of various cytokines in RAW264 cells via the TLR4 signaling pathway. Our results thus suggest that dipterose activates the innate immune response against various pathogenic microorganisms and viral infections. This is the first identification of an innate immune-activating polysaccharide from an animal. PMID:25490773

  17. IgE epitope proximity determines immune complex shape and effector cell activation capacity

    PubMed Central

    Gieras, Anna; Linhart, Birgit; Roux, Kenneth H.; Dutta, Moumita; Khodoun, Marat; Zafred, Domen; Cabauatan, Clarissa R.; Lupinek, Christian; Weber, Milena; Focke-Tejkl, Margarete; Keller, Walter; Finkelman, Fred D.; Valenta, Rudolf

    2016-01-01

    Background IgE-allergen complexes induce mast cell and basophil activation and thus immediate allergic inflammation. They are also important for IgE-facilitated allergen presentation to T cells by antigen-presenting cells. Objective To investigate whether the proximity of IgE binding sites on an allergen affects immune complex shape and subsequent effector cell activation in vitro and in vivo. Methods We constructed artificial allergens by grafting IgE epitopes in different numbers and proximity onto a scaffold protein. The shape of immune complexes formed between artificial allergens and the corresponding IgE was studied by negative-stain electron microscopy. Allergenic activity was determined using basophil activation assays. Mice were primed with IgE, followed by injection of artificial allergens to evaluate their in vivo allergenic activity. Severity of systemic anaphylaxis was measured by changes in body temperature. Results We could demonstrate simultaneous binding of 4 IgE antibodies in close vicinity to each other. The proximity of IgE binding sites on allergens influenced the shape of the resulting immune complexes and the magnitude of effector cell activation and in vivo inflammation. Conclusions Our results demonstrate that the proximity of IgE epitopes on an allergen affects its allergenic activity. We thus identified a novel mechanism by which IgE-allergen complexes regulate allergic inflammation. This mechanism should be important for allergy and other immune complex–mediated diseases. PMID:26684291

  18. Phenoloxidase activity in the infraorder Isoptera: unraveling life-history correlates of immune investment

    NASA Astrophysics Data System (ADS)

    Rosengaus, Rebeca B.; Reichheld, Jennifer L.

    2016-02-01

    Within the area of ecological immunology, the quantification of phenoloxidase (PO) activity has been used as a proxy for estimating immune investment. Because termites have unique life-history traits and significant inter-specific differences exist regarding their nesting and foraging habits, comparative studies on PO activity can shed light on the general principles influencing immune investment against the backdrop of sociality, reproductive potential, and gender. We quantified PO activity across four termite species ranging from the phylogenetically basal to the most derived, each with their particular nesting/foraging strategies. Our data indicate that PO activity varies across species, with soil-dwelling termites exhibiting significantly higher PO levels than the above-ground wood nester species which in turn have higher PO levels than arboreal species. Moreover, our comparative approach suggests that pathogenic risks can override reproductive potential as a more important driver of immune investment. No gender-based differences in PO activities were recorded. Although termite PO activity levels vary in accordance with a priori predictions made from life-history theory, our data indicate that nesting and foraging strategies (and their resulting pathogenic pressures) can supersede reproductive potential and other life-history traits in influencing investment in PO. Termites, within the eusocial insects, provide a unique perspective for inferring how different ecological pressures may have influenced immune function in general and their levels of PO activity, in particular.

  19. Phenoloxidase activity in the infraorder Isoptera: unraveling life-history correlates of immune investment.

    PubMed

    Rosengaus, Rebeca B; Reichheld, Jennifer L

    2016-02-01

    Within the area of ecological immunology, the quantification of phenoloxidase (PO) activity has been used as a proxy for estimating immune investment. Because termites have unique life-history traits and significant inter-specific differences exist regarding their nesting and foraging habits, comparative studies on PO activity can shed light on the general principles influencing immune investment against the backdrop of sociality, reproductive potential, and gender. We quantified PO activity across four termite species ranging from the phylogenetically basal to the most derived, each with their particular nesting/foraging strategies. Our data indicate that PO activity varies across species, with soil-dwelling termites exhibiting significantly higher PO levels than the above-ground wood nester species which in turn have higher PO levels than arboreal species. Moreover, our comparative approach suggests that pathogenic risks can override reproductive potential as a more important driver of immune investment. No gender-based differences in PO activities were recorded. Although termite PO activity levels vary in accordance with a priori predictions made from life-history theory, our data indicate that nesting and foraging strategies (and their resulting pathogenic pressures) can supersede reproductive potential and other life-history traits in influencing investment in PO. Termites, within the eusocial insects, provide a unique perspective for inferring how different ecological pressures may have influenced immune function in general and their levels of PO activity, in particular. PMID:26838762

  20. Pregnancy Associated with Systemic Lupus Erythematosus: Immune Tolerance in Pregnancy and Its Deficiency in Systemic Lupus Erythematosus—An Immunological Dilemma

    PubMed Central

    Velciov, Silvia; Gluhovschi, Adrian

    2015-01-01

    Pregnancy is a physiological condition that requires immune tolerance to the product of conception. Systemic lupus erythematosus (SLE) is a disease with well-represented immune mechanisms that disturb immune tolerance. The association of pregnancy with systemic lupus erythematosus creates a particular immune environment in which the immune tolerance specific of pregnancy is required to coexist with alterations of the immune system caused by SLE. The main role is played by T regulatory (Treg) cells, which attempt to regulate and adapt the immune system of the mother to the new conditions of pregnancy. Other components of the immune system also participate to maintain maternal-fetal immune tolerance. If the immune system of pregnant women with SLE is not able to maintain maternal immune tolerance to the fetus, pregnancy complications (miscarriage, fetal hypotrophy, and preterm birth) or maternal complications (preeclampsia or activation of SLE, especially in conditions of lupus nephritis) may occur. In certain situations this can be responsible for neonatal lupus. At the same time, it must be noted that during pregnancy, the immune system is able to achieve immune tolerance while maintaining the anti-infectious immune capacity of the mother. Immunological monitoring of pregnancy during SLE, as well as of the mother's disease, is required. It is important to understand immune tolerance to grafts in transplant pathology. PMID:26090485

  1. Regulatory T cells and chronic immune activation in human immunodeficiency virus 1 (HIV-1)-infected children

    PubMed Central

    Freguja, R; Gianesin, K; Mosconi, I; Zanchetta, M; Carmona, F; Rampon, O; Giaquinto, C; De Rossi, A

    2011-01-01

    The function of CD4+ T cells with regulatory activity (Tregs) is the down-regulation of immune responses. This suppressive activity may limit the magnitude of effector responses, resulting in failure to control human immunodeficiency virus 1 (HIV-1) infection, but may also suppress chronic immune activation, a characteristic feature of HIV-1 disease. We evaluated the correlation between viral load, immune activation and Tregs in HIV-1-infected children. Eighty-nine HIV-1-infected children (aged 6–14 years) were included in the study and analysed for HIV-1 plasmaviraemia, HIV-1 DNA load, CD4 and CD8 cell subsets. Treg cells [CD4+ CD25highCD127lowforkhead box P3 (FoxP3high)] and CD8-activated T cells (CD8+CD38+) were determined by flow cytometry. Results showed that the number of activated CD8+CD38+ T cells increased in relation to HIV-1 RNA plasmaviraemia (r = 0·403, P < 0·0001). The proportion of Tregs also correlated positively with HIV-1 plasmaviraemia (r = 0·323, P = 0·002), but correlated inversely with CD4+ cells (r = −0·312, P = 0·004), thus suggesting a selective expansion along with increased viraemia and CD4+ depletion. Interestingly, a positive correlation was found between the levels of Tregs and CD8+CD38+ T cells (r = 0·305, P = 0·005), and the percentage of Tregs tended to correlate with HIV-1 DNA load (r = 0·224, P = 0·062). Overall, these findings suggest that immune activation contributes to the expansion of Treg cells. In turn, the suppressive activity of Tregs may impair effector responses against HIV-1, but appears to be ineffective in limiting immune activation. PMID:21438872

  2. Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism.

    PubMed

    Boontanrart, Mandy; Hall, Samuel D; Spanier, Justin A; Hayes, Colleen E; Olson, Julie K

    2016-03-15

    Microglia become activated immune cells during infection or disease in the central nervous system (CNS). However, the mechanisms that downregulate activated microglia to prevent immune-mediated damage are not completely understood. Vitamin D3 has been suggested to have immunomodulatory affects, and high levels of vitamin D3 have been correlated with a decreased risk for developing some neurological diseases. Recent studies have demonstrated the synthesis of active vitamin D3, 1,25-dihydroxyvitamin D3, within the CNS, but its cellular source and neuroprotective actions remain unknown. Therefore, we wanted to determine whether microglia can respond to vitamin D3 and whether vitamin D3 alters immune activation of microglia. We have previously shown that microglia become activated by IFNγ or LPS or by infection with virus to express pro-inflammatory cytokines, chemokines, and effector molecules. In this study, activated microglia increased the expression of the vitamin D receptor and Cyp27b1, which encodes the enzyme for converting vitamin D3 into its active form, thereby enhancing their responsiveness to vitamin D3. Most importantly, the activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines, IL-6, IL-12, and TNFα, and increased expression of IL-10. The reduction in pro-inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3). Therefore, vitamin D3 increases the expression of IL-10 creating a feedback loop via SOCS3 that downregulates the pro-inflammatory immune response by activated microglia which would likewise prevent immune mediated damage in the CNS. PMID:26943970

  3. Influence of immune activation and inflammatory response on cardiovascular risk associated with the human immunodeficiency virus

    PubMed Central

    Beltrán, Luis M; Rubio-Navarro, Alfonso; Amaro-Villalobos, Juan Manuel; Egido, Jesús; García-Puig, Juan; Moreno, Juan Antonio

    2015-01-01

    Patients infected with the human immunodeficiency virus (HIV) have an increased cardiovascular risk. Although initially this increased risk was attributed to metabolic alterations associated with antiretroviral treatment, in recent years, the attention has been focused on the HIV disease itself. Inflammation, immune system activation, and endothelial dysfunction facilitated by HIV infection have been identified as key factors in the development and progression of atherosclerosis. In this review, we describe the epidemiology and pathogenesis of cardiovascular disease in patients with HIV infection and summarize the latest knowledge on the relationship between traditional and novel inflammatory, immune activation, and endothelial dysfunction biomarkers on the cardiovascular risk associated with HIV infection. PMID:25609975

  4. Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.

    PubMed

    Ramsingh, Arlene I; Manley, Kevin; Rong, Yinghui; Reilly, Andrew; Messer, Anne

    2015-11-01

    Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlapping HTT Exon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared with wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general. PMID:26307082

  5. Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms?

    PubMed

    Hughes, Patrick A; Zola, Heddy; Penttila, Irmeli A; Blackshaw, L Ashley; Andrews, Jane M; Krumbiegel, Doreen

    2013-07-01

    Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder. PMID:23649183

  6. Potential capacity of aptamers to trigger immune activation in human blood.

    PubMed

    Avci-Adali, Meltem; Steinle, Heidrun; Michel, Tatjana; Schlensak, Christian; Wendel, Hans P

    2013-01-01

    Target specific short single-stranded DNA (ssDNA) molecules, called aptamers, are auspicious ligands for numerous in vivo applications. However, aptamers are synthetic molecules, which might be recognized by the immune cells in vivo and induce an activation of the innate immune system. Thus, immune activation potential of synthetic ssDNA oligonucleotides (ODNs) was determined using a well established closed-loop circulation model. Fresh human blood was incubated at 37°C for 2 or 4 hours with ssDNA ODNs (SB_ODN) or CpG ODN as positive control. Transcriptional changes were determined by microarray analyses. Blood samples containing SB_ODN demonstrated after 4 hours a significant regulation of 295 transcripts. Amongst others, CCL8, CXCL10, CCL7 and CXCL11 were highest regulated genes. Gene Ontology terms and KEGG pathway analyses exhibited that the differentially expressed genes belong to the transcripts that are regulated during an immune and inflammatory response, and were overrepresented in TLR signaling pathway. This study shows for the first time the potential of aptamers to activate immune system after systemic application into the human blood. Thus, we highly recommend performing of these preclinical tests with potential aptamer-based therapeutics. PMID:23935890

  7. Adverse neuro-immune-endocrine interactions in patients with active tuberculosis.

    PubMed

    Bottasso, Oscar; Bay, María Luisa; Besedovsky, Hugo; Del Rey, Adriana

    2013-03-01

    The nervous, endocrine and immune systems play a crucial role in maintaining homeostasis and interact with each other for a successful defensive strategy against injurious agents. However, the situation is different in long-term diseases with marked inflammation, in which defensive mechanisms become altered. In the case of tuberculosis (TB), this is highlighted by several facts: an imbalance of plasma immune and endocrine mediators, that results in an adverse environment for mounting an adequate response against mycobacteria and controlling inflammation; the demonstration that dehidroepiandrosterone (DHEA) secretion by a human adrenal cell line can be inhibited by culture supernatants from Mycobacterium tuberculosis-stimulated peripheral blood mononuclear cells - PBMC - of TB patients, with this effect being partly reverted when neutralizing transforming growth factor-β in such supernantants; the in vitro effects of adrenal steroids on the specific immune response of PBMC from TB patients, that is a cortisol inhibition of mycobacterial antigen-driven lymphoproliferation and interferon-γ production as well as a suppression of TGF-β production in DHEA-treated PBMC; and lastly the demonstration that immune and endocrine compounds participating in the regulation of energy sources and immune activity correlated with the consumption state of TB patients. Collectively, immune-endocrine disturbances of TB patients are involved in critical components of disease pathology with implications in the impaired clinical status and unfavorable disease outcome. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID:23147110

  8. Tumoral Immune Suppression by Macrophages Expressing Fibroblast Activation Protein-Alpha and Heme Oxygenase-1

    PubMed Central

    Arnold, James N.; Magiera, Lukasz; Kraman, Matthew; Fearon, Douglas T.

    2013-01-01

    The depletion of tumor stromal cells that are marked by their expression of the membrane protein fibroblast activation protein-α (FAP) overcomes immune suppression and allows an anti-cancer cell immune response to control tumor growth. In subcutaneous tumors established with immunogenic Lewis lung carcinoma cells expressing ovalbumin (LL2/OVA), the FAP+ population comprises CD45+ and CD45− cells. In the present study, we further characterize the tumoral FAP+/CD45+ population as a minor sub-population of F4/80hi/CCR2+/CD206+ M2 macrophages. Using bone marrow chimeric mice in which the primate diphtheria toxin receptor (DTR) is restricted either to the FAP+/CD45+ or to the FAP+/CD45− subset, we demonstrate by conditionally depleting each subset that both independently contribute to the immune suppressive tumor microenvironment. A basis for the function of the FAP+/CD45+ subset is shown to be the immune inhibitory enzyme, heme oxygenase-1 (HO-1). The FAP+/CD45+ cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Since this observation of immune suppression by HO-1 expressed by the FAP+/CD45+ stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy. PMID:24778275

  9. Immune effects and antiacetylcholinesterase activity of Polygonum hydropiper L.

    PubMed

    Miyazaki, Yoshiko

    2016-01-01

    To determine the potential utility of Polygonum hydropiper (tade) as an anti-dementia functional food, the present study assessed the acetylcholinesterase inhibitory and anti-inflammatory activities of tade crude extracts in human cells. Crude extracts of tade were obtained by homogenizing tade in distilled water and then heating the resulting crude extracts. The hot aqueous extracts were purified by centrifugation and freeze-dried. The inhibition of acetylcholinesterase (AChE) by tade was investigated quantitatively by Ellman's method. Furthermore, the in vitro effects on human leukocytes (phagocytic activity, phagosome-lysosome fusion, and superoxide anion release) of coating inactive Staphylococcus aureus cells with tade crude extracts were studied. The tade crude extracts inhibited AChE activity. Furthermore, they increased phagocytic activity and phagosome-lysosome fusion in human neutrophils and monocytes in a nominally dose-dependent manner. However, the tade crude extracts did not alter superoxide anion release (O2 (-)) from neutrophils. Our results confirmed that crude extracts of P. hydropiper exhibit antiacetylcholinesterase and immunostimulation activities in vitro. P. hydropiper thus is a candidate functional food for the prevention of dementia. PMID:27200260

  10. Immune effects and antiacetylcholinesterase activity of Polygonum hydropiper L.

    PubMed Central

    MIYAZAKI, Yoshiko

    2015-01-01

    To determine the potential utility of Polygonum hydropiper (tade) as an anti-dementia functional food, the present study assessed the acetylcholinesterase inhibitory and anti-inflammatory activities of tade crude extracts in human cells. Crude extracts of tade were obtained by homogenizing tade in distilled water and then heating the resulting crude extracts. The hot aqueous extracts were purified by centrifugation and freeze-dried. The inhibition of acetylcholinesterase (AChE) by tade was investigated quantitatively by Ellman’s method. Furthermore, the in vitro effects on human leukocytes (phagocytic activity, phagosome-lysosome fusion, and superoxide anion release) of coating inactive Staphylococcus aureus cells with tade crude extracts were studied. The tade crude extracts inhibited AChE activity. Furthermore, they increased phagocytic activity and phagosome-lysosome fusion in human neutrophils and monocytes in a nominally dose-dependent manner. However, the tade crude extracts did not alter superoxide anion release (O2−) from neutrophils. Our results confirmed that crude extracts of P. hydropiper exhibit antiacetylcholinesterase and immunostimulation activities in vitro. P. hydropiper thus is a candidate functional food for the prevention of dementia. PMID:27200260

  11. Effects of immunomodulators on functional activity of innate immunity cells infected with Streptococcus pneumoniae.

    PubMed

    Plekhova, N G; Kondrashova, N M; Somova, L M; Drobot, E I; Lyapun, I N

    2015-02-01

    Low activity of bactericidal enzymes was found in innate immunity cells infected with S. pneumonia. The death of these cells was fastened under these conditions. On the contrary, treatment with antibiotic maxifloxacin was followed by an increase in activity of bactericidal enzymes in phagocytes and induced their death via necrosis. Analysis of the therapeutic properties of immunomodulators tinrostim and licopid in combination with maxifloxacin showed that these combinations correct functional activity of cells infected with S. pneumonia. PMID:25708326

  12. A critical role for pannexin-1 in activation of innate immune cells of the choroid plexus

    PubMed Central

    Maslieieva, Valentyna; Thompson, Roger J

    2014-01-01

    Epiplexus cells are a population of innate immune cells in the choroid plexus of the brain ventricles. They are thought to contribute to the immune component of the blood-cerebrospinal-fluid-barrier (BCSFB). Here we have developed a novel technique for studying epiplexus cells in acutely isolated, live and intact choroid plexus. We show that epiplexus cells are potently activated by exogenous ATP, increasing their motility within the tissue. This ATP-induced chemokinesis required activation of pannexin-1 channels, which are expressed by the epithelial cells of the choroid plexus and not the epiplexus cells themselves. Furthermore, ATP acts at least in part through the P2X4 ionotropic purinergic receptor. Thus, the resident immune cells of the choroid plexus appear to be in communication with the epithelial cells through pannexin-1 channels. PMID:24418937

  13. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

    PubMed

    Fairfax, Benjamin P; Humburg, Peter; Makino, Seiko; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C

    2014-03-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants. PMID:24604202

  14. Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression

    PubMed Central

    Fairfax, Benjamin P.; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C.

    2014-01-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor–modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants. PMID:24604202

  15. The effect of maternal stress activation on the offspring during lactation in light of vasopressin.

    PubMed

    Fodor, Anna; Zelena, Dóra

    2014-01-01

    Although it is obvious that preconceptional effects as well as stressors during pregnancy profoundly influence the progeny, the lactation period seems to be at least as important. Here we summarize how maternal stressors during the lactation period affect the offspring. As vasopressin is one of the crucial components both for stress adaptation and social behavior, special emphasis was given to this neuropeptide. We can conclude that stressing the mother does not have the same acute effect on the hypothalamo-pituitary-adrenocortical axis (as the main target of stress adaptation) of the pups as stressing the pups, but later endocrine and behavioral consequences can be similar. Vasopressin plays a role in acute and later consequences of perinatal stressor applied either to the mother or to the offspring, thereby contributing to transmitting the mothers' stress to the progeny. This mother-infant interaction does not necessarily mean a direct transmission of molecules, but rather is the result of programming the brain development through changes in maternal behavior. Thus, there is a time lag between maternal stress and stress-related changes in the offspring. The interactions are bidirectional as not only stress in the dam but also stress in the progeny has an effect on nursing. PMID:24550698

  16. Motolimod effectively drives immune activation in advanced cancer patients

    PubMed Central

    Dietsch, Gregory N.

    2016-01-01

    ABSTRACT A novel approach to immunotherapy is the activation of toll-like receptor 8 (TLR8). Motolimod, a selective TLR8 agonist can act in concert with approved immunotherapies to sensitize T cells and augment natural killer (NK) cell function. Despite treatment with chemotherapeutic agents and advance disease, cancer patients remain sensitive to motolimod.

  17. Pros and cons of VP1-specific maternal IgG for the protection of Enterovirus 71 infection.

    PubMed

    Kim, Young-In; Song, Jae-Hyoung; Kwon, Bo-Eun; Kim, Ha-Neul; Seo, Min-Duk; Park, KwiSung; Lee, SangWon; Yeo, Sang-Gu; Kweon, Mi-Na; Ko, Hyun-Jeong; Chang, Sun-Young

    2015-11-27

    Enterovirus 71 (EV71) causes hand, foot, and mouth diseases and can result in severe neurological disorders when it infects the central nervous system. Thus, there is a need for the development of effective vaccines against EV71 infection. Here we report that viral capsid protein 1 (VP1), one of the main capsid proteins of EV71, efficiently elicited VP1-specific immunoglobulin G (IgG) in the serum of mice immunized with recombinant VP1. The VP1-specific IgG produced in female mice was efficiently transferred to their offspring, conferring protection against EV71 infection immediately after birth. VP1-specific antibody can neutralize EV71 infection and protect host cells. VP1-specific maternal IgG in offspring was maintained for over 6 months. However, the pre-existence of VP1-specific maternal IgG interfered with the production of VP1-specific IgG antibody secreting cells by active immunization in offspring. Therefore, although our results showed the potential for VP1-specific maternal IgG protection against EV71 in neonatal mice, other strategies must be developed to overcome the hindrance of maternal IgG in active immunization. In this study, we developed an effective and feasible animal model to evaluate the protective efficacy of humoral immunity against EV71 infection using a maternal immunity concept. PMID:26529069

  18. Innate immune-stimulating and immune genes up-regulating activities of three types of alginate from Sargassum siliquosum in Pacific white shrimp, Litopenaeus vannamei.

    PubMed

    Yudiati, Ervia; Isnansetyo, Alim; Murwantoko; Ayuningtyas; Triyanto; Handayani, Christina Retna

    2016-07-01

    The Total Haemocyte Count (THC), phenoloxidase (PO), Superoxide Dismutase (SOD) activity, Phagocytic Activity/Index and Total Protein Plasma (TPP) were examined after feeding the white shrimp Litopenaeus vannamei with diets supplemented with three different types of alginates (acid, calcium and sodium alginates). Immune-related genes expression was evaluated by quantitative Real Time PCR (qRT-PCR). Results indicated that the immune parameters directly increased according to the doses of alginates and time. The 2.0 g kg(-1) of acid and sodium alginate treatments were gave better results. Four immune-related genes expression i.e. LGBP, Toll, Lectin, proPO were up regulated. It is therefore concluded that the supplementation of alginate of Sargassum siliquosum on the diet of L. vannamei enhanced the innate immunity as well as the expression of immune-related genes. It is the first report on the simultaneous evaluation of three alginate types to enhance innate immune parameters and immune-related genes expression in L. vannamei. PMID:26993614

  19. Quantitative Evaluation of Stomatal Cytoskeletal Patterns during the Activation of Immune Signaling in Arabidopsis thaliana

    PubMed Central

    Shimono, Masaki; Higaki, Takumi; Kaku, Hanae; Shibuya, Naoto; Hasezawa, Seiichiro

    2016-01-01

    Historically viewed as primarily functioning in the regulation of gas and water vapor exchange, it is now evident that stomata serve an important role in plant immunity. Indeed, in addition to classically defined functions related to cell architecture and movement, the actin cytoskeleton has emerged as a central component of the plant immune system, underpinning not only processes related to cell shape and movement, but also receptor activation and signaling. Using high resolution quantitative imaging techniques, the temporal and spatial changes in the actin microfilament array during diurnal cycling of stomatal guard cells has revealed a highly orchestrated transition from random arrays to ordered bundled filaments. While recent studies have demonstrated that plant stomata close in response to pathogen infection, an evaluation of stimulus-induced changes in actin cytoskeletal dynamics during immune activation in the guard cell, as well as the relationship of these changes to the function of the actin cytoskeleton and stomatal aperture, remains undefined. In the current study, we employed quantitative cell imaging and hierarchical clustering analyses to define the response of the guard cell actin cytoskeleton to pathogen infection and the elicitation of immune signaling. Using this approach, we demonstrate that stomatal-localized actin filaments respond rapidly, and specifically, to both bacterial phytopathogens and purified pathogen elicitors. Notably, we demonstrate that higher order temporal and spatial changes in the filament array show distinct patterns of organization during immune activation, and that changes in the naïve diurnal oscillations of guard cell actin filaments are perturbed by pathogens, and that these changes parallel pathogen-induced stomatal gating. The data presented herein demonstrate the application of a highly tractable and quantifiable method to assign transitions in actin filament organization to the activation of immune signaling in

  20. Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation

    PubMed Central

    Zhang, Qi; Deng, Yafei; Lai, Wenjing; Guan, Xiao; Sun, Xiongshan; Han, Qi; Wang, Fangjie; Pan, Xiaodong; Ji, Yan; Luo, Hongqin; Huang, Pei; Tang, Yuan; Gu, Liangqi; Dan, Guorong; Yu, Jianhua; Namaka, Michael; Zhang, Jianxiang; Deng, Youcai; Li, Xiaohui

    2016-01-01

    Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood. PMID:27443826

  1. Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation.

    PubMed

    Zhang, Qi; Deng, Yafei; Lai, Wenjing; Guan, Xiao; Sun, Xiongshan; Han, Qi; Wang, Fangjie; Pan, Xiaodong; Ji, Yan; Luo, Hongqin; Huang, Pei; Tang, Yuan; Gu, Liangqi; Dan, Guorong; Yu, Jianhua; Namaka, Michael; Zhang, Jianxiang; Deng, Youcai; Li, Xiaohui

    2016-01-01

    Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood. PMID:27443826

  2. Persistent Activation of the Innate Immune Response in Adult Drosophila Following Radiation Exposure During Larval Development

    PubMed Central

    Sudmeier, Lisa J.; Samudrala, Sai-Suma; Howard, Steven P.; Ganetzky, Barry

    2015-01-01

    Cranial radiation therapy (CRT) is an effective treatment for pediatric central nervous system malignancies, but survivors often suffer from neurological and neurocognitive side effects that occur many years after radiation exposure. Although the biological mechanisms underlying these deleterious side effects are incompletely understood, radiation exposure triggers an acute inflammatory response that may evolve into chronic inflammation, offering one avenue of investigation. Recently, we developed a Drosophila model of the neurotoxic side effects of radiation exposure. Here we use this model to investigate the role of the innate immune system in response to radiation exposure. We show that the innate immune response and NF-ĸB target gene expression is activated in the adult Drosophila brain following radiation exposure during larval development, and that this response is sustained in adult flies weeks after radiation exposure. We also present preliminary data suggesting that innate immunity is radioprotective during Drosophila development. Together our data suggest that activation of the innate immune response may be beneficial initially for survival following radiation exposure but result in long-term deleterious consequences, with chronic inflammation leading to impaired neuronal function and viability at later stages. This work lays the foundation for future studies of how the innate immune response is triggered by radiation exposure and its role in mediating the biological responses to radiation. These studies may facilitate the development of strategies to reduce the deleterious side effects of CRT. PMID:26333838

  3. Role of Toll-Like Receptors in Immune Activation and Tolerance in the Liver

    PubMed Central

    Nakamoto, Nobuhiro; Kanai, Takanori

    2014-01-01

    Liver has a unique vascular system receiving the majority of the blood supply from the gastrointestinal tract through the portal vein and faces continuous exposure to foreign pathogens and commensal bacterial products. These gut-derived antigens stimulate liver cells and result in a distinctive immune response via a family of pattern recognition receptors, the Toll-like receptors (TLRs). TLRs are expressed on Kupffer cells, dendritic cells, hepatic stellate cells, endothelial cells, and hepatocytes in the liver. The crosstalk between gut-derived antigens and TLRs on immune cells trigger a distinctive set of mechanisms to induce immunity, contributing to various acute and chronic liver diseases including liver cirrhosis and hepatocellular carcinoma. Accumulating evidence has shown that TLRs stimulation by foreign antigens induces the production of immunoactivating and immunoregulatory cytokines. Furthermore, the immunoregulatory arm of TLR stimulation can also control excessive tissue damage. With this knowledge at hand, it is important to clarify the dual role of disease-specific TLRs as activators and regulators, especially in the liver. We will review the current understanding of TLR signaling and subsequent immune activation and tolerance by the innate immune system in the liver. PMID:24904576

  4. Autoimmune activation toward embryo implantation is rare in immune-privileged human endometrium.

    PubMed

    Haller-Kikkatalo, Kadri; Altmäe, Signe; Tagoma, Aili; Uibo, Raivo; Salumets, Andres

    2014-09-01

    Human embryo implantation represents embryo apposition, adhesion to the endometrial epithelium, and invasion into the stromal extracellular matrix within 1 to 2 days during days 6 to 9 after ovulation. The major molecular mechanisms mediating implantation include adhesion molecules, including mucins, selectins, integrins, and cadherins; extracellular matrix components, such as laminins and collagens and their degrading enzymes; phospholipids and immune regulatory molecules, including prostaglandins, cytokines; and immunosuppressive molecules expressed by invasive trophoblasts and endometrial cells. Many of these molecules are the targets for autoimmune reactions in autoimmune diseases and cancer; however, the relevance of those in immune-mediated implantation failure has not been defined. In this review, we will describe the molecules involved in 2-day event of human embryo implantation, which may also be involved in immune system activation and subsequently cause immune-mediated implantation failure. We speculate that the data in the literature are limited concerning antiendometrial antibodies because the endometrium might be taken as an immune-privileged site that avoids autoimmune activation that might harm the implantation process. Antibodies affecting human fertility in ways other than impairing implantation are outside the scope of the current article and will not be discussed. PMID:24959819

  5. Effect of Solar Particle Event Radiation on Gastrointestinal Tract Bacterial Translocation and Immune Activation

    PubMed Central

    Ni, Houping; Balint, Klara; Zhou, Yu; Gridley, Daila S.; Maks, Casey; Kennedy, Ann R.; Weissman, Drew

    2013-01-01

    Space flight conditions within the protection of Earth’s gravitational field have been shown to alter immune responses, which could lead to potentially detrimental pathology. An additional risk of extended space travel outside the Earth’s gravitational field is the effect of solar particle event (SPE) radiation exposure on the immune system. Organisms that could lead to infection include endogenous, latent viruses, colonizing pathogenics, and commensals, as well as exogenous microbes present in the spacecraft or other astronauts. In this report, the effect of SPE-like radiation on containment of commensal bacteria and the innate immune response induced by its breakdown was investigated at the radiation energies, doses and dose rates expected during an extravehicular excursion outside the Earth’s gravitational field. A transient increase in serum lipopolysaccharide was observed 1 day after irradiation and was accompanied by an increase in acute-phase reactants and circulating proinflammatory cytokines, indicating immune activation. Baseline levels were reestablished by 5 days postirradiation. These findings suggest that astronauts exposed to SPE radiation could have impaired containment of colonizing bacteria and associated immune activation. PMID:21294608

  6. Influence of Physical Activity and Nutrition on Obesity-Related Immune Function

    PubMed Central

    Zourdos, Michael C.; Jo, Edward; Ormsbee, Michael J.

    2013-01-01

    Research examining immune function during obesity suggests that excessive adiposity is linked to impaired immune responses leading to pathology. The deleterious effects of obesity on immunity have been associated with the systemic proinflammatory profile generated by the secretory molecules derived from adipose cells. These include inflammatory peptides, such as TNF-α, CRP, and IL-6. Consequently, obesity is now characterized as a state of chronic low-grade systemic inflammation, a condition considerably linked to the development of comorbidity. Given the critical role of adipose tissue in the inflammatory process, especially in obese individuals, it becomes an important clinical objective to identify lifestyle factors that may affect the obesity-immune system relationship. For instance, stress, physical activity, and nutrition have each shown to be a significant lifestyle factor influencing the inflammatory profile associated with the state of obesity. Therefore, the purpose of this review is to comprehensively evaluate the impact of lifestyle factors, in particular psychological stress, physical activity, and nutrition, on obesity-related immune function with specific focus on inflammation. PMID:24324381

  7. Maternal deprivation of rat pups increases clinical symptoms of experimental autoimmune encephalomyelitis at adult age.

    PubMed

    Teunis, Marc A T; Heijnen, Cobi J; Sluyter, Frans; Bakker, Joost M; Van Dam, Anne-Marie M W; Hof, Maleen; Cools, Alexander R; Kavelaars, Annemieke

    2002-12-01

    Maternal deprivation of neonatal animals has been shown to induce long-lasting changes in the reactivity of the neuroendocrine system. The aim of the present study was to investigate whether maternal deprivation also affects susceptibility to immune-mediated diseases such as experimental autoimmune encephalomyelitis (EAE) in adult life. To this end, 9-day-old rat pups were subjected to a short-lasting maternal deprivation for a period of 24 h. At the age of 8 weeks, we induced EAE in these rats by immunization with myelin basic protein (MBP) in complete Freund's adjuvant. Our data demonstrate that short-lasting maternal deprivation induces a marked increase in the severity of EAE in the animals in later life. The histopathological evaluation of spinal cord and cerebellum corresponded with the observed differences in clinical symptoms of EAE. Moreover, neonatal maternal deprivation affects macrophage functioning at adult age. In contrast, no differences were observed in in vitro mitogen- and MBP-induced cytokine production by splenocytes. LPS-induced corticosterone release did not differ either between maternally deprived and control animals. We conclude that short-lasting neonatal maternal deprivation of rat pups has long-lasting consequences for macrophage activity and for susceptibility to the inflammatory autoimmune disease EAE. PMID:12446005

  8. Short Communication: Immune Activation Is Present in HIV-1-Exposed Seronegative Individuals and Is Independent of Microbial Translocation.

    PubMed

    Saulle, Irma; Biasin, Mara; Gnudi, Federica; Rainone, Veronica; Ibba, Salomè Valentina; Caputo, Sergio Lo; Mazzotta, Francesco; Trabattoni, Daria; Clerici, Mario

    2016-02-01

    Analyses of immune activation in HIV-exposed seronegative individuals (HESN) yielded discrepant results. To clarify this issue we performed an extensive investigation of immune parameters in HESN and, in particular, we analyzed in these individuals the possible presence of microbial translocation, the most widely accepted reason driving immune activation in HIV-infected patients. Results showed that immune activation, a skewing of T lymphocyte maturation, and increased responsiveness to lipopolysaccharide (LPS) characterize the HESN phenotype; this is not driven by alterations of the gastrointestinal barrier and microbial translocation. The activation state seen in HESN may influence the induction of stronger adaptive antiviral immune responses and may represent a virus exposure-induced innate immune protective phenotype against HIV. PMID:26414485

  9. The placenta in toxicology. Part II: Systemic and local immune adaptations in pregnancy.

    PubMed

    Svensson-Arvelund, Judit; Ernerudh, Jan; Buse, Eberhard; Cline, J Mark; Haeger, Jan-Dirk; Dixon, Darlene; Markert, Udo R; Pfarrer, Christiane; De Vos, Paul; Faas, Marijke M

    2014-01-01

    During pregnancy, the maternal immune system is challenged by the semiallogeneic fetus, which must be tolerated without compromising fetal or maternal health. This review updates the systemic and local immune changes taking place during human pregnancy, including some examples in rodents. Systemic changes are induced by contact of maternal blood with placental factors and include enhanced innate immunity with increased activation of granulocytes and nonclassical monocytes. Although a bias toward T helper (Th2) and regulatory T cell (Treg) immunity has been associated with healthy pregnancy, the relationship between different circulating Th cell subsets is not straightforward. Instead, these adaptations appear most evidently at the fetal-maternal interface, where for instance Tregs are enriched and promote fetal tolerance. Also innate immune cells, that is, natural killer cells and macrophages, are enriched, constituting the majority of decidual leukocytes. These cells not only contribute to immune regulation but also aid in establishing the placenta by promoting trophoblast recruitment and angiogenesis. Thus, proper interaction between leukocytes and placental trophoblasts is necessary for normal placentation and immune adaptation. Consequently, spontaneous maladaptation or interference of the immune system with toxic substances may be important contributing factors for the development of pregnancy complications such as preeclampsia, preterm labor, and recurrent miscarriages. PMID:23531796

  10. Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression.

    PubMed

    Pinton, Laura; Solito, Samantha; Damuzzo, Vera; Francescato, Samuela; Pozzuoli, Assunta; Berizzi, Antonio; Mocellin, Simone; Rossi, Carlo Riccardo; Bronte, Vincenzo; Mandruzzato, Susanna

    2016-01-12

    The expansion of myeloid derived suppressor cells (MDSCs), a suppressive population able to hamper the immune response against cancer, correlates with tumor progression and overall survival in several cancer types. We have previously shown that MDSCs can be induced in vitro from precursors present in the bone marrow and observed that these cells are able to actively proliferate in the presence of activated T cells, whose activation level is critical to drive the suppressive activity of MDSCs. Here we investigated at molecular level the mechanisms involved in the interplay between MDSCs and activated T cells. We found that activated T cells secrete IL-10 following interaction with MDSCs which, in turn, activates STAT3 phosphorylation on MDSCs then leading to B7-H1 expression. We also demonstrated that B7-H1+ MDSCs are responsible for immune suppression through a mechanism involving ARG-1 and IDO expression. Finally, we show that the expression of ligands B7-H1 and MHC class II both on in vitro-induced MDSCs and on MDSCs in the tumor microenvironment of cancer patients is paralleled by an increased expression of their respective receptors PD-1 and LAG-3 on T cells, two inhibitory molecules associated with T cell dysfunction. These findings highlight key molecules and interactions responsible for the extensive cross-talk between MDSCs and activated T cells that are at the basis of immune suppression. PMID:26700461

  11. Scavenging iron: a novel mechanism of plant immunity activation by microbial siderophores.

    PubMed

    Aznar, Aude; Chen, Nicolas W G; Rigault, Martine; Riache, Nassima; Joseph, Delphine; Desmaële, Didier; Mouille, Grégory; Boutet, Stéphanie; Soubigou-Taconnat, Ludivine; Renou, Jean-Pierre; Thomine, Sébastien; Expert, Dominique; Dellagi, Alia

    2014-04-01

    Siderophores are specific ferric iron chelators synthesized by virtually all microorganisms in response to iron deficiency. We have previously shown that they promote infection by the phytopathogenic enterobacteria Dickeya dadantii and Erwinia amylovora. Siderophores also have the ability to activate plant immunity. We have used complete Arabidopsis transcriptome microarrays to investigate the global transcriptional modifications in roots and leaves of Arabidopsis (Arabidopsis thaliana) plants after leaf treatment with the siderophore deferrioxamine (DFO). Physiological relevance of these transcriptional modifications was validated experimentally. Immunity and heavy-metal homeostasis were the major processes affected by DFO. These two physiological responses could be activated by a synthetic iron chelator ethylenediamine-di(o-hydroxyphenylacetic) acid, indicating that siderophores eliciting activities rely on their strong iron-chelating capacity. DFO was able to protect Arabidopsis against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. Siderophore treatment caused local modifications of iron distribution in leaf cells visible by ferrocyanide and diaminobenzidine-H₂O₂ staining. Metal quantifications showed that DFO causes a transient iron and zinc uptake at the root level, which is presumably mediated by the metal transporter iron regulated transporter1 (IRT1). Defense gene expression and callose deposition in response to DFO were compromised in an irt1 mutant. Consistently, plant susceptibility to D. dadantii was increased in the irt1 mutant. Our work shows that iron scavenging is a unique mechanism of immunity activation in plants. It highlights the strong relationship between heavy-metal homeostasis and immunity. PMID:24501001

  12. Scavenging Iron: A Novel Mechanism of Plant Immunity Activation by Microbial Siderophores1[C][W

    PubMed Central

    Aznar, Aude; Chen, Nicolas W.G.; Rigault, Martine; Riache, Nassima; Joseph, Delphine; Desmaële, Didier; Mouille, Grégory; Boutet, Stéphanie; Soubigou-Taconnat, Ludivine; Renou, Jean-Pierre; Thomine, Sébastien; Expert, Dominique; Dellagi, Alia

    2014-01-01

    Siderophores are specific ferric iron chelators synthesized by virtually all microorganisms in response to iron deficiency. We have previously shown that they promote infection by the phytopathogenic enterobacteria Dickeya dadantii and Erwinia amylovora. Siderophores also have the ability to activate plant immunity. We have used complete Arabidopsis transcriptome microarrays to investigate the global transcriptional modifications in roots and leaves of Arabidopsis (Arabidopsis thaliana) plants after leaf treatment with the siderophore deferrioxamine (DFO). Physiological relevance of these transcriptional modifications was validated experimentally. Immunity and heavy-metal homeostasis were the major processes affected by DFO. These two physiological responses could be activated by a synthetic iron chelator ethylenediamine-di(o-hydroxyphenylacetic) acid, indicating that siderophores eliciting activities rely on their strong iron-chelating capacity. DFO was able to protect Arabidopsis against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. Siderophore treatment caused local modifications of iron distribution in leaf cells visible by ferrocyanide and diaminobenzidine-H2O2 staining. Metal quantifications showed that DFO causes a transient iron and zinc uptake at the root level, which is presumably mediated by the metal transporter iron regulated transporter1 (IRT1). Defense gene expression and callose deposition in response to DFO were compromised in an irt1 mutant. Consistently, plant susceptibility to D. dadantii was increased in the irt1 mutant. Our work shows that iron scavenging is a unique mechanism of immunity activation in plants. It highlights the strong relationship between heavy-metal homeostasis and immunity. PMID:24501001

  13. Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection.

    PubMed

    Hsu, Denise C; Sereti, Irini

    2016-04-01

    In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available. PMID:26915027

  14. The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1.

    PubMed

    Jacobson, Jeffrey M; Bosinger, Steven E; Kang, Minhee; Belaunzaran-Zamudio, Pablo; Matining, Roy M; Wilson, Cara C; Flexner, Charles; Clagett, Brian; Plants, Jill; Read, Sarah; Purdue, Lynette; Myers, Laurie; Boone, Linda; Tebas, Pablo; Kumar, Princy; Clifford, David; Douek, Daniel; Silvestri, Guido; Landay, Alan L; Lederman, Michael M

    2016-07-01

    Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390. PMID:26935044

  15. Passive immunization and active vaccination against Hendra and Nipah viruses.

    PubMed

    Broder, C C

    2013-01-01

    Hendra virus and Nipah virus are viral zoonoses first recognized in the mid and late 1990's and are now categorized as the type species of the genus Henipavirus within the family Paramyxoviridae. Their broad species tropism together with their capacity to cause severe and often fatal disease in both humans and animals make Hendra and Nipah "overlap agents" and significant biosecurity threats. The development of effective vaccination strategies to prevent or treat henipavirus infection and disease has been an important area of research. Here, henipavirus active and passive vaccination strategies that have been examined in animal challenge models of Hendra and Nipah virus disease are summarized and discussed. PMID:23689890

  16. Maternal immunoglobulin E and childhood leukemia.

    PubMed

    Chang, Jeffrey S; Buffler, Patricia A; Metayer, Catherine; Chokkalingam, Anand P; Patoka, Joe; Kronish, Daniel; Wiemels, Joseph L

    2009-08-01

    Childhood leukemia, particularly acute lymphoblastic leukemia (ALL), has long been hypothesized to be affected by abnormal immune responses to microbial challenges stemming from a lack of immune modulation in early childhood. Studies of allergies suggest that a child's immune development may be modulated by maternal immune status. We conducted a study to explore the relationship between maternal immunoglobulin E (IgE) and childhood leukemia and to investigate whether maternal immune status can influence childhood leukemia risk. Serum total and specific IgE (respiratory and food) were measured in biological mothers of 352 children (193 healthy controls and 159 leukemia cases, including 139 ALL cases) ages <8 years who were enrolled in the Northern California Childhood Leukemia Study. Odds ratios associated with maternal IgE were calculated using unconditional logistic regression adjusted for child's age, sex, race/ethnicity, and annual household income. A positive association between childhood leukemia or ALL and elevated levels of maternal serum total IgE was observed, especially among Hispanics. In addition, a positive association was observed between childhood leukemia or ALL and maternal respiratory or food IgE status. These results suggest that maternal immune function may play a crucial role in the etiology of childhood leukemia, although additional studies need to be conducted to confirm the results of this study and provide a perspective on mechanisms. PMID:19622720

  17. Immunity Against Parainfluenza-3 Virus in Cattle: Anti-Neuraminidase Activity in Serum and Nasal Secretion

    PubMed Central

    Morein, B.; Höglund, S.; Bergman, R.

    1973-01-01

    The antigenicity of two parainfluenza=3 virus strains, a “neuraminidasestrong” and a “neuraminidase-weak,” was compared. For both strains the amount of hemagglutinin units was equal. The antibody responses to neuraminidase and hemagglutinin were measured on samples of serum and nasal secretion and were found to be similar, irrespective of the strain used for immunization. Anti-neuraminidase activity was demonstrated in the gel phase of nasal secretion of immunized cattle. Immunglobulin A was found attached to the peplomers of inhibited virus by immuno-electron microscopy. Images PMID:4355138

  18. Effect of paeonol on antioxidant and immune regulatory activity in hepatocellular carcinoma rats.

    PubMed

    Chen, Bendong; Ning, Mingliang; Yang, Guangshun

    2012-01-01

    The study investigated the immunity and antioxidant potential of paeonol by employing a hepatocellular carcinoma (HCC) rat model. Three doses of paeonol (20, 40, 60 mg/kg b.w. orally) were administrated to diethylnitrosamine (DEN)-induced HCC rats. Results showed that paeonol significantly reduced the serum AST, ALT, ALP, GGT, AFU and liver MDA levels, increased serum WBC, TP, ALB, A/G, TNF-α and IFN-γ and liver antioxidant enzymes activities (SOD, CAT, GSH-Px, GR) in HCC rats. Altogether, these results suggest that the paeonol could effectively decrease oxidative injury and improve immunity function in HCC rats. PMID:22522397

  19. STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia.

    PubMed

    Curran, Emily; Chen, Xiufen; Corrales, Leticia; Kline, Douglas E; Dubensky, Thomas W; Duttagupta, Priyanka; Kortylewski, Marcin; Kline, Justin

    2016-06-14

    Type I interferon (IFN), essential for spontaneous T cell priming against solid tumors, is generated through recognition of tumor DNA by STING. Interestingly, we observe that type I IFN is not elicited in animals with disseminated acute myeloid leukemia (AML). Further, survival of leukemia-bearing animals is not diminished in the absence of type I IFN signaling, suggesting that STING may not be triggered by AML. However, the STING agonist, DMXAA, induces expression of IFN-β and other inflammatory cytokines, promotes dendritic cell (DC) maturation, and results in the striking expansion of leukemia-specific T cells. Systemic DMXAA administration significantly extends survival in two AML models. The therapeutic effect of DMXAA is only partially dependent on host type I IFN signaling, suggesting that other cytokines are important. A synthetic cyclic dinucleotide that also activates human STING provided a similar anti-leukemic effect. These data demonstrate that STING is a promising immunotherapeutic target in AML. PMID:27264175

  20. Intracellular sensing of complement C3 activates cell autonomous immunity

    PubMed Central

    Tam, Jerry C.H.; Bidgood, Susanna R.; McEwan, William A.; James, Leo C.

    2014-01-01

    Pathogens traverse multiple barriers during infection including cell membranes. Here we show that during this transition pathogens carry covalently attached complement C3 into the cell, triggering immediate signalling and effector responses. Sensing of C3 in the cytosol activates MAVS-dependent signalling cascades and induces proinflammatory cytokine secretion. C3 also flags viruses for rapid proteasomal degradation, thereby preventing their replication. This system can detect both viral and bacterial pathogens but is antagonized by enteroviruses, such as rhinovirus and poliovirus, which cleave C3 using their 3C protease. The antiviral Rupintrivir inhibits 3C protease and prevents C3 cleavage, rendering enteroviruses susceptible to intracellular complement sensing. Thus, complement C3 allows cells to detect and disable pathogens that have invaded the cytosol. PMID:25190799

  1. Intracellular sensing of complement C3 activates cell autonomous immunity.

    PubMed

    Tam, Jerry C H; Bidgood, Susanna R; McEwan, William A; James, Leo C

    2014-09-01

    Pathogens traverse multiple barriers during infection, including cell membranes. We found that during this transition, pathogens carried covalently attached complement C3 into the cell, triggering immediate signaling and effector responses. Sensing of C3 in the cytosol activated mitochondrial antiviral signaling (MAVS)-dependent signaling cascades and induced proinflammatory cytokine secretion. C3 also flagged viruses for rapid proteasomal degradation, preventing their replication. This system could detect both viral and bacterial pathogens but was antagonized by enteroviruses, such as rhinovirus and poliovirus, which cleave C3 using their 3C protease. The antiviral rupintrivir inhibited 3C protease and prevented C3 cleavage, rendering enteroviruses susceptible to intracellular complement sensing. Thus, complement C3 allows cells to detect and disable pathogens that have invaded the cytosol. PMID:25190799

  2. Ubiquitin in the activation and attenuation of innate antiviral immunity

    PubMed Central

    Heaton, Steven M.

    2016-01-01

    Viral infection activates danger signals that are transmitted via the retinoic acid–inducible gene 1–like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. PMID:26712804

  3. Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure

    PubMed Central

    Schechter, Daniel S.; Moser, Dominik A.; Paoloni-Giacobino, Ariane; Stenz, Ludwig; Gex-Fabry, Marianne; Aue, Tatjana; Adouan, Wafae; Cordero, María I.; Suardi, Francesca; Manini, Aurelia; Sancho Rossignol, Ana; Merminod, Gaëlle; Ansermet, Francois; Dayer, Alexandre G.; Rusconi Serpa, Sandra

    2015-01-01

    Prior research has shown that mothers with Interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) report greater difficulty in parenting their toddlers. Relative to their frequent early exposure to violence and maltreatment, these mothers display dysregulation of their hypothalamic pituitary adrenal axis (HPA-axis), characterized by hypocortisolism. Considering methylation of the promoter region of the glucocorticoid receptor gene NR3C1 as a marker for HPA-axis functioning, with less methylation likely being associated with less circulating cortisol, the present study tested the hypothesis that the degree of methylation of this gene would be negatively correlated with maternal IPV-PTSD severity and parenting stress, and positively correlated with medial prefrontal cortical (mPFC) activity in response to video-stimuli of stressful versus non-stressful mother–child interactions. Following a mental health assessment, 45 mothers and their children (ages 12–42 months) participated in a behavioral protocol involving free-play and laboratory stressors such as mother–child separation. Maternal DNA was extracted from saliva. Interactive behavior was rated on the CARE-Index. During subsequent fMRI scanning, mothers were shown films of free-play and separation drawn from this protocol. Maternal PTSD severity and parenting stress were negatively correlated with the mean percentage of methylation of NR3C1. Maternal mPFC activity in response to video-stimuli of mother–child separation versus play correlated positively to NR3C1 methylation, and negatively to maternal IPV-PTSD and parenting stress. Among interactive behavior variables, child cooperativeness in play was positively correlated with NR3C1 methylation. Thus, the present study is the first published report to our knowledge, suggesting convergence of behavioral, epigenetic, and neuroimaging data that form a psychobiological signature of parenting-risk in the context of early life stress and PTSD

  4. Formation of disulfide bonds in insect prophenoloxidase enhances immunity through improving enzyme activity and stability.

    PubMed

    Lu, Anrui; Peng, Qin; Ling, Erjun

    2014-06-01

    Type 3 copper proteins, including insect prophenoloxidase (PPO), contain two copper atoms in the active site pocket and can oxidize phenols. Insect PPO plays an important role in immunity. Insects and other invertebrates show limited recovery from pathogen invasion and wounds if phenoloxidase (PO) activity is low. In most insect PPOs, two disulfide bonds are present near the C-terminus. However, in Pimpla hypochondriaca (a parasitoid wasp), each PPO contains one disulfide bond. We thus questioned whether the formation of two sulfide bonds in insect PPOs improved protein stability and/or increased insect innate immunity over time. Using Drosophila melanogaster PPO1 as a model, one or two disulfide bonds were deleted to evaluate the importance of disulfide bonds in insect immunity. rPPO1 and mutants lacking disulfide bonds could be expressed and showed PO activity. However, the PO activities of mutants lacking one or two disulfide bonds significantly decreased. Deletion of disulfide bonds also reduced PPO thermostability. Furthermore, antibacterial activities against Escherichia coli and Bacillus subtilis significantly decreased when disulfide bonds were deleted. Therefore, the formation of two disulfide bond(s) in insect PPO enhances antibacterial activity by increasing PO activity and stability. PMID:24480295

  5. Bacterial pathogens activate plasminogen to breach tissue barriers and escape from innate immunity.

    PubMed

    Peetermans, Marijke; Vanassche, Thomas; Liesenborghs, Laurens; Lijnen, Roger H; Verhamme, Peter

    2016-11-01

    Both coagulation and fibrinolysis are tightly connected with the innate immune system. Infection and inflammation cause profound alterations in the otherwise well-controlled balance between coagulation and fibrinolysis. Many pathogenic bacteria directly exploit the host's hemostatic system to increase their virulence. Here, we review the capacity of bacteria to activate plasminogen. The resulting proteolytic activity allows them to breach tissue barriers and evade innate immune defense, thus promoting bacterial spreading. Yersinia pestis, streptococci of group A, C and G and Staphylococcus aureus produce a specific bacterial plasminogen activator. Moreover, surface plasminogen receptors play an established role in pneumococcal, borrelial and group B streptococcal infections. This review summarizes the mechanisms of bacterial activation of host plasminogen and the role of the fibrinolytic system in infections caused by these pathogens. PMID:26485450

  6. Exploiting Innate Immune Cell Activation of a Copper-Dependent Antimicrobial Agent during Infection

    PubMed Central

    Festa, Richard A.; Helsel, Marian E.; Franz, Katherine J.; Thiele, Dennis J.

    2014-01-01

    SUMMARY Recalcitrant microbial infections demand new therapeutic options. Here we present an approach that exploits two prongs of the host immune cell antimicrobial response: the oxidative burst and the compartmentalization of copper (Cu) within phagolysosomes. The prochelator QBP is a nontoxic protected form of 8-hydroxyquinoline (8HQ) in which a pinanediol boronic ester blocks metal ion coordination by 8HQ. QBP is deprotected via reactive oxygen species produced by activated macrophages, creating 8HQ and eliciting Cu-dependent killing of the fungal pathogen Cryptococcus neoformans in vitro and in mouse pulmonary infection. 8HQ ionophoric activity increases intracellular Cu, overwhelming the Cu-resistance mechanisms of C. neoformans to elicit fungal killing. The Cu-dependent antimicrobial activity of 8HQ against a spectrum of microbial pathogens suggests that this strategy may have broad utility. The conditional activation of Cu ionophores by innate immune cells intensifies the hostile antimicrobial environment and represents a promising approach to combat infectious disease. PMID:25088681

  7. Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation

    PubMed Central

    Cai, Xin; Chen, Jueqi; Xu, Hui; Liu, Siqi; Jiang, Qiu-Xing; Halfmann, Randal; Chen, Zhijian J.

    2014-01-01

    SUMMARY Pathogens and cellular danger signals activate sensors such as RIG-I and NLRP3 to produce robust immune and inflammatory responses through respective adaptor proteins MAVS and ASC, which harbor essential N-terminal CARD and PYRIN domains, respectively. Here, we show that CARD and PYRIN function as bona fide prions in yeast and their prion forms are inducible by their respective upstream activators. Likewise, a yeast prion domain can functionally replace CARD and PYRIN in mammalian cell signaling. Mutations in MAVS and ASC that disrupt their prion activities in yeast also abrogate their ability to signal in mammalian cells. Furthermore, fibers of recombinant PYRIN can convert ASC into functional polymers capable of activating caspase-1. Remarkably, a conserved fungal NOD-like receptor and prion pair can functionally reconstitute signaling of NLRP3 and ASC PYRINs in mammalian cells. These results indicate that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation. PMID:24630723

  8. Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation

    PubMed Central

    Qi, QIAO; Hao, WU

    2016-01-01

    Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the μm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways. PMID:26511517

  9. Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation.

    PubMed

    Qiao, Qi; Wu, Hao

    2015-11-01

    Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the µm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways. PMID:26511517

  10. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection.

    PubMed

    Shankar, Esaki M; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie

    2015-02-12

    Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis. PMID:25674514

  11. Integrative inflammasome activity in the regulation of intestinal mucosal immune responses.

    PubMed

    Elinav, E; Henao-Mejia, J; Flavell, R A

    2013-01-01

    The mammalian intestinal tract harbors a vast and diverse ecosystem of microbes that are separated from the sterile host milieu by a single layer of epithelial cells. While this bio-geographical configuration is critical for host biological processes, it imposes a risk for microbial penetration and life-threatening systemic invasion. Inflammasomes are cytosolic multi-protein platforms that sense both microbial and damage-associated molecular patterns and initiate a potent innate immune anti-microbial response. In this review, we will highlight the role of inflammasomes in the orchestration and regulation of the intestinal immune response, focusing on the roles of inflammasomes in maintenance of intestinal homeostasis, enteric infection, auto-inflammation, and tumorigenesis. We highlight the centrality of inflammasome signaling in the complex cross-talk between host mucosal immune arms and the environment, in particular the microflora, with emphasis on the spatial and temporal integration of inflammasome activation with signals from other innate signaling platforms. PMID:23212196

  12. Activation of cutaneous immune responses in complex regional pain syndrome

    PubMed Central

    Birklein, Frank; Drummond, Peter D.; Li, Wenwu; Schlereth, Tanja; Albrecht, Nahid; Finch, Philip M.; Dawson, Linda F.; Clark, J. David; Kingery, Wade S.

    2014-01-01

    The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but TNF-α and IL-6 are elevated in experimental skin blister fluid from CRPS affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS there was reduced keratinocyte proliferation with epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS. PMID:24462502

  13. Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response

    PubMed Central

    Mavrogiorgos, Nikolaos; Mekasha, Samrawit; Yang, Yibin; Kelliher, Michelle A.; Ingalls, Robin R.

    2013-01-01

    Nucleotide-binding oligomerization domain (NOD)-1 and NOD2 are members of the NOD-like receptor family of cytosolic pattern recognition receptors that recognize specific fragments of the bacterial cell wall component peptidoglycan. Neisseria species are unique amongst Gram-negative bacteria in that they turn over large amounts of peptidoglycan during growth. In this study we examined the ability of NOD1 and NOD2 to recognize N. gonorrhoeae, and determined the role of NOD-dependent signaling in regulating the immune response to gonococcal infection. We found that gonococci, as well as conditioned medium from mid-logarithmic phase grown bacteria, were capable of activating both human NOD1 and NOD2, as well as mouse NOD2, leading to the activation of the transcription factor NF-κB and polyubiquitination of the adaptor receptor-interacting serine-threonine kinase 2 (RIPK2). We identified a number of cytokines and chemokines that were differentially expressed in wild type vs. NOD2 deficient macrophages in response to gonococcal infection. Moreover, NOD2 signaling upregulated complement pathway components and cytosolic nucleic acid sensors, suggesting a broad impact of NOD activation on innate immunity. These data demonstrate that NOD1 and NOD2 are important intracellular regulators of the immune response to infection with N. gonorrhoeae. Given the intracellular lifestyle of this pathogen, we believe these cytosolic receptors may provide a key innate immune defense mechanism for the host during gonococcal infection. PMID:23884094

  14. Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response.

    PubMed

    Mavrogiorgos, Nikolaos; Mekasha, Samrawit; Yang, Yibin; Kelliher, Michelle A; Ingalls, Robin R

    2014-05-01

    NOD1 and NOD2 are members of the NOD-like receptor family of cytosolic pattern recognition receptors that recognize specific fragments of the bacterial cell wall component peptidoglycan. Neisseria species are unique amongst Gram-negative bacteria in that they turn over large amounts of peptidoglycan during growth. We examined the ability of NOD1 and NOD2 to recognize Neisseria gonorrhoeae, and determined the role of NOD-dependent signaling in regulating the immune response to gonococcal infection. Gonococci, as well as conditioned medium from mid-logarithmic phase grown bacteria, were capable of activating both human NOD1 and NOD2, as well as mouse NOD2, leading to the activation of the transcription factor NF-κB and polyubiquitination of the adaptor receptor-interacting serine-threonine kinase 2. We identified a number of cytokines and chemokines that were differentially expressed in wild type versus NOD2-deficient macrophages in response to gonococcal infection. Moreover, NOD2 signaling up-regulated complement pathway components and cytosolic nucleic acid sensors, suggesting a broad impact of NOD activation on innate immunity. Thus, NOD1 and NOD2 are important intracellular regulators of the immune response to infection with N. gonorrhoeae. Given the intracellular lifestyle of this pathogen, we believe these cytosolic receptors may provide a key innate immune defense mechanism for the host during gonococcal infection. PMID:23884094

  15. Inducible factors with antimicrobial activity after immune challenge in the haemolymph of Red Palm Weevil (Insecta).

    PubMed

    Mastore, Maristella; Binda Rossetti, Simona; Giovannardi, Stefano; Scarì, Giorgio; Brivio, Maurizio F

    2015-05-01

    Insects are capable of innate immune responses elicited after microbial infection. In this process, the receptor-mediated recognition of foreign bodies and the subsequent activation of immunocompetent cells lead to the synthesis ex novo of a peptide pool with antimicrobial activity. We investigated the inducible immune response of a coleopteran, Rhynchophorus ferrugineus, challenged with both Gram-negative and Gram-positive bacteria. After immunization, we evaluated the presence of antimicrobial peptides using either biochemical analyses or microbiological techniques. The antimicrobial properties of the newly synthesized protein pool, detectable in haemolymph fractions of low molecular mass, showed strong antibacterial activity against various bacterial strains (Escherichia coli, Pseudomonas sp. OX1, Bacillus subtilis and Micrococcus luteus). In addition to the preliminary study of the mechanism of action of the pool of antimicrobial peptides, we also investigated its effects on bacterial cell walls by means of fluorescence microscopy and scanning electron microscopy. The data suggest that the main effects seem to be directed at destabilizing and damaging the bacterial wall. This study provides data that help us to understand some aspects of the inducible innate immunity in a system model that lacks anticipatory responses. However, the weevil has finely tuned its defensive strategies to counteract effectively microbial infection. PMID:25114180

  16. Pathogen Recognition and Activation of the Innate Immune Response in Zebrafish

    PubMed Central

    van der Vaart, Michiel; Spaink, Herman P.; Meijer, Annemarie H.

    2012-01-01

    The zebrafish has proven itself as an excellent model to study vertebrate innate immunity. It presents us with possibilities for in vivo imaging of host-pathogen interactions which are unparalleled in mammalian model systems. In addition, its suitability for genetic approaches is providing new insights on the mechanisms underlying the innate immune response. Here, we review the pattern recognition receptors that identify invading microbes, as well as the innate immune effector mechanisms that they activate in zebrafish embryos. We compare the current knowledge about these processes in mammalian models and zebrafish and discuss recent studies using zebrafish infection models that have advanced our general understanding of the innate immune system. Furthermore, we use transcriptome analysis of zebrafish infected with E. tarda, S. typhimurium, and M. marinum to visualize the gene expression profiles resulting from these infections. Our data illustrate that the two acute disease-causing pathogens, E. tarda and S. typhimurium, elicit a highly similar proinflammatory gene induction profile, while the chronic disease-causing pathogen, M. marinum, induces a weaker and delayed innate immune response. PMID:22811714

  17. Push and release: TLR9 activation plus STAT3 blockade for systemic antitumor immunity.

    PubMed

    Kortylewski, Marcin; Kuo, Ya-Huei

    2014-01-01

    Proper immunostimulation ("push") and immune checkpoint blockade ("release") are both critical for the efficacy of anticancer immunotherapy. We have recently shown that activating Toll-like receptor 9 (TLR9) while specifically blocking signal transducer and activator of transcription 3 (STAT3) in leukemic cells enhances their immunogenicity, allowing for CD8(+) T cell-mediated tumor eradication. These findings underscore the therapeutic potential of such a "Push & Release" strategy against hematological malignancies. PMID:24800162

  18. 22 CFR 40.25 - Certain aliens involved in serious criminal activity who have asserted immunity from prosecution...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Certain aliens involved in serious criminal activity who have asserted immunity from prosecution. 40.25 Section 40.25 Foreign Relations DEPARTMENT OF... involved in serious criminal activity who have asserted immunity from prosecution....

  19. 22 CFR 40.25 - Certain aliens involved in serious criminal activity who have asserted immunity from prosecution...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Certain aliens involved in serious criminal activity who have asserted immunity from prosecution. 40.25 Section 40.25 Foreign Relations DEPARTMENT OF... involved in serious criminal activity who have asserted immunity from prosecution....

  20. 22 CFR 40.25 - Certain aliens involved in serious criminal activity who have asserted immunity from prosecution...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Certain aliens involved in serious criminal activity who have asserted immunity from prosecution. 40.25 Section 40.25 Foreign Relations DEPARTMENT OF... involved in serious criminal activity who have asserted immunity from prosecution....

  1. 22 CFR 40.25 - Certain aliens involved in serious criminal activity who have asserted immunity from prosecution...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Certain aliens involved in serious criminal activity who have asserted immunity from prosecution. 40.25 Section 40.25 Foreign Relations DEPARTMENT OF... involved in serious criminal activity who have asserted immunity from prosecution....

  2. 22 CFR 40.25 - Certain aliens involved in serious criminal activity who have asserted immunity from prosecution...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Certain aliens involved in serious criminal activity who have asserted immunity from prosecution. 40.25 Section 40.25 Foreign Relations DEPARTMENT OF... involved in serious criminal activity who have asserted immunity from prosecution....

  3. Inorganic nanoparticles and the immune system: detection, selective activation and tolerance

    NASA Astrophysics Data System (ADS)

    Bastús, Neus G.; Sánchez-Tilló, Ester; Pujals, Silvia; Comenge, Joan; Giralt, Ernest; Celada, Antonio; Lloberas, Jorge; Puntes, Victor F.

    2012-03-01

    The immune system is the responsible for body integrity and prevention of external invasion. On one side, nanoparticles are no triggers that the immune system is prepared to detect, on the other side it is known that foreign bodies, not only bacteria, viruses and parasites, but also inorganic matter, can cause various pathologies such as silicosis, asbestosis or inflammatory reactions. Therefore, nanoparticles entering the body, after interaction with proteins, will be either recognized as self-agents or detected by the immune system, encompassing immunostimulation or immunosuppression responses. The nature of these interactions seems to be dictated not specially by the composition of the material but by modifications of NP coating (composition, surface charge and structure). Herein, we explore the use of gold nanoparticles as substrates to carry multifunctional ligands to manipulate the immune system in a controlled manner, from undetection to immunostimulation. Murine bone marrow macrophages can be activated with artificial nanometric objects consisting of a gold nanoparticle functionalized with peptides. In the presence of some conjugates, macrophage proliferation was stopped and pro-inflammatory cytokines were induced. The biochemical type of response depended on the type of conjugated peptide and was correlated with the degree of ordering in the peptide coating. These findings help to illustrate the basic requirements involved in medical NP conjugate design to either activate the immune system or hide from it, in order to reach their targets before being removed by phagocytes. Additionally, it opens up the possibility to modulate the immune response in order to suppress unwanted responses resulting from autoimmunity, or allergy or to stimulate protective responses against pathogens.

  4. Molecular and genetic properties of tumors associated with local immune cytolytic activity

    PubMed Central

    Rooney, Michael S.; Shukla, Sachet A.; Wu, Catherine J.; Getz, Gad; Hacohen, Nir

    2015-01-01

    Summary How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic datasets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity. PMID:25594174

  5. Human immunodeficiency virus-like particles activate multiple types of immune cells

    SciTech Connect

    Sailaja, Gangadhara; Skountzou, Ioanna; Quan, Fu-Shi; Compans, Richard W. . E-mail: compans@microbio.emory.edu; Kang, Sang-Moo . E-mail: skang2@emory.edu

    2007-06-05

    The rapid spread of human immunodeficiency virus (HIV) worldwide makes it a high priority to develop an effective vaccine. Since live attenuated or inactivated HIV is not likely to be approved as a vaccine due to safety concerns, HIV virus like particles (VLPs) offer an attractive alternative because they are safe due to the lack of a viral genome. Although HIV VLPs have been shown to induce humoral and cellular immune responses, it is important to understand the mechanisms by which they induce such responses and to improve their immunogenicity. We generated HIV VLPs, and VLPs containing Flt3 ligand (FL), a dendritic cell growth factor, to target VLPs to dendritic cells, and investigated the roles of these VLPs in the initiation of adaptive immune responses in vitro and in vivo. We found that HIV-1 VLPs induced maturation of dendritic cells and monocyte/macrophage populations in vitro and in vivo, with enhanced expression of maturation markers and cytokines. Dendritic cells pulsed with VLPs induced activation of splenocytes resulting in increased production of cytokines. VLPs containing FL were found to increase dendritic cells and monocyte/macrophage populations in the spleen when administered to mice. Administration of VLPs induced acute activation of multiple types of cells including T and B cells as indicated by enhanced expression of the early activation marker CD69 and down-regulation of the homing receptor CD62L. VLPs containing FL were an effective form of antigen in activating immune cells via dendritic cells, and immunization with HIV VLPs containing FL resulted in enhanced T helper type 2-like immune responses.

  6. Active and Avoidant Coping and Coping Efficacy as Mediators of the Relation of Maternal Involvement to Depressive Symptoms among Urban Adolescents

    ERIC Educational Resources Information Center

    Mosher, Catherine E.; Prelow, Hazel M.

    2007-01-01

    Our study tested an extension of the social resource model in an urban sample of 129 African American and 114 European American adolescents. Maternal involvement was positively related to the use of active and avoidant coping strategies among youth of both ethnicities. Additionally, use of active coping strategies was related to greater coping…

  7. Effect of maternally supplied n-3 and n-6 oils on the fatty acid composition and mononuclear immune cell distribution of lymphatic tissue from the gastrointestinal tract of suckling piglets.

    PubMed

    Binter, Claudia; Khol-Parisini, Annabella; Gerner, Wilhelm; Schäfer, Klaus; Hulan, Howard W; Saalmüller, Armin; Zentek, Jürgen

    2011-10-01

    Fatty acids are essential for immune cell function. Maternal dietary fatty acid supply influences body fat composition of their offspring. As a first step to study immunonutritional interactions at an early age of pigs, four sows were fed a diet containing sunflower oil or oil from seal blubber during pregnancy and lactation. Corresponding piglets were sacrificed at three consecutive time points in the suckling period and their mesenteric lymph nodes and spleen were analysed by gas chromatography for levels of fatty acid. At the same time mononuclear cells of these organs and of the intestinal lymphoid tissue from the jejunum were isolated and subpopulations characterised by flow cytometry. Levels of fatty acids from the lymphatic organs of the piglets were significantly influenced by the maternal diet. The concentration of the fatty acids 20:5n-3, 22:5n-3 and 22:6n-3 were higher in the spleen and mesenteric lymph node of piglets suckled to sows of the test diet. Additionally, suckling time affected the levels of some long chain polyunsaturated fatty acids. Dietary effects were seen on some subpopulations including CD4-CD8alpha+ lymphocytes of the mesenteric lymph nodes and CD4+CD8alpha+ lymphocytes of the lamina propria, which were higher in the group fed seal blubber oil. The levels of CD21+ B-cells were higher in the group fed sunflower oil. The results indicate that the maternal diet and suckling time affect the fatty acid status of the investigated lymphatic tissues of piglets, but may have minor effects on the investigated lymphocyte subpopulations. PMID:22164956

  8. In vitro assessment of agave fructans (Agave salmiana) as prebiotics and immune system activators.

    PubMed

    Moreno-Vilet, L; Garcia-Hernandez, M H; Delgado-Portales, R E; Corral-Fernandez, N E; Cortez-Espinosa, N; Ruiz-Cabrera, M A; Portales-Perez, D P

    2014-02-01

    The prebiotic effect of agave fructans (Agave salmiana) was evaluated through the growth of two lactic acid bacterial (LAB) strains (Lactobacillus casei and Bifidobacterium lactis). The immune system was activated through the stimulation of peripheral blood mononuclear cells (PBMC) of healthy subjects testing fructans, LAB or a mixture of these compounds at different concentrations. Immune responses, such as early cell activation (CD69), cell cycle progression, nitric oxide (NO) production and the expression of transcription factors for lymphocyte differentiation, were analyzed. Compared with other fructans, the extracted agave fructans showed the highest prebiotic activity and increased levels of CD69 expression, proliferative activity and NO production when administered with the probiotic L. casei. The Th1 lymphocyte differentiation produced through LAB stimulation was greatly diminished after the incorporation of agave fructans. In conclusion, these types of fructans (A. salmiana) are involved in the activation and selective differentiation of cells of the immune system through interactions with probiotics. Thus, agave fructans represent a novel immunomodulator that might benefit the functional food industry. PMID:24211431

  9. Soluble Immune Mediators and Vaginal Bacteria Impact Innate Genital Mucosal Antimicrobial Activity in Young Women

    PubMed Central

    Madan, Rebecca Pellett; Dezzutti, Charlene S.; Rabe, Lorna; Hillier, Sharon L.; Marrazzo, Jeanne; McGowan, Ian; Richardson, Barbra A.; Herold, Betsy C.

    2015-01-01

    Introduction Innate activity against Escherichia coli in female genital secretions may represent contributions from vaginal bacteria and host soluble immune mediators. We analyzed the relationship between E. coli inhibitory activity, soluble immune mediators, and vaginal bacteria in participants in MTN-004, a placebo-controlled trial of VivaGel®, a candidate product for topical HIV pre-exposure prophylaxis. Methods Escherichia coli inhibitory activity was quantified by colony reduction assay. Endocervical concentrations of interleukin (IL)-1β, IL-6, IL-12p40, macrophage inflammatory protein (MIP)-1α, granulocyte– macrophage colony-stimulating factor (GM-CSF), lactoferrin, and secretory leukocyte protease inhibitor (SLPI) were quantified to generate a cumulative mediator score. Vaginal bacteria were characterized by quantitative cultures. Results In the two placebo arms, higher soluble immune mediator score was associated with greater E. coli inhibitory activity (β = 17.49, 95% CI [12.77, 22.21] and β = 13.28, 95% CI [4.76, 21.80]). However, in the VivaGel arm, higher concentrations of E. coli (β = −3.80, 95% CI [−6.36, −1.25]) and group B Streptococcus (β = −3.91, 95% CI [−6.21, −1.60]) were associated with reduced E. coli inhibitory activity. Conclusions Both host mediators and vaginal bacteria impact E. coli inhibition in genital secretions. The relative contributions of host mediators and bacteria varied between women who used VivaGel vs placebos. PMID:26118476

  10. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals.

    PubMed

    Vázquez-Castellanos, J F; Serrano-Villar, S; Latorre, A; Artacho, A; Ferrús, M L; Madrid, N; Vallejo, A; Sainz, T; Martínez-Botas, J; Ferrando-Martínez, S; Vera, M; Dronda, F; Leal, M; Del Romero, J; Moreno, S; Estrada, V; Gosalbes, M J; Moya, A

    2015-07-01

    Altered interplay between gut mucosa and microbiota during treated HIV infection may possibly contribute to increased bacterial translocation and chronic immune activation, both of which are predictors of morbidity and mortality. Although a dysbiotic gut microbiota has recently been reported in HIV+ individuals, the metagenome gene pool associated with HIV infection remains unknown. The aim of this study is to characterize the functional gene content of gut microbiota in HIV+ patients and to define the metabolic pathways of this bacterial community, which is potentially associated with immune dysfunction. We determined systemic markers of innate and adaptive immunity in a cohort of HIV-infected individuals on successful antiretroviral therapy without comorbidities and in healthy non-HIV-infected subjects. Metagenome sequencing revealed an altered functional profile, with enrichment of the genes involved in various pathogenic processes, lipopolysaccharide biosynthesis, bacterial translocation, and other inflammatory pathways. In contrast, we observed depletion of genes involved in amino acid metabolism and energy processes. Bayesian networks showed significant interactions between the bacterial community, their altered metabolic pathways, and systemic markers of immune dysfunction. This study reveals altered metabolic activity of microbiota and provides novel insight into the potential host-microbiota interactions driving the sustained inflammatory state in successfully treated HIV-infected patients. PMID:25407519

  11. Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors.

    PubMed

    Schölch, Sebastian; Rauber, Conrad; Tietz, Alexandra; Rahbari, Nuh N; Bork, Ulrich; Schmidt, Thomas; Kahlert, Christoph; Haberkorn, Uwe; Tomai, Mark A; Lipson, Kenneth E; Carretero, Rafael; Weitz, Jürgen; Koch, Moritz; Huber, Peter E

    2015-03-10

    In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy. PMID:25609199

  12. Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors

    PubMed Central

    Tietz, Alexandra; Rahbari, Nuh N.; Bork, Ulrich; Schmidt, Thomas; Kahlert, Christoph; Haberkorn, Uwe; Tomai, Mark A.; Lipson, Kenneth E.; Carretero, Rafael; Weitz, Jürgen; Koch, Moritz; Huber, Peter E.

    2015-01-01

    In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy. PMID:25609199

  13. Comparative Analysis of Immune Cells Activation and Cytotoxicity upon Exposure Pathogen and Glycoconjugates

    NASA Astrophysics Data System (ADS)

    Saheb, Entsar; Tarasenko, Olga

    2010-04-01

    Peripheral mononuclear cells (PMNC) including macrophages are key players in the immune responses against pathogens. Any infection could be attenuated if PMNC would be activated and capable to kill pathogen on exposure. It was shown that glycoconjugates (GCs) play an important role in adhesion to, activation, and recognition of pathogens. Nitric oxide (NO) is a regulatory molecule released by immune cells against pathogens that include bacteria, protozoa, helminthes, and fungi. NO is a highly reactive and diffusible molecule that controls replication or intracellular killing of pathogens during infection and immune responses against infections caused by pathogens. Avirulent Bacillus anthracis Sterne spores were used as a model in our study. The purpose of this study was two-fold: A) to analyze PMNC activation through NO production and B) to determine the cytotoxicity effect based on lactate dehydrogenase (LDH) upon exposure to pathogen exerted by GCs. The latter were used "prior to," "during," and "following" PMNC exposure to pathogen in order to modulate immune responses to spores during phagocytosis. Post-phagocytosis study involved the assessment of NO and LDH release by macrophages upon exposure to spores. Results have shown that untreated PMNC released low levels of NO. However, in the presence of GCs, PMNC were activated and produced high levels of NO under all experimental conditions. In addition, the results showed that GC1, GC3 are capable of increasing PMNC activity as evidenced by higher NO levels under the "prior," "during" and "following" to pathogen exposure conditions. On the other hand, GCs were capable of controlling cytotoxicity and decreased LDH levels during phagocytosis of spores. Our findings suggest that GCs stimulate NO production by activating PMNC and decrease cytotoxicity caused by pathogens on PMNC.

  14. Depressive Symptoms in Crohn's Disease: Relationship with Immune Activation and Tryptophan Availability

    PubMed Central

    Guloksuz, Sinan; Wichers, Marieke; Kenis, Gunter; Russel, Maurice G. V. M.; Wauters, Annick; Verkerk, Robert; Arts, Baer; van Os, Jim

    2013-01-01

    Crohn's disease (CD) is associated with immune activation and depressive symptoms. This study determines the impact of anti-tumor necrosis factor (TNF)-α treatment in CD patients on depressive symptoms and the degree to which tryptophan (TRP) availability and immune markers mediate this effect. Fifteen patients with CD, eligible for anti-TNF-α treatment were recruited. Disease activity (Harvey-Bradshaw Index (HBI), Crohn's Disease Activity Index (CDAI)), fatigue (Multidimensional Fatigue Inventory (MFI)), quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ)), symptoms of depression and anxiety (Symptom Checklist (SCL-90), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS)), immune activation (acute phase proteins (APP)), zinc and TRP availability were assessed before treatment and after 2, 4 and 8 weeks. Anti-TNF-α increased IBDQ scores and reduced all depression scores; however only SCL-90 depression scores remained decreased after correction for HBI. Positive APPs decreased, while negative APPs increased after treatment. After correction for HBI, both level and percentage of γ fraction were associated with SCL-90 depression scores over time. After correction for HBI, patients with current/past depressive disorder displayed higher levels of positive APPs and lower levels of negative APPs and zinc. TRP availability remained invariant over time and there was no association between SCL-90 depression scores and TRP availability. Inflammatory reactions in CD are more evident in patients with comorbid depression, regardless of disease activity. Anti-TNF-α treatment in CD reduces depressive symptoms, in part independently of disease activity; there was no evidence that this effect was mediated by immune-induced changes in TRP availability. PMID:23544139