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Sample records for experimentally-induced immune activation

  1. Experimentally-induced immune activation in natural hosts of SIV induces significant increases in viral replication and CD4+ T cell depletion

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    Ribeiro, Ruy M [Los Alamos National Laboratory

    2008-01-01

    Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable non-pathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and stable viral loads (VLs) for long periods of time. In vivo administration of lipopolysaccharide (LPS) or an IL-2/diphtheria toxin fusion protein (Ontak) to chronically SIVagm-infected AGMs triggered increases in immune activation and subsequently of viral replication and depletion of intestinal CD4{sup +} T cells. Our study indicates that circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell prolifeation are key factors in AIDS pathogenesis.

  2. Immune Cells and Molecular Networks in Experimentally Induced Pulpitis.

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    Renard, E; Gaudin, A; Bienvenu, G; Amiaud, J; Farges, J C; Cuturi, M C; Moreau, A; Alliot-Licht, B

    2016-02-01

    Dental pulp is a dynamic tissue able to resist external irritation during tooth decay by using immunocompetent cells involved in innate and adaptive responses. To better understand the immune response of pulp toward gram-negative bacteria, we analyzed biological mediators and immunocompetent cells in rat incisor pulp experimentally inflamed by either lipopolysaccharide (LPS) or saline solution (phosphate-buffered saline [PBS]). Untreated teeth were used as control. Expression of pro- and anti-inflammatory cytokines, chemokine ligands, growth factors, and enzymes were evaluated at the transcript level, and the recruitment of the different leukocytes in pulp was measured by fluorescence-activated cell-sorting analysis after 3 h, 9 h, and 3 d post-PBS or post-LPS treatment. After 3 d, injured rat incisors showed pulp wound healing and production of reparative dentin in both LPS and PBS conditions, testifying to the reversible pulpitis status of this model. IL6, IL1-β, TNF-α, CCL2, CXCL1, CXCL2, MMP9, and iNOS gene expression were significantly upregulated after 3 h of LPS stimulation as compared with PBS. The immunoregulatory cytokine IL10 was also upregulated after 3 h, suggesting that LPS stimulates not only inflammation but also immunoregulation. Fluorescence-activated cell-sorting analysis revealed a significant, rapid, and transient increase in leukocyte levels 9 h after PBS and LPS stimulation. The quantity of dendritic cells was significantly upregulated with LPS versus PBS. Interestingly, we identified a myeloid-derived suppressor cell-enriched cell population in noninjured rodent incisor dental pulp. The percentage of this population, known to regulate immune response, was higher 9 h after inflammation triggered with PBS and LPS as compared with the control. Taken together, these data offer a better understanding of the mechanisms involved in the regulation of dental pulp immunity that may be elicited by gram-negative bacteria. © International & American

  3. Experimentally Induced Stress Validated by EMG Activity

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    Luijcks, Rosan; Hermens, Hermie J.; Bodar, Lonneke; Vossen, Catherine J.; Os, Jim van.; Lousberg, Richel

    2014-01-01

    Experience of stress may lead to increased electromyography (EMG) activity in specific muscles compared to a non-stressful situation. The main aim of this study was to develop and validate a stress-EMG paradigm in which a single uncontrollable and unpredictable nociceptive stimulus was presented. EMG activity of the trapezius muscles was the response of interest. In addition to linear time effects, non-linear EMG time courses were also examined. Taking into account the hierarchical structure of the dataset, a multilevel random regression model was applied. The stress paradigm, executed in N = 70 subjects, consisted of a 3-minute baseline measurement, a 3-minute pre-stimulus stress period and a 2-minute post-stimulus phase. Subjects were unaware of the precise moment of stimulus delivery and its intensity level. EMG activity during the entire experiment was conform a priori expectations: the pre-stimulus phase showed a significantly higher mean EMG activity level compared to the other two phases, and an immediate EMG response to the stimulus was demonstrated. In addition, the analyses revealed significant non-linear EMG time courses in all three phases. Linear and quadratic EMG time courses were significantly modified by subjective anticipatory stress level, measured just before the start of the stress task. Linking subjective anticipatory stress to EMG stress reactivity revealed that subjects with a high anticipatory stress level responded with more EMG activity during the pre-stimulus stress phase, whereas subjects with a low stress level showed an inverse effect. Results suggest that the stress paradigm presented here is a valid test to quantify individual differences in stress susceptibility. Further studies with this paradigm are required to demonstrate its potential use in mechanistic clinical studies. PMID:24736740

  4. Experimentally induced stress validated by EMG activity.

    Science.gov (United States)

    Luijcks, Rosan; Hermens, Hermie J; Bodar, Lonneke; Vossen, Catherine J; Van Os, Jim; Lousberg, Richel

    2014-01-01

    Experience of stress may lead to increased electromyography (EMG) activity in specific muscles compared to a non-stressful situation. The main aim of this study was to develop and validate a stress-EMG paradigm in which a single uncontrollable and unpredictable nociceptive stimulus was presented. EMG activity of the trapezius muscles was the response of interest. In addition to linear time effects, non-linear EMG time courses were also examined. Taking into account the hierarchical structure of the dataset, a multilevel random regression model was applied. The stress paradigm, executed in N = 70 subjects, consisted of a 3-minute baseline measurement, a 3-minute pre-stimulus stress period and a 2-minute post-stimulus phase. Subjects were unaware of the precise moment of stimulus delivery and its intensity level. EMG activity during the entire experiment was conform a priori expectations: the pre-stimulus phase showed a significantly higher mean EMG activity level compared to the other two phases, and an immediate EMG response to the stimulus was demonstrated. In addition, the analyses revealed significant non-linear EMG time courses in all three phases. Linear and quadratic EMG time courses were significantly modified by subjective anticipatory stress level, measured just before the start of the stress task. Linking subjective anticipatory stress to EMG stress reactivity revealed that subjects with a high anticipatory stress level responded with more EMG activity during the pre-stimulus stress phase, whereas subjects with a low stress level showed an inverse effect. Results suggest that the stress paradigm presented here is a valid test to quantify individual differences in stress susceptibility. Further studies with this paradigm are required to demonstrate its potential use in mechanistic clinical studies.

  5. Experimentally induced stress validated by EMG activity.

    Directory of Open Access Journals (Sweden)

    Rosan Luijcks

    Full Text Available Experience of stress may lead to increased electromyography (EMG activity in specific muscles compared to a non-stressful situation. The main aim of this study was to develop and validate a stress-EMG paradigm in which a single uncontrollable and unpredictable nociceptive stimulus was presented. EMG activity of the trapezius muscles was the response of interest. In addition to linear time effects, non-linear EMG time courses were also examined. Taking into account the hierarchical structure of the dataset, a multilevel random regression model was applied. The stress paradigm, executed in N = 70 subjects, consisted of a 3-minute baseline measurement, a 3-minute pre-stimulus stress period and a 2-minute post-stimulus phase. Subjects were unaware of the precise moment of stimulus delivery and its intensity level. EMG activity during the entire experiment was conform a priori expectations: the pre-stimulus phase showed a significantly higher mean EMG activity level compared to the other two phases, and an immediate EMG response to the stimulus was demonstrated. In addition, the analyses revealed significant non-linear EMG time courses in all three phases. Linear and quadratic EMG time courses were significantly modified by subjective anticipatory stress level, measured just before the start of the stress task. Linking subjective anticipatory stress to EMG stress reactivity revealed that subjects with a high anticipatory stress level responded with more EMG activity during the pre-stimulus stress phase, whereas subjects with a low stress level showed an inverse effect. Results suggest that the stress paradigm presented here is a valid test to quantify individual differences in stress susceptibility. Further studies with this paradigm are required to demonstrate its potential use in mechanistic clinical studies.

  6. The influence of experimentally induced pain on shoulder muscle activity.

    Science.gov (United States)

    Diederichsen, Louise Pyndt; Winther, Annika; Dyhre-Poulsen, Poul; Krogsgaard, Michael R; Nørregaard, Jesper

    2009-04-01

    Muscle function is altered in painful shoulder conditions. However, the influence of shoulder pain on muscle coordination of the shoulder has not been fully clarified. The aim of the present study was to examine the effect of experimentally induced shoulder pain on shoulder muscle function. Eleven healthy men (range 22-27 years), with no history of shoulder or cervical problems, were included in the study. Pain was induced by 5% hypertonic saline injections into the supraspinatus muscle or subacromially. Seated in a shoulder machine, subjects performed standardized concentric abduction (0 degrees -105 degrees) at a speed of approximately 120 degrees/s, controlled by a metronome. During abduction, electromyographic (EMG) activity was recorded by intramuscular wire electrodes inserted in two deeply located shoulder muscles and by surface-electrodes over six superficially located shoulder muscles. EMG was recorded before pain, during pain and after pain had subsided and pain intensity was continuously scored on a visual analog scale (VAS). During abduction, experimentally induced pain in the supraspinatus muscle caused a significant decrease in activity of the anterior deltoid, upper trapezius and the infraspinatus and an increase in activity of lower trapezius and latissimus dorsi muscles. Following subacromial injection a significantly increased muscle activity was seen in the lower trapezius, the serratus anterior and the latissimus dorsi muscles. In conclusion, this study shows that acute pain both subacromially and in the supraspinatus muscle modulates coordination of the shoulder muscles during voluntary movements. During painful conditions, an increased activity was detected in the antagonist (latissimus), which support the idea that localized pain affects muscle activation in a way that protects the painful structure. Further, the changes in muscle activity following subacromial pain induction tend to expand the subacromial space and thereby decrease the load

  7. Creatine kinase activity in dogs with experimentally induced acute inflammation

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    Dimitrinka Zapryanova

    2013-01-01

    Full Text Available The main purpose of this study was to investigate the effect of acute inflammation on total creatine kinase (CK activity in dogs. In these animals, CK is an enzyme found predominantly in skeletal muscle and significantly elevated serum activity is largely associated with muscle damage. Plasma increases in dogs are associated with cell membrane leakage and will therefore be seen in any condition associated with muscular inflammation. The study was induced in 15 mongrel male dogs (n=9 in experimental group and n=6 in control group at the age of two years and body weight 12-15 kg. The inflammation was reproduced by inoculation of 2 ml turpentine oil subcutaneously in lumbar region. The plasma activity of creatine kinase was evaluated at 0, 6, 24, 48, 72 hours after inoculation and on days 7, 14 and 21 by a kit from Hospitex Diagnostics. In the experimental group, the plasma concentrations of the CK-activity were increased at the 48th hour (97.48±6.92 U/L and remained significantly higher (p<0.05 at the 72 hour (97.43±2.93 U/L compared to the control group (77.08±5.27 U/L. The results of this study suggest that the evaluation of creatine kinase in dogs with experimentally induced acute inflammation has a limited diagnostic value. It was observed that the creatine kinase activity is slightly affected by the experimentally induced acute inflammation in dogs.

  8. The influence of experimentally induced pain on shoulder muscle activity

    DEFF Research Database (Denmark)

    Diederichsen, Louise Pyndt; Winther, Annika; Dyhre-Poulsen, Poul

    2009-01-01

    Muscle function is altered in painful shoulder conditions. However, the influence of shoulder pain on muscle coordination of the shoulder has not been fully clarified. The aim of the present study was to examine the effect of experimentally induced shoulder pain on shoulder muscle function. Eleven...... healthy men (range 22-27 years), with no history of shoulder or cervical problems, were included in the study. Pain was induced by 5% hypertonic saline injections into the supraspinatus muscle or subacromially. Seated in a shoulder machine, subjects performed standardized concentric abduction (0 degrees...... -105 degrees) at a speed of approximately 120 degrees/s, controlled by a metronome. During abduction, electromyographic (EMG) activity was recorded by intramuscular wire electrodes inserted in two deeply located shoulder muscles and by surface-electrodes over six superficially located shoulder muscles...

  9. The influence of experimentally induced pain on shoulder muscle activity

    DEFF Research Database (Denmark)

    Diederichsen, L.P.; Winther, A.; Dyhre-Poulsen, P.

    2009-01-01

    Muscle function is altered in painful shoulder conditions. However, the influence of shoulder pain on muscle coordination of the shoulder has not been fully clarified. The aim of the present study was to examine the effect of experimentally induced shoulder pain on shoulder muscle function. Eleven...... healthy men (range 22-27 years), with no history of shoulder or cervical problems, were included in the study. Pain was induced by 5% hypertonic saline injections into the supraspinatus muscle or subacromially. Seated in a shoulder machine, subjects performed standardized concentric abduction (0A degrees......-105A degrees) at a speed of approximately 120A degrees/s, controlled by a metronome. During abduction, electromyographic (EMG) activity was recorded by intramuscular wire electrodes inserted in two deeply located shoulder muscles and by surface-electrodes over six superficially located shoulder...

  10. Antistressor activity of Ocimum sanctum (Tulsi) against experimentally induced oxidative stress in rabbits.

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    Jyoti, S; Satendra, S; Sushma, S; Anjana, T; Shashi, S

    2007-01-01

    Fresh leaves of Ocimum sanctum (O. sanctum) were evaluated for antistress activity against experimentally induced oxidative stress in albino rabbits. Animals of the test group received supplementation of 2 g fresh leaves of O. sanctum per rabbit for 30 days. Anemic hypoxia was induced chemically by injecting the rabbits with 15 mg sodium nitrite per 100 g body weight intraperitoneally. Results indicated that O. sanctum administration blunted the changes in cardiorespiratory (BP, HR, RR) parameters in response to stress. A significant (p sanctum leaves. Significant increase (p sanctum. Oxidative stress led to a lesser depletion of reduced glutathione (28.80%) and plasma superoxide dismutase (23.04%) in O. sanctum-treated rabbits. The results of this study suggest that the potential antistressor activity of O. sanctum is partly attributable to its antioxidant properties.

  11. Experimentally induced masseter-pain changes masseter but not sternocleidomastoid muscle-related activity during mastication.

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    Pasinato, Fernanda; Santos-Couto-Paz, Clarissa C; Zeredo, Jorge Luis Lopes; Macedo, Sergio Bruzadelli; Corrêa, Eliane C R

    2016-12-01

    The aim of this study was to verify the effects of induced masseter-muscle pain on the amplitude of muscle activation, symmetry and coactivation of jaw- and neck-muscles during mastication. Twenty-eight male volunteers, mean age±SD 20.6±2.0years, participated in this study. Surface electromyography of the masseter and sternocleidomastoid (SCM) muscles was performed bilaterally during mastication of a gummy candy before and after injections of monosodium glutamate solution and isotonic saline solution. As a result, we observed a decrease in the amplitude of activation of the masseter muscle on the working side (p=0.009; d=0.34) and a reduction in the asymmetry between the working and the balancing side during mastication (p=0.007; d=0.38). No changes were observed either on the craniocervical electromyographic variables. In conclusion, experimentally induced pain reduced the masseter muscle activation on the working side, thereby reducing the physiological masseters' recruitment asymmetry between the two sides during mastication. No effects on SCM activity were detected. These results may partly explain the initial maladaptative changes underlying TMD conditions. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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    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. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

  13. Effects of experimentally induced pain and fear of pain on trunk coordination and back muscle activity during walking.

    NARCIS (Netherlands)

    Lamoth, C.J.C.; Daffertshofer, A.; Meijer, O.G.; Moseley, G.; Wuisman, P.I.J.M.; Beek, P.J.

    2004-01-01

    OBJECTIVE: To examine the effects of experimentally induced pain and fear of pain on trunk coordination and erector spinae EMG activity during gait. DESIGN: In 12 healthy subjects, hypertonic saline (acute pain) and isotonic saline (fear of pain) were injected into erector spinae muscle, and

  14. Costs and benefits of experimentally induced changes in the allocation of growth versus immune function under differential exposure to ectoparasites.

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    Natalia Pitala

    Full Text Available BACKGROUND: Ecological immunology has focused on the costs of investment in immunocompetence. However, understanding optimal resource allocation to immune defence requires also identification of its benefits, which are likely to occur only when parasites are abundant. METHODOLOGY: We manipulated the abundance of parasitic hen fleas in blue tit (Cyanistes caeruleus nests, and supplemented their hosts, the nestlings, with methionine (a sulphur amino acid enhancing cell-mediated immunity during day 3-6. We found a significant interaction between these two experimental factors on the development of immune defences and growth rates. Only in parasitized nests did methionine supplementation boost immune (PHA response, and did nestling with experimentally increased immunocompetence show a relatively faster growth rate than control nestlings between days 6-9. Hence, the allocation of resources into immune defence and its growth-benefits are apparent only in presence of parasites. The main cost of methionine-induced increased allocation to the immune system was an increase in mortality, independently of ectoparasites. Nestlings in all treatments compensated initial growth reduction and all reached equal body size at day 16 (just prior to fledging, indicating a lack of long-term benefits. In addition, methionine treatment tended (P = 0.09 to lower circulating plasma immunoglobulin levels, possibly indicating a trade-off between the cell-mediated and humoral components of the immune system. CONCLUSIONS: We found no strong benefits of an increased investment in immunocompetence in a parasite-rich environment. Any deviation from the growth trajectory (due to changes in allocation induced by methionine is largely detrimental for survival. Hence, while costs are apparent identifying the benefits of investment in immunocompetence during ontogeny is challenging.

  15. Costs and benefits of experimentally induced changes in the allocation of growth versus immune function under differential exposure to ectoparasites.

    Science.gov (United States)

    Pitala, Natalia; Siitari, Heli; Gustafsson, Lars; Brommer, Jon E

    2010-05-25

    Ecological immunology has focused on the costs of investment in immunocompetence. However, understanding optimal resource allocation to immune defence requires also identification of its benefits, which are likely to occur only when parasites are abundant. We manipulated the abundance of parasitic hen fleas in blue tit (Cyanistes caeruleus) nests, and supplemented their hosts, the nestlings, with methionine (a sulphur amino acid enhancing cell-mediated immunity) during day 3-6. We found a significant interaction between these two experimental factors on the development of immune defences and growth rates. Only in parasitized nests did methionine supplementation boost immune (PHA) response, and did nestling with experimentally increased immunocompetence show a relatively faster growth rate than control nestlings between days 6-9. Hence, the allocation of resources into immune defence and its growth-benefits are apparent only in presence of parasites. The main cost of methionine-induced increased allocation to the immune system was an increase in mortality, independently of ectoparasites. Nestlings in all treatments compensated initial growth reduction and all reached equal body size at day 16 (just prior to fledging), indicating a lack of long-term benefits. In addition, methionine treatment tended (P = 0.09) to lower circulating plasma immunoglobulin levels, possibly indicating a trade-off between the cell-mediated and humoral components of the immune system. We found no strong benefits of an increased investment in immunocompetence in a parasite-rich environment. Any deviation from the growth trajectory (due to changes in allocation induced by methionine) is largely detrimental for survival. Hence, while costs are apparent identifying the benefits of investment in immunocompetence during ontogeny is challenging.

  16. Immune suppression and immune activation in depression.

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

    2011-02-01

    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, and 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 pre-clinical 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

  17. Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses.

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    Helena Shifrin

    Full Text Available The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM, rivastigmine (1 µM significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg but not (0.5 mg/kg, injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS, reduced the disease activity index (DAI by 60% and damage to colon structure. Rivastigmine (1 mg/kg also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages

  18. Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses.

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    Shifrin, Helena; Nadler-Milbauer, Mirela; Shoham, Shai; Weinstock, Marta

    2013-01-01

    The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in

  19. Wound healing activity of Carica papaya L. in experimentally induced diabetic rats.

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    Nayak, Shivananda B; Pinto Pereira, Lexley; Maharaj, Dale

    2007-08-01

    The aqueous extract of C. papaya fruit (100 mg kg(-1) day(-1) for 10 days) was evaluated for its wound healing activity in streptozotocin-induced diabetic rats using excision and dead space wound models. Extract-treated animals exhibited 77% reduction in the wound area when compared to controls which was 59%. The extract treated wounds were found to epithelize faster as compared to controls. The wet and dry granulation tissue weight and hydroxyproline content increased significantly when compared to controls. The extract exhibited antimicrobial activity against the five organisms tested. Carica papaya promotes significant wound healing in diabetic rats and further evaluation of this activity in humans is suggested.

  20. Antidiarrheal activity of Pterocarpus erinaceus methanol leaf extract in experimentally-induced diarrhea.

    Science.gov (United States)

    Ezeja, I Maxwell; Ezeigbo, Ihechiluru I; Madubuike, Kelechi G; Udeh, Nkiru E; Ukweni, Iheanacho A; Akomas, Stella C; Ifenkwe, Daniel C

    2012-02-01

    To investigate the antidiarrheal activity of the methanol leaf extract of Pterocarpus erinaceus in vivo. The methanol leaf extract of Pterocarpus erinaceus was evaluated using different doses (100, 200 and 400 mg/kg body weight) orally for antidiarrheal activity using castor oil-induced diarrhea, charcoal meal transit time and castor oil-induced enteropooling in different groups of albino Wistar mice. The activity of the extract at different doses were compared to diphenoxylate (5 mg/kg) and atropine sulphate (3 mg/kg) which were used as standard reference drugs and also to the distilled water administered negative control group of mice. The extract at the doses used caused a significant (PPterocarpus erinaceus extract produced significant antidiarrheal activity and the action may attribute to inhibition of gastrointestinal movement and fluid secretion. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  1. Antiangiogenic activity of vitexicarpine in experimentally induced hepatocellular carcinoma: Impact on vascular endothelial growth factor pathway.

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    Hassoun, Shimaa M; Abdel-Rahman, Noha; Eladl, Entsar I; El-Shishtawy, Mamdouh M

    2017-06-01

    Angiogenesis plays important roles in progression of hepatocellular carcinoma. The antiangiogenic mechanisms of vitexicarpine are not fully defined. Therefore, we conducted the following study to evaluate the antiangiogenic mechanism and antitumor activity of vitexicarpine in vivo model of hepatocellular carcinoma through modulation of vascular endothelial growth factor signaling pathway. Hepatocellular carcinoma was induced in Sprague Dawley rats by thioacetamide. Hepatocellular carcinoma was assessed by measuring serum alpha-fetoprotein and investigating liver sections stained with hematoxylin/eosin. Hepatocellular carcinoma rats were injected with vitexicarpine (150 mg/kg) for 2 weeks. Hepatic vascular endothelial growth factor was measured by enzyme-linked immunosorbent assay. Protein and expression of hepatic phospho-Ser473-AKT (p-AKT) and phospho-Tyr419-Src (p-Src) were determined. The apoptotic pathway was evaluated by assessment of protein expression of caspase-3. Vitexicarpine increased rats' survival time and decreased serum alpha-fetoprotein as well as it ameliorated fibrosis and massive hepatic tissue breakdown. It attenuated hepatocellular carcinoma-induced protein and gene expression of vascular endothelial growth factor, p-AKT, p-Src, and caspase-3. In conclusion, this study suggests that vitexicarpine possesses both antiangiogenic and antitumor activities through inhibition of vascular endothelial growth factor, p-AKT/AKT, and p-Src with subsequent inhibition of apoptotic pathway.

  2. vaccination using profilin and NetB proteins in Montanide IMS adjuvant increases protective immunity against experimentally-induced necrotic enteritis

    Directory of Open Access Journals (Sweden)

    Hyun Soon Lillehoj

    2017-10-01

    Full Text Available Objective The effects of vaccinating 18-day-old chicken embryos with the combination of recombinant Eimeria profilin plus Clostridium perfringens (C. perfringens NetB proteins mixed in the Montanide IMS adjuvant on the chicken immune response to necrotic enteritis (NE were investigated using an Eimeria maxima (E. maxima/C. perfringens co-infection NE disease model that we previously developed. Methods Eighteen-day-old broiler embryos were injected with 100 μL of phosphate-buffered saline, profilin, profilin plus necrotic enteritis B-like (NetB, profilin plus NetB/Montanide adjuvant (IMS 106, and profilin plus Net-B/Montanide adjuvant (IMS 101. After post-hatch birds were challenged with our NE experimental disease model, body weights, intestinal lesions, serum antibody levels to NetB, and proinflammatory cytokine and chemokine mRNA levels in intestinal intraepithelial lymphocytes were measured. Results Chickens in ovo vaccinated with recombinant profilin plus NetB proteins/IMS106 and recombinant profilin plus NetB proteins/IMS101 showed significantly increased body weight gains and reduced gut damages compared with the profilin-only group, respectively. Greater antibody response to NetB toxin were observed in the profilin plus NetB/IMS 106, and profilin plus NetB/IMS 101 groups compared with the other three vaccine/adjuvant groups. Finally, diminished levels of transcripts encoding for proinflammatory cytokines such as lipopolysaccharide-induced tumor necrosis factor-α factor, tumor necrosis factor superfamily 15, and interleukin-8 were observed in the intestinal lymphocytes of chickens in ovo injected with profilin plus NetB toxin in combination with IMS 106, and profilin plus NetB toxin in combination with IMS 101 compared with profilin protein alone bird. Conclusion These results suggest that the Montanide IMS adjuvants potentiate host immunity to experimentally-induced avian NE when administered in ovo in conjunction with the profilin and

  3. Immunizations: Active vs. Passive

    Science.gov (United States)

    ... immunizations for hepatitis A (gamma globulin) may be helpful for people traveling to a part of the world where hepatitis A is common. They are typically given before children or adults leave on their trip. These are used less now that there is a vaccine for hepatitis A. If there is enough time, ...

  4. Changes in the zonation of lactate dehydrogenase activity in lobules of rat liver after experimentally induced colon carcinoma metastases

    NARCIS (Netherlands)

    Griffini, P.; Freitas, I.; Vigorelli, E.; van Noorden, C. J.

    1994-01-01

    Visualization of lactate dehydrogenase (LDH) activity with Neotetrazolium as final electron acceptor under anaerobic conditions and an incubation medium containing polyvinyl alcohol showed that under normal physiological conditions a zonal distribution of LDH activity is present in the liver lobule

  5. A pharmacological evaluation of antidiarrhoeal activity of leaves extract of Murraya koenigii in experimentally induced diarrhoea in rats

    Directory of Open Access Journals (Sweden)

    Praveen Sharma

    2012-06-01

    Full Text Available Objective: To evaluate anti-diarrhoeal activity of aqueous and alcoholic extract of the leaves of Murraya koenigii (M. koenigiiby using models of castor oil induced diarrhoea, charcoal meal test and PGE 2 induced diarrhoea. Methods: Alcoholic extract (400 mg/kg and aqueous extract (200 mg/kg of leaves of Murraya koenigii were used with loperamide as standard. Albino Wistar rats of both sexes weighing between 150-250 g were used for the anti-diarrhoeal activity. Results: The result suggested that it could act centrally and inhibit the PGE2 to give anti-diarrhoeal effects. Result of charcoal meal test also suggested its anti-muscarnic activity. Conclusions: These findings indicate that aqueous extract of the leaves of M. koenigii displays good antidiarrhoeal activity, corroborating the folk use of M. koenigii preparations and contributing for its pharmacological validation.

  6. Effects of Pistacia atlantica (subsp. Mutica oil extracts on antioxidant activities during experimentally induced cutaneous wound healing in rats

    Directory of Open Access Journals (Sweden)

    Ahmad Reza Hamidi

    2015-01-01

    Full Text Available The fruits of Pistacia atlantica (subsp. mutica have been used traditionally for the treatment of peptic ulcer, as a mouth freshener and have recently been introduced as a source of antioxidant vegetable oils. The aim of this study was to investigate the antioxidant activity of the gel forms, from P. atlantica (subsp. mutica oil extraction on enzymatic antioxidants in experimental wound created in rat. A square-shaped skin defect (2×2 cm was created aseptically by surgical excision at the first thoracic vertebrae. Then animals were randomly allocated in four groups (I, untreated controls; II, topically treated base gel; III, topically treated 5% gel; IV, topically treated 10% gel. Blood sampling was accomplished at 3, 7, 10, 14 and 21 days post-injury. Samples were collected for measuring antioxidant enzymes activities (superoxide dismutase, catalase and glutathione peroxidase activity in red cells and lipid peroxidation (plasma malondialdehyde. The data analysis generally evidenced that the activities of the main antioxidant enzymes began to decrease significantly at 7 days after the wound was created in control and base gel groups. This remarkable decline became more evident in the period between 10 to 21 days post injury but increased progressively in P. atlantica (subsp. mutica treatment groups, especially in gel 10% treatment group during wound healing. The results of this study suggest that excision of the wound leads to oxidative stress and topical administration of P. atlantica (subsp. mutica gels causes remarkable changes in antioxidant parameter during wound closure (especially gel 10% via pro-oxidative, and antioxidant activity can improve oxidative stress.

  7. Resveratrol protects against experimental induced Reye's syndrome by prohibition of oxidative stress and restoration of complex I activity.

    Science.gov (United States)

    Abdin, Amany; Sarhan, Naglaa

    2014-09-01

    This study was designed to investigate whether resveratrol could provide protection against Reye's syndrome induced by 4-pentenoic acid in Wistar albino rats. Compared with rats with untreated Reye's syndrome, 1 h pretreatment by low dose resveratrol (10 mg/kg by oral gavage) resulted in marked amelioration in liver functions in the form of significant decrease in serum transaminases (AST, ALT) and plasma ammonia levels, shortening of prothrombin time, and increase in serum albumin levels. In addition, resveratrol prohibited oxidative stress markers, as indicated by a significant increase in GSH and decrease in MDA, with restoration of complex I activity in liver tissues. The classical histopathological presentation in Reye's syndrome of microvesicular steatosis by light microscope and mitochondria distortion by electron microscope has been improved by resveratrol pretreatment. The efficient protection by resveratrol was determined by normalization in serum levels of AST and albumin, as well as complex I activity, GSH, and MDA. In conclusion, pretreatment by resveratrol in low doses could protect against Reye's syndrome partially via prohibition of oxidative stress and restoration of complex I activity. This may provide the opportunity to reconsider aspirin therapy for infants and young children. However, the verification of such results in clinical practice remains a challenge.

  8. Cardiac allograft immune activation: current perspectives

    Directory of Open Access Journals (Sweden)

    Chang D

    2014-12-01

    Full Text Available David Chang, Jon Kobashigawa Cedars-Sinai Heart Institute, Los Angeles, CA, USA Abstract: Heart transplant remains the most durable option for end-stage heart disease. Cardiac allograft immune activation and heart transplant rejection remain among the main complications limiting graft and recipient survival. Mediators of the immune system can cause different forms of rejection post-heart transplant. Types of heart transplant rejection include hyperacute rejection, cellular rejection, antibody-mediated rejection, and chronic rejection. In this review, we will summarize the innate and adaptive immune responses which influence the post-heart transplant recipient. Different forms of rejection and their clinical presentation, detection, and immune monitoring will be discussed. Treatment of heart transplant rejection will be examined. We will discuss potential treatment strategies for preventing rejection post-transplant in immunologically high-risk patients with antibody sensitization. Keywords: heart transplant, innate immunity, adaptive immunity, rejection, immunosuppression

  9. Experiences from polio supplementary immunization activities in ...

    African Journals Online (AJOL)

    2014-05-31

    May 31, 2014 ... borders with other States where polio cases were previously reported.[10] The high level of commercial activities in the. State attracts people from within and outside Nigeria. The risk of importation of poliovirus from unimmunized or partially immunized children of travelers and migrants is a public health ...

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

    National Research Council Canada - National Science Library

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

    2015-01-01

    ... 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...

  11. Innate Pathways of Immune Activation in Transplantation

    OpenAIRE

    Brennan, Todd V.; Lunsford, Keri E.; Kuo, Paul C.

    2010-01-01

    Studies of the immune mechanisms of allograft rejection have predominantly focused on the adaptive immune system that includes T cells and B cells. Recent investigations into the innate immune system, which recognizes foreign antigens through more evolutionarily primitive pathways, have demonstrated a critical role of the innate immune system in the regulation of the adaptive immune system. Innate immunity has been extensively studied in its role as the host's first-line defense against micro...

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

    Science.gov (United States)

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

    2012-06-06

    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. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Ultrasound v. sham ultrasound for experimentally induced delayed ...

    African Journals Online (AJOL)

    In a double-blind controlled trial, delayed-onset muscle soreness (DOMS) was experimentally induced in both bicep muscles of 15 females. Sham US was applied to one bicep (n=15 biceps) and pulsed active US to the other bicep (n=15 biceps) of each participant, 48 and 72 h after induction of DOMS. Primary and ...

  14. HIV-1 Reservoir Association with Immune Activation

    Directory of Open Access Journals (Sweden)

    Alejandro Vallejo

    2015-09-01

    Full Text Available In this issue of EBioMedicine, Ruggiero and colleagues describe immune activation biomarkers associated with the size of the HIV reservoir in a carefully designed cross-sectional study. The cohort consists of a homogeneous sample of HIV-1-infected patients with long-term plasma HIV-1 RNA suppression under antiretroviral treatment (ART. It is crucial to explore the potential utility of biomarkers that are easier (less labor intensive, less expensive to measure than integrated HIV DNA load, in order to quickly and accurately quantify cellular reservoirs of HIV.

  15. Suggestions to Reduce Clinical Fibromyalgia Pain and Experimentally Induced Pain Produce Parallel Effects on Perceived Pain but Divergent Functional MRI-Based Brain Activity.

    Science.gov (United States)

    Derbyshire, Stuart W G; Whalley, Matthew G; Seah, Stanley T H; Oakley, David A

    Hypnotic suggestion is an empirically validated form of pain control; however, the underlying mechanism remains unclear. Thirteen fibromyalgia patients received suggestions to alter their clinical pain, and 15 healthy controls received suggestions to alter experimental heat pain. Suggestions were delivered before and after hypnotic induction with blood oxygen level-dependent (BOLD) activity measured concurrently. Across groups, suggestion produced substantial changes in pain report (main effect of suggestion, F2, 312 = 585.8; p pain report in regions previously associated with pain, including thalamus and anterior cingulate cortex. In controls, BOLD response decreased with pain report. All changes were greater after induction. Region-of-interest analysis revealed largely linear patient responses with increasing pain report. Control responses, however, were higher after suggestion to increase or decrease pain from baseline. Based on behavioral report alone, the mechanism of suggestion could be interpreted as largely similar regardless of the induction or type of pain experience. The functional magnetic resonance imaging data, however, demonstrated larger changes in brain activity after induction and a radically different pattern of brain activity for clinical pain compared with experimental pain. These findings imply that induction has an important effect on underlying neural activity mediating the effects of suggestion, and the mechanism of suggestion in patients altering clinical pain differs from that in controls altering experimental pain. Patient responses imply that suggestions altered pain experience via corresponding changes in pain-related brain regions, whereas control responses imply suggestion engaged cognitive control.

  16. Piracetam Facilitates the Anti-Amnesic but not Anti-Diabetic Activity of Metformin in Experimentally Induced Type-2 Diabetic Encephalopathic Rats.

    Science.gov (United States)

    Pandey, Shruti; Garabadu, Debapriya

    2017-07-01

    Piracetam exhibits anti-amnesic activity in several animal models of dementia. However, its anti-amnesic potential has yet to be evaluated in type-2 diabetes mellitus (T2DM)-induced encephalopathy. Therefore, in the present study, piracetam (25, 50 and 100 mg/kg) was screened for anti-amnesic and anti-diabetic activity in T2DM-induced encephalopathic male rats. Subsequently, anti-amnesic and anti-diabetic activities were evaluated for piracetam, metformin and their combination in T2DM-induced encephalopathic animals. Rats received streptozotocin (45 mg/kg) and nicotinamide (110 mg/kg) injections on day-1 (D-1) of the experimental schedule and were kept undisturbed for 35 days to exhibit T2DM-induced encephalopathy. All drug treatments were continued from D-7 to D-35 in both experiments. Piracetam (100 mg/kg) attenuated loss in learning and memory in terms of increase in escape latency on D-4 (D-34) and decrease in time spent in the target quadrant on D-5 (D-35) of Morris water maze test protocol, and spatial memory in terms of reduced spontaneous alternation behavior in Y-maze test of encephalopathic rats. Additionally, piracetam attenuated altered levels of fasting plasma glucose and insulin, HOMA-IR and HOMA-B in encephalopathic animals, comparatively lesser than metformin. In the next experiment, combination of piracetam and metformin exhibited better anti-amnesic but not anti-diabetic activity than respective monotherapies in encephalopathic rats. Further, the combination attenuated reduced acetylcholine level and increased acetylcholinesterase activity, increased glycogen synthase kinase-3β level and decreased brain-derived neurotropic factor level in hippocampus and pre-frontal cortex of encephalopathic animals. Thus, piracetam could be used as an adjuvant to metformin in the management of dementia in T2DM-induced encephalopathy.

  17. Structure-activity relationship of piperine and its synthetic amide analogs for therapeutic potential to prevent experimentally induced ER stress in vitro.

    Science.gov (United States)

    Hammad, Ayat S; Ravindran, Sreenithya; Khalil, Ashraf; Munusamy, Shankar

    2017-05-01

    Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using normal rat kidney (NRK-52E) cells. Five amide-substituted piperine analogs were synthesized and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability, and the expression of ER chaperone GRP78, the pro-apoptotic ER stress marker CHOP, and apoptotic caspases 3 and 12 (via western blotting). Our findings indicate that exposure to tunicamycin (0.5 μg/mL) for 2 h induces the expression of GRP78 and CHOP, and apoptotic markers (caspase-3 and caspase-12) and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP and cell death. Taken together, our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stress-related renal disorders. Graphical Abstract Piperine (PIP) reduces the expression of ER stress markers (GRP78 and CHOP) induced by pathologic stimuli and consequently decreases the activation of apoptotic caspase-12 and caspase-3; all of which contributes to its chemical chaperone and cytoprotective properties to protect

  18. Generalized immune activation and innate immune responses in simian immunodeficiency virus infection.

    Science.gov (United States)

    Bosinger, Steven E; Sodora, Donald L; Silvestri, Guido

    2011-09-01

    Chronic immune activation is a key factor driving the immunopathogenesis of AIDS. During pathogenic HIV/simian immunodeficiency virus (SIV) infections, innate and adaptive antiviral immune responses contribute to chronic immune activation. In contrast, nonpathogenic SIV infections of natural hosts such as sooty mangabeys and African green monkeys (AGMs) are characterized by low immune activation despite similarly high viremia. This review focuses on the role of innate immune responses in SIV infection. Several studies have examined the role of innate immune responses to SIV as potential drivers of immune activation. The key result of these studies is that both pathogenic SIV infection of macaques and nonpathogenic SIV infections of natural hosts are associated with strong innate immune responses to the virus, high production of type I interferons by plasmacytoid dendritic cells, and upregulation of interferon-stimulated genes (ISGs). However, SIV-infected sooty mangabeys and AGMs (but not SIV-infected macaques) rapidly downmodulate the interferon response within 4-6 weeks of infection, thus resulting in a state of limited immune activation during chronic infection. Studies in nonhuman primates suggest that chronic innate/interferon responses may contribute to AIDS pathogenesis. Further, the ability of natural host species to resolve innate immune responses after infection provides a novel avenue for potential immunotherapy.

  19. Dynamics of innate immunity are key to chronic immune activation in AIDS.

    Science.gov (United States)

    Benecke, Arndt; Gale, Michael; Katze, Michael G

    2012-01-01

    We propose here that the dynamics rather than the structure of cellular and viral networks play a determining role in chronic immune activation of HIV-infected individuals. A number of novel avenues of experimental analysis and modeling strategies are discussed to conclusively address these network dynamics in the future. Recent insights into the molecular dynamics of immune activation and its control following simian immunodeficiency virus (SIV) infection in natural host primates has provided possible alternate interpretations of SIV and HIV pathogenesis. Concomitant with insights gained in other host-pathogen systems, as well as an increased understanding of innate immune activation mechanisms, these observations lead to a new model for the timing of innate HIV immune responses and a possible primordial role of this timing in programming chronic immune activation. Chronic immune activation is today considered the leading cause of AIDS in HIV-infected individuals. Systems biology has recently lent arguments for considering chronic immune activation a result of untimely innate immune responses by the host to the infection. Future strategies for the analysis, comprehension, and incorporation of the dynamic component of immune activation into HIV vaccination strategies are discussed.

  20. Activation of the Innate Immune Receptors: Guardians of the Micro Galaxy : Activation and Functions of the Innate Immune Receptors.

    Science.gov (United States)

    De Nardo, Dominic

    2017-01-01

    The families of innate immune receptors are the frontline responders to danger. These superheroes of the host immune systems populate innate immune cells, surveying the extracellular environment and the intracellular endolysosomal compartments and cytosol for exogenous and endogenous danger signals. As a collective the innate immune receptors recognise a wide array of stimuli, and in response they initiate specific signalling pathways leading to activation of transcriptional or proteolytic pathways and the production of inflammatory molecules to destroy foreign pathogens and/or resolve tissue injury. In this review, I will give an overview of the innate immune system and the activation and effector functions of the families of receptors it comprises. Current key concepts will be described throughout, including innate immune memory, formation of innate immune receptor signalosomes, inflammasome formation and pyroptosis, methods of extrinsic cell communication and examples of receptor cooperation. Finally, several open questions and future directions in the field of innate immunity will be presented and discussed.

  1. [Immune polypeptides activity in bee hemolymph].

    Science.gov (United States)

    Sokół, R

    1999-01-01

    The honeybee developed through evolution efficient inborn and acquired immune mechanisms which allow it to function in the enviromment. In the inborn immunity phagocytosis is classified to the oldest defensive mechanisms which relies on catching and destruction of the pathogens by the plastmocytes and granulocytes in the hemolymph and lysozymes - the most important components of the natural humoral immunity. Acquired immunity covers, above all, polypeptides and immune proteins e. g. apidaecin and abbacin. Apidaecins represent one of the most important anti-bacterial elements of acquired immunity. Apidaecins arise from fat bodies appearing soon after bacterial infection, also protect the insect from envirommental pathogens. Abaccin acts mainly on Gram positive bacteria. Its characteristic quality is delayed action in camparision to apidaecins, synergy with bee hemolymph anti-bacterial factors as well as assistance in anti-bacterial defense.

  2. Innate Immune Activation in Intestinal Homeostasis

    OpenAIRE

    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 prot...

  3. Experimentally induced Porcine Coccidiosis | Onawunmi | Nigerian ...

    African Journals Online (AJOL)

    Journal Home > Vol 4, No 2 (1977) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. DOWNLOAD FULL TEXT Open Access DOWNLOAD FULL TEXT Subscription or Fee Access. Experimentally induced Porcine Coccidiosis. OA Onawunmi. Abstract. No abstract.

  4. Does cold activate the Drosophila melanogaster immune system?

    Science.gov (United States)

    Salehipour-Shirazi, Golnaz; Ferguson, Laura V; Sinclair, Brent J

    2017-01-01

    Cold exposure appears to activate aspects of the insect immune system; however, the functional significance of the relationship between cold and immunity is unclear. Insect success at low temperatures is shaped in part by interactions with biotic stressors, such as pathogens, thus it is important to understand how and why immunity might be activated by cold. Here we explore which components of the immune system are activated, and whether those components differ among different kinds of cold exposure. We exposed Drosophila melanogaster to both acute (2h, -2°C) and sustained (10h, -0.5°C) cold, and measured potential (antimicrobial peptide expression, phenoloxidase activity, haemocyte counts) and realised (survival of fungal infection, wound-induced melanisation, bacterial clearance) immunity following recovery. Acute cold increased circulating haemocyte concentration and the expression of Turandot-A and diptericin, but elicited a short-term decrease in the clearance of gram-positive bacteria. Sustained cold increased the expression of Turandot-A, with no effect on other measures of potential or realised immunity. We show that measures of potential immunity were up-regulated by cold, whereas realised immunity was either unaffected or down-regulated. Thus, we hypothesize that cold-activation of potential immunity in Drosophila may be a compensatory mechanism to maintain stable immune function during or after low temperature exposure. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Experiences from polio supplementary immunization activities in ...

    African Journals Online (AJOL)

    2014-05-31

    May 31, 2014 ... immunization was low. Adopting proper planning and supervision, financial and political support, community involvement, improved vaccine logistics, and other measures utilized during the SIAs could help to improve routine immunization. Key words: Community involvement/participation, polio eradication, ...

  6. Effects of carotenoids, immune activation and immune suppression on the intensity of chronic coccidiosis in greenfinches.

    Science.gov (United States)

    Sepp, Tuul; Karu, Ulvi; Sild, Elin; Männiste, Marju; Hõrak, Peeter

    2011-03-01

    Allocation trade-offs of carotenoids between their use in the immune system and production of integumentary colouration have been suggested as a proximate mechanism maintaining honesty of signal traits. We tested how dietary carotenoid supplementation, immune activation and immune suppression affect intensity of coccidian infection in captive greenfinches Carduelis chloris, a passerine with carotenoid-based plumage. Immune activation with phytohaemagglutinin (PHA) decreased body mass among birds not supplemented with lutein, while among the carotenoid-fed birds, PHA had no effect on mass dynamics. Immune suppression with dexamethasone (DEX) induced loss of body mass and reduced the swelling response to PHA. DEX and PHA increased the concentration of circulating heterophils. Lutein supplementation increased plasma carotenoid levels but had no effect on the swelling response induced by PHA. PHA and DEX treatments did not affect plasma carotenoids. Immune stimulation by PHA suppressed the infection, but only among carotenoid-supplemented birds. Priming of the immune system can thus aid in suppressing chronic infection but only when sufficient amount of carotenoids is available. Our experiment shows the importance of carotenoids in immune response, but also the complicated nature of this impact, which could be the reason for inconsistent results in studies investigating the immunomodulatory effects of carotenoids. The findings about involvement of carotenoids in modulation of an immune response against coccidiosis suggest that carotenoid-based ornaments may honestly signal individuals' ability to manage chronic infections. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. Immunization promotion activities: are they effective in encouraging mothers to immunize their children?

    Science.gov (United States)

    Pérez-Cuevas, R; Reyes, H; Pego, U; Tomé, P; Ceja, K; Flores, S; Gutiérrez, G

    1999-10-01

    Mass media communication is an important strategy for increasing parental uptake and to promote community participation when large-scale immunization activities are carried out. In Mexico, the National Vaccination Council (CONAVA) launches three immunization campaigns every year accompanied by three vaccination promotion campaigns. This study was conducted to assess whether communication activities to promote CONAVA's Second National Health Week (SNHW) were effective in providing information to mothers about the importance of immunizing their children under five years of age and in prompting them to seek immunization services. A probability sample of mothers living in the metropolitan area of Mexico City and having at least one child under five years old was selected for the study. Four outcome variables were defined as measuring the impact of the campaign: (1) mothers' knowledge about the SNHW; (2) mothers' comprehension indicating how well they understood the campaign messages (aware, partly aware and unaware); (3) mothers' motivation, i.e. whether or not they sought out immunizations for their children under the age of five and (4) mothers' opinion of how well they liked the messages. A total of 935 mothers were interviewed; 88.2% knew about the SNHW, 64.3% were aware that the campaign aimed to provide immunizations, and most held a favorable opinion about the messages. Among aware mothers, 87.5% of their children received immunizations. In this group 72.1% were prompted by the information in the campaign to seek immunizations for their children while 27.9% had to be personally invited to participate in the campaign. The latter occurred either when health workers or volunteers visited mothers in their homes or by soliciting mothers' participation as they visited or passed by immunization health posts. In the unaware mothers group, 72.7% of their children received immunizations; 62.5% of the mothers took their children because of information they received through

  8. Experiences from polio supplementary immunization activities in ...

    African Journals Online (AJOL)

    The proportion of zero‑dose children decreased from 6% to 4.7%, and the vaccine wastage rate ranged from 6% to 6.6%. In that same year, the state did not achieve the target coverage of >80% for routine oral polio vaccine (OPV3) immunization in any of the months and only 29% of the LGAs exceeded the routine OPV3 ...

  9. Candesartan Ameliorates Impaired Fear Extinction Induced by Innate Immune Activation

    OpenAIRE

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

    2015-01-01

    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 l...

  10. Innate Immune Signaling Activated by MDR Bacteria in the Airway

    Science.gov (United States)

    Parker, Dane; Ahn, Danielle; Cohen, Taylor; Prince, Alice

    2015-01-01

    Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation. PMID:26582515

  11. E. fischeriana Root Compound Dpo Activates Antiviral Innate Immunity

    Directory of Open Access Journals (Sweden)

    Jingxuan Chen

    2017-10-01

    Full Text Available E. fischeriana has long been used as a traditional Chinese medicine. Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrated that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA-seq analysis revealed that the induction of ISGs by viral infection could be synergized by Dpo. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7, or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection.

  12. Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40(+) monocyte differentiation.

    Science.gov (United States)

    Dai, Jin; Fang, Pu; Saredy, Jason; Xi, Hang; Ramon, Cueto; Yang, William; Choi, Eric T; Ji, Yong; Mao, Wei; Yang, Xiaofeng; Wang, Hong

    2017-07-24

    Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response. We classify immune checkpoint into two categories: one-way immune checkpoint for forward signaling towards TC only, and two-way immune checkpoint for both forward and reverse signaling towards TC and APC, respectively. Recently, we and others provided evidence suggesting that metabolic risk factors (RF) activate innate and adaptive immunity, involving the induction of immune checkpoint molecules. We summarize these findings and suggest a novel theory, metabolism-associated danger signal (MADS) recognition, by which metabolic RF activate innate and adaptive immunity. We emphasize that MADS activates the reverse immune checkpoint which leads to APC inflammation in innate and adaptive immunity. Our recent evidence is shown that metabolic RF, such as uremic toxin or hyperhomocysteinemia, induced immune checkpoint molecule CD40 expression in monocytes (MC) and elevated serum soluble CD40 ligand (sCD40L) resulting in CD40(+) MC differentiation. We propose that CD40(+) MC is a novel pro-inflammatory MC subset and a reliable biomarker for chronic kidney disease severity. We summarize that CD40:CD40L immune checkpoint can induce TC and APC activation via forward stimulatory, reverse stimulatory, and TC contact-independent immune checkpoints. Finally, we modeled metabolic RF-induced two-way stimulatory immune checkpoint amplification and discussed potential signaling pathways including AP-1, NF-κB, NFAT, STAT, and DNA methylation and their

  13. Activation of the innate immune response by endogenous retroviruses.

    Science.gov (United States)

    Hurst, Tara P; Magiorkinis, Gkikas

    2015-06-01

    The human genome comprises 8 % endogenous retroviruses (ERVs), the majority of which are defective due to deleterious mutations. Nonetheless, transcripts of ERVs are found in most tissues, and these transcripts could either be reverse transcribed to generate ssDNA or expressed to generate proteins. Thus, the expression of ERVs could produce nucleic acids or proteins with viral signatures, much like the pathogen-associated molecular patterns of exogenous viruses, which would enable them to be detected by the innate immune system. The activation of some pattern recognition receptors (PRRs) in response to ERVs has been described in mice and in the context of human autoimmune diseases. Here, we review the evidence for detection of ERVs by PRRs and the resultant activation of innate immune signalling. This is an emerging area of research within the field of innate antiviral immunity, showing how ERVs could initiate immune signalling pathways and might have implications for numerous inflammatory diseases. © 2015 The Authors.

  14. Activation and Regulation of DNA-Driven Immune Responses

    Science.gov (United States)

    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

  15. Innate immune sensing 2.0 - from linear activation pathways to fine tuned and regulated innate immune networks.

    Science.gov (United States)

    Volz, Thomas; Kaesler, Susanne; Biedermann, Tilo

    2012-01-01

    The innate immune system is based on pathogen recognition receptors that bind conserved microbial molecular structures, so called pathogen-associated molecular patterns (PAMPs). The characterization of the innate immune system was long based on a linear step-wise concept of recognition, activation pathways and effector defense mechanisms. Only more recently it was recognized that the innate immune system needs regulatory elements, sideways and crosstalks that allows it to fine tune and adapt its response. Thus, it is an emerging field within innate immunity research to try to understand how the immune outcome of innate immune sensing is regulated and why immune responses can be substantially different, even though the same PAMPs may have been 'sensed' at the surface organs such as the skin. Only the expansion of the innate immune system from 'pure' linear activation pathways to fine tuned and regulated innate immune networks allows us to integrate the generation of gradually accentuated and qualitatively different effector and tolerogenic immune responses. This article provides a review of the basic concepts and players of the innate immune system and will present some of the newer data defining the innate immune networks effectively regulating the immune homoeostasis and immune effector mechanisms with special focus on the skin as one of the organs involved in regulating the immune interface between the environment and the organism. © 2011 John Wiley & Sons A/S.

  16. Visceral Inflammation and Immune Activation Stress the Brain

    Science.gov (United States)

    Holzer, Peter; Farzi, Aitak; Hassan, Ahmed M.; Zenz, Geraldine; Jačan, Angela; Reichmann, Florian

    2017-01-01

    Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut–brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut–brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience

  17. Activation of innate immunity during systemic Candida infections

    OpenAIRE

    Ifrim, D.C.

    2015-01-01

    Despite the increased knowledge on the mechanisms of Candida recognition and the networks of innate and adaptive host defense activated during infection, much remains to be learned regarding the distinctive modulatory effects of Candida spp on host immune responses. We showed that the chronic exposure of primary human immune cells to C. albicans primes them for subsequent stimulation with different microorganisms, mechanism that could explain the potential stimulatory effects of the fungus in...

  18. Immunization

    Science.gov (United States)

    ... 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. ...

  19. Pathogen-secreted proteases activate a novel plant immune pathway.

    Science.gov (United States)

    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

    2015-05-14

    Mitogen-activated protein kinase (MAPK) cascades play central roles in innate immune signalling networks in plants and animals. In plants, however, the molecular mechanisms of how signal perception is transduced to MAPK activation remain elusive. Here we report that pathogen-secreted proteases activate a previously unknown signalling pathway in Arabidopsis thaliana involving the Gα, Gβ, and Gγ subunits of heterotrimeric G-protein complexes, which function upstream of an 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 signalling to downstream activation of an MAPK cascade. The protease-G-protein-RACK1-MAPK cascade modules identified in these studies are distinct from previously described plant immune signalling pathways such as that elicited by bacterial flagellin, in which G proteins function downstream of or in parallel to an MAPK cascade without the involvement of the RACK1 scaffolding protein. The discovery of the new protease-mediated immune signalling 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 immunoregulatory strategies that account for its niche adaptation to diverse host tissues and immune systems.

  20. Immunizations

    Science.gov (United States)

    ... Why Exercise Is Wise Are Detox Diets Safe? Immunizations KidsHealth > For Teens > Immunizations Print A A A What's in this article? ... fault if you don't have all the immunizations (vaccinations) you need. Shots that doctors recommend today ...

  1. Innate immune recognition and activation during HIV infection

    Science.gov (United States)

    2010-01-01

    The pathogenesis of HIV infection, and in particular the development of immunodeficiency, remains incompletely understood. Whichever intricate molecular mechanisms are at play between HIV and the host, it is evident that the organism is incapable of restricting and eradicating the invading pathogen. Both innate and adaptive immune responses are raised, but they appear to be insufficient or too late to eliminate the virus. Moreover, the picture is complicated by the fact that the very same cells and responses aimed at eliminating the virus seem to play deleterious roles by driving ongoing immune activation and progressive immunodeficiency. Whereas much knowledge exists on the role of adaptive immunity during HIV infection, it has only recently been appreciated that the innate immune response also plays an important part in HIV pathogenesis. In this review, we present current knowledge on innate immune recognition and activation during HIV infection based on studies in cell culture, non-human primates, and HIV-infected individuals, and discuss the implications for the understanding of HIV immunopathogenesis. PMID:20569472

  2. Active protection against rotavirus infection of mice following intraperitoneal immunization.

    Science.gov (United States)

    McNeal, M M; Sheridan, J F; Ward, R L

    1992-11-01

    Active immunity to rotavirus has been demonstrated following oral inoculation with live virus but little is known about the effects of parenteral immunization. In this study, adult mice were immunized by intraperitoneal (ip) inoculation with live rotaviruses and later orally challenged with murine rotavirus (EDIM) to measure active immunity against infection. Three doses of EDIM (8 micrograms/dose) given intraperitoneally (ip) provided full protection against EDIM infection, whether administered with or without Freund's adjuvant. Only partial protection was found when the quantity of immunogen was reduced to protection of all mice. Significant protection was also observed after inoculation with one or three doses (2 micrograms/dose) of heterologous rotaviruses. Protection provided by the heterologous strains did not correlate with neutralizing antibody to EDIM, which indicated that neutralizing antibody to the challenge virus was not required for protection. uv-Inactivated EDIM also provided significant protection against EDIM, thus demonstrating that viral replication was not required for protection. These results suggest that parenteral immunization may be an effective method to vaccinate against rotavirus disease.

  3. Innate immune recognition and activation during HIV infection

    Directory of Open Access Journals (Sweden)

    Larsen Carsten S

    2010-06-01

    Full Text Available Abstract The pathogenesis of HIV infection, and in particular the development of immunodeficiency, remains incompletely understood. Whichever intricate molecular mechanisms are at play between HIV and the host, it is evident that the organism is incapable of restricting and eradicating the invading pathogen. Both innate and adaptive immune responses are raised, but they appear to be insufficient or too late to eliminate the virus. Moreover, the picture is complicated by the fact that the very same cells and responses aimed at eliminating the virus seem to play deleterious roles by driving ongoing immune activation and progressive immunodeficiency. Whereas much knowledge exists on the role of adaptive immunity during HIV infection, it has only recently been appreciated that the innate immune response also plays an important part in HIV pathogenesis. In this review, we present current knowledge on innate immune recognition and activation during HIV infection based on studies in cell culture, non-human primates, and HIV-infected individuals, and discuss the implications for the understanding of HIV immunopathogenesis.

  4. Activation of innate immunity during systemic Candida infections

    NARCIS (Netherlands)

    Ifrim, D.C.

    2015-01-01

    Despite the increased knowledge on the mechanisms of Candida recognition and the networks of innate and adaptive host defense activated during infection, much remains to be learned regarding the distinctive modulatory effects of Candida spp on host immune responses. We showed that the chronic

  5. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    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.

  6. Immune activation is associated with decreased thymic function in ...

    African Journals Online (AJOL)

    Background: Reduced thymic function causes poor immunological reconstitution in human immunodeficiency virus (HIV)-positive patients on combined antiretroviral therapy (cART). The association between immune activation and thymic function in asymptomatic HIVpositive treatment-naive individuals has thus far not been ...

  7. Effects of active immunization against androstenedione on the ...

    African Journals Online (AJOL)

    Table 1 Effect of active immunization against androstenedione (Fecundin) on the reproductive performance of Merino ewes. Item. Control. Treated. Number of ewes. 150. 200. Number of ewes lambed. 138. 188. Percentage ewes lambed. 92,0. 94,0 NSa. Number of lambs born. 175. 274. Lambing percentage. 116,7. 137,0".

  8. Photodynamic therapy for cancer and activation of immune response

    Science.gov (United States)

    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.

  9. The role of rare innate immune cells in Type 2 immune activation against parasitic helminths.

    Science.gov (United States)

    Webb, Lauren M; Tait Wojno, Elia D

    2017-09-01

    The complexity of helminth macroparasites is reflected in the intricate network of host cell types that participate in the Type 2 immune response needed to battle these organisms. In this context, adaptive T helper 2 cells and the Type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have been the focus of research for years, but recent work has demonstrated that the innate immune system plays an essential role. Some innate immune cells that promote Type 2 immunity are relatively abundant, such as macrophages and eosinophils. However, we now appreciate that more rare cell types including group 2 innate lymphoid cells, basophils, mast cells and dendritic cells make significant contributions to these responses. These cells are found at low frequency but they are specialized to their roles - located at sites such as the skin, lung and gut, where the host combats helminth parasites. These cells respond rapidly and robustly to worm antigens and worm-induced damage to produce essential cytokines, chemokines, eicosanoids and histamine to activate damaged epithelium and to recruit other effectors. Thus, a greater understanding of how these cells operate is essential to understand how the host protects itself during helminth infection.

  10. Chicken Immune Response after In Ovo Immunization with Chimeric TLR5 Activating Flagellin of Campylobacter jejuni.

    Directory of Open Access Journals (Sweden)

    Katarzyna A Radomska

    Full Text Available Campylobacter jejuni is the main cause of bacterial food-borne diseases in developed countries. Chickens are the most important source of human infection. Vaccination of poultry is an attractive strategy to reduce the number of C. jejuni in the intestinal tract of chickens. We investigated the immunogenicity and protective efficacy of a recombinant C. jejuni flagellin-based subunit vaccine with intrinsic adjuvant activity. Toll-like receptor activation assays demonstrated the purity and TLR5 stimulating (adjuvant activity of the vaccine. The antigen (20-40 μg was administered in ovo to 18 day-old chicken embryos. Serum samples and intestinal content were assessed for antigen-specific systemic and mucosal humoral immune responses. In ovo vaccination resulted in the successful generation of IgY and IgM serum antibodies against the flagellin-based subunit vaccine as determined by ELISA and Western blotting. Vaccination did not induce significant amounts of flagellin-specific secretory IgA in the chicken intestine. Challenge of chickens with C. jejuni yielded similar intestinal colonization levels for vaccinated and control animals. Our results indicate that in ovo delivery of recombinant C. jejuni flagellin subunit vaccine is a feasible approach to yield a systemic humoral immune response in chickens but that a mucosal immune response may be needed to reduce C. jejuni colonization.

  11. Chicken Immune Response after In Ovo Immunization with Chimeric TLR5 Activating Flagellin of Campylobacter jejuni.

    Science.gov (United States)

    Radomska, Katarzyna A; Vaezirad, Mahdi M; Verstappen, Koen M; Wösten, Marc M S M; Wagenaar, Jaap A; van Putten, Jos P M

    2016-01-01

    Campylobacter jejuni is the main cause of bacterial food-borne diseases in developed countries. Chickens are the most important source of human infection. Vaccination of poultry is an attractive strategy to reduce the number of C. jejuni in the intestinal tract of chickens. We investigated the immunogenicity and protective efficacy of a recombinant C. jejuni flagellin-based subunit vaccine with intrinsic adjuvant activity. Toll-like receptor activation assays demonstrated the purity and TLR5 stimulating (adjuvant) activity of the vaccine. The antigen (20-40 μg) was administered in ovo to 18 day-old chicken embryos. Serum samples and intestinal content were assessed for antigen-specific systemic and mucosal humoral immune responses. In ovo vaccination resulted in the successful generation of IgY and IgM serum antibodies against the flagellin-based subunit vaccine as determined by ELISA and Western blotting. Vaccination did not induce significant amounts of flagellin-specific secretory IgA in the chicken intestine. Challenge of chickens with C. jejuni yielded similar intestinal colonization levels for vaccinated and control animals. Our results indicate that in ovo delivery of recombinant C. jejuni flagellin subunit vaccine is a feasible approach to yield a systemic humoral immune response in chickens but that a mucosal immune response may be needed to reduce C. jejuni colonization.

  12. Lymphatic System: An Active Pathway for Immune Protection

    Science.gov (United States)

    Liao, Shan; von der Weid, Pierre-Yves

    2015-01-01

    Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases. PMID:25534659

  13. Tim-3: an activation marker and activation limiter of innate immune cells.

    Science.gov (United States)

    Han, Gencheng; Chen, Guojiang; Shen, Beifen; Li, Yan

    2013-12-10

    Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss (1) how Tim-3 is expressed and regulated on different innate immune cells; (2) how it affects the activity of different innate immune cells; and (3) how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.

  14. Tim-3: An activation marker and activation limiter of innate immune cells

    Directory of Open Access Journals (Sweden)

    Gencheng eHan

    2013-12-01

    Full Text Available Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss 1 how Tim-3 is expressed and regulated on different innate immune cells; 2 how it affects the activity of different innate immune cells; and 3 how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.

  15. Paramyxovirus activation and inhibition of innate immune responses.

    Science.gov (United States)

    Parks, Griffith D; Alexander-Miller, Martha A

    2013-12-13

    Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells. © 2013.

  16. Jungle Honey Enhances Immune Function and Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Miki Fukuda

    2011-01-01

    Full Text Available Jungle honey (JH is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal. After seven injections, peritoneal cells (PC were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2 cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261.

  17. Hepatitis b virus lacks immune activating capacity, but actively inhibits plasmacytoid dendritic cell function

    NARCIS (Netherlands)

    A.M. Woltman (Andrea); M.L.O. den Brouw; P.J. Biesta (Paula); C.C. Shi (Cui); H.L.A. Janssen (Harry)

    2011-01-01

    textabstractChronic hepatitis B virus (HBV) infection is caused by inadequate anti-viral immunity. Activation of plasmacytoid dendritic cells (pDC) leading to IFNα production is important for effective anti-viral immunity. Hepatitis B virus (HBV) infection lacks IFNα induction in animal models and

  18. Partial sleep restriction activates immune response-related gene expression pathways: experimental and epidemiological studies in humans.

    Science.gov (United States)

    Aho, Vilma; Ollila, Hanna M; Rantanen, Ville; Kronholm, Erkki; Surakka, Ida; van Leeuwen, Wessel M A; Lehto, Maili; Matikainen, Sampsa; Ripatti, Samuli; Härmä, Mikko; Sallinen, Mikael; Salomaa, Veikko; Jauhiainen, Matti; Alenius, Harri; Paunio, Tiina; Porkka-Heiskanen, Tarja

    2013-01-01

    Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling (Pimmune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.

  19. Structure-Dependent Immune Modulatory Activity of Protegrin-1 Analogs

    Directory of Open Access Journals (Sweden)

    Susu M. Zughaier

    2014-11-01

    Full Text Available Protegrins are porcine antimicrobial peptides (AMPs that belong to the cathelicidin family of host defense peptides. Protegrin-1 (PG-1, the most investigated member of the protegrin family, is an arginine-rich peptide consisting of 18 amino acid residues, its main chain adopting a β-hairpin structure that is linked by two disulfide bridges. We report on the immune modulatory activity of PG-1 and its analogs in neutralizing bacterial endotoxin and capsular polysaccharides, consequently inhibiting inflammatory mediators’ release from macrophages. We demonstrate that the β-hairpin structure motif stabilized with at least one disulfide bridge is a prerequisite for the immune modulatory activity of this type of AMP.

  20. Role of Leptin in the Activation of Immune Cells

    Directory of Open Access Journals (Sweden)

    Patricia Fernández-Riejos

    2010-01-01

    Full Text Available Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines, and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response.

  1. Animal Models of Maternal Immune Activation in Depression Research

    OpenAIRE

    Ronovsky, Marianne; Berger, Stefanie; Molz, Barbara; Berger, Angelika; Pollak, Daniela D.

    2016-01-01

    Abstract: Background Depression and schizophrenia are debilitating mental illnesses with significant socio-economic impact. The high degree of comorbidity between the two disorders, and shared symptoms and risk factors, suggest partly common pathogenic mechanisms. Supported by human and animal studies, maternal immune activation (MIA) has been intimately associated with the development of schizophrenia. However, the link between MIA and depression has remained less clear, in part due to the l...

  2. Inflammation, Immune Activation, and Antiretroviral Therapy in HIV.

    Science.gov (United States)

    Hileman, Corrilynn O; Funderburg, Nicholas T

    2017-06-01

    This review focuses on the differential effects of contemporary antiretrovirals on systemic inflammation as heightened immune activation is linked to important co-morbidities and mortality with HIV infection. Antiretroviral therapy (ART) reduces dramatically systemic inflammation and immune activation, but not to levels synchronous with HIV-uninfected populations. In one ART initiation trial, integrase inhibitors appear to reduce inflammation to a greater degree than non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not clear that there are beneficial effects on inflammation resulting from treatment with integrase inhibitors compared to PIs, between PIs and NNRTIs, between specific nucleoside reverse transcriptase inhibitors, or with maraviroc in ART-naïve patients. In ART switch studies, changing to an integrase inhibitor from a PI-, NNRTI-, or enfuvirtide-containing regimen has resulted in improvement in several markers of inflammation. Additional research is needed to conclusively state whether there are clear differences in effects of specific antiretrovirals on inflammation and immune activation in HIV.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Immune activation and nutritional status in adult Crohn's disease patients.

    Science.gov (United States)

    Reimund, J-M; Arondel, Y; Escalin, G; Finck, G; Baumann, R; Duclos, B

    2005-06-01

    Recent attention focused on the effect of inflammatory cytokines on intermediary metabolism contributing to the nutritional disturbances observed in acute or chronic inflammatory diseases. To examine the interactions between immune activation and nutritional parameters in adult Crohn's disease patients. We analysed anthropometric and biochemical nutritional parameters in 40 Crohn's disease patients and 26 healthy controls, and related them to inflammatory and immune markers. Weight, body mass index, mid-arm circumference, triceps skinfold thickness, as well as albumin, transthyretin, retinol binding protein, insulin growth factor-I and Vitamin A were significantly decreased in Crohn's disease patients and negatively correlated to disease activity. By contrast, erythrocyte sedimentation rate, fibrinogen, C-reactive protein, alpha1-acylglycoprotein, soluble receptor of interleukin-2, blood neopterin, tumour necrosis factor-alpha and interleukin-1beta concentrations were significantly higher in patients and positively correlated to disease activity. Nutritional parameters and acute phase reactants were linked to tumour necrosis factor-alpha and interleukin-1beta concentrations, and markers of nutritional status were negatively correlated to positive acute phase reactants. In Crohn's disease, inflammatory cytokines appear partly responsible for decreased nutritional status. Thus, nutritional intervention to correct nutritional (in particular protein) depletion, and/or therapeutic intervention reducing inflammation and therefore restoring adequate nutritional proteins synthesis, appears a major therapeutic goal in active Crohn's disease.

  5. Antioxidant and Immunity Activities of Fufang Kushen Injection Liquid

    Directory of Open Access Journals (Sweden)

    Tie-Nan Bi

    2012-05-01

    Full Text Available We investigated the effects of Fufang Kushen Injection Liquid (FFKSIL on gastric immunity and oxidant-antioxidant status during N-methyl-N′-nitro-N-nitroso-guanidine (MNNG-induced gastric carcinogenesis. The extent of lipid peroxidation and the levels of reduced glutathione (GSH and activities of the GSH-dependent enzymes superoxide dismutase (SOD, catalase (CAT and glutathione peroxidase (GSH-Px were used to monitor the peroxidative balance. Enhanced lipid peroxidation in the gastric cancer animals was accompanied by significant decreases in the activities of GSH, GPx, GST and GR. Administration of FFKSIL significantly enhanced serum IgA, IgG, IgM, IL-2, IL-4 and IL-10 levels, decreased serum IL-6 and TNF-α levels, lowered the levels of lipid peroxides and enhanced GSH levels and activities of GSH-dependent enzymes. Our results suggest that FFKSIL blocks experimental gastric carcinogenesis by protecting against carcinogen-induced oxidative damage and improving immunity activity.

  6. Immunosuppressive Activity of 8-Gingerol on Immune Responses in Mice

    Directory of Open Access Journals (Sweden)

    Wenhui Qian

    2011-03-01

    Full Text Available 8-Gingerol is one of the principal components of ginger, which is widely used in China and elsewhere as a food, spice and herb. It shows immunosuppressive activity on the immune responses to ovalbumin (OVA in mice. In the present study, we found that 8-gingerol suppressed lipopolysaccharide (LPS and concanavalin A (ConA-stimulated splenocyte proliferation in vitro. In vivo, 8-gingerol not only significantly suppressed Con A-, LPS- and OVA-induced splenocyte proliferation (P < 0.05 but also decreased the percentage of CD19+ B cells and CD3+ T cell (P < 0.05 at high doses (50, 100 mg/kg. Moreover, OVA-specific IgG, IgG1 and IgG2b levels in OVA-immunized mice were reduced by 8-gingerol at doses of 50, 100 mg/kg. These results suggest that 8-gingerol could suppress humoral and cellular immune responses in mice. The mechanism might be related to direct inhibition of sensitized T and B lymphocytes.

  7. Differential Effects of Naja naja atra Venom on Immune Activity.

    Science.gov (United States)

    Kou, Jian-Qun; Han, Rong; Xu, Yin-Li; Ding, Xiao-Lan; Wang, Shu-Zhi; Chen, Cao-Xin; Ji, Hong-Zhang; Ding, Zhi-Hui; Qin, Zheng-Hong

    2014-01-01

    Previous studies reported that Naja naja atra venom (NNAV) inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1 phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-γ, IL-4) secretion and inhibition of Th17 cytokine (IL-17) production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases.

  8. Differential Effects of Naja naja atra Venom on Immune Activity

    Directory of Open Access Journals (Sweden)

    Jian-Qun Kou

    2014-01-01

    Full Text Available Previous studies reported that Naja naja atra venom (NNAV inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1 phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-γ, IL-4 secretion and inhibition of Th17 cytokine (IL-17 production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases.

  9. Coincident helminth infection modulates systemic inflammation and immune activation in active pulmonary tuberculosis.

    Directory of Open Access Journals (Sweden)

    Parakkal Jovvian George

    Full Text Available 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.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.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.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.

  10. Partial sleep restriction activates immune response-related gene expression pathways: experimental and epidemiological studies in humans.

    Directory of Open Access Journals (Sweden)

    Vilma Aho

    Full Text Available Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9 was restricted to 4 h/night for five nights. The control subjects (N = 4 spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472. Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling (P<0.005. Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.

  11. Immunosuppressive Activity of 8-Gingerol on Immune Responses in Mice

    OpenAIRE

    Wenhui Qian; Guoren Huang; Xuming Deng; Guanghong Xie; Xue Shen; Shuang Guan; Jing Lu

    2011-01-01

    8-Gingerol is one of the principal components of ginger, which is widely used in China and elsewhere as a food, spice and herb. It shows immunosuppressive activity on the immune responses to ovalbumin (OVA) in mice. In the present study, we found that 8-gingerol suppressed lipopolysaccharide (LPS) and concanavalin A (ConA)-stimulated splenocyte proliferation in vitro. In vivo, 8-gingerol not only significantly suppressed Con A-, LPS- and OVA-induced splenocyte proliferation (P < 0.05) but a...

  12. An Update on Post-infectious Irritable Bowel Syndrome: Role of Genetics, Immune Activation, Serotonin and Altered Microbiome.

    Science.gov (United States)

    Spiller, Robin; Lam, Ching

    2012-07-01

    The literature on post-infectious irritable bowel syndrome (IBS) is reviewed with special emphasis on recent new data. Further accounts of this phenomenon continue to be reported following a range of infections including giardiasis as well as viral and bacterial gastroenteritis. Risk factors such as severity of initial illness, female gender together with adverse psychological factors have been confirmed. Recent evidence of a genetic predisposition needs replication. Animal studies suggest activation of mast cells and inflammation driven impairment of serotonin transporter may be important, which are findings supported by some recent human studies in IBS with diarrhoea. Experimentally induced inflammation leads to damage and remodelling of enteric nerves. Similar changes have been reported in IBS patients with increase in nerves expressing transient receptor potential cation channel V1. While changes in microbiota are very likely this area has yet to be explored using modern techniques. Since the prognosis is for slow improvement, treatments should currently target the key symptoms of diarrhoea and abdominal pain. Future therapies aimed at correcting underlying mechanisms including immune activation and serotonin excess are currently being explored and may provide better treatments in the future.

  13. Immune Activities of Polycationic Vectors for Gene Delivery

    Directory of Open Access Journals (Sweden)

    Xiaotian Zhao

    2017-08-01

    Full Text Available Polycationic vectors are used widely in the field of gene delivery, while currently their immune activities in vivo are poorly understood. In this comprehensive review, we aim to present an overview of existing mechanisms of adverse immune responses induced by the polycation/gene complexes, which includes the polycations themselves, the gene sequences and the ROS produced by them. These causes can induce pro-inflammatory cytokines, hypersensitivity as well as the activation of toll-like receptors, and finally the immunostimulation occur. In addition, we introduce some different opinions and research results on the immunogenicity of classical polycations such as polylysine (PLL, polyethyleneimine (PEI, polyamidoamine dendrimers (PAMAM, chitosan and gelatin, most of which have immunogenicity and can induce immunoreactions in vivo. The methods now used to adjust their immunogenicity are shown in the final part of this review. Nowadays, there is still no accurate conclusion on immunogenicity of polycations, which confuses researchers seriously in in vivo test. We conclude that further research is needed in order to skillfully utilize or inhibit the immunogenicity of these polycationic vectors.

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

    Science.gov (United States)

    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. Copyright © 2015 International Society of Exercise and Immunology. All rights reserved.

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

    Science.gov (United States)

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

    2015-09-01

    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.

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

    Science.gov (United States)

    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

  17. Protection against HIV-disease progression: From immune activation to T-cell immunity

    NARCIS (Netherlands)

    Spits, H.B.

    2015-01-01

    HIV infection undermines the immune system by causing a gradual loss of CD4+ T cells. Eventually, the weakened immune system is no longer able to offer resistance to opportunistic infections and the HIV-infected individual will develop AIDS. Even after 30 years of intensive research on HIV, there is

  18. Active or passive immunization in unexplained recurrent miscarriage

    DEFF Research Database (Denmark)

    Christiansen, Ole B; Nielsen, Henriette Svarre; Pedersen, Bjorn

    2004-01-01

    carried out as Cochrane reviews have concluded than none of the different forms of immunotherapy has proved effective in the total RM population. However, the included trials have generally been small and very heterogenous with respect to the clinical histories of patients and the immunization protocols......Controversy exists as to whether active immunotherapy with allogeneic lymphocyte transfusions (ALT) or passive immunotherapy with intravenous immunoglobulin (IvIg) improve the chance of live birth in women with unexplained recurrent miscarriages (RM). Meta-analyses of the placebo-controlled trials....... Thus, other meta-analyses which have looked at the efficacy in subgroups of RM patients have reported that ALT and IvIg may be effective in women with primary RM and secondary RM, respectively. In RM clinics in Denmark, ALT with donor lymphocytes or IvIg immunotherapy have been tested in several...

  19. Effect of ES products from Anisakis (Nematoda: Anisakidae) on experimentally induced colitis in adult zebrafish

    DEFF Research Database (Denmark)

    Haarder, Simon; Kania, Per Walter; Holm, Thomas

    2017-01-01

    with helminth-derived substances have supported this notion, but underlying mechanisms remain unclear. This study therefore dissects to what extent a series of immune-related genes are modulated in zebrafish with experimentally induced colitis following exposure to excretory-secretory (ES) products isolated...... from larval Anisakis, a widely distributed fish nematode. Adult zebrafish intrarectally exposed to the colitis-inducing agent TNBS developed severe colitis leading to 80% severe morbidity, but if co-injected (ip) with Anisakis ES products, the morbidity rate was 50% at the end of the experiment (48...... hours post-exposure). Gene expression studies of TNBS-treated zebrafish showed clear upregulation of a range of genes encoding inflammatory cytokines and effector molecules and some induction of genes related to the adaptive response. A distinct innate-driven immune response was seen in both TNBS...

  20. Experimentally Induced Learned Helplessness: How Far Does it Generalize?

    Science.gov (United States)

    Tuffin, Keith; And Others

    1985-01-01

    Assessed whether experimentally induced learned helplessness on a cognitive training task generalized to a situationally dissimilar social interaction test task. No significant differences were observed between groups on the subsequent test task, showing that helplessness failed to generalize. (Author/ABB)

  1. The Immune Pathogenesis of Immune Reconstitution Inflammatory Syndrome Associated with Highly Active Antiretroviral Therapy in AIDS

    Science.gov (United States)

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

    2014-01-01

    Abstract 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

  2. Decreased peripheral natural killer cells activity in the immune activated stage of chronic hepatitis B.

    Directory of Open Access Journals (Sweden)

    Yuan Li

    Full Text Available BACKGROUND & AIMS: The natural course of chronic hepatitis B virus (HBV infection is characterized by different immune responses, ranging from immune tolerant (IT to immune activated (IA stages. In our study, we investigated the natural killer (NK cells activity in patients at different immunological stages of chronic HBV infection. METHODS: Blood samples obtained from 57 HBeAg positive patients with chronic hepatitis B (CHB, including 15 patients in the immune tolerant (IT stage, 42 patients in the immune activated (IA stage, and 18 healthy individuals (HI. The analyses included flow cytometry to detect NK cells, the determination of cytokine levels as well as of surface receptor expression and cytotoxicity. RESULTS: NK cells in peripheral blood were significantly lower in patients in the IA stage of CHB compared to HI (p<0.05. Patients in the IA stage of CHB had lower levels of NK cells activating receptor NKp30 and NKG2D expression, cytokine interferon-γ (IFN-γ and tumor necrosis factor-α (TNF-α production, as compared to patients in the IT stage and HI, respectively (p<0.05. Cytotoxicity of NK cells was lower in patients in the IA stage of CHB compared to patients in the IT stage and HI, respectively (p<0.05. The level of IFN-γ but not level of TNF-α and cytotoxicity of NK cells was inversely correlated with serum HBV load in patients with CHB. Peripheral NK cells activity did not correlate with ALT level. CONCLUSION: NK cells activity was lower in CHB patients, especially in those in the IA stage.

  3. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; Van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-01-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues1–3. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption4–6, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs. PMID:28854172

  4. Discovery of stimulation-responsive immune enhancers with CRISPR activation

    Science.gov (United States)

    Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K.; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

    2017-09-01

    The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Arunita Chatterjee

    2016-06-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  8. Immune adjuvant activity of the olive, soybean and corn oils

    Directory of Open Access Journals (Sweden)

    Ana Claudia Marinho da Silva

    2016-08-01

    Full Text Available In the last half of the century, a large amount of substances has been used as immune adjuvant. The immune adjuvant effect of olive, soybean and corn oils in Swiss mice immunized with ovalbumin (OVA plus aluminum hydroxide or emulsified in Marcol, soybean, olive or corn oils was evaluated through the OVA-specific antibodies determined by ELISA and Passive Cutaneous Anaphylaxis. In this work the comparison of the intensity of the immune response was established by the Bayesian analysis. The adjuvant effect of the vegetable oils was shown to be more effective than aluminium hydroxide. Regarding to OVA-specific IgE synthesis, olive oil had the slowest adjuvant effect of the three vegetable oils. Accordingly, olive oil was the most convenient among the vegetable oils to be used as immune adjuvant, since it stimulated a higher production of OVA-specific Ig and lower levels of anti-OVA IgE.

  9. Metabolic pathways in immune cell activation and quiescence.

    Science.gov (United States)

    Pearce, Erika L; Pearce, Edward J

    2013-04-18

    Studies of immune system metabolism ("immunometabolism") segregate along two paths. The first investigates the effects of immune cells on organs that regulate whole-body metabolism, such as adipose tissue and liver. The second explores the role of metabolic pathways within immune cells and how this regulates immune response outcome. Distinct metabolic pathways diverge and converge at many levels, and, therefore, cells face choices as to how to achieve their metabolic goals. There is interest in fully understanding how and why immune cells commit to particular metabolic fates and in elucidating the immunologic consequences of reaching a metabolic endpoint by one pathway versus another. This is particularly intriguing, given that metabolic commitment is influenced not only by substrate availability but also by signaling pathways elicited by metabolites. Thus, metabolic choices in cells enforce fate and function, and this area will be the subject of this review. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Unveiling Unexpected Immune Activities Induced by Your Pneumococcal Vaccine

    Directory of Open Access Journals (Sweden)

    Julia L. Hurwitz

    2016-03-01

    Full Text Available 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.

  11. Functional Bowel Disorders Are Associated with a Central Immune Activation

    Directory of Open Access Journals (Sweden)

    Per G. Farup

    2017-01-01

    Full Text Available Background. Subjects with depression and unexplained neurological symptoms have a high prevalence of gastrointestinal comorbidity probably related to the brain-gut communication. This study explored associations between functional gastrointestinal disorders (FGID and inflammatory markers in subjects with these disorders. Methods. The FGID, including irritable bowel syndrome (IBS, were classified according to the Rome III criteria, and degree of symptoms was assessed with IBS symptom severity score (IBS-SSS. A range of interleukins (IL, chemokines and growth factors, tryptophan, and kynurenine were analysed in serum and the cerebrospinal fluid (CSF, and short-chain fatty acids (SCFA were analysed in the faeces. The results are reported as partial correlation (pc and p values. Results. Sixty-six subjects were included. IBS was associated with high levels of tryptophan (p=0.048 and kynurenine (p=0.019 and low level of IL-10 (p=0.047 in the CSF. IBS-SSS was associated with high tumor necrosis factor and low IL-10 in the CSF; pc=0.341 and p=0.009 and pc=−0.299 and p=0.023, respectively. Propionic minus butyric acid in faeces was negatively associated with IL-10 in the CSF (pc=−0.416, p=0.005. Conclusions. FGID were associated with a proinflammatory immune activation in the central nervous system and a disturbed tryptophan metabolism that could have been mediated by the faecal microbiota.

  12. The association between immune activation and manic symptoms in patients with a depressive disorder

    NARCIS (Netherlands)

    Becking, K.; Boschloo, L.; Vogelzangs, N.; Haarman, B. C. M.; Riemersma-van der Lek, R.; Penninx, B. W. J. H.; Schoevers, R. A.

    2013-01-01

    Although recent studies have shown that immunological processes play an important role in the pathophysiology of mood disorders, immune activation may only be present in specific subgroups of patients. Our study aimed to examine whether immune activation was associated with (a) the presence of manic

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Immune activation suppresses initiation of lytic Epstein-Barr virus infection.

    Science.gov (United States)

    Ladell, Kristin; Dorner, Marcus; Zauner, Ludwig; Berger, Christoph; Zucol, Franziska; Bernasconi, Michele; Niggli, Felix K; Speck, Roberto F; Nadal, David

    2007-08-01

    Primary infection with Epstein-Barr virus (EBV) is asymptomatic in children with immature immune systems but may manifest as infectious mononucleosis, a vigorous immune activation, in adolescents or adults with mature immune systems. Infectious mononucleosis and chronic immune activation are linked to increased risk for EBV-associated lymphoma. Here we show that EBV initiates progressive lytic infection by expression of BZLF-1 and the late lytic genes gp85 and gp350/220 in cord blood mononuclear cells (CBMC) but not in peripheral blood mononuclear cells (PBMC) from EBV-naive adults after EBV infection ex vivo. Lower levels of proinflammatory cytokines in CBMC, used to model a state of minimal immune activation and immature immunity, than in PBMC were associated with lytic EBV infection. Triggering the innate immunity specifically via Toll-like receptor-9 of B cells substantially suppressed BZLF-1 mRNA expression in acute EBV infection ex vivo and in anti-IgG-stimulated chronically latently EBV-infected Akata Burkitt lymphoma cells. This was mediated in part by IL-12 and IFN-gamma. These results identify immune activation as critical factor for the suppression of initiation of lytic EBV infection. We hypothesize that immune activation contributes to EBV-associated lymphomagenesis by suppressing lytic EBV and in turn promotes latent EBV with transformation potential.

  15. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation.

    Science.gov (United States)

    Rose, Destanie R; Careaga, Milo; Van de Water, Judy; McAllister, Kim; Bauman, Melissa D; Ashwood, Paul

    2017-07-01

    Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA.An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays.At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production

  16. Immune activation by casein dietary antigens in bipolar disorder

    NARCIS (Netherlands)

    Severance, E.G.; Dupont, D.; Dickerson, F.B.; Stallings, C.R.; Origoni, A.E.; Krivogorsky, B.; Yang, S.; Haasnoot, W.; Yolken, R.H.

    2010-01-01

    Objectives: Inflammation and other immune processes are increasingly linked to psychiatric diseases. Antigenic triggers specific to bipolar disorder are not yet defined. We tested whether antibodies to bovine milk caseins were associated with bipolar disorder, and whether patients recognized

  17. The immune diet: meeting the metabolic demands of lymphocyte activation.

    Science.gov (United States)

    Wang, Ruoning; Green, Douglas R

    2012-01-01

    During the adaptive immune response, lymphocytes undergo dramatic changes in metabolism that accompany the proliferative burst and differentiation into functional subsets. This brief overview focuses on recent advances in understanding the mechanisms of this metabolic reprogramming in T lymphocytes.

  18. The immune diet: meeting the metabolic demands of lymphocyte activation

    OpenAIRE

    Wang, Ruoning; Green, Douglas R.

    2012-01-01

    During the adaptive immune response, lymphocytes undergo dramatic changes in metabolism that accompany the proliferative burst and differentiation into functional subsets. This brief overview focuses on recent advances in understanding the mechanisms of this metabolic reprogramming in T lymphocytes.

  19. Nutrition, Physical Activity, and Obesity - National Immunization Survey (Breastfeeding)

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset includes breastfeeding data from the National Immunization Survey (NIS). This data is used for DNPAO's Data, Trends, and Maps database, which provides...

  20. Activation and pathogenic manipulation of the sensors of the innate immune system.

    Science.gov (United States)

    Odendall, Charlotte; Kagan, Jonathan C

    The innate immune system detects the presence of microbes through different families of pattern-recognition receptors (PRRs). PRRs detect pathogens of all origins and trigger signaling events that activate innate and adaptive immunity. These events need to be tightly regulated in order to ensure optimal activation when required, and minimal signaling in the absence of microbial encounters. This regulation is achieved, at least in part, through the precise subcellular positioning of receptors and downstream signaling proteins. Consequently, mislocalization of these proteins inhibits innate immune pathways, and pathogens have evolved to alter host protein localization as a strategy to evade immune detection. This review describes the importance of subcellular localization of various PRR families and their adaptors, and highlights pathogenic immune evasion strategies that operate by altering immune protein localization. Copyright © 2017. Published by Elsevier Masson SAS.

  1. Effect of balanced low pressure drying of curcuma longa leaf on skin immune activation activities.

    Science.gov (United States)

    Choi, Wooseok; Lim, Hye Won; Lee, Hyeon Yong

    2014-01-01

    The effect of balanced low pressure drying pretreatment associated with ultrasonication extraction (BU) on the enhancement of skin immune modulatory activities of Curcuma longa leaf was studied by comparing with conventional hot air drying (HE), freeze drying (FE) and balanced low pressure drying (BE) pretreatment processes. In considering skin immune activation activities such as the inhibition of hyaluronidase activity, the BU extract showed ca. 10% higher than those of HE, and even higher than that of the FE extract. Nitric oxide production from macrophage of the BU extract in adding 1.0 mg/mL was increased up to 16.5 μM. When measuring inhibition of IL-6 and TNF-a production from the human T lymphocytes (T cell), the BU extract also showed 53% and 78% of inhibition effect, respectively. It is found that the BU extract could effectively suppress the expression levels of skin inflammation related genes such as Cox-2 and iNOS, down to 80% and 85% compared to the control, respectively. Balanced low pressure drying process was especially active on dehydration of the leaves with minimizing the destruction and making easier elution of the bioactive substances, which resulted in higher extraction yield and better biological activities.

  2. HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation.

    Science.gov (United States)

    Tsang, Jhen; Chain, Benjamin M; Miller, Robert F; Webb, Benjamin L J; Barclay, Wendy; Towers, Greg J; Katz, David R; Noursadeghi, Mahdad

    2009-11-13

    The cellular innate immune response to HIV-1 is poorly characterized. In view of HIV-1 tropism for macrophages, which can be activated via pattern recognition receptors to trigger antimicrobial defences, we investigated innate immune responses to HIV-1 by monocyte-derived macrophages. In a model of productive HIV-1 infection, cellular innate immune responses to HIV-1 were investigated, at the level of transcription factor activation, specific gene expression and genome-wide transcriptional profiling. In addition, the viral determinants of macrophage responses and the physiological effect of innate immune cellular activation on HIV-1 replication were assessed. Productive HIV-1 infection did not activate nuclear factor-kappaB and interferon regulatory factor 3 transcription factors or interferon gene expression (IFN) and caused remarkably small changes to the host-cell transcriptome, with no evidence of inflammatory or IFN signatures. Evasion of IFN induction was not dependent on HIV-1 envelope-mediated cellular entry, inhibition by accessory proteins or reverse transcription of ssRNA that may reduce innate immune cellular activation by viral RNA. Furthermore, IFNbeta priming did not sensitize responses to HIV-1. Importantly, exogenous IFNbeta or stimulation with the RNA analogue poly I:C to simulate innate immune activation invoked HIV-1 restriction. We conclude that macrophages lack functional pattern recognition receptors for this virus and that HIV-1 tropism for macrophages helps to establish a foothold in the host without triggering innate immune cellular activation, which would otherwise block viral infection effectively.

  3. Immune-enhancing activity of extracellular polysaccharides isolated from Rhizopus nigricans.

    Science.gov (United States)

    Yu, Zhidan; Kong, Mengli; Zhang, Pengying; Sun, Qingjie; Chen, Kaoshan

    2016-09-05

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Immune challenge affects basal metabolic activity in wintering great tits.

    OpenAIRE

    Ots, I.; Kerimov, A. B.; Ivankina, E. V.; Ilyina, T. A.; Hõrak, P.

    2001-01-01

    The costs of exploiting an organism's immune function are expected to form the basis of many life-history trade-offs. However, there has been debate about whether such costs can be paid in energetic and nutritional terms. We addressed this question in a study of wintering, free-living, male great tits by injecting them with a novel, non-pathogenic antigen (sheep red blood cells) and measuring the changes in their basal metabolic rates and various condition indices subsequent to immune challen...

  5. Active Immunization Of Rabbit With Gamma Irradiated Cobra (Naja haje) Venom Toxoid

    OpenAIRE

    Esmat A. Shaban

    2005-01-01

    Cobra (Naja haje) venom detoxified by gamma radiation (15KGy or 25KGy) was used as toxoid for active immunization of rabbits following a short schedule ( on day 0, 7,21) of immunization with complete Freund's adjuvant. Effective neutralization of venom toxin by immune sera of rabbits was observed. The presence of antibody in the immune sera was detected by immuno-diffusion test. The non-irradiated and the two dose levels gamma irradiated Naja haje venom, against the antivenin antibody produce...

  6. Abdominal fat mass is associated with adaptive immune activation: the CODAM study

    NARCIS (Netherlands)

    Thewissen, M.M.; Damoiseaux, J.G.; Duijvestijn, A.M.; Greevenbroek, M.M.; Kallen, van der C.J.H.; Feskens, E.J.M.; Blaak, E.E.; Schalkwijk, C.G.; Stehouwer, C.D.A.; Cohen Tervaert, J.W.; Ferreira, I.

    2011-01-01

    Abdominal fat-related activation of the innate immune system and insulin resistance (IR) are implicated in the pathogenesis of cardiovascular diseases. Recent data support an important role of the adaptive immune system as well. In this study, we investigate the association between waist

  7. Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats

    DEFF Research Database (Denmark)

    Soe, Niels H.; Jensen, Nina Vendel; Jensen, Asger Lundorff

    2017-01-01

    Background/Aim: Staphylococcus aureus infection associated with orthopedic implants cannot always be controlled. We used a knee prosthesis model with implant-related osteomyelitis in rats to explore induction of an effective immune response with active and passive immunization. Materials and Meth...

  8. TNF-mediated survival of CD169(+) cells promotes immune activation during vesicular stomatitis virus infection

    DEFF Research Database (Denmark)

    Shinde, Prashant V; Xu, Haifeng C; Maney, Sathish Kumar

    2017-01-01

    Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169(+) cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169(+) cells during viral infections remain ...

  9. Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats.

    Science.gov (United States)

    Søe, Niels H; Jensen, Nina Vendel; Jensen, Asger Lundorff; Koch, Janne; Poulsen, Steen Seier; Pier, Gerald B; Johansen, Helle Krogh

    2017-01-02

    Staphylococcus aureus infection associated with orthopedic implants cannot always be controlled. We used a knee prosthesis model with implant-related osteomyelitis in rats to explore induction of an effective immune response with active and passive immunization. Fifty-two Sprague-Dawley rats were divided into active (N=28) and passive immunization groups (N=24). A bacterial inoculum of 10(3) S. aureus MN8 was injected into the tibia and the femur marrow before insertion of a non-constrained knee prosthesis in each rat. The active-immunization group received a synthetic oligosaccharide of polysaccharide poly-N-acetylglucosamine (PNAG), 9G1cNH2 and the passive-immunization group received immunization with immunoglobulin from rabbits infected with S. aureus. Active immunization against PNAG significantly reduced the consequences of osteomyelitis infection from PNAG-producing intercellular adhesion (ica(+)) but not ica(-) S. aureus. Passive immunization resulted in better clinical assessments in animals challenged with either ica(+) or ica(-) S. aureus, suggesting a lack of specificity in this antiserum. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  10. Restoration of innate immune activation accelerates Th1-cell priming and protection following pulmonary mycobacterial infection.

    Science.gov (United States)

    Lai, Rocky; Jeyanathan, Mangalakumari; Shaler, Christopher R; Damjanovic, Daniela; Khera, Amandeep; Horvath, Carly; Ashkar, Ali A; Xing, Zhou

    2014-05-01

    The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Interaction Between Familial Transmission and a Constitutively Active Immune System Shapes Gut Microbiota in Drosophila melanogaster

    Science.gov (United States)

    Mistry, Rupal; Kounatidis, Ilias; Ligoxygakis, Petros

    2017-01-01

    Resident gut bacteria are constantly influencing the immune system, yet the role of the immune system in shaping microbiota composition during an organism’s life span has remained unclear. Experiments in mice have been inconclusive due to differences in husbandry schemes that led to conflicting results. We used Drosophila as a genetically tractable system with a simpler gut bacterial population structure streamlined genetic backgrounds and established cross schemes to address this issue. We found that, depending on their genetic background, young flies had microbiota of different diversities that converged with age to the same Acetobacteraceae-dominated pattern in healthy flies. This pattern was accelerated in immune-compromised flies with higher bacterial load and gut cell death. Nevertheless, immune-compromised flies resembled their genetic background, indicating that familial transmission was the main force regulating gut microbiota. In contrast, flies with a constitutively active immune system had microbiota readily distinguishable from their genetic background with the introduction and establishment of previously undetectable bacterial families. This indicated the influence of immunity over familial transmission. Moreover, hyperactive immunity and increased enterocyte death resulted in the highest bacterial load observed starting from early adulthood. Cohousing experiments showed that the microenvironment also played an important role in the structure of the microbiota where flies with constitutive immunity defined the gut microbiota of their cohabitants. Our data show that, in Drosophila, constitutively active immunity shapes the structure and density of gut microbiota. PMID:28413160

  12. Antiviral and immune stimulant activities of glycyrrhizin against duck ...

    African Journals Online (AJOL)

    This study was conducted to investigate the effect of glycyrrhizin as an immune stimulant against duck hepatitis virus (DHV). In vitro study was carried out to determine cytotoxic and antiviral effects of glycyrrhizin in VERO cells. In vivo study was performed on 40 one-day-old White Pekin ducklings. –and the birds weres ...

  13. Effects of active immunization against androstenedione on the ...

    African Journals Online (AJOL)

    hypothalamus, pituitary gland and ovaries is to ensure regular ovulation. Changes in this feedback system e.g. immunization against androgens, may interfere with ovarian function and alter the ovulation rate of sheep. (Martin, Scaramuzzi, Cox & Gherardi, 1979; Scaramuzzi,. Baird, Clarke, Martensz & Van Look, 1980).

  14. Immunopathogenesis of experimentally induced proliferative enteropathy in pigs.

    Science.gov (United States)

    MacIntyre, N; Smith, D G E; Shaw, D J; Thomson, J R; Rhind, S M

    2003-07-01

    To characterize the immune response associated with Lawsonia intracellularis infection, twenty-eight, 7-week-old pigs were dosed orally with a pure culture of L. intracellularis. Animals were killed 3, 7, 14, 21, 28, 35, and 42 days postinfection. Light microscopic studies were undertaken to immunophenotype the immunologic response using specific antibodies to T-cell subsets (CD3, CD4, and CD8), B cells, major histocompatibility complex class II, cadherin, and macrophages over the course of time. The results indicate that there is a direct association between the presence of L. intracellularis and reduced T-cell and B-cell numbers. For the first time, this provides evidence of the presence of an immunosuppressive mechanism operating in this disease. Furthermore, macrophage marker studies indicated that macrophages may play a more complex and significant role in the disease process than has been previously reported, with activated macrophages accumulating in infected hyperplastic crypts.

  15. CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection.

    Directory of Open Access Journals (Sweden)

    Christophe Côme

    Full Text Available 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.

  16. Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

    Science.gov (United States)

    Heidegger, Simon; Anz, David; Stephan, Nicolas; Bohn, Bernadette; Herbst, Tina; Fendler, Wolfgang Peter; Suhartha, Nina; Sandholzer, Nadja; Kobold, Sebastian; Hotz, Christian; Eisenächer, Katharina; Radtke-Schuller, Susanne; Endres, Stefan; Bourquin, Carole

    2013-10-10

    Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

  17. Hypolipidemic effect of arborium plus in experimentally induced hypercholestermic rabbits.

    Science.gov (United States)

    Murty, Devarakonda; Rajesh, Enjamoori; Raghava, Doonaboina; Raghavan, Tangaraj Vijaya; Surulivel, Mukanthan Karupiah Munirajan

    2010-06-01

    Hypercholesteremia is one of the risk factors for coronary artery disease. The present study highlights the efficacy of the ayurvedic herbal formulation Arborium Plus [Hyppophae ramnoides L. fruit juice (S) and Rhododendron arboreum Sm. Linn flower juice (R) in a 1:4 ratio] on triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), atherogenic index (AI), high-density lipoprotein (HDL), and high-sensitivity c-reactive protein (hs CRP) in experimentally induced hypercholesterolemic rabbits. Four groups of rabbits were subjected to different treatments for 8 weeks: control group, CHOL group (1% w/w cholesterol for 8 weeks), S+R group (1% w/w cholesterol and Arborium Plus for 8 weeks), and A group (1% w/w cholesterol and atorvastatin for 8 weeks). The results showed significant increases in TG, TC, LDL, AI, and hs CRP in hypercholesterolemic rabbits which was significantly reduced in Arborium Plus-treated hypercholesterolemic rabbits. The data demonstrated that the Arborium Plus formulation was associated with hypolipidemic effects in experimentally induced hypercholesterolemic rabbits.

  18. Innate immune system activation by viral RNA: How to predict it?

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Differential proteomics reveals age-dependent liver oxidative costs of innate immune activation in mice.

    Science.gov (United States)

    Plumel, Marine I; Benhaim-Delarbre, Margaux; Rompais, Magali; Thiersé, Danièle; Sorci, Gabriele; van Dorsselaer, Alain; Criscuolo, François; Bertile, Fabrice

    2016-03-01

    Individual response to an immune challenge results from the optimization of a trade-off between benefits and costs of immune cell activation. Age-related immune disorders may have several mechanistic bases, from immune cell defects to chronic pro-inflammatory status and oxidative imbalance, but we are still lacking experimental data showing the relative importance of each of these mechanisms. Using a proteomic approach and subsequent biochemical validations of proteomics-derived hypotheses, we found age-dependent regulations in the liver of 3-months and 1-year old-mice in response to an acute innate immune activation. Old mice presented a chronic up-regulation of several proteins involved in pathways related to oxidative stress control. Interestingly, these pathways were weakly affected by the innate immune activation in old compared to young individuals. In addition, old mice suffered from lower glutathione-S-transferase activity and from higher oxidative damage at the end of the experiment, thus suggesting that they paid a higher immune-related cost than young individuals. On the whole, our data showed that a substantial fraction of the liver costs elicited by an activation of the innate immune response is effectively related to oxidative stress, and that ageing impairs the capacity of old individuals to control it. Our paper tackles the open question of the cost of mounting an innate immune response. Evolutionary biologists are familiar since a long time with the concept of trade-offs among key traits of an organism, trade-offs that shape life history trajectories of species and individuals, ultimately in terms of reproduction and survival. On the other hand, medicine and molecular biologists study the intimate mechanisms of immune senescence and underline that oxidative imbalance is probably playing a key role in the progressive loss of immune function with age. This paper merges the two fields by exploring the nature of the cellular pathways that are mainly

  20. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation.

    Science.gov (United States)

    Weber-Stadlbauer, U; Richetto, J; Labouesse, M A; Bohacek, J; Mansuy, I M; Meyer, U

    2017-01-01

    Prenatal exposure to infectious or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components, including schizophrenia, autism and bipolar disorder. It remains unknown, however, if such immune-mediated brain anomalies can be transmitted to subsequent generations. Using an established mouse model of prenatal immune activation by the viral mimetic poly(I:C), we show that reduced sociability and increased cued fear expression are similarly present in the first- and second-generation offspring of immune-challenged ancestors. We further demonstrate that sensorimotor gating impairments are confined to the direct descendants of infected mothers, whereas increased behavioral despair emerges as a novel phenotype in the second generation. These transgenerational effects are mediated via the paternal lineage and are stable until the third generation, demonstrating transgenerational non-genetic inheritance of pathological traits following in-utero immune activation. Next-generation sequencing further demonstrated unique and overlapping genome-wide transcriptional changes in first- and second-generation offspring of immune-challenged ancestors. These transcriptional effects mirror the transgenerational effects on behavior, showing that prenatal immune activation leads to a transgenerational transmission (presence of similar phenotypes across generations) and modification (presence of distinct phenotypes across generations) of pathological traits. Together, our study demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations. These findings thus highlight a novel pathological aspect of this early-life adversity in shaping disease risk across generations.

  1. Immune activation in the central nervous system throughout the course of HIV infection.

    Science.gov (United States)

    Spudich, Serena S

    2016-03-01

    Robust and dynamic innate and adaptive responses characterize the acute central nervous system (CNS) response to HIV and other viral infections. In a state of chronic infection or viral latency, persistent immune activation associates with abnormality in the CNS. Understanding this process is critical, as immune-mediated abnormality in nonrenewable CNS cells may result in long-term neurologic sequelae for HIV-infected individuals. In humans, immune activation is reduced by suppressive combination antiretroviral therapy, but persists at abnormally elevated levels on treatment. CNS immune activation is initiated in acute infection and progressively increases until combination antiretroviral therapy is started. Newly identified characteristics of the CNS immune surveillance network include features of homeostasis and function of brain microglial cells, lymphatic drainage from CNS to cervical lymph nodes, and cells in cerebrospinal fluid associated with neurocognitive impairment. More research is required to determine whether early intervention to reduce infection limits the immunopathology established by sustained immune responses that ultimately fail to resolve infection, and to unravel mechanisms of persistent immune activation during treated HIV so that strategies can be developed to therapeutically protect the brain.

  2. Immune and hormonal activity in adults suffering from depression

    Directory of Open Access Journals (Sweden)

    S.O.V. Nunes

    2002-05-01

    Full Text Available 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 ß-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.

  3. Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV

    Directory of Open Access Journals (Sweden)

    Zuri A. Sullivan

    2015-04-01

    Significance: Latent tuberculosis, which affects an estimated 1/3 of the world's population, has long been thought to be a relatively benign, quiescent state of M. tuberculosis infection. While HIV co-infection is known to exacerbate M. tuberculosis infection and increase the risk of developing active TB, little is known about the potential effect of latent TB infection on HIV disease. This study shows that HIV-infected individuals with both active and latent TB have elevated levels of inflammation and immune activation, biomarkers of HIV disease progression and elevated risk of mortality. These results suggest that, in the context of HIV, latent TB infection may be associated with increased risk of progression to AIDS and mortality.

  4. Hypertension and immunity: mechanisms of T cell activation and pathways of hypertension.

    Science.gov (United States)

    Abais-Battad, Justine M; Rudemiller, Nathan P; Mattson, David L

    2015-09-01

    The role of immune mechanisms to amplify hypertension in patients and animal models has been appreciated for decades. This review briefly summarizes recent studies exploring the mechanistic pathways, whereby the immune system participates in hypertension and renal disease. Emphasis in this review is placed upon recent studies exploring the role of T cell subtypes, newly described mechanisms of T cell activation, the identification of potential neoantigens, and environmental influences on immune cell activation. Significant advancements have been made in the search for antigens and pathways responsible for activation of the adaptive immune response, furthering our understanding of the factors contributing to hypertension and potentially leading to the development of new and more effective therapies.

  5. Adjuvant activity of rice oil on the immune response to ovalbumin

    Directory of Open Access Journals (Sweden)

    Isabela Thommen Maciel Sartor

    2011-08-01

    Full Text Available We have evaluated the adjuvant activity of rice oil (RO on the immune response to ovalbumin (OVA, its depots and possible side effects at the injection sites. Immunization of mice with OVA emulsified in rice oil (OVA+RO resulted in an antibody response significantly higher than that determined in mice immunized with soluble OVA. In addition, these high antibody levels were observed for a period as long as 6 weeks after immunization. However, the adjuvant action of RO was significantly lower to incomplete Freund's adjuvant (IFA. In secondary immune response, the pattern of OVA-specific antibodies stimulated by RO was predominantly IgG1. Despite of the significant humoral response enhanced by RO at no time was noted any lesions at the site of injection. Besides, histological analysis showed that inflammatory reaction caused by RO was mild and transient, suggesting that RO appears to be a safe, effective and chemically define alternative to IFA in many situations.

  6. Neurogenic cardiomyopathy in rabbits with experimentally induced rabies.

    Science.gov (United States)

    Kesdangsakonwut, S; Sunden, Y; Yamada, K; Nishizono, A; Sawa, H; Umemura, T

    2015-05-01

    Cardiomyopathies have been rarely described in rabbits. Here we report myocardial necrosis of the ventricular wall in rabbits with experimentally induced rabies. Myocardial lesions were found only in rabbits with brain lesions, and the severity of the cardiac lesions was proportional to that of the brain lesions. Neither the frequency nor the cumulative dose of anesthesia was related to the incidence or the severity of the myocardial lesions. The myocardial lesions were characterized by degeneration and/or necrosis of myocardial cells and were accompanied by contraction band necrosis, interstitial fibrosis, and infiltration of inflammatory cells. The brain lesions due to rabies virus infection were most prominent in the cerebral cortex, thalamus, hypothalamus, brainstem, and medulla. Rabies virus antigen was not found in the hearts of any rabbits. Based on these findings, the myocardial lesions were classified as neurogenic cardiomyopathy. © The Author(s) 2014.

  7. Lgt processing is an essential step in Streptococcus suis lipoprotein mediated innate immune activation.

    Directory of Open Access Journals (Sweden)

    Paul J Wichgers Schreur

    Full Text Available 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. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] 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.

  8. Microbiota activation and regulation of innate and adaptive immunity.

    Science.gov (United States)

    Alexander, Katie L; Targan, Stephan R; Elson, Charles O

    2014-07-01

    The human host has coevolved 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 to 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. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Effect of ES products from Anisakis (Nematoda: Anisakidae) on experimentally induced colitis in adult zebrafish.

    Science.gov (United States)

    Haarder, S; Kania, P W; Holm, T L; von Gersdorff Jørgensen, L; Buchmann, K

    2017-10-01

    Inflammatory bowel disease (IBD) in developed countries is linked with elevated hygienic standards. One of the several factors involved in this question may be reduced exposure to the immunomodulatory effects of parasitic helminths. Several investigations on treatment of mice and humans with helminth-derived substances have supported this notion, but underlying mechanisms remain unclear. This study therefore dissects to what extent a series of immune-related genes are modulated in zebrafish with experimentally induced colitis following exposure to excretory-secretory (ES) products isolated from larval Anisakis, a widely distributed fish nematode. Adult zebrafish intrarectally exposed to the colitis-inducing agent TNBS developed severe colitis leading to 80% severe morbidity, but if co-injected (ip) with Anisakis ES products, the morbidity rate was 50% at the end of the experiment (48 hours post-exposure). Gene expression studies of TNBS-treated zebrafish showed clear upregulation of a range of genes encoding inflammatory cytokines and effector molecules and some induction of genes related to the adaptive response. A distinct innate-driven immune response was seen in both TNBS and TNBS + ES groups, but expression values were significantly depressed for several important pro-inflammatory genes in the TNBS + ES group, indicating protective mechanisms of Anisakis ES compounds on intestinal immunopathology in zebrafish. © 2017 John Wiley & Sons Ltd.

  10. The FomA Porin from Fusobacterium nucleatum Is a Toll-Like Receptor 2 Agonist with Immune Adjuvant Activity

    OpenAIRE

    Toussi, Deana N.; Liu, Xiuping; Massari, Paola

    2012-01-01

    Many bacterial components selectively activate immune and nonhematopoietic target cells via Toll-like receptor (TLR) signaling; modulation of such host responses defines the immune adjuvant properties of these bacterial products. For example, the outer membrane protein porins from Neisseria, Salmonella, and Shigella are known TLR2 agonists with established systemic and mucosal immune adjuvanticity. Early work indicated that the FomA porin from Fusobacterium nucleatum has immune adjuvant activ...

  11. Salidroside liposome formulation enhances the activity of dendritic cells and immune responses.

    Science.gov (United States)

    Zhao, Xiaojuan; Lu, Yu; Tao, Yang; Huang, Yee; Wang, Deyun; Hu, Yuanliang; Liu, Jiaguo; Wu, Yi; Yu, Yun; Liu, Cui

    2013-12-01

    Salidroside, the important composition, of Rhodiola rosea L. has been reported to have various pharmacological properties. Liposome is known to be effective as drug carriers and immune adjuvant. Therefore, the aim of this study is to investigate immunological adjuvant activity of salidroside liposome. Here we reported the preparation, the effect on DCs in vitro and the immune response in vivo. The immunological adjuvant activity of salidroside liposome formulation was compared with that of salidroside and liposome. The result showed that salidroside liposome formulation not only could promote the maturation of DCs, the stimulation of DCs on MLR proliferation and the antigen presenting ability, but also induced the sustained cellular immune and humoral immune response. Overall, the results showed that salidroside liposome formulation had the potential to act as effective sustained release vaccine delivery systems. © 2013.

  12. Long-term activation of the innate immune system in atherosclerosis.

    Science.gov (United States)

    Christ, Anette; Bekkering, Siroon; Latz, Eicke; Riksen, Niels P

    2016-08-01

    Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque. This suggests that pro-atherogenic stimuli, such as LDL cholesterol and high fat diets may impart longer lived signals on (innate) immune cells that persist even after reversing the pro-atherogenic stimuli. Recently, a series of studies challenged the traditional immunological paradigm that innate immune cells cannot display memory characteristics. Epigenetic reprogramming in these myeloid cell subsets, after exposure to certain stimuli, has been shown to alter the expression of genes upon re-exposure. This phenomenon has been termed trained innate immunity or innate immune memory. The changed responses of 'trained' innate immune cells can confer nonspecific protection against secondary infections, suggesting that innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions as the resulting exaggerated immune responses could contribute to autoimmune and inflammatory diseases, such as atherosclerosis. Pro-atherogenic stimuli most likely cause epigenetic modifications that persist for prolonged time periods even after the initial stimulus has been removed. In this review we discuss the concept of trained innate immunity in the context of a hyperlipidemic environment and atherosclerosis. According to this idea the epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  13. RAC1 activation drives pathologic interactions between the epidermis and immune cells.

    Science.gov (United States)

    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.

  14. Influence of maternal antibodies on active pertussis toxoid immunization of neonatal mice and piglets.

    Science.gov (United States)

    Polewicz, Monika; Gracia, Aleksandra; Buchanan, Rachelle; Strom, Stacy; Halperin, Scott A; Potter, Andrew A; Babiuk, Lorne A; Gerdts, Volker

    2011-10-13

    Whooping cough caused by infection with Bordetella pertussis, is a serious illness in infants and young children. Mortality due to whooping cough is being reported in infants too young to be immunized as well as those who have not completed their series of vaccinations. One of the major factors that interferes with successful active immunization in early life is the presence of maternal antibodies (MatAbs). Using the mouse and pig models, we evaluated the effect of maternal antibodies on active immunization with pertussis toxoid (PTd) and explored strategies to overcome this interference. Our results indicate that passively transferred maternal antibodies interfered with active immunization using pertussis toxoid. The level of passively transferred antibodies directly correlated with the level of interference observed. However, this interference could be overcome by using a second booster immunization or by co-formulating the toxoid with novel adjuvants. These results support the need for novel vaccine formulations that are optimized for the neonate and that can be used not only to modulate the inherently biased neonatal immune system but also to prime the response in the presence of passively transferred maternal antibodies. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Development of embryos in superovulated guinea pigs following active immunization against the inhibin alpha-subunit.

    Science.gov (United States)

    Shi, F; Mochida, K; Suzuki, O; Matsuda, J; Ogura, A; Tsonis, C G; Watanabe, G; Suzuki, A K; Taya, K

    2000-08-01

    Embryo recovery and subsequent embryonic development from guinea pigs treated with or without inhibin vaccines were compared to determine the effect of active immunization against the inhibin alpha-subunit. Twenty female guinea pigs of the Hartley strain were injected 3 times either with 1 ml inhibin vaccine (recombinant ovine inhibin a-subunit in oil emulsion: 50 microg/ml, inhibin-immunized group), or 1 ml placebo (saline in oil emulsion; control group) at 4 week intervals. After one estrous cycle following the last injection, females were naturally mated and embryos were collected at 11:00 hr of day 6 of pregnancy (Day 1: sperm in the vaginal smear) for culture in vitro. Active immunization increased the number of corpora lutea (12.6+/-3.0 vs. 4.6+/-0.2, P0.05). During subsequent 8 day culture in vitro, most of the recovered embryos formed trophoblast outgrowth; 100% (14/14) and 88.2% (15/17) in control and immunized groups, respectively. High levels of inhibin antibody titers were sustained in the inhibin-immunized guinea pigs at least for 5 months after the last injection while no antibody titer was detected in the control animals. These results indicate that active immunization against the inhibin a-subunit is a long-acting and efficient method to induce superovulation with normal embryonic development in the guinea pig.

  16. Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.

    Science.gov (United States)

    Lavezzo, A; Melillo, G; Clavenna, G; Omini, C

    1992-06-01

    The mechanism of action of levodropropizine has been investigated in different models of experimentally-induced cough in guinea-pigs. In particular it has been demonstrated that the antitussive drug has a peripheral site of action by injecting the drug intracerebroventricularly (i.c.v.). In these experiments levodropropizine (40 micrograms/50 microliters i.c.v.) did not prevent electrically-induced cough. On the other hand, codeine (5 micrograms/50 microliters i.c.v.) markedly prevented coughing. A difference in the potency ratio of levodropropizine and codeine has been demonstrated in capsaicin-induced cough; after oral administration, codeine was about two to three times more potent than levodropropizine. However, after aerosol administration the two compounds were equipotent. These data might suggest a peripheral site of action for levodropropizine which is related to sensory neuropeptides. Further support for the role of sensory neuropeptides in the mechanism of action of levodropropizine comes from the results obtained in capsaicin-desensitized animals. In this experimental model levodropropizine failed to prevent the vagally elicited cough in neuropeptide-depleted animals, whereas codeine did not differentiate between control and capsaicin-treated animals. In conclusion, our results support the suggestion that levodropropizine has a peripheral site of action. In addition, the interference with the sensory neuropeptide system may explain, at least in part, its activity in experimentally-induced cough.

  17. Sympathetic‐mediated activation versus suppression of the immune system: consequences for hypertension

    Science.gov (United States)

    Case, Adam J.

    2016-01-01

    Abstract It is generally well‐accepted that the immune system is a significant contributor in the pathogenesis of hypertension. Specifically, activated and pro‐inflammatory T‐lymphocytes located primarily in the vasculature and kidneys appear to have a causal role in exacerbating elevated blood pressure. It has been proposed that increased sympathetic nerve activity and noradrenaline outflow associated with hypertension may be primary contributors to the initial activation of the immune system early in the disease progression. However, it has been repeatedly demonstrated in many different human and experimental diseases that sympathoexcitation is immunosuppressive in nature. Moreover, human hypertensive patients have demonstrated increased susceptibility to secondary immune insults like infections. Thus, it is plausible, and perhaps even likely, that in diseases like hypertension, specific immune cells are activated by increased noradrenaline, while others are in fact suppressed. We propose a model in which this differential regulation is based upon activation status of the immune cell as well as the resident organ. With this, the concept of global immunosuppression is obfuscated as a viable target for hypertension treatment, and we put forth the concept of focused organ‐specific immunotherapy as an alternative option. PMID:26830047

  18. Sympathetic-mediated activation versus suppression of the immune system: consequences for hypertension.

    Science.gov (United States)

    Case, Adam J; Zimmerman, Matthew C

    2016-02-01

    It is generally well-accepted that the immune system is a significant contributor in the pathogenesis of hypertension. Specifically, activated and pro-inflammatory T-lymphocytes located primarily in the vasculature and kidneys appear to have a causal role in exacerbating elevated blood pressure. It has been proposed that increased sympathetic nerve activity and noradrenaline outflow associated with hypertension may be primary contributors to the initial activation of the immune system early in the disease progression. However, it has been repeatedly demonstrated in many different human and experimental diseases that sympathoexcitation is immunosuppressive in nature. Moreover, human hypertensive patients have demonstrated increased susceptibility to secondary immune insults like infections. Thus, it is plausible, and perhaps even likely, that in diseases like hypertension, specific immune cells are activated by increased noradrenaline, while others are in fact suppressed. We propose a model in which this differential regulation is based upon activation status of the immune cell as well as the resident organ. With this, the concept of global immunosuppression is obfuscated as a viable target for hypertension treatment, and we put forth the concept of focused organ-specific immunotherapy as an alternative option. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  19. Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1.

    Science.gov (United States)

    Holder, Beth S; Tower, Clare L; Forbes, Karen; Mulla, Melissa J; Aplin, John D; Abrahams, Vikki M

    2012-06-01

    Envelope glycoproteins of human endogenous retrovirus (HERV), such as syncytin 1 (HERV-W), are highly expressed in the placenta and some family members have immunomodulatory properties. Placental microvesicles (MV), which are shed into the maternal circulation during pregnancy, have been demonstrated to induce immune cell activation. Therefore, the aim of this study was to investigate the immunological properties of the highly expressed placental HERV-W protein, syncytin 1, and its potential involvement in placental MV modulation of immune cell activity. The MV shed from first trimester, normal term and pre-eclamptic term placentas, and from the BeWo trophoblast cell line, all contain syncytin 1. Recombinant syncytin 1 and syncytin 1-positive BeWo trophoblast MV both induced peripheral blood mononuclear cell (PBMC) activation, indicated through production of cytokines and chemokines. Reducing syncytin 1 content in BeWo MV inhibited PBMC activation. Recombinant syncytin 1 and syncytin-1-positive BeWo MV dampened PBMC responses to lipopolysaccharide challenge. Our findings suggest that syncytin 1 is shed from the placenta into the maternal circulation in association with MV, and modulates immune cell activation and the responses of immune cells to subsequent lipopolysaccharide stimulation. These studies implicate placental MV-associated HERV in fetal regulation of the maternal immune system. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.

  20. Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity.

    Directory of Open Access Journals (Sweden)

    Meghan M Painter

    2015-12-01

    Full Text Available 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.

  1. Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity.

    Science.gov (United States)

    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.

  2. Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery.

    Science.gov (United States)

    Robson, Matthew J; Quinlan, Meagan A; Blakely, Randy D

    2017-05-17

    Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD. Supporting this connection, peripheral immune activation results in changes in the function and/or expression of many components of 5-HT signaling that are associated with depressive-like phenotypes. How 5-HT is utilized by the immune system to effect CNS function and ultimately behaviors related to depression is still not well understood. This Review summarizes the evidence that immune system alterations related to depression affect CNS 5-HT signaling that can alter MDD-relevant behaviors and that 5-HT regulates immune system signaling within the CNS and periphery. We suggest that targeting the interrelationships between immune and 5-HT signaling may provide more effective treatments for subsets of those suffering from inflammation-associated MDD.

  3. Subversion of innate and adaptive immune activation induced by structurally modified lipopolysaccharide from Salmonella typhimurium

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    Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Pérez-Shibayama, Christian I; Moreno-Eutimio, Mario A; Cervantes-Barragán, Luisa; Arriaga-Pizano, Lourdes; Ludewig, Burkhard; Cunningham, Adam F; García-Zepeda, Eduardo A; Becker, Ingeborg; Alpuche-Aranda, Celia; Bonifaz, Laura; Gunn, John S; Isibasi, Armando; López-Macías, Constantino

    2011-01-01

    Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4+ T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses. PMID:21631497

  4. Activation of Innate Immunity by Bacterial Ligands of Toll-like Receptors

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    Nelli K. Akhmatova

    2014-03-01

    Full Text Available Tγδ and B1 lymphocytes are essential components of the mucosal immune system, activating different bacterial and viral ligands without costimulatory signals and preprocessing of other immune effectors. This ability enables the immune system to provide rapid protection against pathogens and contributes to the decoding mechanism of the sensitizing activity of mucosal antigens, because the interaction of these cells produces antibodies for immunoglobulin M (IgM and IgA, but not for IgE. We studied 3 routes of introducing antigens for opportunistic microorganisms to activate Tγδ and B1 lymphocytes: subcutaneous, intranasal, and oral. The subcutaneous and intranasal routes produced a significant increase of these cells in lymph nodes associated with the nasal cavity (NALT and in those associated with bronchial tissue (BALT. The oral route significantly increased levels of these cells in the spleen, in NALT, BALT, and in nodes associated with the gut (GALT. We found that mucosal application of the immunomodulator Immunovac-VP-4 (contains antigens of conditionally pathogenic microorganisms, in conjunction with the activation of Tγδ and B1, induces adaptive immune mechanisms not only in the lymphoid formations associated with the respiratory system and with GALT, but also in the spleen (increased expression of cluster of differentiation 3 [CD3], CD4, CD8, CD19, and CD25. This indicates that there is migration of lymphoid cells from the regional lymph nodes and mucosal lymphoid tissues via the lymph and blood to distant organs, lymphoid development, and both local and systemic immunity. Mucosal application of Immunovac-VP-4 in mice potentiates the cytotoxic activity of NK cells in the NALT, BALT and GALT. The highest cytotoxicity was observed in cells, derived from lymphoid tissue of the intestine after oral immunization. Although we found that cytokine production was increased by all 3 immunization routes, it was most intensive after subcutaneous

  5. Mathematical models of e-antigen mediated immune tolerance and activation following prenatal HBV infection.

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    Stanca M Ciupe

    Full Text Available We develop mathematical models for the role of hepatitis B e-antigen in creating immunological tolerance during hepatitis B virus infection and propose mechanisms for hepatitis B e-antigen clearance, subsequent emergence of a potent cellular immune response, and the effect of these on liver damage. We investigate the dynamics of virus-immune cells interactions, and derive parameter regimes that allow for viral persistence. We modify the model to account for mechanisms responsible for hepatitis B e-antigen loss, such as seroconversion and virus mutations that lead to emergence of cellular immune response to the mutant virus. Our models demonstrate that either seroconversion or mutations can induce immune activation and that instantaneous loss of e-antigen by either mechanism is associated with least liver damage and is therefore more beneficial for disease outcomes.

  6. Immediate effects of chocolate on experimentally induced mood states.

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    Macht, Michael; Mueller, Jochen

    2007-11-01

    In this work two hypotheses were tested: (1) that eating a piece of chocolate immediately affects negative, but not positive or neutral mood, and (2) that this effect is due to palatability. Experiment 1 (48 normal-weight and healthy women and men) examined the effects of eating a piece of chocolate and drinking water on negative, positive and neutral mood states induced by film clips. Eating chocolate reduced negative mood compared to drinking water, whereas no or only marginal effects were found on neutral and positive moods. Experiment 2 (113 normal-weight and healthy women and men) compared effects of eating palatable and unpalatable chocolate on negative mood, and examined the duration of chocolate-induced mood change. Negative mood was improved after eating palatable chocolate as compared to unpalatable chocolate or nothing. This effect was short lived, i.e., it disappeared after 3 min. In both experiments, chocolate-induced mood improvement was associated with emotional eating. The present studies demonstrate that eating a small amount of sweet food improves an experimentally induced negative mood state immediately and selectively and that this effect of chocolate is due to palatability. It is hypothesized that immediate mood effects of palatable food contribute to the habit of eating to cope with stress.

  7. Effects of Caffeine and Lycopene in Experimentally Induced Diabetes Mellitus.

    Science.gov (United States)

    Ozmen, Ozlem; Topsakal, Senay; Haligur, Mehmet; Aydogan, Ahmet; Dincoglu, Dilnur

    2016-04-01

    Diabetes mellitus (DM) is a global epidemic with increasing prevalence. The disease is chronic in nature, and patients must use antidiabetic drugs or insulin during their lifespan. Because of the difficulty of using injectable insulin preparations, patients and practitioners prefer to use oral antidiabetic drugs for prophylaxis and treatment. There are, however, numerous adverse effects of antidiabetic drugs and rapidly increasing attention is being paid to new nutraceutical drugs with fewer adverse effects. The purpose of this study was to evaluate the effects of caffeine and lycopene on streptozotocin (STZ)-induced DM in rats. Caffeine and lycopene were administered to the study groups by oral gavages for 1 month whereafter experimental diabetes was induced in 90 rats in 6 groups. There were no pathological effects of lycopene and caffeine on the pancreas. Marked vacuolization and degeneration were observed in STZ-treated groups. Caffeine and lycopene decreased the pathological findings and lowered the blood and urine glucose levels in the rats with STZ-induced DM, whereas these compounds increased serum insulin levels. This study showed that caffeine and lycopene provided protective effects against experimentally induced DM. The protective effects of lycopene were observed to be much greater than those of caffeine.

  8. Local and Systemic Inflammatory Responses to Experimentally Induced Gingivitis

    Science.gov (United States)

    Leishman, Shaneen J.; Seymour, Gregory J.; Ford, Pauline J.

    2013-01-01

    This study profiled the local and systemic inflammatory responses to experimentally induced gingivitis. Eight females participated in a 21-day experimental gingivitis model followed by a 14-day resolution phase. Bleeding on probing and plaque index scores were assessed before, during, and after resolution of gingival inflammation, and samples of saliva, GCF, and plasma were collected. Samples were assessed for biomarkers of inflammation using the BioPlex platform and ELISA. There were no significant changes in GCF levels of cytokines during the experimental phase; however, individual variability in cytokine profiles was noted. During resolution, mean GCF levels of IL-2, IL-6, and TNF-α decreased and were significantly lower than baseline levels (P = 0.003, P = 0.025, and P = 0.007, resp.). Furthermore, changes in GCF levels of IL-2, IL-6, and TNF-α during resolution correlated with changes in plaque index scores (r = 0.88, P = 0.004; r = 0.72, P = 0.042; r = 0.79, P = 0.019, resp.). Plasma levels of sICAM-1 increased significantly during the experimental phase (P = 0.002) and remained elevated and significantly higher than baseline levels during resolution (P gingivitis adds to the systemic inflammatory burden of an individual. PMID:24227893

  9. Activation of human natural killer cells by the novel innate immune modulator recombinant Eimeria antigen.

    Science.gov (United States)

    Aylsworth, Charles F; Aldhamen, Yasser A; Seregin, Sergey S; Godbehere, Sarah; Amalfitano, Andrea

    2013-08-01

    The safe and effective activation of the innate and adaptive immune systems are crucial in the implementation of immunotherapeutic modalities for the prevention and treatment of human diseases. Eimeria antigen (EA) and its recombinantly expressed analog (rEA) are extremely effective activators of innate immunity in mice. The effects of rEA in the mouse are primarily mediated through the TLR11/12 MyD88 signaling system. Human cells lack functional TLR11 and TLR12, suggesting that rEA would not be effective in providing beneficial immune activation in humans. In the current report we provide definitive evidence that the treatment of human peripheral blood mononuclear cell (PBMC) cultures with rEA significantly up regulates CD69, CD107, NKG2D levels on NK cells. Furthermore, rEA stimulates human NK cell effector functions including increasing intracellular levels of IFNγ and Granzyme B. These responses are positively correlated with an improved capacity of rEA stimulated human PBMCs to kill NK cell-sensitive human K562 tumor cells. Importantly, rEA-triggered innate immune responses was not associated with increased pro-inflammatory cytokines and chemokines production. These data confirm a previously unidentified role for rEA in human immune cell activation, and suggests the utilization of rEA in immunotherapies against a variety of infectious diseases and cancers. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  10. [Effect of immune modulation on immunogenic and protective activity of a live plague vaccine].

    Science.gov (United States)

    Karal'nik, B V; Ponomareva, T S; Deriabin, P N; Denisova, T G; Mel'nikova, N N; Tugambaev, T I; Atshabar, B B; Zakarian, S B

    2014-01-01

    Comparative evaluation of the effect of polyoxidonium and betaleukin on immunogenic and protective activity of a live plague vaccine in model animal experiments. Plague vaccine EV, polyoxidonium, betaleukin, erythrocytic antigenic diagnosticum for determination of F1 antibodies and immune reagents for detection of lymphocytes with F1 receptors (LFR) in adhesive test developed by the authors were used. The experiments were carried out in 12 rabbits and 169 guinea pigs. Immune modulation accelerated the appearance and disappearance of LFR (early phase) and ensured a more rapid and intensive antibody formation (effector phase). Activation by betaleukin is more pronounced than by polyoxidonium. The more rapid and intensive was the development of early phase, the more effective was antibody response to the vaccine. Immune modulation in the experiment with guinea pigs significantly increased protective activity of the vaccine. The use of immune modulators increased immunogenic (in both early and effector phases of antigen-specific response) and protective activity of the EV vaccine. A connection between the acceleration of the first phase of antigen-specific response and general intensity of effector phase of immune response to the EV vaccine was detected. ,

  11. Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages.

    Science.gov (United States)

    Cheng, Xiaoming; Xia, Yuchen; Serti, Elisavet; Block, Peter Daniel; Chung, Michelle; Chayama, Kazuaki; Rehermann, Barbara; Liang, T Jake

    2017-12-01

    Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune-mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell-culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV-infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high-level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. HBV behaves like a "stealth" virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long "window period" during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779-1793). © 2017 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

  12. Immune activation alters cellular and humoral responses to yellow fever 17D vaccine.

    Science.gov (United States)

    Muyanja, Enoch; Ssemaganda, Aloysius; Ngauv, Pearline; Cubas, Rafael; Perrin, Helene; Srinivasan, Divya; Canderan, Glenda; Lawson, Benton; Kopycinski, Jakub; Graham, Amanda S; Rowe, Dawne K; Smith, Michaela J; Isern, Sharon; Michael, Scott; Silvestri, Guido; Vanderford, Thomas H; Castro, Erika; Pantaleo, Giuseppe; Singer, Joel; Gillmour, Jill; Kiwanuka, Noah; Nanvubya, Annet; Schmidt, Claudia; Birungi, Josephine; Cox, Josephine; Haddad, Elias K; Kaleebu, Pontiano; Fast, Patricia; Sekaly, Rafick-Pierre; Trautmann, Lydie; Gaucher, Denis

    2014-07-01

    Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. We showed that YF-17D-induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D-neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. Registration is not required for observational studies. This study was funded by Canada's Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases

  13. Vaginal immunization to elicit primary T-cell activation and dissemination.

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    Elena Pettini

    Full Text Available 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.

  14. Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation

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    van Horssen Jack

    2012-07-01

    Full Text Available Abstract Background In brain tissues from multiple sclerosis (MS patients, clusters of activated HLA-DR-expressing microglia, also referred to as preactive lesions, are located throughout the normal-appearing white matter. The aim of this study was to gain more insight into the frequency, distribution and cellular architecture of preactive lesions using a large cohort of well-characterized MS brain samples. Methods Here, we document the frequency of preactive lesions and their association with distinct white matter lesions in a cohort of 21 MS patients. Immunohistochemistry was used to gain further insight into the cellular and molecular composition of preactive lesions. Results Preactive lesions were observed in a majority of MS patients (67% irrespective of disease duration, gender or subtype of disease. Microglial clusters were predominantly observed in the vicinity of active demyelinating lesions and are not associated with T cell infiltrates, axonal alterations, activated astrocytes or blood–brain barrier disruption. Microglia in preactive lesions consistently express interleukin-10 and TNF-α, but not interleukin-4, whereas matrix metalloproteases-2 and −9 are virtually absent in microglial nodules. Interestingly, key subunits of the free-radical-generating enzyme NADPH oxidase-2 were abundantly expressed in microglial clusters. Conclusions The high frequency of preactive lesions suggests that it is unlikely that most of them will progress into full-blown demyelinating lesions. Preactive lesions are not associated with blood–brain barrier disruption, suggesting that an intrinsic trigger of innate immune activation, rather than extrinsic factors crossing a damaged blood–brain barrier, induces the formation of clusters of activated microglia.

  15. 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.

    Science.gov (United States)

    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

    2014-03-04

    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.

  16. Establishing a Proteomics-Based Monocyte Assay To Assess Differential Innate Immune Activation Responses.

    Science.gov (United States)

    Tarasova, Nataliya K; Ytterberg, A Jimmy; Lundberg, Karin; Zhang, Xing-Mei; Harris, Robert A; Zubarev, Roman A

    2016-07-01

    Innate immune cells are complex systems that can be simultaneously activated in a variety of ways. Common methods currently used to estimate the response of innate immune cells to stimuli are usually biased toward a single mode of activation. The aim of this study was to assess the possibility of designing an assay based on unbiased proteome analysis that would be capable of predicting the complex response of the innate immune system to various challenges. Monocytes were used as representative cells of the innate immune system. The underlying hypothesis was that their proteome response to different activating molecules would reflect the immunogenicity of these molecules. To identify the main modes of response, we treated the human monocytic THP-1 cell line with nine different stimuli. Differentiation and activation were determined to be the two major modes of monocyte response, with PMA causing the strongest differentiation and Pam3CSK4 causing the strongest proinflammatory activation. The established assay was applied to characterize the monocyte response to epidermal growth factor peptide containing isoaspartate, which induced differentiation but not proinflammatory activation. Because of its versatility, robustness, and specificity, this new assay is likely to find a niche among the more established immunological methods.

  17. Oxidized lipoproteins are associated with markers of inflammation and immune activation in HIV-1 infection.

    Science.gov (United States)

    Kelesidis, Theodoros; Jackson, Nicholas; McComsey, Grace A; Wang, Xiaoyan; Elashoff, David; Dube, Michael P; Brown, Todd T; Yang, Otto O; Stein, James H; Currier, Judith S

    2016-11-13

    The pathogenesis of immune dysfunction in chronic HIV-1 infection is unclear, and a potential role for oxidized lipids has been suggested. We hypothesize that both oxidized HDL and LDL (HDLox and LDLox) contribute to HIV-1-related immune dysfunction. In the AIDS Clinical Trials Group A5260, 234 HIV-infected antiretroviral therapy (ART)-naive participants were randomized to receive tenofovir-emtricitabine and protease inhibitors or raltegravir and had HIV-1 RNA less than 50 copies/ml by week 24 and thereafter. Associations between biomarkers of inflammation (IL-6, high-sensitivity C-reactive protein and D-dimer), immune activation (sCD163, sCD14, soluble IL-2 receptor, CD38 and HLA-DR), inflammatory monocytes (CD14CD16), T-cell senescence (CD28 and CD57) and exhaustion (PD1), and HDLox, LDLox were assessed at entry and after ART (week 96) with Spearman (partial) correlations. HDLox declined and LDLox increased over 96 weeks of ART. Positive associations were observed at baseline and over time between HDLox (but not consistently for LDLox) and most markers of inflammation and immune activation (but not senescence/exhaustion), even after adjustment for multiple comparisons, demographics, entry CD4 cell count and HIV-1 RNA. HDLox was positively associated with IL-6 (r = 0.19 - 0.29, P lipoproteins may contribute to persistent immune activation on ART.

  18. B-cell exhaustion in HIV infection: the role of immune activation.

    Science.gov (United States)

    Moir, Susan; Fauci, Anthony S

    2014-09-01

    To discuss a component of the pathogenic mechanisms of HIV infection in the context of phenotypic and functional alterations in B cells that are due to persistent viral replication leading to aberrant immune activation and cellular exhaustion. We explore how B-cell exhaustion arises during persistent viremia and how it compares with T-cell exhaustion and similar B-cell alterations in other diseases. HIV-associated B-cell exhaustion was first described in 2008, soon after the demonstration of persistent virus-induced T-cell exhaustion, as well as the identification of a subset B cells in tonsil tissues with immunoregulatory features similar to those observed in T-cell exhaustion. Our understanding of B-cell exhaustion has since expanded in two important areas: the role of inhibitory receptors in the unresponsiveness of exhausted B cells and the increasing evidence that similar B cells are found in other diseases that are associated with aberrant immune activation and inflammation. The phenomenon of B-cell exhaustion is now well established in HIV infection and other diseases characterized by immune activation. Over the coming years, it will be important to understand how cellular exhaustion affects the capacity of the immune system to respond to persisting primary pathogens, as well as to other microbial antigens, whether encountered as secondary infections or following immunization.

  19. MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses.

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    Jong W Yu

    Full Text Available CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.

  20. Systemic Immune Activation and HIV Shedding in the Female Genital Tract.

    Science.gov (United States)

    Spencer, LaShonda Y; Christiansen, Shawna; Wang, Chia-Hao H; Mack, Wendy J; Young, Mary; Strickler, Howard D; Anastos, Kathryn; Minkoff, Howard; Cohen, Mardge; Geenblatt, Ruth M; Karim, Roksana; Operskalski, Eva; Frederick, Toni; Homans, James D; Landay, Alan; Kovacs, Andrea

    2016-02-01

    Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication, and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding. Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38(+)DR(+) and CD38(-)DR(-)) on CD4(+) and CD8(+) T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load >80 copies per milliliter. We tested associations between immune activation and shedding using generalized estimating equations with logit link function. In the univariate model, higher levels of CD4(+) and CD8(+) T-cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs, and genital tract infections, only higher levels of resting CD8(+) T cells (CD38(-)DR(-)) were significantly inversely associated with HIV shedding in the genital tract (odds ratios = 0.44, 95% confidence interval: 0.21 to 0.9, P = 0.02). The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T-cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs, and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared with those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV

  1. The effect of experimentally-induced subacromial pain on proprioception.

    Science.gov (United States)

    Sole, Gisela; Osborne, Hamish; Wassinger, Craig

    2015-02-01

    Shoulder injuries may be associated with proprioceptive deficits, however, it is unknown whether these changes are due to the experience of pain, tissue damage, or a combination of these. The aim of this study was to investigate the effect of experimentally-induced sub-acromial pain on proprioceptive variables. Sub-acromial pain was induced via hypertonic saline injection in 20 healthy participants. Passive joint replication (PJR) and threshold to detection of movement direction (TTDMD) were assessed with a Biodex System 3 Pro isokinetic dynamometer for baseline control, experimental pain and recovery control conditions with a starting position of 60° shoulder abduction. The target angle for PJR was 60° external rotation, starting from 40°. TTDMD was tested from a position of 20° external rotation. Repeated measures ANOVAs were used to determine differences between PJR absolute and variable errors and TTDMD for the control and experimental conditions. Pain was elicited with a median 7 on the Numeric Pain Rating Scale. TTDMD was significantly decreased for the experimental pain condition compared to baseline and recovery conditions (≈30%, P = 0.003). No significant differences were found for absolute (P = 0.152) and variable (P = 0.514) error for PJR. Movement sense was enhanced for the experimental sub-acromial pain condition, which may reflect protective effects of the central nervous system in response to the pain. Where decreased passive proprioception is observed in shoulders with injuries, these may be due to a combination of peripheral tissue injury and neural adaptations that differ from those due to acute pain. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Anticoccidial effect of mananoligosacharide against experimentally induced coccidiosis in broiler.

    Science.gov (United States)

    Chand, Naila; Faheem, Hassan; Khan, Rifat Ullah; Qureshi, Muhammad Subhan; Alhidary, Ibrahim A; Abudabos, Alaeldein M

    2016-07-01

    The aim of this study was to find the effect of mananoligosacharide (MOS) in comparison with amprolium hydrochloride on performance and integrity of gut in experimentally induced coccidiosis in broiler. A total of 300, day-old male broiler chickens (Ross 308) was randomly allocated to four treatments. Each group was further divided into five replicates of 15 birds each. Group A was kept as control; group B was contaminated with Eimeria tenella, while groups C and D were infected with E. tenella and treated with MOS (0.8 g/kg feed) and anticoccidial drug, amprolium hydrochloride (12 g/100 l water), respectively. The results showed that weight gain, feed intake, and feed conversion ratio (FCR) were significantly higher (P coccidiosis during 5th, 7th, 10th, and 12th day post infection (dpi). Furthermore, the OPG was significantly lower (P < 0.05) in infected groups treated with MOS and amprolium at the studied periods (5, 7, and 10 dpi). At 12 dpi, the infected group treated with MOS showed significantly lower OPG compared to the other groups suggesting the effectiveness of MOS in comparison to amprolium. The result of pinpoint hemorrhages, thickness of cecal wall, bloody fecal contents, and mucoid contents in the cecum were significant highly (P < 0.05) in birds fed with infected oocytes. It was also noted that the differences were not significant in these parameters between amprolium and MOS-treated birds showing the effectiveness of the prebiotic agent. It was concluded from the results of the present study that MOS improved growth performance and reversed the lesions of E. tenella.

  3. Microcirculation alterations in experimentally induced gingivitis in dogs.

    Science.gov (United States)

    Matsuo, Masato; Okudera, Toshimitsu; Takahashi, Shun-Suke; Wada-Takahashi, Satoko; Maeda, Shingo; Iimura, Akira

    2017-01-01

    The present study aimed to morphologically examine the gingival microvascular network using a microvascular resin cast (MRC) technique, and to investigate how inflammatory disease functionally affects gingival microcirculation using laser Doppler flowmetry (LDF). We used four beagle dogs with healthy periodontal tissue as experimental animals. To cause periodontal inflammation, dental floss was placed around the cervical neck portions of the right premolars. The unmanipulated left premolars served as controls, and received plaque control every 7 days. After 90 days, gingivitis was induced in the experimental side, while the control side maintained healthy gingiva. To perform morphological examinations, we used an MRC method involving the injection of low-viscosity synthetic resin into the blood vessels, leading to peripheral soft-tissue dissolution and permitting observation of the bone, teeth, and vascular cast. Gingival blood flow was estimated using an LDF meter. The control gingival vasculature showed hairpin-loop-like networks along the tooth surface. The blood vessels had diameters of 20-40 μm and were regularly arranged around the cervical portion. On the other hand, the vasculature in the experimental group was twisted and gathered into spiral forms, with blood vessels that had uneven surfaces and smaller diameters of 8-10 μm. LDF revealed reduced gingival blood flow in the group with experimentally induced gingivitis compared to controls. The actual measurements of gingival blood flow by LDF were in agreement with the alterations that would be expected based on the gingivitis-induced morphological alterations observed with the MRC technique.

  4. DMPD: IRAK-4--a shared NF-kappaB activator in innate and acquired immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17046325 IRAK-4--a shared NF-kappaB activator in innate and acquired immunity. Suzu...F-kappaB activator in innate and acquired immunity. PubmedID 17046325 Title IRAK-4--a shared NF-kappaB activator in innate and acqui

  5. Wolbachia Do Not Induce Reactive Oxygen Species-Dependent Immune Pathway Activation in Aedes albopictus

    Directory of Open Access Journals (Sweden)

    Jennifer C. Molloy

    2015-08-01

    Full Text Available Aedes albopictus is a major vector of dengue (DENV and chikungunya (CHIKV viruses, causing millions of infections annually. It naturally carries, at high frequency, the intracellular inherited bacterial endosymbiont Wolbachia strains wAlbA and wAlbB; transinfection with the higher-density Wolbachia strain wMel from Drosophila melanogaster led to transmission blocking of both arboviruses. The hypothesis that reactive oxygen species (ROS-induced immune activation plays a role in arbovirus inhibition in this species was examined. In contrast to previous observations in Ae. aegypti, elevation of ROS levels was not observed in either cell lines or mosquito lines carrying the wild-type Wolbachia or higher-density Drosophila Wolbachia strains. There was also no upregulation of genes controlling innate immune pathways or with antioxidant/ROS-producing functions. These data suggest that ROS-mediated immune activation is not an important component of the viral transmission-blocking phenotype in this species.

  6. Immune activation in multiple sclerosis and interferon-beta therapy

    DEFF Research Database (Denmark)

    Krakauer, Martin

    2007-01-01

    The PhD dissertation emanated from the Danish MS Research Centre, Rigshosptalet, Copenhagen. Multiple sclerosis (MS) is an inflammatory disease of the CNS. Inflammatory responses by T helper (Th)-lymphocytes are characterised by distinct cytokine expression profiles. In MS, activated Th1...... effects on the expression of apoptosis-related molecules, but no dramatic effects were observed. In a study of chemokines and chemokine receptors we found lower expression of the Th2-related chemokine receptor CCR4 in untreated MS patients compared with healthy controls. IFN-beta therapy decreased...... patients with active disease (not having an acute exacerbation). IFN-beta therapy markedly increased IL-10 mRNA while decreasing IL-23 mRNA expression. These effects were seen as early effects, and tapered quickly after an IFN-beta-injection. No shift towards a Th2 cytokine mRNA expression pattern was seen...

  7. Quantitative Evaluation of Stomatal Cytoskeletal Patterns during the Activation of Immune Signaling in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Masaki Shimono

    Full Text Available 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

  8. Innate immune-stimulating and immune genes up-regulating activities of three types of alginate from Sargassum siliquosum in Pacific white shrimp, Litopenaeus vannamei.

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Persistent Activation of the Innate Immune Response in Adult Drosophila Following Radiation Exposure During Larval Development.

    Science.gov (United States)

    Sudmeier, Lisa J; Samudrala, Sai-Suma; Howard, Steven P; Ganetzky, Barry

    2015-09-01

    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. Copyright © 2015 Sudmeier et al.

  10. Role of Toll-like receptors in immune activation and tolerance in the liver

    Directory of Open Access Journals (Sweden)

    Nobuhiro eNakamoto

    2014-05-01

    Full Text Available 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 controls 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.

  11. Influence of Physical Activity and Nutrition on Obesity-Related Immune Function

    Directory of Open Access Journals (Sweden)

    Chun-Jung Huang

    2013-01-01

    Full Text Available 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.

  12. Passive immunization and active vaccination against Hendra and Nipah viruses.

    Science.gov (United States)

    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.

  13. Immunologic responses in corn snakes (Pantherophis guttatus) after experimentally induced infection with ferlaviruses.

    Science.gov (United States)

    Neul, Annkatrin; Schrödl, Wieland; Marschang, Rachel E; Bjick, Tina; Truyen, Uwe; von Buttlar, Heiner; Pees, Michael

    2017-04-01

    OBJECTIVE To measure immunologic responses of snakes after experimentally induced infection with ferlaviruses. ANIMALS 42 adult corn snakes (Pantherophis guttatus) of both sexes. PROCEDURES Snakes were inoculated intratracheally with genogroup A (n = 12), B (12), or C (12) ferlavirus (infected groups) or cell-culture supernatant (6; control group) on day 0. Three snakes from each infected group were euthanized on days 4, 16, 28, and 49, and 3 snakes from the control group were euthanized on day 49. Blood samples were collected from live snakes on days -6 (baseline), 4, 16, 28, and 49. Hematologic tests were performed and humoral responses assessed via hemagglutination-inhibition assays and ELISAs. Following euthanasia, gross pathological and histologic evaluations and virus detection were performed. RESULTS Severity of clinical signs of and immunologic responses to ferlavirus infection differed among snake groups. Hematologic values, particularly WBC and monocyte counts, increased between days 4 and 16 after infection. A humoral response was identified between days 16 and 28. Serum IgM concentrations increased from baseline earlier than IgY concentrations, but the IgY relative increase was higher at the end of the study. The hemagglutination-inhibition assay revealed that the strongest reactions in all infected groups were against the strain with which they had been infected. Snakes infected with genogroup A ferlavirus had the strongest immune response, whereas those infected with genogroup B had the weakest responses. CONCLUSIONS AND CLINICAL RELEVANCE Results of this experimental study suggested that the ferlavirus strain with the highest virulence induced the weakest immune response in snakes.

  14. Activation of innate immunity by bacterial ligands of toll-like receptors.

    Science.gov (United States)

    Akhmatova, Nelli K; Egorova, Nadezhda B; Kurbatova, Ekaterina A; Akhmatov, Elvin A

    2014-01-01

    Tγδ and B1 lymphocytes are essential components of the mucosal immune system, activated directly by different bacterial and viral ligands without additional costimulatory signals and preprocessing of other immune effectors. This ability enables the immune system to provide rapid protection against pathogens and contributes to the decoding mechanism of the sensitizing activity of mucosal antigens. The early interaction of these cells results in the production of antibodies of immunoglobulin M (IgM) and IgA isotypes, but not immunoglobulin E (IgE). We studied the subcutaneous, intranasal, and oral delivery as three major routes of potential entry for antigens of opportunistic microorganisms, using the immunomodulator Immunovac-VP-4, which is able to activate Tγδ and B1 lymphocytes. The subcutaneous and intranasal routes produced a significant increase of these cells in lymph nodes associated with the nasal cavity (NALT) and in those associated with bronchial tissue (BALT). The oral route significantly increased levels of these cells in the spleen, in NALT, BALT, and in nodes associated with the gut (GALT). We found that mucosal application of Immunovac-VP-4, which contains antigens of conditionally pathogenic microorganisms, in conjunction with the activation of Tγδ and B1, induces adaptive immune mechanisms not only in the lymphoid formations associated with the respiratory system and with GALT, but also in the spleen [increased expression of cluster of differentiation 3 (CD3), CD4, CD8, CD19, and CD25]. This indicates that there is migration of lymphoid cells from the regional lymph nodes and mucosal lymphoid tissues via the lymph and blood to distant organs, resulting in lymphoid development, and both local and systemic immunity. Mucosal application of Immunovac-VP-4 in mice potentiates the cytotoxic activity of NK cells in the NALT, BALT, and GALT. The highest cytotoxicity was observed in cells, derived from lymphoid tissue of the intestine after oral

  15. Individual differences on immunostimulatory activity of raw and black garlic extract in human primary immune cells.

    Science.gov (United States)

    Purev, Uranchimeg; Chung, Mi Ja; Oh, Deog-Hwan

    2012-08-01

    The immunostimulatory activities of garlic extract using a cell line or animal models have been reported; however, no previous studies have evaluated individual differences in regards to the immunostimulatory activities. The immunostimulatory activities such as cell proliferation, tumor necrosis factor (TNF-α) and nitric oxides (NO) production of raw garlic and black garlic extracts on individual primary lymphocytes or macrophages isolated from the blood of 21 volunteers were evaluated. The antioxidant and anticancer effects of raw garlic and black garlic ethanol extract was measured to determine the optimum conditions for extraction. The 70% ethanol black garlic extracts at 70°C for 12 h (70% BGE) showed the strongest antioxidant and anticancer activities. Immunostimulatory activities of garlic extracts extracted under optimal condition on primary immune cells obtained from 21 volunteers were analyzed. Results showed that the cell proliferation, TNF-α and NO production of primary immune cells treated with 70% raw garlic extract (70% RGE) were significantly different; however, little difference was observed for the 70% BGE treatment. BGE showed stronger immunostimulatory activities than RGE. These results indicate that the immunostimulatory activities of RGE and BGE can be strongly correlated with the antioxidant and anticancer activities. Determination of immunostimulatory activities of different types of garlic using immune cells isolated from volunteers was dependent on the individual constituents due to changes in the composition of garlic during processing. Individual primary immune cells might be used as important tools to determine individual differences in all food ingredients for the development of personalized immunostimulatory active foods.

  16. Adaptive and innate immune reactions regulating mast cell activation: from receptor-mediated signaling to responses

    DEFF Research Database (Denmark)

    Tkaczyk, Christine; Jensen, Bettina M; Iwaki, Shoko

    2006-01-01

    In this article, we have described studies that have demonstrated that mast cells can be activated as a consequence of adaptive and innate immune reactions and that these responses can be modified by ligands for other receptors expressed on the surface of mast cells. These various stimuli...

  17. Association of sex work with reduced activation of the mucosal immune system.

    Science.gov (United States)

    Lajoie, Julie; Kimani, Makubo; Plummer, Francis A; Nyamiobo, Francis; Kaul, Rupert; Kimani, Joshua; Fowke, Keith R

    2014-07-15

    Unprotected intercourse and seminal discharge are powerful activators of the mucosal immune system and are important risk factors for transmission of human immunodeficiency virus (HIV). This study was designed to determine if female sex work is associated with changes in the mucosal immunity. Cervicovaginal lavage and plasma from 122 HIV-uninfected female sex workers (FSW) and 44 HIV-uninfected low-risk non-FSW from the same socioeconomic district of Nairobi were analyzed for evidence of immune activation (IA). The cervico-mononuclear cells (CMC) were analyzed for cellular activation by flow cytometry. Lower IA was observed in FSW compared to the low-risk women as demonstrated by the lower level of MIP-3α (P sex work and increased with duration of sex work. This study showed that sex work is associated with important changes in the mucosal immune system. By analyzing chemokine/cytokine levels and CMC activation, we observed a lower mucosal IA in HIV-uninfected FSW compared to low-risk women. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Immune function and phenotype before and after highly active antiretroviral therapy

    DEFF Research Database (Denmark)

    Søndergaard, S R; Aladdin, H; Ullum, H

    1999-01-01

    Immune functions represented by equal CD4 counts before and after highly active antiretroviral therapy (i.e., pre- and post-HAART) in the same HIV-infected patients, were examined. Twelve HIV-infected patients were included. Patients had equal CD4 counts pre- and post-HAART and were studied...

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

    Directory of Open Access Journals (Sweden)

    Tinyiko G. Makhubele

    2016-01-01

    Full Text Available 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.

  20. Prenatal and postnatal animal models of immune activation: relevance to a range of neurodevelopmental disorders.

    Science.gov (United States)

    Harvey, Louise; Boksa, Patricia

    2012-10-01

    Epidemiological evidence has established links between immune activation during the prenatal or early postnatal period and increased risk of developing a range of neurodevelopment disorders in later life. Animal models have been used to great effect to explore the ramifications of immune activation during gestation and neonatal life. A range of behavioral, neurochemical, molecular, and structural outcome measures associated with schizophrenia, autism, cerebral palsy, and epilepsy have been assessed in models of prenatal and postnatal immune activation. However, the epidemiology-driven disease-first approach taken by some studies can be limiting and, despite the wealth of data, there is a lack of consensus in the literature as to the specific dose, timing, and nature of the immunogen that results in replicable and reproducible changes related to a single disease phenotype. In this review, we highlight a number of similarities and differences in models of prenatal and postnatal immune activation currently being used to investigate the origins of schizophrenia, autism, cerebral palsy, epilepsy, and Parkinson's disease. However, we describe a lack of synthesis not only between but also within disease-specific models. Our inability to compare the equivalency dose of immunogen used is identified as a significant yet easily remedied problem. We ask whether early life exposure to infection should be described as a disease-specific or general vulnerability factor for neurodevelopmental disorders and discuss the implications that either classification has on the design, strengths and limitations of future experiments. Copyright © 2012 Wiley Periodicals, Inc.

  1. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection.

    Science.gov (United States)

    Zhen, Anjie; Rezek, Valerie; Youn, Cindy; Lam, Brianna; Chang, Nelson; Rick, Jonathan; Carrillo, Mayra; Martin, Heather; Kasparian, Saro; Syed, Philip; Rice, Nicholas; Brooks, David G; Kitchen, Scott G

    2017-01-03

    Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection.

  2. Self-reported parenting style is associated with children's inflammation and immune activation.

    Science.gov (United States)

    Byrne, Michelle L; Badcock, Paul B; Simmons, Julian G; Whittle, Sarah; Pettitt, Adam; Olsson, Craig A; Mundy, Lisa K; Patton, George C; Allen, Nicholas B

    2017-04-01

    Family environments and parenting have been associated with inflammation and immune activation in children and adolescents; however, it remains unclear which specific aspects of parenting drive this association. In this study, we cross-sectionally examined the association between 5 discrete parenting styles and inflammation and immune activation in late childhood. Data were drawn from 102 families (55 with female children, mean age 9.50 years, SD = 0.34) participating in the Imaging Brain Development in the Childhood to Adolescence Transition Study. Children provided saliva samples from which inflammation (C-reactive protein) and immune competence/activation (secretory immunoglobulin A) were measured. Parents completed the Alabama Parenting Questionnaire, which measures 5 aspects of parenting style-positive parental involvement, positive disciplinary techniques, consistency in disciplinary techniques, corporal punishment, and monitoring and supervision. Results showed that higher scores on the poor parental monitoring scale were associated with higher levels of both inflammation and immune activation in children. This study highlights parental monitoring and supervision as a specific aspect of parenting behavior that may be important for children's physical and mental health. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  3. The Activation and Suppression of Plant Innate Immunity by Parasitic Nematodes

    NARCIS (Netherlands)

    Goverse, A.; Smant, G.

    2014-01-01

    Plant-parasitic nematodes engage in prolonged and intimate relationships with their host plants, often involving complex alterations in host cell morphology and function. It is puzzling how nematodes can achieve this, seemingly without activating the innate immune system of their hosts. Secretions

  4. Scavenging iron: a novel mechanism of plant immunity activation by microbial siderophores.

    Science.gov (United States)

    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.

  5. Scavenging Iron: A Novel Mechanism of Plant Immunity Activation by Microbial Siderophores1[C][W

    Science.gov (United States)

    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

  6. From Wasting to Obesity: The Contribution of Nutritional Status to Immune Activation in HIV Infection.

    Science.gov (United States)

    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. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  7. DISTURBANCE OF METABOLIC ACTIVITY OF INTESTINAL MICROFLORA AND LOCAL IMMUNITY OF ROTAVIRUS INFECTION

    Directory of Open Access Journals (Sweden)

    G. P. Martynova

    2014-01-01

    Full Text Available The paper describes the research on metabolic activity of intestinal microflora and secretory immunoglobulin A (sIgA content in coprofiltrate of rotavirus infection patients depending on disease course. It is established that a long-lasting clinical oppression of metabolic processes of microbiocenosis and local immunity deficiency define a rough course of rotavirus infection. 

  8. DISTURBANCE OF METABOLIC ACTIVITY OF INTESTINAL MICROFLORA AND LOCAL IMMUNITY OF ROTAVIRUS INFECTION

    OpenAIRE

    G. P. Martynova; N. V. Kogan; I. A. Solovyeva

    2014-01-01

    The paper describes the research on metabolic activity of intestinal microflora and secretory immunoglobulin A (sIgA) content in coprofiltrate of rotavirus infection patients depending on disease course. It is established that a long-lasting clinical oppression of metabolic processes of microbiocenosis and local immunity deficiency define a rough course of rotavirus infection. 

  9. Active Immunization with Lipopolysaccharide Pseudomonas Antigen for Chronic Pseudomonas Bronchopneumonia in Guinea Pigs

    OpenAIRE

    Pennington, James E.; Hickey, William F.; Blackwood, Linda L.; Arnaut, M. Amin

    1981-01-01

    Chronic respiratory infection with Pseudomonas aeruginosa is a leading clinical problem among patients with cystic fibrosis. Because antimicrobial agents are usually ineffective in eradicating these infections, additional therapeutic or prophylactic measures should be considered. In this study, an experimental guinea pig model of chronic Pseudomonas aeruginosa bronchopneumonia was utilized to determine whether active immunization with lipopolysaccharide (LPS) P. aeruginosa antigen may favorab...

  10. STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Emily Curran

    2016-06-01

    Full Text Available 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.

  11. The Cell Nucleus in Physiological and Experimentally Induced Hypometabolism

    Science.gov (United States)

    Malatesta, M.

    The main problem for manned space mission is, at present, represented by the mass penalty associated to the human presence. An efficient approach could be the induction of a hypometabolic stasis in the astronauts, thus drastically reducing the physical and psychological requirements of the crew. On the other hand, in the wild, a reduction in resource consumptions physiologi- cally occurs in certain animals which periodically enter hibernation, a hypometabolic state in which both the energy need and energy offer are kept at a minimum. During the last twelve years, we have been studying different tissues of hibernating dormice, with the aim of analyzing their features during the euthermia -hibernation-arousal cycle as well as getting insight into the mechanisms allowing adaptation to hypometabolism. We paid particular attention to the cell nucleus, as it is the site of chief metabolic functions, such as DNA replication and RNA transcription. Our observations revealed no significant modification in the basic features of cell nuclei during hibernation; however, the cell nuclei of hibernating dormice showed unusual nuclear bodies containing molecules involved in RNA pathways. Therefore, we supposed that they could represent storage/assembly sites of several factors for processing some RNA which could be slowly synthesised during hibernation and rapidly and abundantly released in early arousal in order to meet the increased metabolic needs of the cell. The nucleolus also underwent structural and molecular modifications during hibernation, maybe to continue important nucleolar functions, or, alternatively, permit a most efficient reactivation upon arousal. On the basis of the observations made in vivo , we recently tried to experimentally induce a reversible hypometabolic state in in vitro models, using cell lines derived from hibernating and non-hibernating species. By administering the synthetic opioid DADLE, we could significantly reduce both RNA transcrip- tion and

  12. From Tumor Immunosuppression to Eradication: Targeting Homing and Activity of Immune Effector Cells to Tumors

    Directory of Open Access Journals (Sweden)

    Oana Draghiciu

    2011-01-01

    Full Text Available Unraveling the mechanisms used by the immune system to fight cancer development is one of the most ambitious undertakings in immunology. Detailed knowledge regarding the mechanisms of induction of tolerance and immunosuppression within the tumor microenvironment will contribute to the development of highly effective tumor eradication strategies. Research within the last few decades has shed more light on the matter. This paper aims to give an overview on the current knowledge of the main tolerance and immunosuppression mechanisms elicited within the tumor microenvironment, with the focus on development of effective immunotherapeutic strategies to improve homing and activity of immune effector cells to tumors.

  13. Interactions Among Sexual Activity, Menstrual Cycle Phase, and Immune Function in Healthy Women.

    Science.gov (United States)

    Lorenz, Tierney K; Heiman, Julia R; Demas, Gregory E

    2017-11-21

    Past research has found menstrual-cycle-related changes in functional immune response; we examined if sexual activity also changed markers of immune defense. We followed 32 naturally cycling women (15 sexually active with a partner ≥ 1 time/week, 17 sexually abstinent for the last four months) over one menstrual cycle. Participants provided serum and saliva samples at menses and ovulation, and additional saliva samples at midfollicular and midluteal phases. At each phase, participants also self-reported symptoms associated with colds, flu, pain, menstrual discomfort, and premenstrual syndrome. We tested saliva and serum for ability to kill Escherichia coli or Candida albicans, and serum for complement protein activity. For serum-mediated pathogen killing, among sexually active women only, there was a significant midcycle decrease in killing of E. coli. For saliva-mediated pathogen killing, among abstinent women only, there was a significant midcycle decrease in killing of E. coli, and midcycle increase in killing of C. albicans. Sexually active women had significantly lower complement activity than abstinent women overall. Finally, both groups reported lower physical symptoms at midcycle and higher symptoms at menses. There may be important differences in immune function between healthy women who are sexually active versus abstinent. Further replication is warranted.

  14. Activation of cutaneous immune responses in complex regional pain syndrome

    Science.gov (United States)

    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

  15. Stressed power motivation, sympathetic activation, immune function, and illness.

    Science.gov (United States)

    McClelland, D C; Floor, E; Davidson, R J; Saron, C

    1980-01-01

    Previous research has reported that individuals high in the need for Power, high in inhibition, and high in power stress (the HHH group) are more likely than other individuals to report more severe illnesses. The present study investigates the possibility that the mechanism underlying this relationship is greater sympathetic activation in the HHH group which has an immunosuppressive effect. College males with the HHH syndrome reported more frequent and more severe illnesses than other individuals, as in previous studies. More of the HHH than other subjects also showed above average epinephrine excretion rates in urine and below average concentrations of immunoglobulin A in saliva (S-IgA). Furthermore, higher rates of epinephrine excretion were significantly associated with lower S-IgA concentrations, and lower S-IgA concentrations were significantly associated with reports of more frequent illnesses. The findings are interpreted as consistent with the hypothesis that a strong need for Power, if it is inhibited and stressed, leads to chronic sympathetic overactivity which has an immunosuppressive effect making individuals characterized by this syndrome more susceptible to illness.

  16. STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia.

    Science.gov (United States)

    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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Involvement of glucocorticoids in testicular involution after active immunization of boars against GnRH.

    Science.gov (United States)

    Wagner, A; Claus, R

    2004-02-01

    Active GnRH immunization of boars inhibits LH and testicular steroids but the consequences for spermatogenesis are unknown. Six boars were immunized three times against GnRH at 20, 24 and 28 weeks. Another six boars served as controls. Plasma LH and FSH were determined at 28 and 31 weeks. Testosterone and cortisol were determined before killing the pigs at 32 weeks. Tissue samples were taken for histology and fluid from the seminiferous tubuli for steroid determination. Individual germ cells were counted in histological sections. The glucocorticoid receptor (GCR), mitosis of spermatogonia and apoptosis were characterized by immunocytochemistry. Immunization reduced LH and testosterone to base levels whereas FSH was not changed. Testis weight was reduced by 64% due to a loss of Leydig cell cytoplasm (90.3%) and a decrease of tubule diameters (60.6%). Except for A-spermatogonia, all other spermatogenic cells were reduced by about 60%. Mitosis was reduced in immunized boars. Expression of GCRs was limited to spermatogonia and differed between immunized boars (8% of spermatogonia) and controls (2%). In the controls, androgen concentrations in tubular fluid were tenfold higher compared with immunized boars. Cortisol concentrations were of the order of 40 nmol/l both in the tubular fluid and blood plasma. These concentrations did not differ between groups. Apoptosis occurred only in spermatogonia and pachytene spermatocytes and was twofold higher in immunized boars compared with controls. Thus the availability of glucocorticoids in the tubuli and the expression of GCRs initiate apoptosis, which in turn reduces sperm yield. Testosterone is known to be an inhibitor of GCR expression, thus increasing the efficiency of spermatogenesis.

  18. Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation.

    Science.gov (United States)

    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.

  19. The Dual Role of Exosomes in Hepatitis A and C Virus Transmission and Viral Immune Activation.

    Science.gov (United States)

    Longatti, Andrea

    2015-12-17

    Exosomes are small nanovesicles of about 100 nm in diameter that act as intercellular messengers because they can shuttle RNA, proteins and lipids between different cells. Many studies have found that exosomes also play various roles in viral pathogenesis. Hepatitis A virus (HAV; a picornavirus) and Hepatitis C virus (HCV; a flavivirus) two single strand plus-sense RNA viruses, in particular, have been found to use exosomes for viral transmission thus evading antibody-mediated immune responses. Paradoxically, both viral exosomes can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate immune activation and type I interferon production. This article will review recent findings regarding these two viruses and outline how exosomes are involved in their transmission and immune sensing.

  20. Immune reconstitution inflammatory syndrome after initiating highly active antiretroviral therapy in HIV-infected children

    Energy Technology Data Exchange (ETDEWEB)

    Kilborn, Tracy [Red Cross War Memorial Children' s Hospital, Department of Paediatric Radiology, Cape Town (South Africa); Zampoli, Marco [Red Cross War Memorial Children' s Hospital, Department of Paediatric Pulmonology, Cape Town (South Africa)

    2009-06-15

    The outcome of HIV infection has improved since the widespread availability of highly active antiretroviral therapy (HAART). Some patients, however, develop a clinical and radiological deterioration following initiation of HAART due to either the unmasking of occult subclinical infection or an enhanced inflammatory response to a treated infection. This phenomenon is believed to result from the restored ability to mount an immune response and is termed immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution disease. IRIS is widely reported in the literature in adult patients, most commonly associated with mycobacterial infections. There is, however, a paucity of data documenting the radiological findings of IRIS in children. Radiologists need to be aware of this entity. As a diagnosis of exclusion it is essential that the radiological findings be assessed in the context of the clinical presentation. This article reviews the common clinical and radiological manifestations of IRIS in HIV-infected children. (orig.)

  1. Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response.

    Science.gov (United States)

    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.

  2. Effect of shark cartilage on the cytotoxic activity of NK cells immune system

    Directory of Open Access Journals (Sweden)

    Afshar Bargahi

    2009-12-01

    Full Text Available Background: On the basis of traditional medicine Shark cartilage have been used in the treatment of cancer especially immune related cancers. Then, we hypotheses that shark cartilage contains immune stimulatory ingredients. Methods: The immune stimulatory effect of shark cartilage derived proteins on the cytotoxic activity of natural killer cells(NK cells from healthy human peripheral blood mononuclear cells (hPBMN was studied. Shark cartilage proteins were purified by ion-exchange chromatography and ultra filtration. The effect of each protein fraction on the modulation of cytotoxicity of NK cells, as effectors, against K562, as target cells, was assayed by enzymatic LDH test. Results: The results from cytotoxic assay of NK cells and SDS- Polyacrylamide gell electrophoresis of shark cartilage protein fractions indicated that AR10 fraction, containing proteins with molecular weight of about 14.5 KDa is the most active ingredients of shark cartilage. Conclusion: Shark cartilage contains a 14.5 KDa protein that modulates NK cells activity of human immune system.

  3. Passive and active immunity of broiler chickens against Campylobacter jejuni and ways of disease transmission

    Directory of Open Access Journals (Sweden)

    Silvia Ondrašovičová

    2012-01-01

    Full Text Available The study deals with passive and active immunity of fifty-three broiler chickens after infection with culture of Campylobacter jejuni. Potential transfer of infection by faecal-oral and aerogenic routes was also investigated. Cloacal swabs and ceacal content were analyzed microbiologically. Identification of C. jejuni was carried out by polymerase chain reaction. Observation of passive immunity of broilers from 3 days of age showed that no transfer of C. jejuni infection occurred up to 12 day post-infection (p.i.. Observations of active immunity in fourteen 21 days old chickens infected with C. jejuni showed that 6 chickens were positive on day 3 p.i. and all infected chickens were positive on day 5 p.i. Investigations of the transfer of C. jejuni by faecal-oral route revealed positivity in two broilers on day 3 p.i. and in all tested chickens on day 5 p.i. Aerogenic transfer of infection was not recorded. This was one of the first studies in our country dealing with passive and active immunity of broiler chickens against C. jejuni and spreading of this zoonotic disease.

  4. Gender-dependent effects of maternal immune activation on the behavior of mouse offspring.

    Directory of Open Access Journals (Sweden)

    Ingrid C Y Xuan

    Full Text Available Autism spectrum disorders are neurodevelopmental disorders characterized by two core symptoms; impaired social interactions and communication, and ritualistic or repetitive behaviors. Both epidemiological and biochemical evidence suggests that a subpopulation of autistics may be linked to immune perturbations that occurred during fetal development. These findings have given rise to an animal model, called the "maternal immune activation" model, whereby the offspring from female rodents who were subjected to an immune stimulus during early or mid-pregnancy are studied. Here, C57BL/6 mouse dams were treated mid-gestation with saline, lipopolysaccharide (LPS to mimic a bacterial infection, or polyinosinic:polycytidylic acid (Poly IC to mimic a viral infection. Autism-associated behaviors were examined in the adult offspring of the treated dams. Behavioral tests were conducted to assess motor activity, exploration in a novel environment, sociability, and repetitive behaviors, and data analyses were carried independently on male and female mice. We observed a main treatment effect whereby male offspring from Poly IC-treated dams showed reduced motor activity. In the marble burying test of repetitive behavior, male offspring but not female offspring from both LPS and Poly IC-treated mothers showed increased marble burying. Our findings indicate that offspring from mothers subjected to immune stimulation during gestation show a gender-specific increase in stereotyped repetitive behavior.

  5. Time Course of Immune Activity in Response to Two Acute Stressors

    Science.gov (United States)

    1994-04-14

    1991). In addition, the strength of the immune system and of immunosurveillance 2 is thought to mediate the effects of stress on cancer progression...Cohen et al. (under review) also observed decreased NK activity in men. In this case, subjects were exposed to a mild 30-minute Stroop stressor, and...types of laboratory stressors on mitogen response. Using an active psychologicaV perfonnance stressor (20 min of mental arithmetic and the Stroop

  6. The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation.

    Science.gov (United States)

    Klarström Engström, K; Khalaf, H; Kälvegren, H; Bengtsson, T

    2015-02-01

    Platelets are considered to have important functions in inflammatory processes and as actors in the innate immunity. Several studies have shown associations between cardiovascular disease and periodontitis, where the oral anaerobic pathogen Porphyromonas gingivalis has a prominent role in modulating the immune response. Porphyromonas gingivalis has been found in atherosclerotic plaques, indicating spreading of the pathogen via the circulation, with an ability to interact with and activate platelets via e.g. Toll-like receptors (TLR) and protease-activated receptors. We aimed to evaluate how the cysteine proteases, gingipains, of P. gingivalis affect platelets in terms of activation and chemokine secretion, and to further investigate the mechanisms of platelet-bacteria interaction. This study shows that primary features of platelet activation, i.e. changes in intracellular free calcium and aggregation, are affected by P. gingivalis and that arg-gingipains are of great importance for the ability of the bacterium to activate platelets. The P. gingivalis induced a release of the chemokine RANTES, however, to a much lower extent compared with the TLR2/1-agonist Pam3 CSK4 , which evoked a time-dependent release of the chemokine. Interestingly, the TLR2/1-evoked response was abolished by a following addition of viable P. gingivalis wild-types and gingipain mutants, showing that both Rgp and Kgp cleave the secreted chemokine. We also demonstrate that Pam3 CSK4 -stimulated platelets release migration inhibitory factor and plasminogen activator inhibitor-1, and that also these responses were antagonized by P. gingivalis. These results supports immune-modulatory activities of P. gingivalis and further clarify platelets as active players in innate immunity and in sensing bacterial infections, and as target cells in inflammatory reactions induced by P. gingivalis infection. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. 22 CFR 40.25 - Certain aliens involved in serious criminal activity who have asserted immunity from prosecution...

    Science.gov (United States)

    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. ...

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

    Directory of Open Access Journals (Sweden)

    Silke eSmolders

    2015-08-01

    Full Text Available 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.

  9. Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring.

    Science.gov (United States)

    Corradini, Irene; Focchi, Elisa; Rasile, Marco; Morini, Raffaella; Desiato, Genni; Tomasoni, Romana; Lizier, Michela; Ghirardini, Elsa; Fesce, Riccardo; Morone, Diego; Barajon, Isabella; Antonucci, Flavia; Pozzi, Davide; Matteoli, Michela

    2017-11-14

    The association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined. Pregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses. Prenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na+-K+-2Cl- cotransporter 1 and the K+-Cl- cotransporter 2 (KCC2). This results in delayed gamma-aminobutyric acid switch and higher susceptibility to seizures, which endures up to adulthood. Chromatin immunoprecipitation experiments reveal increased binding of the repressor factor RE1-silencing transcription (also known as neuron-restrictive silencer factor) to position 509 of the KCC2 promoter that leads to downregulation of KCC2 transcription in prenatally exposed offspring. Interleukin-1 receptor type I knockout mice, which display braked immune response and no brain cytokine elevation upon maternal immune activation, do not display KCC2/Na+-K+-2Cl- cotransporter 1 imbalance when implanted in a wild-type dam and prenatally exposed. Notably, pretreatment of pregnant dams with magnesium sulfate is sufficient to prevent the early inflammatory state and the delay in excitatory-to-inhibitory switch associated to maternal immune activation. We provide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to-inhibitory gamma-aminobutyric acid switch; defects in this switch have been unequivocally linked to diseases such as autism spectrum disorder or epilepsy. These data open the avenue for a safe pharmacological treatment that may prevent the neurodevelopmental defects caused by prenatal immune activation in a specific pregnancy time window. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights

  10. Merck Ad5/HIV induces broad innate immune activation that predicts CD8⁺ T-cell responses but is attenuated by preexisting Ad5 immunity.

    Science.gov (United States)

    Zak, Daniel E; Andersen-Nissen, Erica; Peterson, Eric R; Sato, Alicia; Hamilton, M Kristina; Borgerding, Joleen; Krishnamurty, Akshay T; Chang, Joanne T; Adams, Devin J; Hensley, Tiffany R; Salter, Alexander I; Morgan, Cecilia A; Duerr, Ann C; De Rosa, Stephen C; Aderem, Alan; McElrath, M Juliana

    2012-12-11

    To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

  11. Tryptophan catabolism and immune activation in primary and chronic HIV infection.

    Science.gov (United States)

    Gelpi, Marco; Hartling, Hans J; Ueland, Per M; Ullum, Henrik; Trøseid, Marius; Nielsen, Susanne D

    2017-05-16

    Kynurenine/Tryptophan ratio (KTR) is increased in HIV infection, and linked to immune activation. We hypothesized that early cART initiation results in lower KTR compared to late initiation. Furthermore, we hypothesized that KTR prior to cART is a predictor of the magnitude of subsequent reduction in immune activation. Prospective study including 57 HIV-infected individuals (primary HIV infection (N = 14), early presenters (>350 CD4+ T cells/μL, N = 24), late presenters (tryptophan were analysed by liquid chromatography-tandem mass spectrometry. Total CD4+ and CD8+ T cells were determined and proportion of activated CD38 + HLA-DR+ Tcells was measured using flow cytometry at baseline and after 6 and 12 months of cART. At baseline, primary HIV infection had higher KTR than early presenters. However, similar KTR in primary HIV infection and early presenters was found after cART initiation, while late presenters had higher KTR at all time points. In primary HIV infection and early presenters, KTR was positively associated with proportion of activated cells at baseline. Furthermore, in early presenters the KTR at baseline was associated with proportion of activated cells after 6 and 12 months. Interestingly, in primary HIV infection the KTR at baseline was positively associated with reduction in proportion of CD8 + CD38 + HLA-DR T cells after 6 and 12 months. Lower kynurenine/tryptophan ratio during follow-up was found after early initiation of cART. KTR in primary HIV infection and early presenters was positively associated with immune activation. Importantly, KTR in primary HIV infection predicted the magnitude of subsequent reduction in immune activation. Thus, a beneficial effect of early cART on KTR was suggested.

  12. Tryptophan catabolism and immune activation in primary and chronic HIV infection

    DEFF Research Database (Denmark)

    Gelpi, Marco; Hartling, Hans J; Ueland, Per Magne

    2017-01-01

    BACKGROUND: Kynurenine/Tryptophan ratio (KTR) is increased in HIV infection, and linked to immune activation. We hypothesized that early cART initiation results in lower KTR compared to late initiation. Furthermore, we hypothesized that KTR prior to cART is a predictor of the magnitude...... of subsequent reduction in immune activation. METHODS: Prospective study including 57 HIV-infected individuals (primary HIV infection (N = 14), early presenters (>350 CD4+ T cells/μL, N = 24), late presenters (...-tandem mass spectrometry. Total CD4+ and CD8+ T cells were determined and proportion of activated CD38 + HLA-DR+ Tcells was measured using flow cytometry at baseline and after 6 and 12 months of cART. RESULTS: At baseline, primary HIV infection had higher KTR than early presenters. However, similar KTR...

  13. Macrophage activation and polarization as an adaptive component of innate immunity.

    Science.gov (United States)

    Locati, Massimo; Mantovani, Alberto; Sica, Antonio

    2013-01-01

    Innate immunity has an adaptive component, which has been referred to as "memory," "trained," "imprinted" or "adaptive." Plasticity is a hallmark of cells of the monocyte-macrophage lineage. Microbial recognition and cytokines profoundly affect macrophage function causing a range of adaptive responses including activation, priming, or tolerance. These adaptive responses of macrophages include production of humoral fluid-phase pattern recognition molecules such as the prototypic long pentraxin PTX3. These components of humoral innate immunity in turn cooperate with and regulate phagocyte function. Progress has been made in defining the molecular basis underlying the polarized activation of macrophages, including signaling mediators, transcription factors, epigenetic modifications, and the microRNA network. The definition of molecules and mechanisms associated with plasticity and polarized activation of macrophages may provide a basis for innovative diagnostic and therapeutic approaches. © 2013 Elsevier Inc. All rights reserved.

  14. Bacterial Nucleotidyl Cyclase Inhibits the Host Innate Immune Response by Suppressing TAK1 Activation.

    Science.gov (United States)

    He, Chenxi; Zhou, Yilong; Liu, Feng; Liu, Haipeng; Tan, Hao; Jin, Shouguang; Wu, Weihui; Ge, Baoxue

    2017-09-01

    Exoenzyme Y (ExoY) is a type III secretion system effector found in 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY is a soluble nucleotidyl cyclase that increases the cytoplasmic levels of nucleoside 3',5'-cyclic monophosphates (cNMPs) to mediate endothelial Tau phosphorylation and permeability, its functional role in the innate immune response is still poorly understood. Transforming growth factor β-activated kinase 1 (TAK1) is critical for mediating Toll-like receptor (TLR) signaling and subsequent activation of NF-κB and AP-1, which are transcriptional activators of innate immunity. Here, we report that ExoY inhibits proinflammatory cytokine production through suppressing the activation of TAK1 as well as downstream NF-κB and mitogen-activated protein (MAP) kinases. Mice infected with ExoY-deficient P. aeruginosa had higher levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6), more neutrophil recruitment, and a lower bacterial load in lung tissue than mice infected with wild-type P. aeruginosa Taken together, our findings identify a previously unknown mechanism by which P. aeruginosa ExoY inhibits the host innate immune response. Copyright © 2017 American Society for Microbiology.

  15. Activity of Fusion Prophenoloxidase-GFP and Its Potential Applications for Innate Immunity Study

    Science.gov (United States)

    Yang, Bing; Lu, Anrui; Peng, Qin; Ling, Qing-Zhi; Ling, Erjun

    2013-01-01

    Insect prophenoloxidase (PPO) is essential for physiological functions such as melanization of invading pathogens, wound healing and cuticle sclerotization. The insect PPO activation pathway is well understood. However, it is not very clear how PPO is released from hemocytes and how PPO takes part in cellular immunity. To begin to assess this, three Drosophila melanogaster PPO genes were separately fused with GFP at the C-terminus (rPPO-GFP) and were over-expressed in S2 cells. The results of staining and morphological observation show that rPPO-GFP expressed in S2 cells has green fluorescence and enzyme activity if Cu2+ was added during transfection. Each rPPO-GFP has similar properties as the corresponding rPPO. However, cells with rPPO-GFP over-expressed are easier to trace without PO activation and staining. Further experiments show that rPPO1-GFP is cleaved and activated by Drosophila serine protease, and rPPO1-GFP binds to Micrococcus luteus and Beauveria bassiana spores as silkworm plasma PPO. The above research indicates that the GFP-tag has no influence on the fusion enzyme activation and PPO-involved innate immunity action in vitro. Thus, rPPO-GFP may be a convenient tool for innate immunity study in the future if it can be expressed in vivo. PMID:23717543

  16. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals.

    Science.gov (United States)

    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.

  17. Rejuvenating activity of salidroside (SDS): dietary intake of SDS enhances the immune response of aged rats.

    Science.gov (United States)

    Lu, Linlin; Yuan, Jiangshui; Zhang, Shicui

    2013-06-01

    It is well known that immune response decreases with aging. Salidroside (SDS), an antioxidant component isolated from the traditional Chinese medicine roseroot Rhodiola rosea, has been demonstrated to possess potent anti-aging and health-promoting activities. However, the mechanism underlying these activities is poorly understood. In this study, we clearly demonstrated that (1) dietary intake of SDS induced a considerable increase in total T cells (CD3(+)) and T helper cells (CD4(+)) in aged (21 months old) Wistar male rats; (2) SDS supplementation significantly increased the DTH response, a T cell-mediated immune response, in aged rats; and (3) SDS supplementation remarkably promoted the production of total anti-KLH IgG, anti-KLH IgG1, and anti-KLH IgG2α in aged rats without disturbing immune homeostasis. These indicate that SDS is able to counteract immunosenescence, thereby resulting in rejuvenation. Practically, SDS may be used to help the elderly to generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.

  18. Parasitic and immune modulation of flight activity in honey bees tracked with optical counters.

    Science.gov (United States)

    Alaux, Cédric; Crauser, Didier; Pioz, Maryline; Saulnier, Cyril; Le Conte, Yves

    2014-10-01

    Host-parasite interactions are often characterized by changes in the host behaviour, which are beneficial to either the parasite or the host, or are a non-adaptive byproduct of parasitism. These interactions are further complicated in animal society because individual fitness is associated with group performance. However, a better understanding of host-parasite interaction in animal society first requires the identification of individual host behavioural modification. Therefore, we challenged honey bee (Apis mellifera) workers with the parasite Nosema ceranae or an immune stimulation and tracked their flight activity over their lifetime with an optic counter. We found that bees responded differently to each stress: both Nosema-infected and immune-challenged bees performed a lower number of daily flights compared with control bees, but the duration of their flights increased and decreased over time, respectively. Overall, parasitized bees spent more time in the field each day than control bees, and the inverse was true for immune-challenged bees. Despite the stress of immune challenge, bees had a survival similar to that of control bees likely because of their restricted activity. We discuss how those different behavioural modifications could be adaptive phenotypes. This study provides new insights into how biological stress can affect the behaviour of individuals living in society and how host responses have evolved. © 2014. Published by The Company of Biologists Ltd.

  19. [Cytotoxicity of Naja Naja Actra Venom Component combined with activated immune cells on leukemia cell line KG1a].

    Science.gov (United States)

    He, Yan-Jie; Li, Yu-Hua; Tu, San-Fang; Wu, Hai-Yan; Guo, Kun-Yuan

    2013-10-01

    This study was aimed to investigate the cytotoxic effect of the Naja Naja Actra Venom Component (NNAVC) combined with activated immune cells on human acute myeloblastic leukemia line KG1a cells. The cytotoxic effects of NNAVC at different concentrations on KG1a cells were measured by CCK-8 method. LDH releasing assay was used to detect the cytotoxic effects of activated immune cells, NNAVC combined with activated immune cells on KG1a cells and the sensitivity of KG1a treated with NNAVC to activated immune cells. The results showed that the inhibitory rate of NNAVC on KG1a cells increased with the concentration enhancement, the cytotoxicity of activated immune cells at the different effector to target (E:T) ratios(6.25:1, 12.5:1, 25:1) on KG1a cells were 12.30%, 24.85% and 52.26%. The cytotoxicity of NNAVC combined with activated immune cells at the different E:T cell ratios (10:1, 20: 1) on KG1a cells were 56.21% and 85.59%, which were higher than that of NNAVC or activated immune cells alone. The cytotoxicity of activated immune cells at the E: T cell ratio of 10:1 on KG1a cells treated with NNAVC at different concentrations were 25.65%, 31.33%, 28.63% and 16.78%, respectively, and that at the E:T cell ratio of 20: 1 were 40.62%, 44.70%, 44.62% and 40.72%. It is concluded that:both of NNAVC and activated immune cells have lethal effect on KG1a cells, and the combination of NNAVC and activated immune cells can strengthen their effect on KG1a.

  20. Comparative Analysis of Immune Cells Activation and Cytotoxicity upon Exposure Pathogen and Glycoconjugates

    Science.gov (United States)

    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.

  1. Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways.

    Science.gov (United States)

    Bourque, Daniel L; Bhuiyan, Taufiqur Rahman; Genereux, Diane P; Rashu, Rasheduzzaman; Ellis, Crystal N; Chowdhury, Fahima; Khan, Ashraful I; Haq Alam, Nur; Lazina Hossain, Anik Paul; Mayo-Smith, Leslie M; Charles, Richelle C; Weil, Ana A; LaRocque, Regina C; Calderwood, Stephen B; Ryan, Edward T; Karlsson, Elinor K; Qadri, Firdausi; Harris, Jason B

    2017-11-13

    To better understand the innate immune response to Vibrio cholerae infection, we tracked gene expression in the duodenal mucosa of eleven Bangladeshi adults with cholera, using biopsies obtained immediately after rehydration and at 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-κB, MAPK, and TLR-mediated signaling pathways, which unexpectedly persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across eleven participants. These genes included the endosomal toll like receptor, TLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signaling in vivo, our pathway analysis found that IRF7 and interferons β1 and α2 were among the top upstream regulators activated during cholera. Among innate immune effectors, we found that DUOX2, an NADPH-oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases in DUOX2 and TLR8 expression were also modeled in vitro when stimulating Caco-2 or THP-1 cells, respectively, with live V. cholerae but not with heat killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response to V. cholerae extend our understanding mucosal immune signaling pathways and effectors activated in vivo following cholera. Copyright © 2017 American Society for Microbiology.

  2. Immune activity, body condition and human-associated environmental impacts in a wild marine mammal.

    Directory of Open Access Journals (Sweden)

    Patrick M Brock

    Full Text Available Within individuals, immunity may compete with other life history traits for resources, such as energy and protein, and the damage caused by immunopathology can sometimes outweigh the protective benefits that immune responses confer. However, our understanding of the costs of immunity in the wild and how they relate to the myriad energetic demands on free-ranging organisms is limited. The endangered Galapagos sea lion (Zalophus wollebaeki is threatened simultaneously by disease from domestic animals and rapid changes in food availability driven by unpredictable environmental variation. We made use of this unique ecology to investigate the relationship between changes in immune activity and changes in body condition. We found that during the first three months of life, changes in antibody concentration were negatively correlated with changes in mass per unit length, skinfold thickness and serum albumin concentration, but only in a sea lion colony exposed to anthropogenic environmental impacts. It has previously been shown that changes in antibody concentration during early Galapagos sea lion development were higher in a colony exposed to anthropogenic environmental impacts than in a control colony. This study allows for the possibility that these relatively large changes in antibody concentration are associated with negative impacts on fitness through an effect on body condition. Our findings suggest that energy availability and the degree of plasticity in immune investment may influence disease risk in natural populations synergistically, through a trade-off between investment in immunity and resistance to starvation. The relative benefits of such investments may change quickly and unpredictably, which allows for the possibility that individuals fine-tune their investment strategies in response to changes in environmental conditions. In addition, our results suggest that anthropogenic environmental impacts may impose subtle energetic costs on

  3. Experimentally induced mastitis and metritis modulate soy bean derived isoflavone biotransformation in diary cows.

    Science.gov (United States)

    Kowalczyk-Zieba, I; Woclawek-Potocka, I; Piskula, M K; Piotrowska-Tomala, K K; Boruszewska, D; Bah, M M; Siemieniuch, M J; Skarzynski, D J

    2011-12-01

    The present study compared the changes in isoflavone (daidzein and genistein) and their metabolite (equol and para-ethyl-phenol) concentrations in the blood plasma of cows with induced mastitis and metritis after feeding with soy bean. Sixteen cows were divided into four groups: control for mastitis group, cows with induced mastitis group, control for metritis group, and cows with induced metritis group. All cows were fed a single dose of 2.5 kg of soy bean and then blood samples were taken from the jugular vein for 8 h at predetermined intervals. The concentrations of soy bean-derived isoflavones and their active metabolites were measured in the blood plasma on HPLC system. β-Glucuronidase activity in the blood plasma of cows was measured by fluorometric method. In the blood plasma of cows with induced mastitis and metritis, we found considerably higher concentrations and time-dependent increase in isoflavone metabolites (equol and para-ethyl-phenol) with reference to cyclic cows (P cows with induced metritis compared with control cows (P cows with induced metritis, we found an increase in β-glucuronidase activity compared with control cows (P cows. Experimentally induced mastitis and metritis increased isoflavone absorption, biotransformation and metabolism. Therefore, we suggest that cows with induced mastitis and metritis are more exposed to active isoflavone metabolite actions than healthy cows. Copyright © 2011. Published by Elsevier Inc.

  4. Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

    Science.gov (United States)

    Jensen, Kara; dela Pena-Ponce, Myra Grace; Piatak, Michael; Shoemaker, Rebecca; Oswald, Kelli; Jacobs, William R.; Fennelly, Glenn; Lucero, Carissa; Mollan, Katie R.; Hudgens, Michael G.; Amedee, Angela; Kozlowski, Pamela A.; Estes, Jacob D.; Lifson, Jeffrey D.; Van Rompay, Koen K. A.; Larsen, Michelle

    2016-01-01

    ABSTRACT Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants. PMID:27655885

  5. Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine.

    Science.gov (United States)

    Jensen, Kara; Dela Pena-Ponce, Myra Grace; Piatak, Michael; Shoemaker, Rebecca; Oswald, Kelli; Jacobs, William R; Fennelly, Glenn; Lucero, Carissa; Mollan, Katie R; Hudgens, Michael G; Amedee, Angela; Kozlowski, Pamela A; Estes, Jacob D; Lifson, Jeffrey D; Van Rompay, Koen K A; Larsen, Michelle; De Paris, Kristina

    2017-01-01

    Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants. Copyright © 2017 American Society for Microbiology.

  6. Defense Against Pathogens: Structural Insights into the Mechanism of Chitin Induced Activation of Innate Immunity.

    Science.gov (United States)

    Squeglia, Flavia; Berisio, Rita; Shibuya, Naoto; Kaku, Hanae

    2017-11-24

    Pattern recognition receptors on the plant cell surface mediate the recognition of microbe-associated molecular patterns, in a process which activates downstream immune signaling. These receptors are plasma membrane-localized kinases which need to be autophosphorylated to activate downstream responses. Perception of attacks from fungi occurs through recognition of chitin, a polymer of an N-acetylglucosamine which is a characteristic component of the cell walls of fungi. This process is regulated in Arabidopsis by chitin elicitor receptor kinase CERK1. A more complex process characterizes rice, in which regulation of chitin perception is operated by a complex composed of OsCERK1, a homolog of CERK1, and the chitin elicitor binding protein OsCEBiP. Recent literature has provided a mechanistic description of the complex regulation of activation of innate immunity in rice and an advance in the structural description of molecular players involved in this process. This review describes the current status of the understanding of molecular events involved in innate immunity activation in rice. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Active Immunity Induced by Passive IgG Post-Exposure Protection against Ricin

    Directory of Open Access Journals (Sweden)

    Charles Chen Hu

    2014-01-01

    Full Text Available Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab’2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were observed between IgG and F(ab’2 when compared at the same molar concentration. In a murine ricin intoxication model, both IgG and F(ab’2 could rescue 100% of the mice by one dose (3 nmol administration of antibodies 1 hour after 5 × LD50 ricin challenge. Nine days later, when the rescued mice received a second ricin challenge (5 × LD50, only the IgG-treated mice survived; the F(ab’2-treated mice did not. The experimental design excluded the possibility of residual goat IgG responsible for the protection against the second ricin challenge. Results confirmed that the active immunity against ricin in mice was induced quickly following the passive delivery of a single dose of goat IgG post-exposure. Furthermore, it was demonstrated that the induced active immunity against ricin in mice lasted at least 5 months. Therefore, passive IgG therapy not only provides immediate protection to the victim after ricin exposure, but also elicits an active immunity against ricin that subsequently results in long term protection.

  8. Targeting TNF and TNF Receptor Pathway in HIV-1 Infection: from Immune Activation to Viral Reservoirs.

    Science.gov (United States)

    Pasquereau, Sébastien; Kumar, Amit; Herbein, Georges

    2017-03-30

    Several cellular functions such as apoptosis, cellular proliferation, inflammation, and immune regulation involve the tumor necrosis factor-α (TNF)/TNF receptor (TNFR) pathway. Human immunodeficiency virus 1 (HIV-1) interacts with the TNF/TNFR pathway. The activation of the TNF/TNFR pathway impacts HIV-1 replication, and the TNF/TNFR pathway is the target of HIV-1 proteins. A hallmark of HIV-1 infection is immune activation and inflammation with increased levels of TNF in the plasma and the tissues. Therefore, the control of the TNF/TNFR pathway by new therapeutic approaches could participate in the control of immune activation and impact both viral replication and viral persistence. In this review, we will describe the intricate interplay between HIV-1 proteins and TNF/TNFR signaling and how TNF/TNFR activation modulates HIV-1 replication and discuss new therapeutic approaches, especially anti-TNF therapy, that could control this pathway and ultimately favor the clearance of infected cells to cure HIV-infected patients.

  9. Spirulina elicits the activation of innate immunity and increases resistance against Vibrio alginolyticus in shrimp.

    Science.gov (United States)

    Chen, Yu-Yuan; Chen, Jiann-Chu; Tayag, Carina Miranda; Li, Hui-Fang; Putra, Dedi Fazriansyah; Kuo, Yi-Hsuan; Bai, Jia-Chin; Chang, Yu-Hsuan

    2016-08-01

    The effect of Spirulina dried powder (SDP) on the immune response of white shrimp Litopenaeus vannamei was studied in vitro and in vivo. Incubating shrimp haemocytes in 0.5 mg ml(-1) SDP caused the degranulation of haemocytes and a reduction in the percentage of large cells within 30 min. Shrimp haemocytes incubated in 1 mg ml(-1) SDP significantly increased their phenoloxidase (PO) activity, serine proteinase activity, and respiratory burst activity (RB, release of superoxide anion). A recombinant protein of lipopolysaccharide and β-1,3-glucan binding protein (LGBP) of the white shrimp was produced, named rLvLGBP, and examined for its binding with SDP. An ELISA binding assay showed that rLvLGBP binds to SDP with a dissociation constant of 0.0507 μM. In another experiment, shrimp fed diets containing SDP at 0 (control), 30, and 60 g kg(-1) after four weeks were examined for LGBP transcript level and lysozyme activity, as well as phagocytic activity, clearance efficiency, and resistance to Vibrio alginolyticus. These parameters were significantly higher in shrimp receiving diets containing SDP at 60 g kg(-1) or 30 g kg(-1) than in controls. In conclusion, shrimp haemocytes receiving SDP provoked the activation of innate immunity as evidenced by the recognition and binding of LGBP, degranulation of haemocytes, reduction in the percentage of large cells, increases in PO activity, serine proteinase activity, superoxide anion levels, and up-regulated LGBP transcript levels. Shrimp receiving diets containing SDP had increased lysozyme activity and resistance against V. alginolyticus infection. This study showed the mechanism underlying the immunostimulatory action of Spirulina and its immune response in shrimp. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Distinct patterns of innate immune activation by clinical isolates of respiratory syncytial virus.

    Science.gov (United States)

    Levitz, Ruth; Gao, Yajing; Dozmorov, Igor; Song, Ran; Wakeland, Edward K; Kahn, Jeffrey S

    2017-01-01

    Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and young children. Multiple strains of both subgroup A and B viruses circulate during each seasonal epidemic. Genetic heterogeneity among RSV genomes, in large part due to the error prone RNA-dependent, RNA polymerase, could mediate variations in pathogenicity. We evaluated clinical strains of RSV for their ability to induce the innate immune response. Subgroup B viruses were used to infect human pulmonary epithelial cells (A549) and primary monocyte-derived human macrophages (MDM) from a variety of donors. Secretions of IL-6 and CCL5 (RANTES) from infected cells were measured following infection. Host and viral transcriptome expression were assessed using RNA-SEQ technology and the genomic sequences of several clinical isolates were determined. There were dramatic differences in the induction of IL-6 and CCL5 in both A549 cells and MDM infected with a variety of clinical isolates of RSV. Transcriptome analyses revealed that the pattern of innate immune activation in MDM was virus-specific and host-specific. Specifically, viruses that induced high levels of secreted IL-6 and CCL5 tended to induce cellular innate immune pathways whereas viruses that induced relatively low level of IL-6 or CCL5 did not induce or suppressed innate immune gene expression. Activation of the host innate immune response mapped to variations in the RSV G gene and the M2-1 gene. Viral transcriptome data indicated that there was a gradient of transcription across the RSV genome though in some strains, RSV G was the expressed in the highest amounts at late times post-infection. Clinical strains of RSV differ in cytokine/chemokine induction and in induction and suppression of host genes expression suggesting that these viruses may have inherent differences in virulence potential. Identification of the genetic elements responsible for these differences may lead to novel approaches to antiviral agents and vaccines.

  11. Distinct patterns of innate immune activation by clinical isolates of respiratory syncytial virus

    Science.gov (United States)

    Levitz, Ruth; Wakeland, Edward K.

    2017-01-01

    Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and young children. Multiple strains of both subgroup A and B viruses circulate during each seasonal epidemic. Genetic heterogeneity among RSV genomes, in large part due to the error prone RNA-dependent, RNA polymerase, could mediate variations in pathogenicity. We evaluated clinical strains of RSV for their ability to induce the innate immune response. Subgroup B viruses were used to infect human pulmonary epithelial cells (A549) and primary monocyte-derived human macrophages (MDM) from a variety of donors. Secretions of IL-6 and CCL5 (RANTES) from infected cells were measured following infection. Host and viral transcriptome expression were assessed using RNA-SEQ technology and the genomic sequences of several clinical isolates were determined. There were dramatic differences in the induction of IL-6 and CCL5 in both A549 cells and MDM infected with a variety of clinical isolates of RSV. Transcriptome analyses revealed that the pattern of innate immune activation in MDM was virus-specific and host-specific. Specifically, viruses that induced high levels of secreted IL-6 and CCL5 tended to induce cellular innate immune pathways whereas viruses that induced relatively low level of IL-6 or CCL5 did not induce or suppressed innate immune gene expression. Activation of the host innate immune response mapped to variations in the RSV G gene and the M2-1 gene. Viral transcriptome data indicated that there was a gradient of transcription across the RSV genome though in some strains, RSV G was the expressed in the highest amounts at late times post-infection. Clinical strains of RSV differ in cytokine/chemokine induction and in induction and suppression of host genes expression suggesting that these viruses may have inherent differences in virulence potential. Identification of the genetic elements responsible for these differences may lead to novel approaches to antiviral agents and vaccines

  12. Leukocytes respiratory burst activity as indicator of innate immunity of pacu Piaractus mesopotamicus

    Directory of Open Access Journals (Sweden)

    JD Biller-Takahashi

    Full Text Available The present study evaluated the assay to quantify the respiratory burst activity of blood leukocytes of pacu as an indicator of the innate immune system, using the reduction of nitroblue tetrazolium (NBT to formazan as a measure of the production of reactive oxygen species (ROS. In order to assess the accuracy of the assay, fish were challenged by Aeromonas hydrophila and sampled one week after challenge. The A. hydrophila infection increased the leukocyte respiratory burst activity. The protocol showed a reliable and easy assay, appropriate to determine the respiratory burst activity of blood leukocytes of pacu, a neotropical fish, in the present experimental conditions.

  13. Immune activation in amniotic fluid from Zika virus-associated microcephaly.

    Science.gov (United States)

    Ornelas, Alice M M; Pezzuto, Paula; Silveira, Paola P; Melo, Fabiana O; Ferreira, Thales A; Oliveira-Szejnfeld, Patricia S; Leal, Jeime I; Amorim, Melania M R; Hamilton, Stuart; Rawlinson, William D; Cardoso, Cynthia C; Nixon, Douglas F; Tanuri, Amilcar; Melo, Adriana S; Aguiar, Renato S

    2017-01-01

    Recent advances in the understanding of neuropathogenesis associated with Zika virus (ZIKV) infection has led to descriptions of neonatal microcephaly cases. However, none of these reports have evaluated the humoral response during ZIKV infection. We report here polyfunctional immune activation associated with increased interferon-gamma-inducible protein 10, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), monocyte chemoattractive protein 1 (MCP-1), and granulocyte colony-stimulating factor (G-CSF) levels in the amniotic fluid of ZIKV-positive pregnant women with neonatal microcephaly. These cytokines have been associated not only with neuronal damage, but also with differentiation and proliferation of neural progenitor cells. Our results suggested that the immune activation caused by ZIKV infection in the uterine environment could also interfere with fetal development. ANN NEUROL 2017;81:152-156. © 2016 American Neurological Association.

  14. The role of innate immunity activation in house dust mite allergy.

    Science.gov (United States)

    Jacquet, Alain

    2011-10-01

    House dust mite (HDM) allergy is a frequent inflammatory disease found worldwide. Although allergen-specific CD4(+) Th2 cells orchestrate the HDM allergic response, notably through induction of IgE directed towards mite allergens, recent studies have demonstrated that innate immunity activation also plays a critical role in HDM-induced allergy pathogenesis. HDM allergens can not only be considered proteins that induce adaptive Th2-biased responses in susceptible subjects but also as strong activators of innate immune cells, including skin keratinocytes and airway epithelial cells. The contribution of microbial adjuvant factors, derived from HDM carriers or the environment, is also essential in such cell stimulation. This review highlights how HDM allergens, together with microbial compounds, promote allergic responses through pattern recognition receptor-dependent pathways. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Th2 immune responses and alternatively activated macrophages (AAMacs) in helminth infection in aged mice.

    Science.gov (United States)

    Sugawara, Yasuhiro; Azuma, Noritsugu; Onodera, Sachi; Tsunoka, Yuichi; Morimoto, Motoko

    2011-04-01

    This study aims to understand Th2 immune responses and alternative macrophage activation against nematode parasites in aged mice. Eighteen-month (18 M) and three-month (3 M) old C3H/HeN mice were inoculated with Heligmosomoides polygyrus (Hp) larvae. Real-time PCR analysis indicated that interleukin (IL)-4 and IL-13 gene expression was elevated in both groups after infection, but the expression level was significantly low in 18 M mice. Macrophage phenotype was monitored by measuring arginase-1 gene expression and immunofluorescence staining in small intestine, showing a decrease in the number of alternatively activated macrophages (AAMacs) around worm cysts in 18 M mice. These results suggest that the Th2 immune response in aged mice against a nematode parasite was not sufficiently induced to promote AAMacs.

  16. Immune Complexes Isolated from Patients with Pulmonary Tuberculosis Modulate the Activation and Function of Normal Granulocytes

    Science.gov (United States)

    Senbagavalli, P.; Hilda, J. Nancy; Ramanathan, V. D.; Kumaraswami, V.; Nutman, Thomas B.

    2012-01-01

    Circulating immune complexes (ICs) are associated with the pathogenesis of several diseases. Very little is known about the effect of ICs on the host immune response in patients with tuberculosis (TB). The effects of ICs isolated from patients with TB in modulating the release of calcium, cytokines, and granular proteins were studied in normal granulocytes, as were their chemotactic, phagocytic, and oxidative burst processes. ICs from TB patients induced decreased production of cytokines and platelet-activating factor (PAF) from normal granulocytes. ICs from TB patients also induced enhanced chemotaxis and phagocytosis but caused diminished oxidative burst. This was accompanied by an increased release in intracellular calcium. On the other hand, ICs from TB patients induced increased release of the granular proteins human neutrophil peptides 1 to 3 (HNP1–3). Thus, ICs from patients with TB exhibit a profound effect on granulocyte function with activation of certain effector mechanisms and dampening of others. PMID:23100480

  17. The effect of calcineurin activator, extracted from Chinese herbal medicine, on memory and immunity in mice.

    Science.gov (United States)

    Luo, Jing; Yin, Jiang-Hua; Wei, Qun

    2003-07-01

    Calcineurin (CN) is a highly abundant phosphatase in the brain and it is the only Ca(2+)- and calmodulin-dependent protein serine/threonine phosphatase. There is considerable evidence to suggest that CN plays an essential role in activity-dependent modulation of synaptic efficacy. It has been shown recently that inhibitors of CN, such as CsA or FK506, impair memory formation in day-old chicks. In our present study, extract of Fructus cannabis (EFC) with activation of CN, extracted from Chinese traditional medicine, was used to determine the effects on memory and immunity. In the step-down-type passive avoidance test, the plant extract (0.2 g/kg) significantly improved amnesia induced by chemical drugs in mice, and greatly enhanced the ability of cell-mediated type hypersensitivity and nonspecific immune responses in normal mice. The present study provided pharmacological evidence for Chinese herbal medicine screening from molecular model.

  18. Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4

    Directory of Open Access Journals (Sweden)

    Bo Yoon Chang

    2015-10-01

    Full Text Available Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE. MFE stimulated the production of cytokines, nitric oxide (NO and tumor necrosis factor-α (TNF-α and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase and nuclear factor-κB (NF-κB signaling pathways downstream from toll-like receptor (TLR 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK cell activity, cytotoxic T lymphocyte (CTL activity and IFN-γ production. Immunoglobulin G (IgG antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.

  19. Outrunning the Red Queen: bystander activation as a means of outpacing innate immune subversion by intracellular pathogens.

    Science.gov (United States)

    Holmgren, Alicia M; McConkey, Cameron A; Shin, Sunny

    2017-01-01

    Originally described by the late evolutionary biologist Leigh Van Valen, the Red Queen hypothesis posits that the evolutionary arms race between hosts and their pathogens selects for discrete, genetically encoded events that lead to competitive advantages over the other species. Examples of immune evasion strategies are seen throughout the co-evolution of the mammalian immune system and pathogens, such as the enzymatic inactivation of nuclear factor-κB signaling or host translation by pathogen-encoded virulence factors. Such immunoevasive maneuvers would be expected to select for the evolution of innate immune counterstrategies. Recent advances in our understanding of host immunity and microbial pathogenesis have provided insight into a particular innate immune adaptation, termed bystander activation. Bystander activation occurs as a consequence of infected cells alerting and instructing neighboring uninfected cells to produce inflammatory mediators, either through direct cell contact or paracrine signals. Thus, bystander activation can allow the immune system to overcome the ability of pathogens to disarm immune signaling in directly infected cells. This review presents an overview of the general hallmarks of bystander activation and their emerging role in innate immunity to intracellular pathogens, as well as examples of recent mechanistic discoveries relating to the bystander activation during infection with specific pathogens relevant to human health and disease.

  20. Adenosine can thwart antitumor immune responses elicited by radiotherapy. Therapeutic strategies alleviating protumor ADO activities

    Energy Technology Data Exchange (ETDEWEB)

    Vaupel, Peter [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Multhoff, Gabriele [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Helmholtz Zentrum Muenchen, Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Neuherberg (Germany)

    2016-05-15

    By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT. An overview of the generation, accumulation, and ADO-related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided. Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 + T and CD8 + T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis. ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters. (orig.) [German] Untersuchungen des bioenergetischen Status ergaben, dass Tumorhypoxie neben vielen anderen bedeutsamen biologischen Effekten zu einem starken

  1. Mechanisms of innate immune activation by gluten peptide p31-43 in mice.

    Science.gov (United States)

    Araya, Romina E; Gomez Castro, María Florencia; Carasi, Paula; McCarville, Justin L; Jury, Jennifer; Mowat, Allan M; Verdu, Elena F; Chirdo, Fernando G

    2016-07-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Innate immunity contributes to the pathogenesis of CD, but the mechanisms remain poorly understood. Although previous in vitro work suggests that gliadin peptide p31-43 acts as an innate immune trigger, the underlying pathways are unclear and have not been explored in vivo. Here we show that intraluminal delivery of p31-43 induces morphological changes in the small intestinal mucosa of normal mice consistent with those seen in CD, including increased cell death and expression of inflammatory mediators. The effects of p31-43 were dependent on MyD88 and type I IFNs, but not Toll-like receptor 4 (TLR4), and were enhanced by coadministration of the TLR3 agonist polyinosinic:polycytidylic acid. Together, these results indicate that gliadin peptide p31-43 activates the innate immune pathways in vivo, such as IFN-dependent inflammation, relevant to CD. Our findings also suggest a common mechanism for the potential interaction between dietary gluten and viral infections in the pathogenesis of CD. Copyright © 2016 the American Physiological Society.

  2. Lymphatic Vessels Balance Viral Dissemination and Immune Activation following Cutaneous Viral Infection.

    Science.gov (United States)

    Loo, Christopher P; Nelson, Nicholas A; Lane, Ryan S; Booth, Jamie L; Loprinzi Hardin, Sofia C; Thomas, Archana; Slifka, Mark K; Nolz, Jeffrey C; Lund, Amanda W

    2017-09-26

    Lymphatic vessels lie at the interface between peripheral sites of pathogen entry, adaptive immunity, and the systemic host. Though the paradigm is that their open structure allows for passive flow of infectious particles from peripheral tissues to lymphoid organs, virus applied to skin by scarification does not spread to draining lymph nodes. Using cutaneous infection by scarification, we analyzed the effect of viral infection on lymphatic transport and evaluated its role at the host-pathogen interface. We found that, in the absence of lymphatic vessels, canonical lymph-node-dependent immune induction was impaired, resulting in exacerbated pathology and compensatory, systemic priming. Furthermore, lymphatic vessels decouple fluid and cellular transport in an interferon-dependent manner, leading to viral sequestration while maintaining dendritic cell transport for immune induction. In conclusion, we found that lymphatic vessels balance immune activation and viral dissemination and act as an "innate-like" component of tissue host viral defense. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Regulation of intestinal immune responses through TLR activation: implications for pro- and prebiotics

    Directory of Open Access Journals (Sweden)

    Sander eDe Kivit

    2014-02-01

    Full Text Available The intestinal mucosa is constantly facing a high load of antigens including bacterial antigens derived from the microbiota and food. Despite this, the immune cells present in the gastrointestinal tract do not initiate a pro-inflammatory immune response. Toll-like receptors (TLRs are pattern recognition receptors expressed by various cells in the gastrointestinal tract, including intestinal epithelial cells (IEC and resident immune cells in the lamina propria. Many diseases, including chronic intestinal inflammation (e.g. inflammatory bowel disease, irritable bowel syndrome (IBS, allergic gastroenteritis (e.g. eosinophilic gastroenteritis and allergic IBS and infections are nowadays associated with a deregulated microbiota. The microbiota may directly interact with TLR. In addition, differences in intestinal TLR expression in health and disease may suggest that TLR play an essential role in disease pathogenesis and may be novel targets for therapy. TLR signaling in the gut is involved in either maintaining intestinal homeostasis or the induction of an inflammatory response. This mini review provides an overview of the current knowledge regarding the contribution of intestinal epithelial TLR signaling in both tolerance induction or promoting intestinal inflammation, with a focus on food allergy. We will also highlight a potential role of the microbiota in regulating gut immune responses, especially through TLR activation.

  4. Active and passive immunization protects against lethal, extreme drug resistant-Acinetobacter baumannii infection.

    Directory of Open Access Journals (Sweden)

    Guanpingshen Luo

    Full Text Available Extreme-drug-resistant (XDR Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. New methods to prevent and treat such infections are a critical unmet medical need. To conduct a rational vaccine discovery program, OmpA was identified as the primary target of humoral immune response after intravenous infection by A. baumannii in mice. OmpA was >99% conserved at the amino acid level across clinical isolates harvested between 1951 and 2009 from cerebrospinal fluid, blood, lung, and wound infections, including carbapenem-resistant isolates, and was ≥89% conserved among other sequenced strains, but had minimal homology to the human proteome. Vaccination of diabetic mice with recombinant OmpA (rOmpA with aluminum hydroxide adjuvant markedly improved survival and reduced tissue bacterial burden in mice infected intravenously. Vaccination induced high titers of anti-OmpA antibodies, the levels of which correlated with survival in mice. Passive transfer with immune sera recapitulated protection. Immune sera did not enhance complement-mediated killing but did enhance opsonophagocytic killing of A. baumannii. These results define active and passive immunization strategies to prevent and treat highly lethal, XDR A. baumannii infections.

  5. A novel nematode effector suppresses plant immunity by activating host reactive oxygen species-scavenging system.

    Science.gov (United States)

    Lin, Borong; Zhuo, Kan; Chen, Shiyan; Hu, Lili; Sun, Longhua; Wang, Xiaohong; Zhang, Lian-Hui; Liao, Jinling

    2016-02-01

    Evidence is emerging that plant-parasitic nematodes can secrete effectors to interfere with the host immune response, but it remains unknown how these effectors can conquer host immune responses. Here, we depict a novel effector, MjTTL5, that could suppress plant immune response. Immunolocalization and transcriptional analyses showed that MjTTL5 is expressed specifically within the subventral gland of Meloidogyne javanica and up-regulated in the early parasitic stage of the nematode. Transgenic Arabidopsis lines expressing MjTTL5 were significantly more susceptible to M. javanica infection than wild-type plants, and vice versa, in planta silencing of MjTTL5 substantially increased plant resistance to M. javanica. Yeast two-hybrid, coimmunoprecipitation and bimolecular fluorescent complementation assays showed that MjTTL5 interacts specifically with Arabidopsis ferredoxin : thioredoxin reductase catalytic subunit (AtFTRc), a key component of host antioxidant system. The expression of AtFTRc is induced by the infection of M. javanica. Interaction between AtFTRc and MjTTL could drastically increase host reactive oxygen species-scavenging activity, and result in suppression of plant basal defenses and attenuation of host resistance to the nematode infection. Our results demonstrate that the host ferredoxin : thioredoxin system can be exploited cunningly by M. javanica, revealing a novel mechanism utilized by plant-parasitic nematodes to subjugate plant innate immunity and thereby promoting parasitism. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  6. Technical note: A procedure to estimate glucose requirements of an activated immune system in steers.

    Science.gov (United States)

    Kvidera, S K; Horst, E A; Abuajamieh, M; Mayorga, E J; Sanz Fernandez, M V; Baumgard, L H

    2016-11-01

    Infection and inflammation impede efficient animal productivity. The activated immune system ostensibly requires large amounts of energy and nutrients otherwise destined for synthesis of agriculturally relevant products. Accurately determining the immune system's in vivo energy needs is difficult, but a better understanding may facilitate developing nutritional strategies to maximize productivity. The study objective was to estimate immune system glucose requirements following an i.v. lipopolysaccharide (LPS) challenge. Holstein steers (148 ± 9 kg; = 15) were jugular catheterized bilaterally and assigned to 1 of 3 i.v. control (CON; 3 mL saline; = 5), LPS-administered controls (LPS-C; 055:B5; 1.5 mg/kg BW; = 5), and LPS + euglycemic clamp (LPS-Eu; 1.5 mg/kg BW; 50% dextrose infusion to maintain euglycemia; = 5). In LPS-Eu steers, postbolus blood samples were analyzed for glucose every 10 min. Dextrose infusion rates were adjusted to maintain euglycemia for 720 min. All steers were fasted during the challenge. Samples for later analysis were obtained at 180, 360, 540, and 720 min relative to LPS administration. Rectal temperature was increased ∼0.5°C in both LPS treatments relative to CON steers ( = 0.01). Steers in both LPS treatments were hyperglycemic for ∼3 h postbolus; thereafter, blood glucose was markedly decreased (30%; large amount of glucose needed to maintain euglycemia indicates extensive repartitioning of nutrients away from growth and the importance of glucose as a fuel for the immune system.

  7. Measles supplementary immunization activities and GAVI funds as catalysts for improving injection safety in Africa.

    Science.gov (United States)

    Hoekstra, Edward J; van den Ent, Maya M V X; Dao, Halima; Khalaf, Hala; Salovaara, Annika

    2011-07-01

    In 2000, reuse of disposable syringes and inadequately sterilized syringes resulted in 39% of all injections being unsafe, causing 22 million infections. We describe the contribution of measles supplemental immunization activities (SIAs) and Global Alliance for Vaccines and Immunisation (GAVI) funding in replacing disposable and sterilizable syringes with auto-disable (AD) syringes to improve injection safety in 39 African countries. We assessed trends in nationwide introduction of AD syringes against measles catch-up SIAs and GAVI funding using World Health Organization/United Nations Children's Fund (UNICEF) Joint Reporting Form for Immunization and UNICEF supply data. In 19 (49%) of 39 countries, the measles program catalyzed the introduction of injection safety equipment, including AD syringes and safety boxes, training, and procurement of safety equipment during SIAs. GAVI was catalytic through financial support in 14 countries (36%) for including safe injection equipment in routine immunization. Additionally, GAVI funded 21 countries that had already introduced AD syringes in their national program. UNICEF AD syringe shipments to sub-Saharan Africa increased from 11 million to 461 million from 1997 to 2008. All 39 countries stopped using sterilizable syringes by 2004. The measles mortality reduction program and GAVI complemented each other in improving injection safety. All countries continued with AD syringes for immunization after measles catch-up SIAs and GAVI funding ended. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

  8. Quantitative profiling of innate immune activation by viral infection in single cells.

    Science.gov (United States)

    Timm, Andrea C; Warrick, Jay W; Yin, John

    2017-09-18

    Cells infected by viruses can exhibit diverse patterns of viral and cellular gene expression. The patterns arise in part from the stochastic or noisy reaction kinetics associated with the small number of genomes, enzymes, and other molecules that typically initiate virus replication and activate cellular anti-viral defenses. It is not known what features, if any, of the early viral or cellular gene expression correlate with later processes of viral replication or cell survival. Here we used two fluorescent reporters to visualize innate immune activation of human prostate cancer (PC3) cells against infection by vesicular stomatitis virus. The cells were engineered to express green-fluorescent protein under control of the promoter for IFIT2, an interferon-sensitive component of the anti-viral response, while red-fluorescent protein was expressed as a byproduct of virus infection. To isolate and quantitatively analyze single-cells, we used a unique microwell array device and open-source image processing software. Kinetic analysis of viral and cellular reporter profiles from hundreds of cells revealed novel relationships between gene expression and the outcome of infection. Specifically, the relative timing rather than the magnitude of the viral gene expression and innate immune activation correlated with the infection outcome. Earlier viral or anti-viral gene expression favored or hindered virus growth, respectively. Further, analysis of kinetic parameters estimated from these data suggests a trade-off between robust antiviral signaling and cell death, as indicated by a higher rate of detectable cell lysis in infected cells with a detectable immune response. In short, cells that activate an immune response lyse at a higher rate. More broadly, we demonstrate how the intrinsic heterogeneity of individual cell behaviors can be exploited to discover features of viral and host gene expression that correlate with single-cell outcomes, which will ultimately impact whether or

  9. Drosophila immunity: analysis of PGRP-SB1 expression, enzymatic activity and function.

    Directory of Open Access Journals (Sweden)

    Anna Zaidman-Rémy

    Full Text Available Peptidoglycan is an essential and specific component of the bacterial cell wall and therefore is an ideal recognition signature for the immune system. Peptidoglycan recognition proteins (PGRPs are conserved from insects to mammals and able to bind PGN (non-catalytic PGRPs and, in some cases, to efficiently degrade it (catalytic PGRPs. In Drosophila, several non-catalytic PGRPs function as selective peptidoglycan receptors upstream of the Toll and Imd pathways, the two major signalling cascades regulating the systemic production of antimicrobial peptides. Recognition PGRPs specifically activate the Toll pathway in response to Lys-type peptidoglycan found in most Gram-positive bacteria and the Imd pathway in response to DAP-type peptidoglycan encountered in Gram-positive bacilli-type bacteria and in Gram-negative bacteria. Catalytic PGRPs on the other hand can potentially reduce the level of immune activation by scavenging peptidoglycan. In accordance with this, PGRP-LB and PGRP-SC1A/B/2 have been shown to act as negative regulators of the Imd pathway. In this study, we report a biochemical and genetic analysis of PGRP-SB1, a catalytic PGRP. Our data show that PGRP-SB1 is abundantly secreted into the hemolymph following Imd pathway activation in the fat body, and exhibits an enzymatic activity towards DAP-type polymeric peptidoglycan. We have generated a PGRP-SB1/2 null mutant by homologous recombination, but its thorough phenotypic analysis did not reveal any immune function, suggesting a subtle role or redundancy of PGRP-SB1/2 with other molecules. Possible immune functions of PGRP-SB1 are discussed.

  10. Persistent Immune Activation and Carotid Atherosclerosis in HIV-Infected Ugandans Receiving Antiretroviral Therapy.

    Science.gov (United States)

    Siedner, Mark J; Kim, June-Ho; Nakku, Ruth Sentongo; Bibangambah, Prossy; Hemphill, Linda; Triant, Virginia A; Haberer, Jessica E; Martin, Jeffrey N; Mocello, A Rain; Boum, Yap; Kwon, Douglas S; Tracy, Russell P; Burdo, Tricia; Huang, Yong; Cao, Huyen; Okello, Samson; Bangsberg, David R; Hunt, Peter W

    2016-02-01

    Human immunodeficiency virus (HIV) infection and associated immune activation predict the risk of cardiovascular disease in resource-rich areas. Less is known about these relationships in sub-Saharan Africa. Beginning in 2005, we enrolled subjects in southwestern Uganda into a cohort at the time of antiretroviral therapy (ART) initiation. Multiple immune activation measures were assessed before and 6 months after ART initiation. Beginning in 2013, participants aged >40 years underwent metabolic profiling, including measurement of hemoglobin A1c and lipid levels and carotid ultrasonography. We fit regression models to identify traditional and HIV-specific correlates of common carotid intima media thickness (CCIMT). A total of 105 participants completed carotid ultrasonography, with a median completion time of 7 years following ART initiation. Age, low-density lipoprotein cholesterol level, and pre-ART HIV load were correlated with CCIMT. No association was found between CCIMT and any pre-ART biomarkers of immune activation. However, in multivariable models adjusted for cardiovascular disease risk factors, lower absolute levels of soluble CD14 and interleukin 6 and greater declines in the CD14 level and kynurenine-tryptophan ratio after 6 months of ART predicted a lower CCIMT years later (P < .01). Persistent immune activation despite ART-mediated viral suppression predicts the future atherosclerotic burden among HIV-infected Ugandans. Future work should focus on clinical correlates of these relationships, to elucidate the long-term health priorities for HIV-infected people in the region. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  11. Vitamin D supplementation decreases immune activation and exhaustion in HIV-1-infected youth.

    Science.gov (United States)

    Eckard, Allison Ross; O'Riordan, Mary Ann; Rosebush, Julia C; Lee, Seungeun Thera; Habib, Jakob G; Ruff, Joshua H; Labbato, Danielle; Daniels, Julie E; Uribe-Leitz, Monika; Tangpricha, Vin; Chahroudi, Ann; McComsey, Grace A

    2017-10-10

    Heightened immune activation and exhaustion drive HIV disease progression and co-morbidities. Vitamin D has pleiotropic immunomodulatory effects, but little is known about the effects of supplementation in HIV. Our study investigates changes in immune activation and exhaustion markers after 12 months of supplementation in virologically-suppressed HIV-infected youth with vitamin D insufficiency. This is a randomized, active-control, double-blind trial investigating with 3 different vitamin D 3 doses [18,000 (standard/active-control dose), 60,000 (moderate dose) and 120,000 IU/monthly (high dose)] in 8-26 year old HIV-infected youth on combination antiretroviral therapy with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations ≤30 ng/mL. Only subjects (N=51) who maintained an undetectable HIV-1 RNA over the 12-month study period were included in this analysis. Baseline serum 25(OH)D concentrations and immune activation/exhaustion markers were not different between groups. By 12 months, 25(OH)D increased significantly within each dosing group with the greatest increase and most sustained concentrations ≥30 ng/mL in the high-dose group. Overall, all measured markers decreased with CD4 activation (CD4+CD38+HLA-DR+), CD8 activation (CD8+CD38+HLA-DR+), CD4 exhaustion (CD4+CD38+HLA-DR+PD1+), and inflammatory monocytes (CD14+CD16+) reaching statistical significance. When analyzed separately, there were no significant decreases in the moderate- or standard-dose groups, but CD4 and CD8 activation and inflammatory monocytes decreased significantly in the high-dose group. Vitamin D supplementation decreased markers of T-cell activation/exhaustion and monocyte activation in HIV-infected youth, with subjects given the highest dose (120,000 IU/month) showing the greatest decreases. These data suggest that high-dose vitamin D supplementation may attenuate immune activation and exhaustion and serve as adjuvant therapy to antiretroviral therapy in HIV.

  12. Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity.

    Science.gov (United States)

    Case, James Brett; Li, Yize; Elliott, Ruth; Lu, Xiaotao; Graepel, Kevin W; Sexton, Nicole R; Smith, Everett Clinton; Weiss, Susan R; Denison, Mark R

    2018-01-01

    Coronaviruses (CoVs) are positive-sense RNA viruses that infect numerous mammalian and avian species and are capable of causing severe and lethal disease in humans. CoVs encode several innate immune antagonists that counteract the host innate immune response to facilitate efficient viral replication. CoV nonstructural protein 14 (nsp14) encodes 3'-to-5' exoribonuclease activity (ExoN), which performs a proofreading function and is required for high-fidelity replication. Outside of the order Nidovirales, arenaviruses are the only RNA viruses that encode an ExoN, which functions to degrade double-stranded RNA (dsRNA) replication intermediates. In this study, we tested the hypothesis that CoV ExoN also functions to antagonize the innate immune response. We demonstrate that viruses lacking ExoN activity [ExoN(-)] are sensitive to cellular pretreatment with interferon beta (IFN-β) in a dose-dependent manner. In addition, ExoN(-) virus replication was attenuated in wild-type bone marrow-derived macrophages (BMMs) and partially restored in interferon alpha/beta receptor-deficient (IFNAR-/-) BMMs. ExoN(-) virus replication did not result in IFN-β gene expression, and in the presence of an IFN-β-mediated antiviral state, ExoN(-) viral RNA levels were not substantially reduced relative to those of untreated samples. However, ExoN(-) virus generated from IFN-β-pretreated cells had reduced specific infectivity and decreased relative fitness, suggesting that ExoN(-) virus generated during an antiviral state is less viable to establish a subsequent infection. Overall, our data suggest murine hepatitis virus (MHV) ExoN activity is required for resistance to the innate immune response, and antiviral mechanisms affecting the viral RNA sequence and/or an RNA modification act on viruses lacking ExoN activity.IMPORTANCE CoVs encode multiple antagonists that prevent or disrupt an efficient innate immune response. Additionally, no specific antiviral therapies or vaccines currently

  13. Monocyte-lymphocyte cross-communication via soluble CD163 directly links innate immune system activation and adaptive immune system suppression following ischemic stroke.

    Science.gov (United States)

    O'Connell, Grant C; Tennant, Connie S; Lucke-Wold, Noelle; Kabbani, Yasser; Tarabishy, Abdul R; Chantler, Paul D; Barr, Taura L

    2017-10-11

    CD163 is a scavenger receptor expressed on innate immune cell populations which can be shed from the plasma membrane via the metalloprotease ADAM17 to generate a soluble peptide with lympho-inhibitory properties. The purpose of this study was to investigate CD163 as a possible effector of stroke-induced adaptive immune system suppression. Liquid biopsies were collected from ischemic stroke patients (n = 39), neurologically asymptomatic controls (n = 20), and stroke mimics (n = 20) within 24 hours of symptom onset. Peripheral blood ADAM17 activity and soluble CD163 levels were elevated in stroke patients relative to non-stroke control groups, and negatively associated with post-stroke lymphocyte counts. Subsequent in vitro experiments suggested that this stroke-induced elevation in circulating soluble CD163 likely originates from activated monocytic cells, as serum from stroke patients stimulated ADAM17-dependant CD163 shedding from healthy donor-derived monocytes. Additional in vitro experiments demonstrated that stroke-induced elevations in circulating soluble CD163 can elicit direct suppressive effects on the adaptive immune system, as serum from stroke patients inhibited the proliferation of healthy donor-derived lymphocytes, an effect which was attenuated following serum CD163 depletion. Collectively, these observations provide novel evidence that the innate immune system employs protective mechanisms aimed at mitigating the risk of post-stroke autoimmune complications driven by adaptive immune system overactivation, and that CD163 is key mediator of this phenomenon.

  14. Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women.

    Science.gov (United States)

    Martin, Genevieve E; Gouillou, Maelenn; Hearps, Anna C; Angelovich, Thomas A; Cheng, Allen C; Lynch, Fiona; Cheng, Wan-Jung; Paukovics, Geza; Palmer, Clovis S; Novak, Richard M; Jaworowski, Anthony; Landay, Alan L; Crowe, Suzanne M

    2013-01-01

    Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women. This cross-sectional study of HIV positive and negative women used whole blood flow cytometric analysis to characterize monocyte and CD8(+) T cell subsets. Plasma markers of innate immune activation were measured using standard ELISA-based assays. HIV positive women exhibited elevated plasma levels of the innate immune activation markers CXCL10 (pinnate immune aging biomarkers sCD163 and the proportion of CD16(+) monocytes were equivalent to those observed in HIV negative women aged 14.5 and 10.6 years older, respectively. CXCL10 increased with age at an accelerated rate in HIV positive women (p = 0.002) suggesting a synergistic effect between HIV and aging on innate immune activation. Multivariable modeling indicated that age-related increases in innate immune biomarkers CXCL10 and sCD163 are independent of senescent changes in CD8(+) T lymphocytes. Quantifying the impact of HIV on immune aging reveals that HIV infection in women confers the equivalent of a 10-14 year increase in the levels of innate immune aging markers. These changes may contribute to the increased risk of inflammatory age-related diseases in HIV positive women.

  15. Infection of goats with goatpox virus triggers host antiviral defense through activation of innate immune signaling.

    Science.gov (United States)

    Zeng, Xiancheng; Wang, Song; Chi, Xiaojuan; Chen, Shi-long; Huang, Shile; Lin, Qunqun; Xie, Baogui; Chen, Ji-Long

    2016-02-01

    Goatpox, caused by goatpox virus (GTPV), is one of the most serious infectious diseases associated with high morbidity and mortality in goats. However, little is known about involvement of host innate immunity during the GTPV infection. For this, goats were experimentally infected with GTPV. The results showed that GTPV infection significantly induced mRNA expression of type I interferon (IFN)-α and IFN-β in peripheral blood lymphocytes, spleen and lung. In addition, GTPV infection enhanced expression of several inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-18; and tumor necrosis factor-α (TNF-α). Strikingly, infection with GTPV activated signal transducers and activators of transcription 3 (STAT3), a critical cytokine signaling molecule. Interestingly, the virus infection induced expression of suppressor of cytokine signaling (SOCS)-1. Importantly, the infection resulted in an increased expression of some critical interferon-stimulated genes, such as interferon-induced transmembrane protein (IFITM) 1, IFITM3, interferon stimulated gene (ISG) 15 and ISG20. Furthermore, we found that infection with GTPV up-regulated expression of Toll-like receptor (TLR) 2 and TLR9. These results revealed that GTPV infection activated host innate immune signaling and thereby triggered antiviral innate immunity. The findings provide novel insights into complex mechanisms underlying GTPV-host interaction and pathogenesis of GTPV. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Impact of Hot Environment on Fluid and Electrolyte Imbalance, Renal Damage, Hemolysis, and Immune Activation Postmarathon

    Directory of Open Access Journals (Sweden)

    Rodrigo Assunção Oliveira

    2017-01-01

    Full Text Available Previous studies have demonstrated the physiological changes induced by exercise exposure in hot environments. We investigated the hematological and oxidative changes and tissue damage induced by marathon race in different thermal conditions. Twenty-six male runners completed the São Paulo International Marathon both in hot environment (HE and in temperate environment (TE. Blood and urine samples were collected 1 day before, immediately after, 1 day after, and 3 days after the marathon to analyze the hematological parameters, electrolytes, markers of tissue damage, and oxidative status. In both environments, the marathon race promotes fluid and electrolyte imbalance, hemolysis, oxidative stress, immune activation, and tissue damage. The marathon runner’s performance was approximately 13.5% lower in HE compared to TE; however, in HE, our results demonstrated more pronounced fluid and electrolyte imbalance, renal damage, hemolysis, and immune activation. Moreover, oxidative stress induced by marathon in HE is presumed to be related to protein/purine oxidation instead of other oxidative sources. Fluid and electrolyte imbalance and protein/purine oxidation may be important factors responsible for hemolysis, renal damage, immune activation, and impaired performance after long-term exercise in HE. Nonetheless, we suggested that the impairment on performance in HE was not associated to the muscle damage and lipoperoxidation.

  17. Activation of cell-mediated immunity by Morinda citrifolia fruit extract and its constituents.

    Science.gov (United States)

    Murata, Kazuya; Abe, Yumi; Futamura-Masudaa, Megumi; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki

    2014-04-01

    Morinda citrifolia, commonly known as noni, is a traditional natural medicine in French Polynesia and Hawaii. Functional foods derived from M. citrifolia fruit have been marketed to help prevent diseases and promote good health. The objective of this study was to assess the effects of M. citrifolia fruit on cell-mediated immunity. In the picryl chloride-induced contact dermatitis test, M. citrifolia fruit extract (Noni-ext) inhibited the suppression of cell-mediated immunity by immunosuppressive substances isolated from freeze-dried ascites of Ehrlich carcinoma-bearing mice (EC-sup). In addition, Noni-ext inhibited reduction of IL-2 production in EC-sup-treated mice and activated natural killer cells in normal mice. These results suggest that Noni-ext has multiple effects on the recovery of cell-mediated immunity. Furthermore, we investigated the active principles of Noni-ext and identified an iridoid glycoside, deacetylasperulosidic acid. Oral administration of deacetylasperulosidic acid inhibited the reduction of ear swelling, and also cancelled the suppression of IL-2 production along with the activation of natural killer cells in the same manner as that of Noni-ext.

  18. Active random noise control using adaptive learning rate neural networks with an immune feedback law

    Science.gov (United States)

    Sasaki, Minoru; Kuribayashi, Takumi; Ito, Satoshi

    2005-12-01

    In this paper an active random noise control using adaptive learning rate neural networks with an immune feedback law is presented. The adaptive learning rate strategy increases the learning rate by a small constant if the current partial derivative of the objective function with respect to the weight and the exponential average of the previous derivatives have the same sign, otherwise the learning rate is decreased by a proportion of its value. The use of an adaptive learning rate attempts to keep the learning step size as large as possible without leading to oscillation. In the proposed method, because of the immune feedback law change a learning rate of the neural networks individually and adaptively, it is expected that a cost function minimize rapidly and training time is decreased. Numerical simulations and experiments of active random noise control with the transfer function of the error path will be performed, to validate the convergence properties of the adaptive learning rate Neural Networks with the immune feedback law. Control results show that adaptive learning rate Neural Networks control structure can outperform linear controllers and conventional neural network controller for the active random noise control.

  19. Influence of immune activation and inflammatory response on cardiovascular risk associated with the human immunodeficiency virus

    Directory of Open Access Journals (Sweden)

    Beltrán LM

    2015-01-01

    Full Text Available Luis M Beltrán,1 Alfonso Rubio-Navarro,2 Juan Manuel Amaro-Villalobos,2 Jesús Egido,2–4 Juan García-Puig,1 Juan Antonio Moreno21Metabolic-Vascular Unit, Fundación IdiPAZ-Hospital Universitario La Paz, Madrid, Spain; 2Vascular, Renal, and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain; 3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, Madrid, Spain; 4Fundación Renal Iñigo Alvarez de Toledo-Instituto Reina Sofía de Investigaciones Nefrológicas (FRIAT-IRSIN, Madrid, SpainAbstract: 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.Keywords: HIV, cardiovascular disease, immune activation, inflammation, antiretroviral therapy

  20. Arginase 1 activity worsens lung-protective immunity against Streptococcus pneumoniae infection.

    Science.gov (United States)

    Knippenberg, Sarah; Brumshagen, Christina; Aschenbrenner, Franziska; Welte, Tobias; Maus, Ulrich A

    2015-06-01

    Type 2 helper cell (Th2) dominated chronic lung diseases such as asthma are characterized by an increased risk for bacterial lung infections. However, the underlying mechanisms are poorly defined. Arginase 1 (Arg1) has been suggested to play an important role in the pathophysiology of asthma, and is rapidly induced in lung macrophages by Th2 cytokines, thereby limiting macrophage-derived antimicrobial nitric oxide (NO) production. Here we examined the effect of Th2 cytokine induced upregulation or lung myeloid cell specific conditional knockdown of Arg1 on lung resistance against Streptococcus pneumoniae (Spn) in mice. Lung macrophages responded with a profound induction of Arg1 mRNA and protein to treatment with IL-13 both in vitro and in vivo. IL-13-induced Arg1 activity in the lungs of mice led to significantly attenuated lung-protective immunity against Spn, while conditional Arg1 knockdown had no effect on lung-protective immunity against Spn. Collectively, the data show that Th2 cytokine induced increased Arg1 activity worsens lung-protective immunity against Spn, and interventions to block Th2 cytokine induced lung Arg1 activity may thus be a novel immunomodulatory strategy to lower the risk of bacterial infections in asthmatic patients. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men.

    Science.gov (United States)

    Muehlenbein, Michael P; Hirschtick, Jana L; Bonner, Julia Z; Swartz, Ann M

    2010-01-01

    There is a paucity of data on the energetic demands of human immune functions, despite the fact that both clinical medicine and evolutionary biology would benefit from further clarification of these costs. To better understand the energetic requirements of mounting a mild immune response, as well as some of the major hormonal changes underlying these metabolic changes, we examined changes in resting metabolic rate (RMR) and hormones during and after respiratory tract infection in young adult men. An epidemiologic passive detection design was used to recruit 25 nonfebrile subjects naturally infected with respiratory tract pathogens. Symptomology, percent body fat, RMR, salivary testosterone and cortisol, and other information were collected at a minimum of three time points during and after convalescence. Comparisons of the differences in RMR, testosterone, and cortisol between sampling days within individual cases were made using paired t-tests. Participants experienced 8% higher RMR during illness, and a subset of these men experienced a mean increase greater than 14%. The participants also experienced 10% lower testosterone levels during illness, and a subset of these participants experienced a mean decrease of 30%, although cortisol levels did not change significantly. These results document elevated RMR following natural pathogen exposure in adult humans, demonstrating that even mild immune reactions can elicit significant increases in energy expenditure. Understanding the costs of immunity and the immunomodulatory actions of hormones are central to understanding the role of immunity in human life history evolution.

  2. Phagocytic receptors activate and immune inhibitory receptor SIRPalpha inhibits phagocytosis through paxillin and cofilin

    Directory of Open Access Journals (Sweden)

    Miri eGitik

    2014-04-01

    Full Text Available The innate-immune function of phagocytosis of apoptotic cells, tissue-debris, pathogens and cancer cells is essential for homeostasis, tissue repair, fighting infection and combating malignancy. Phagocytosis is carried out in the CNS by resident microglia and in both CNS and PNS by recruited macrophages. While phagocytosis proceeds, bystander healthy cells protect themselves by sending a do not eat me message to phagocytes as CD47 on their surface ligates immune inhibitory receptor SIRPα on the surface of phagocytes and SIRPα then produces the signaling which inhibits phagocytosis. This helpful mechanism becomes harmful when tissue-debris and unhealthy cells inhibit their own phagocytosis by employing the same mechanism. However, the inhibitory signaling that SIRPα produces has not been fully revealed. We focus here on how SIRPα inhibits the phagocytosis of the tissue-debris degenerated-myelin which hinders repair in axonal injury and neurodegenerative diseases. We tested whether SIRPα inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a the cytoskeleton generates the mechanical forces that drive phagocytosis and (b both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPα expression was knocked-down by SIRPα-shRNA. Further, levels of phagocytosis, paxillin activation and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPα produces by promoting the inactivation of paxillin and cofilin.

  3. Baseline immune activity is associated with date rather than moult stage in the arctic-breeding barnacle goose (Branta leucopsis)

    NARCIS (Netherlands)

    Loonen, Maarten J.J.E.; Sandström, Cecilia A.M.; Prop, Jouke; van der Jeugd, Henk

    2014-01-01

    Variation in immune defence in birds is often explained either by external factors such as food availability and disease pressure or by internal factors such as moult and reproductive effort. We explored these factors together in one sampling design by measuring immune activity over the time frame

  4. The FomA porin from Fusobacterium nucleatum is a Toll-like receptor 2 agonist with immune adjuvant activity.

    Science.gov (United States)

    Toussi, Deana N; Liu, Xiuping; Massari, Paola

    2012-07-01

    Many bacterial components selectively activate immune and nonhematopoietic target cells via Toll-like receptor (TLR) signaling; modulation of such host responses defines the immune adjuvant properties of these bacterial products. For example, the outer membrane protein porins from Neisseria, Salmonella, and Shigella are known TLR2 agonists with established systemic and mucosal immune adjuvanticity. Early work indicated that the FomA porin from Fusobacterium nucleatum has immune adjuvant activity in mice. Using a purified recombinant FomA, we have verified its immune stimulatory properties and have defined a role for TLR2 signaling in its in vitro and in vivo activity. FomA induces interleukin 8 (IL-8) secretion and NF-κB-dependent luciferase activity in HEK cells expressing TLR2, IL-6 secretion, and cell surface upregulation of CD86 and major histocompatibility complex (MHC) II in primary B cells from wild-type mice, but it fails to activate cells from TLR2 knockout mice. Accordingly, the immune adjuvant activity of FomA is also TLR2 dependent. In a mouse model of immunization with ovalbumin (OVA), FomA induces enhanced production of OVA-specific IgM and IgG, including IgG1 and IgG2b antibodies, as well as enhanced secretion of IL-10 and IL-6, consistent with a Th2-type adjuvant effect. We also observe a moderate production of anti-FomA antibodies, suggesting that FomA is also immunogenic, a quality that is also TLR2 dependent. Therefore, modulation of host immune responses by FomA may be effective for targeting general host immunity not only to pathogens (as a novel TLR2 adjuvant) but also to F. nucleatum itself (as an antigen), expanding its use as a self-adjuvanted antigen in an immunization strategy against polymicrobial infections, including those by F. nucleatum.

  5. Interaction Between Familial Transmission and a Constitutively Active Immune System Shapes Gut Microbiota inDrosophila melanogaster.

    Science.gov (United States)

    Mistry, Rupal; Kounatidis, Ilias; Ligoxygakis, Petros

    2017-06-01

    Resident gut bacteria are constantly influencing the immune system, yet the role of the immune system in shaping microbiota composition during an organism's life span has remained unclear. Experiments in mice have been inconclusive due to differences in husbandry schemes that led to conflicting results. We used Drosophila as a genetically tractable system with a simpler gut bacterial population structure streamlined genetic backgrounds and established cross schemes to address this issue. We found that, depending on their genetic background, young flies had microbiota of different diversities that converged with age to the same Acetobacteraceae-dominated pattern in healthy flies. This pattern was accelerated in immune-compromised flies with higher bacterial load and gut cell death. Nevertheless, immune-compromised flies resembled their genetic background, indicating that familial transmission was the main force regulating gut microbiota. In contrast, flies with a constitutively active immune system had microbiota readily distinguishable from their genetic background with the introduction and establishment of previously undetectable bacterial families. This indicated the influence of immunity over familial transmission. Moreover, hyperactive immunity and increased enterocyte death resulted in the highest bacterial load observed starting from early adulthood. Cohousing experiments showed that the microenvironment also played an important role in the structure of the microbiota where flies with constitutive immunity defined the gut microbiota of their cohabitants. Our data show that, in Drosophila , constitutively active immunity shapes the structure and density of gut microbiota. Copyright © 2017 Mistry et al.

  6. A Force-Activated Trip Switch Triggers Rapid Dissociation of a Colicin from Its Immunity Protein

    Science.gov (United States)

    Farrance, Oliver E.; Hann, Eleanore; Kaminska, Renata; Housden, Nicholas G.; Derrington, Sasha R.; Kleanthous, Colin; Radford, Sheena E.; Brockwell, David J.

    2013-01-01

    Colicins are protein antibiotics synthesised by Escherichia coli strains to target and kill related bacteria. To prevent host suicide, colicins are inactivated by binding to immunity proteins. Despite their high avidity (Kd≈fM, lifetime ≈4 days), immunity protein release is a pre-requisite of colicin intoxication, which occurs on a timescale of minutes. Here, by measuring the dynamic force spectrum of the dissociation of the DNase domain of colicin E9 (E9) and immunity protein 9 (Im9) complex using an atomic force microscope we show that application of low forces (force-triggered increase in off-rate a trip bond. Using mutational analysis, we elucidate the mechanism of this switch in affinity. We show that the N-terminal region of E9, which has sparse contacts with the hydrophobic core, is linked to an allosteric activator region in E9 (residues 21–30) whose remodelling triggers immunity protein release. Diversion of the force transduction pathway by the introduction of appropriately positioned disulfide bridges yields a force resistant complex with a lifetime identical to that measured by ensemble techniques. A trip switch within E9 is ideal for its function as it allows bipartite complex affinity, whereby the stable colicin:immunity protein complex required for host protection can be readily converted to a kinetically unstable complex whose dissociation is necessary for cellular invasion and competitor death. More generally, the observation of two force phenotypes for the E9:Im9 complex demonstrates that force can re-sculpt the underlying energy landscape, providing new opportunities to modulate biological reactions in vivo; this rationalises the commonly observed discrepancy between off-rates measured by dynamic force spectroscopy and ensemble methods. PMID:23431269

  7. A force-activated trip switch triggers rapid dissociation of a colicin from its immunity protein.

    Directory of Open Access Journals (Sweden)

    Oliver E Farrance

    Full Text Available Colicins are protein antibiotics synthesised by Escherichia coli strains to target and kill related bacteria. To prevent host suicide, colicins are inactivated by binding to immunity proteins. Despite their high avidity (K(d ≈ fM, lifetime ≈ 4 days, immunity protein release is a pre-requisite of colicin intoxication, which occurs on a timescale of minutes. Here, by measuring the dynamic force spectrum of the dissociation of the DNase domain of colicin E9 (E9 and immunity protein 9 (Im9 complex using an atomic force microscope we show that application of low forces (<20 pN increases the rate of complex dissociation 10(6-fold, to a timescale (lifetime ≈ 10 ms compatible with intoxication. We term this catastrophic force-triggered increase in off-rate a trip bond. Using mutational analysis, we elucidate the mechanism of this switch in affinity. We show that the N-terminal region of E9, which has sparse contacts with the hydrophobic core, is linked to an allosteric activator region in E9 (residues 21-30 whose remodelling triggers immunity protein release. Diversion of the force transduction pathway by the introduction of appropriately positioned disulfide bridges yields a force resistant complex with a lifetime identical to that measured by ensemble techniques. A trip switch within E9 is ideal for its function as it allows bipartite complex affinity, whereby the stable colicin:immunity protein complex required for host protection can be readily converted to a kinetically unstable complex whose dissociation is necessary for cellular invasion and competitor death. More generally, the observation of two force phenotypes for the E9:Im9 complex demonstrates that force can re-sculpt the underlying energy landscape, providing new opportunities to modulate biological reactions in vivo; this rationalises the commonly observed discrepancy between off-rates measured by dynamic force spectroscopy and ensemble methods.

  8. Systemic innate immune activation in food protein-induced enterocolitis syndrome.

    Science.gov (United States)

    Goswami, Ritobrata; Blazquez, Ana Belen; Kosoy, Roman; Rahman, Adeeb; Nowak-Węgrzyn, Anna; Berin, M Cecilia

    2017-06-01

    Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy of infancy whose pathophysiology is poorly understood. We set out to identify and phenotype allergen-responsive cells in peripheral blood of a cohort of subjects undergoing supervised food challenge for FPIES. We profiled antigen-responsive cells in PBMCs by flow cytometry, and examined cells in whole blood obtained before and after challenge by CyTOF mass cytometry and RNAseq. Using a CD154-based detection approach, we observed that milk, soy, or rice-responsive T cells, and TNF-α-producing CD154(+) T cells, were significantly lower in those with outgrown FPIES compared with those with active FPIES. However, levels were within the normal range and were inconsistent with a role in the pathophysiology of FPIES. Profiling of whole blood by CyTOF demonstrated profound activation of cells of the innate immune system after food challenge, including monocytes, neutrophils, natural killer cells, and eosinophils. Activation was not observed in children with outgrown FPIES. We confirmed this pattern of innate immune activation in a larger cohort by RNAseq. Furthermore, we observed pan-T-cell activation and redistribution from the circulation after a positive food challenge but not in those who had outgrown their FPIES. Our data demonstrate a compelling role of systemic innate immune activation in adverse reactions elicited by foods in FPIES. Further investigation is needed to identify the mechanism of antigen specificity of adverse reactions to foods in FPIES. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. Differential regulation of innate immune cytokine production through pharmacological activation of Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) in burn patient immune cells and monocytes.

    Science.gov (United States)

    Eitas, Timothy K; Stepp, Wesley H; Sjeklocha, Lucas; Long, Clayton V; Riley, Caitlin; Callahan, James; Sanchez, Yolanda; Gough, Peter; Knowlin, Laquanda; van Duin, David; Ortiz-Pujols, Shiara; Jones, Samuel W; Maile, Robert; Hong, Zhi; Berger, Scott; Cairns, Bruce A

    2017-01-01

    Burn patients suffer from immunological dysfunction for which there are currently no successful interventions. Similar to previous observations, we find that burn shock patients (≥15% Total Burn Surface Area (TBSA) injury) have elevated levels of the innate immune cytokines Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1)/CC-motif Chemokine Ligand 2(CCL2) early after hospital admission (0-48 Hours Post-hospital Admission (HPA). Functional immune assays with patient Peripheral Blood Mononuclear Cells (PBMCs) revealed that burn shock patients (≥15% TBSA) produced elevated levels of MCP-1/CCL2 after innate immune stimulation ex vivo relative to mild burn patients. Interestingly, treatment of patient PBMCs with the Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) agonist, CDDO-Me(bardoxolone methyl), reduced MCP-1 production but not IL-6 or Interleukin-10 (IL-10) secretion. In enriched monocytes from healthy donors, CDDO-Me(bardoxolone methyl) also reduced LPS-induced MCP1/CCL2 production but did not alter IL-6 or IL-10 secretion. Similar immunomodulatory effects were observed with Compound 7, which activates the NRF2 pathway through a different and non-covalent Mechanism Of Action (MOA). Hence, our findings with CDDO-Me(bardoxolone methyl) and Compound 7 are likely to reflect a generalizable aspect of NRF2 activation. These observed effects were not specific to LPS-induced immune responses, as NRF2 activation also reduced MCP-1/CCL2 production after stimulation with IL-6. Pharmacological NRF2 activation reduced Mcp-1/Ccl2 transcript accumulation without inhibiting either Il-6 or Il-10 transcript levels. Hence, we describe a novel aspect of NRF2 activation that may contribute to the beneficial effects of NRF2 agonists during disease. Our work also demonstrates that the NRF2 pathway is retained and can be modulated to regulate important immunomodulatory functions in burn patient immune cells.

  10. Impaired activation of the innate immune response to bacterial challenge in Tourette syndrome.

    Science.gov (United States)

    Weidinger, Elif; Krause, Daniela; Wildenauer, Agnes; Meyer, Sebastian; Gruber, Rudolf; Schwarz, Markus J; Müller, Norbert

    2014-08-01

    Infections resulting in immune activation have been proposed to play an etiological role in a subgroup of patients with Tourette syndrome (TS). In order to further characterize the interaction between pathogens and the innate immune system the toll-like receptor (TLR) 4 on CD14 + monocytes and soluble CD14 (sCD14) levels were analyzed in the serum of 33 Tourette patients and 31 healthy controls. Moreover, collected blood samples were stimulated with lipopolysaccharide (LPS) mimicking a bacterial infection. TLR4 was analysed by flow cytometry, sCD14 was analysed by enzyme-linked immunosorbent assay. Patients had a lower receptor expression of TLR4 after stimulation with LPS (P = 0.045) and higher levels of sCD14 (unstimulated P = 0.014, after LPS P = 0.045). The increase in TLR4 expression after stimulation with LPS was significantly higher in the control group (P = 0.041). Higher levels of sCD14, lower levels of TLR4 expression after stimulation and a diminished up-regulation of TLR4 expression after LPS stimulation in patients might represent an impaired activation of the innate immune response in TS, especially in regard to bacterial infection. The impaired response to pathogens could eventually lead to a higher susceptibility for infections. Recurring infections and a chronic inflammation could trigger and maintain the symptoms of TS.

  11. Nanoparticle impact on innate immune cell pattern-recognition receptors and inflammasomes activation.

    Science.gov (United States)

    Silva, Ana Luísa; Peres, Carina; Conniot, João; Matos, Ana I; Moura, Liane; Carreira, Bárbara; Sainz, Vanessa; Scomparin, Anna; Satchi-Fainaro, Ronit; Préat, Véronique; Florindo, Helena F

    2017-09-20

    Nanotechnology-based strategies can dramatically impact the treatment, prevention and diagnosis of a wide range of diseases. Despite the unprecedented success achieved with the use of nanomaterials to address unmet biomedical needs and their particular suitability for the effective application of a personalized medicine, the clinical translation of those nanoparticulate systems has still been impaired by the limited understanding on their interaction with complex biological systems. As a result, unexpected effects due to unpredicted interactions at biomaterial and biological interfaces have been underlying the biosafety concerns raised by the use of nanomaterials. This review explores the current knowledge on how nanoparticle (NP) physicochemical and surface properties determine their interactions with innate immune cells, with particular attention on the activation of pattern-recognition receptors and inflammasome. A critical perspective will additionally address the impact of biological systems on the effect of NP on immune cell activity at the molecular level. We will discuss how the understanding of the NP-innate immune cell interactions can significantly add into the clinical translation by guiding the design of nanomedicines with particular effect on targeted cells, thus improving their clinical efficacy while minimizing undesired but predictable toxicological effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Effect of poly(amidoamine) dendrimers on the structure and activity of immune molecules.

    Science.gov (United States)

    Lin, Jiansheng; Hua, Wenxi; Zhang, Yi; Li, Chenghua; Xue, Wei; Yin, Jian; Liu, Zonghua; Qiu, Xiaozhong

    2015-02-01

    Poly(amidoamine) (PAMAM) dendrimers are widely used biomedical polymers, which are extensively applied in drug delivery, gene delivery, contrast agent, etc. In these biomedical applications, the bio-safety of the PAMAM dendrimers is a critical issue, which affects not only their toxicity to the host but also the expected in vivo biofunctions of the materials. To clarify the bio-safety of PAMAM dendrimers, the effects of generation 5 PAMAM dendrimers with amine, hydroxyl or carboxyl groups on immune molecules were explored in this work. Specifically, the effect of the PAMAM dendrimers on the secondary structure and conformation of immune molecule γ-globulin was studied by using ultraviolet-visible, fluorescence, and circular dichroism spectroscopies. The effect of the PAMAM dendrimers on complement activation was determined by enzyme-linked immunosorbent assay. Further, the effect of the PAMAM dendrimers on antigen-antibody reaction was studied by using human red blood cell agglutination assay. The results showed that, the PAMAM dendrimers could affect the secondary structure and conformation of γ-globulin, and inhibited complement activation. Generation 5 PAMAM dendrimer with carboxyl group at 10mg/mL impaired red blood cell (RBC) antigen-antibody reaction. From these results, the effects of the PAMAM dendrimers on immune molecules depend on their bulk structure and surface groups. This work provides important information for the immunocompatibility evaluation, preclinical design, and clinical applications of PAMAM dendrimers. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Fibroblast activation protein is dispensable in the anti-influenza immune response in mice.

    Directory of Open Access Journals (Sweden)

    Sioh-Yang Tan

    Full Text Available Fibroblast activation protein alpha (FAP is a unique dual peptidase of the S9B serine protease family, being capable of both dipeptidyl peptidase and endopeptidase activities. FAP is expressed at low level in healthy adult organs including the pancreas, cervix, uterus, submaxillary gland and the skin, and highly upregulated in embryogenesis, chronic inflammation and tissue remodelling. It is also expressed by cancer-associated stromal fibroblasts in more than 90% of epithelial tumours. FAP has enzymatic and non-enzymatic functions in the growth, immunosuppression, invasion and cell signalling of tumour cells. FAP deficient mice are fertile and viable with no gross abnormality, but little data exist on the role of FAP in the immune system. FAP is upregulated in association with microbial stimulation and chronic inflammation, but its function in infection remains unknown. We showed that major populations of immune cells including CD4+ and CD8+ T cells, B cells, dendritic cells and neutrophils are generated and maintained normally in FAP knockout mice. Upon intranasal challenge with influenza virus, FAP mRNA was increased in the lungs and lung-draining lymph nodes. Nonetheless, FAP deficient mice showed similar pathologic kinetics to wildtype controls, and were capable of supporting normal anti-influenza T and B cell responses. There was no evidence of compensatory upregulation of other DPP4 family members in influenza-infected FAP-deficient mice. FAP appears to be dispensable in anti-influenza adaptive immunity.

  14. Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation.

    Science.gov (United States)

    Casas, Christiane; Paul, Carle; Lahfa, Morad; Livideanu, Bulai; Lejeune, Ophélie; Alvarez-Georges, Sandrine; Saint-Martory, Christine; Degouy, Arnaud; Mengeaud, Valérie; Ginisty, Hervé; Durbise, Elizabeth; Schmitt, Anne M; Redoulès, Daniel

    2012-12-01

    The aim of this study is to quantify D. folliculorum colonisation in rosacea subtypes and age-matched controls and to determine the relationship between D. folliculorum load, rosacea subtype and skin innate immune system activation markers. We set up a multicentre, cross-sectional, prospective study in which 98 adults were included: 50 with facial rosacea, including 18 with erythematotelangiectatic rosacea (ETR), and 32 with papulopustular rosacea (PPR) and 48 age- and sex-matched healthy volunteers. Non-invasive facial samples were taken to quantify D. folliculorum infestation by quantitative PCR and evaluate inflammatory and immune markers. Analysis of the skin samples show that D. folliculorum was detected more frequently in rosacea patients than age-matched controls (96% vs 74%, P rosacea patients than in healthy volunteers. Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR. Overexpression of LL-37 and VEGF, as well as CD45RO, MPO and CD163, was observed, indicating broad immune system activation in patients with rosacea. In conclusion, D. folliculorum density is highly increased in patients with rosacea, irrespective of rosacea subtype. There appears to be an inverse relationship between D. folliculorum density and inflammation markers in the skin of rosacea patients, with clear differences between rosacea subtypes. © 2012 John Wiley & Sons A/S.

  15. Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Lin Wang

    2017-11-01

    Full Text Available Background/Aims: Cetuximab is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of epidermal growth factor receptor. This antibody is widely used for colorectal cancer (CRC treatment but its influence on the immune system is incompletely understood. Methods: The immune influence of cetuximab therapy in CRC patients was investigated by analyzing peripheral blood mononuclear cells using flow cytometry. We undertook in vitro cytotoxicity and cytokine-profile assays to ascertain the immunomodulatory effect of cetuximab treatment. Results: The number of CD3+ T, CD8+ T, and natural killer (NK cells was increased significantly and T-regulatory cells reduced gradually after cetuximab treatment. Percentage of CD4+ T, natural killer T (NKT-like, invariant NKT, and dendritic cells was similar between baseline patients and cetuximab patients. Expression of CD137 on NK and CD8+ T cells was increased significantly after 4 weeks of cetuximab therapy. In vitro cetuximab treatment markedly increased expression of CD137 and CD107a on NK and CD8+ T cells. Cetuximab treatment promoted the cytotoxic activity of NK and CD8+ T cells against tumor cells. Conclusion: Cetuximab treatment promotes activation of the immune response but alleviates immunosuppression: this might be the underlying anti-CRC effect of cetuximab.

  16. Active immunization against vasoactive intestinal polypeptide decreases neuronal recruitment and inhibits reproduction in zebra finches.

    Science.gov (United States)

    Vistoropsky, Yulia; Heiblum, Rachel; Smorodinsky, Nechama-Ina; Barnea, Anat

    2016-08-15

    Neurogenesis and neuronal recruitment occur in adult brains of many vertebrates, and the hypothesis is that these phenomena contribute to the brain plasticity that enables organisms to adjust to environmental changes. In mammals, vasoactive intestinal polypeptide (VIP) is known to have many neuroprotective properties, but in the avian brain, although widely distributed, its role in neuronal recruitment is not yet understood. In the present study we actively immunized adult zebra finches against VIP conjugated to KLH and compared neuronal recruitment in their brains, with brains of control birds, which were immunized against KLH. We looked at two forebrain regions: the nidopallium caudale (NC), which plays a role in vocal communication, and the hippocampus (HC), which is involved in the processing of spatial information. Our data demonstrate that active immunization against VIP reduces neuronal recruitment, inhibits reproduction, and induces molting, with no change in plasma prolactin levels. Thus, our observations suggest that VIP has a direct positive role in neuronal recruitment and reproduction in birds. J. Comp. Neurol. 524:2516-2528, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Body awareness and responses to experimentally Induced pain

    National Research Council Canada - National Science Library

    M. Minev; M. Petkova; B. Petrova; R. Strebkova

    2017-01-01

    PURPOSE. The aim of this study is to discuss personal and demographic factors that influence the relationship between physical activity and awareness of one's own body, as well as the pain response...

  18. Effect of menthol in experimentally induced ulcers: pathways of gastroprotection.

    Science.gov (United States)

    Rozza, A L; Hiruma-Lima, C A; Takahira, R K; Padovani, C R; Pellizzon, C H

    2013-11-25

    Based on ethnopharmacological indications that Mentha species may be used in the treatment of gastrointestinal diseases, this study aimed to characterize the gastroprotective mechanisms of menthol (ME), the major compound of the essential oil from species of the genus Mentha. The gastroprotective action of ME was analyzed in gastric ulcers that were induced by ethanol or indomethacin in Wistar male rats. The mechanisms responsible for the gastroprotective effect were assessed by analyzing the amount of mucus secreted, involvement of non-protein sulfhydryl (NP-SH) compounds, involvement of calcium ion channels and NO/cGMP/K(+)ATP pathway, gastric antisecretory activity and the prostaglandin E2 (PGE2) production. The anti-diarrheal activity and acute toxicity of ME were also evaluated. Oral treatment with ME (50mg/kg) offered 88.62% and 72.62% of gastroprotection against ethanol and indomethacin, respectively. There was an increased amount of mucus and PGE2 production. The gastroprotective activity of ME involved NP-SH compounds and the stimulation of K(+)ATP channels, but not the activation of calcium ion channels or the production of NO. The oral administration of ME induced an antisecretory effect as it decreased the H(+) concentration in gastric juice. ME displayed anti-diarrheal and antiperistaltic activity. There were no signs of toxicity in the biochemical analyses performed in the rats' serum. These results demonstrated that ME provides gastroprotective and anti-diarrheal activities with no toxicity in rats. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Changes in proHB-EGF expression after functional activation of the immune system cells

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    T. O. Chudina

    2017-12-01

    Full Text Available The level of proHB-EGF expression on J774, Raji, KG-1 cells derived from different types of human and mouse immune system cells under the standard in vitro culture conditions and during functional activation of these cells was investigated. Changes in the proHB-EGF expression on the cell surface were found to depend on the density of cell population, the content of fetal bovine serum in the culture medium, the effect of mitogenic factors – bacterial lipopolysaccharide, an inactive full-size form of diphtheria toxin (CRM197 and recombinant soluble HB-EGF – rsHB-EGF. The results obtained are important for the understanding of the functional role of proHB-EGF receptor on the surface of macrophage-like cells and B lymphocytes and indicate the involvement of this receptor in immune response regulation in an organism.

  20. Acupuncture May Stimulate Anticancer Immunity via Activation of Natural Killer Cells

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    Michael Francis Johnston

    2011-01-01

    Full Text Available This article presents the hypothesis that acupuncture enhances anticancer immune functions by stimulating natural killer (NK cells. It provides background information on acupuncture, summarizes the current scientific understanding of the mechanisms through which NK cells act to eliminate cancer cells, and reviews evidence that acupuncture is associated with increases in NK cell quantity and function in both animals and humans. The key contribution of this article involves the use of cellular immunology and molecular biological theory to interpret and synthesize evidence from disparate animal and human studies in formulating the ‘acupuncture immuno-enhancement hypothesis’: clinicians may use acupuncture to promote the induction and secretion of NK-cell activating cytokines that engage specific NK cell receptors that endogenously enhance anticancer immune function.

  1. Gastroprotective Efficacy and Safety Evaluation of Scoparone Derivatives on Experimentally Induced Gastric Lesions in Rodents

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    Dong Ju Son

    2015-03-01

    Full Text Available This study investigated the gastroprotective efficacy of synthesized scoparone derivatives on experimentally induced gastritis and their toxicological safety. Six scoparone derivatives were synthesized and screened for gastroprotective activities against HCl/ethanol- and indomethacin-induced gastric ulcers in rats. Among these compounds, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin were found to have gastroprotective activity greater than the standard drug rebamipide; 6-methoxy-7,8-methylenedioxycoumarin, 6-methoxy-7,8-(1-methoxy-methylenedioxycoumarin, 6,7-methylenedioxycoumarin, and 6,7-(1-methoxy-methylenedioxycoumarin were found to be equipotent or less potent that of rebamipide. Pharmacological studies suggest that the presence of a methoxy group at position C-5 or C-8 of the scoparone’s phenyl ring significantly improves gastroprotective activity, whereas the presence of a dioxolane ring at C-6, C-7, or C-8 was found to have decreased activity. In order to assess toxicological safety, two of the potent gastroprotective scoparone derivatives—5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin—were examined for their acute toxicity in mice as well as their effect on cytochrome P450 (CYP enzyme activity. These two compounds showed low acute oral toxicity in adult male and female mice, and caused minimal changes to CYP3A4 and CYP2C9 enzyme activity. These results indicate that compared to other scoparone derivatives, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin can improve gastroprotective effects, and they have low toxicity and minimal effects on drug-metabolizing enzymes.

  2. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans.

    Science.gov (United States)

    Kox, Matthijs; van Eijk, Lucas T; Zwaag, Jelle; van den Wildenberg, Joanne; Sweep, Fred C G J; van der Hoeven, Johannes G; Pickkers, Peter

    2014-05-20

    Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-α, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases.

  3. Transcriptome profiling indicating canine parvovirus type 2a as a potential immune activator.

    Science.gov (United States)

    Fan, Xu-Xu; Gao, Yuan; Shu, Long; Wei, Yan-Quan; Yao, Xue-Ping; Cao, Sui-Zhong; Peng, Guang-Neng; Liu, Xiang-Tao; Sun, Shi-Qi

    2016-12-01

    Canine parvovirus type 2a (CPV-2a) is a variant of CPV-2, which is a highly contagious pathogen causing severe gastroenteritis and death in young dogs. However, how CPV-2 participates in cell regulation and immune response remains unknown. In this study, persistently infected MDCK cells were generated through culture passage of the CPV-2a-infected cells for ten generations. Our study showed that CPV-2a induces cell proliferation arrest and cell morphology alternation before the fourth generation, whereas, the cell morphology returns to normal after five times of passages. PCR detection of viral VP2 gene demonstrated that CPV-2a proliferate with cell passage. An immunofluorescence assay revealed that CPV-2a particles were mainly located in the cell nuclei of MDCK cell. Then transcriptome microarray revealed that gene expression pattern of MDCK with CPV-2a persistent infection is distinct compared with normal cells. Gene ontology annotation and Kyoto Encyclopedia of Genes and Genome pathway analysis demonstrated that CPV-2a infection induces a series of membrane-associated genes expression, including many MHC protein or MHC-related complexes. These genes are closely related to signaling pathways of virus-host interaction, including antigen processing and presentation pathway, intestinal immune network, graft-versus-host disease, and RIG-I-like helicases signaling pathway. In contrast, the suppressed genes mediated by CPV-2a showed low enrichment in any category, and were only involved in pathways linking to synthesis and metabolism of amino acids, which was confirmed by qPCR analysis. Our studies indicated that CPV-2a is a natural immune activator and has the capacity to activate host immune responses, which could be used for the development of antiviral strategy and biomaterial for medicine.

  4. Priming of metabolic dysfunctions by prenatal immune activation in mice: relevance to schizophrenia.

    Science.gov (United States)

    Pacheco-López, Gustavo; Giovanoli, Sandra; Langhans, Wolfgang; Meyer, Urs

    2013-03-01

    Schizophrenia is associated with increased risk for multiple metabolic abnormalities, including altered glucose homeostasis, type-2 diabetes, obesity, and cardiovascular disease. Some of the metabolic alterations can already exist in psychosis-prone subjects prior to the onset of chronic schizophrenic disease and pharmacotherapy, indicating that they may have a developmental origin. In the present study, we tested the hypothesis that metabolic alterations pertinent to schizophrenic disease can be primed by an environmental risk factor associated with the disorder, namely prenatal exposure to immune challenge. We used a well-established mouse model of prenatal immune challenge induced by maternal gestational treatment with poly(I:C) (="polyriboinosinic-polyribocytidilic acid"), an analog of double-stranded RNA that stimulates a cytokine-associated viral-like acute phase response. Metabolic effects were studied using high-resolution computed tomography and fully automated indirect calorimetry system, along with an oral glucose tolerance test and plasma cytokine and corticosterone measurements. We found that prenatal immune activation caused altered glycemic regulation and abnormal ingestive behavior in periadolescence and led to an adult onset of excess visceral and subcutaneous fat deposition. These effects were accompanied by age-dependent changes in peripheral secretion of proinflammatory (interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and T cell-related (IL-2 and interferon [IFN]-γ) cytokines and by increased release of the stress hormone corticosterone in periadolescence. Our findings show that schizophrenia-relevant metabolic and physiological abnormalities can be primed by prenatal viral-like immune activation, but at the same time, our study emphasizes that this environmental insult is unlikely to precipitate the full spectrum of metabolic and immunological changes pertinent to chronic schizophrenic disease.

  5. Salidroside exhibits anti-dengue virus activity by upregulating host innate immune factors.

    Science.gov (United States)

    Sharma, Navita; Mishra, K P; Ganju, Lilly

    2016-12-01

    Dengue is an arboviral disease with no effective therapy available. Therefore, there is an urgent need to find a potent antiviral agent against dengue virus (DENV). In the present study, salidroside, a main bioactive compound of Rhodiola rosea, was evaluated for its antiviral potential against DENV serotype-2 infection and its effect on host innate immune factors. Antiviral effects of salidroside were examined in DENV-infected cells by western blotting, flow cytometry and real-time PCR. Its underlying mechanism involved in antiviral action was determined by evaluating expression of host innate immune factors including RIG-I, IRF-3, IRF-7, PKR, P-eIF2α and NF-κB. Salidroside potently inhibited DENV infection by decreasing DENV envelope protein expression more than tenfold. Salidroside exerts its antiviral activity by increasing expression of RNA helicases such as RIG-I, thereby initiating a downstream signaling cascade that induces upregulation of IRF-3 and IRF-7. It prevents viral protein synthesis by increasing the expression of PKR and P-eIF2α while decreasing NF-κB expression. It was also found to induce the expression of IFN-α. In addition, the number of NK cells and CD8(+) T cells were also found to be increased by salidroside treatment in human PBMCs, which are important in limiting DENV replication during early stages of infection. The findings presented here suggest that salidroside exhibits antiviral activity against DENV by inhibiting viral protein synthesis and boosting host immunity by increasing the expression of host innate immune factors and hence could be considered for the development of an effective therapeutic agent against DENV infection.

  6. Advantages of laparoscopic compared to conventional surgery are not related to an innate immune response of peritoneal immune activation: an animal study in rats.

    Science.gov (United States)

    Lingohr, Philipp; Dohmen, Jonas; Matthaei, Hanno; Schwandt, Timo; Stein, Kathy; Hong, Gun-Soo; Steitz, Julia; Longerich, Thomas; Bölke, Edwin; Wehner, Sven; Kalff, Jörg C

    2017-06-01

    Laparoscopic surgery (LS) has proved superior compared to conventional surgery (CS) regarding morbidity, length of hospital stay, rate of wound infection and time until recovery. An improved preservation of the postoperative immune function is assumed to contribute to these benefits though the role of the local peritoneal immune response is still poorly understood. Our study investigates the peritoneal immune response subsequent to abdominal surgery and compares it between laparoscopic and conventional surgery to find an immunological explanation for the clinically proven benefits of LS. Wistar rats (N = 140) underwent laparoscopic cecum resection (LCR; N = 28), conventional cecum resection (CCR; N = 28), laparoscopic sham operation (LSO; N = 28), conventional sham operation (CSO; N = 28), or no surgical treatment (CTRL; N = 28). Postoperatively, peritoneal lavages were performed, leukocytes isolated and analyzed regarding immune function and phagocytosis activity. Immune function was inhibited postoperatively in animals undergoing LCR or CCR compared to CTRL reflected by a lower TNF-α (CTRL 3956.65 pg/ml, LCR 2018.48 pg/ml (p = 0.023), CCR 2793.78 pg/ml (n.s.)) and IL-6 secretion (CTRL 625.84 pg/ml, LCR 142.84 pg/ml (p = 0.009), CCR 169.53 pg/ml (p = 0.01)). Phagocytosis was not affected in rats undergoing any kind of surgery compared to CTRL. Neither cytokine secretion nor phagocytosis activity differed significantly between laparoscopic and conventional surgery. According to our findings the benefits associated with LS compared to CS cannot be explained by differences in the postoperative peritoneal innate immune response. Further studies are needed to elucidate the causes for a more favorable postoperative outcome in patients after LS compared to CS.

  7. Innate Immune B Cell Activation by Leishmania donovani Exacerbates Disease and Mediates Hypergammaglobulinemia.

    Science.gov (United States)

    Silva-Barrios, Sasha; Smans, Mélina; Duerr, Claudia U; Qureshi, Salman T; Fritz, Jörg H; Descoteaux, Albert; Stäger, Simona

    2016-06-14

    Participation of B cells in the immune response by various antibody-independent mechanisms has recently been uncovered. B cells producing cytokines have been described for several infections and appear to regulate the adaptive immune response. B cell activation by Leishmania donovani results in disease exacerbation. How Leishmania activates B cells is still unknown. We show that L. donovani amastigotes activate B cells by triggering endosomal TLRs; this activation leads to the induction of various cytokines. Cytokine expression is completely abrogated in B cells from Ifnar(-/-) mice upon exposure to L. donovani, suggesting an involvement of IFN-I in a positive feedback loop. IFN-I also appears to enhance the expression of endosomal TLRs following exposure to L. donovani. Cell-specific ablation of endosomal TLR signaling in B cells revealed that innate B cell activation by L. donovani is responsible for disease exacerbation through IL-10 and IFN-I production and for the promotion of hypergammaglobulinemia. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. Inflammasome Activation by Helicobacter pylori and Its Implications for Persistence and Immunity.

    Science.gov (United States)

    Pachathundikandi, Suneesh Kumar; Müller, Anne; Backert, Steffen

    2016-01-01

    Infection with the Gram-negative pathogen Helicobacter pylori is the most prevalent chronic bacterial infection affecting about 50 % of the human world population and is the main risk factor for gastric cancer development. The pro-inflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors, and polymorphisms in the IL-1 gene cluster resulting in increased IL-1β production have been associated with increased risk for gastric cancer. Recently, Helicobacter pylori was postulated to activate the inflammasome in human and mouse immune cells, and the molecular mechanisms and the bacterial virulence factors activating the inflammasome were elucidated in cell culture as well as animal models. It appears that H. pylori-induced IL-1β secretion is mediated by activation of toll-like receptor 2 (TLR-2), Nod-like receptor family member NLRP3 and caspase-1. The cag pathogenicity island-encoded type IV secretion system, lipopolysaccharide, vacuolating cytotoxin, and urease B subunit appear to play a role in inflammasome activation. In addition, recent results indicate that the TLR-2 → NLRP3 → caspase-1 → IL-18 axis is critical to H. pylori-specific immune regulation conferring protection against allergen-induced asthma and inflammatory bowel disease in murine models. The present chapter will review the proposed mechanisms of NLRP3 inflammasome activation during H. pylori infection and discuss the recent progress in this important research field.

  9. Effect of Ginkgo Biloba Extract 50 on Immunity and Antioxidant Enzyme Activities in Ischemia Reperfusion Rats

    Directory of Open Access Journals (Sweden)

    Xia Guo

    2011-11-01

    Full Text Available The aim of the study was to investigate the effect of Ginkgo biloba extract 50 (GBE50, a well-known natural antioxidant, against immunity and antioxidant enzyme activities in ischemia reperfusion (IR rats. Rats were then divided into six groups fed for 15 days with the same diet: three groups (IV, V, VI were treated by different doses of GBE50 suspension [20, 40, or 60 mg/kg body weight by oral gavage every day at a fixed time (10.00 a.m.] (equal to 5, 10 and 20 times, respectively, the maximum recommended human dose, and three groups (I, II, III were untreated. At the end of the experiment, rats’ hearts were subjected to 30 min of ischemia followed by 90 min of reperfusion. Results showed that IR significantly enhanced heart rate, S-T height, myocardium (myeloperoxidase MPO activity and blood interleukin-8 (IL-8, tumor necrosis factor Alpha (TNF-a, interleukin-1β (IL-1β levels, blood aspartate transaminase (AST, lactate dehydrogenase (LDH, and creatinine kinase (CK activities, reduced myocardium sodium-potassium adenosine triphosphatase (Na+-K+-ATPase, calcium-magnesium adenosine triphosphatase (Ca2+-Mg2+-ATPase activities and antioxidant enzyme activities in IR group (III compared to sham control group (II. Pretreatment of GBE50 markedly significantly reduced heart rate, S-T height, myocardium MPO activity and blood IL-8, TNF-a, IL-1β levels, blood AST, LDH, and CK activities, enhanced myocardium Na+-K+-ATPase, Ca2+-Mg2+-ATPase activities and antioxidant enzyme activities in IR group (II compared to IR group (III. The results suggested that the GBE50 may reduce the oxidative stress in the reperfused myocardium, and increased immunity and antioxidant activities in IR rats.

  10. Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

    Science.gov (United States)

    Shah, Nishel Mohan; Herasimtschuk, Anna A; Boasso, Adriano; Benlahrech, Adel; Fuchs, Dietmar; Imami, Nesrina; Johnson, Mark R

    2017-01-01

    During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.

  11. High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort

    Directory of Open Access Journals (Sweden)

    Colebunders Robert

    2011-02-01

    Full Text Available Abstract Background Antiretroviral therapy (ART partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated. Methods T-cell activation (CD38+HLA-DR+ and immune exhaustion (PD-1+ were measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: Suboptimal [median CD4 count increase 129 (-43-199 cells/μl], N = 34 ], optimal [282 (200-415 cells/μl, N = 64] and super-optimal [528 (416-878 cells/μl, N = 30]. Results Both CD4+ and CD8 T-cell activation was significantly higher among suboptimal CD4 T-cell responders compared to super-optimal responders. In a multivariate model, CD4+CD38+HLADR+ T-cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4-23, P = 0.014]. T-cell exhaustion (CD4+PD1+ and CD8+PD1+ was higher among suboptimal relative to optimal (P P = 0.022]. Conclusion T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART.

  12. Activation of immunity, immune response, antioxidant ability, and resistance against Vibrio alginolyticus in white shrimp Litopenaeus vannamei decrease under long-term culture at low pH.

    Science.gov (United States)

    Chen, Yu-Yuan; Chen, Jiann-Chu; Tseng, Kuei-Chi; Lin, Yong-Chin; Huang, Chien-Lun

    2015-10-01

    The growth, activation of immunity, immune parameters, and transcript levels of cytMnSOD, mtMnSOD, ecCuZnSOD, glutathione peroxidase (GPx), catalase, lysozyme, and penaeidin 3a were examined in white shrimp Litopenaeus vannamei reared at pH 6.8 and 8.1 after 24 weeks. No significant difference in growth was observed between the two groups. An in vitro study indicated that phenoloxidase activity and respiratory bursts (RB, release of the superoxide anion) were significantly higher in the haemocytes of pH 8.1 shrimp (shrimp reared at pH 8.1) than in pH 6.8 shrimp (shrimp reared at pH 6.8). An in vivo study indicated that the levels of immune parameters of pH 8.1 shrimp were significantly higher than in pH 6.8 shrimp, and the transcript levels of cytMnSOD, ecCuZnSOD, glutathione peroxidase, lysozyme, and penaeidin 3a were down-regulated in pH 6.8 shrimp. In another experiment, shrimp reared at pH 6.8 and 8.1 for 24 weeks were challenged with Vibrio alginolyticus. The mortality rate of pH 6.8 shrimp was significantly higher than in pH 8.1 shrimp over 12-168 h. Phagocytic activity, phagocytic index, and clearance efficiency to V. alginolyticus were significantly lower in pH 6.8 shrimp. We concluded that shrimp under long-term culture at pH 6.8 exhibited decreased resistance against V. alginolyticus as evidenced by reductions in the activation of immunity and immune parameters together with decreased transcript levels of cytMnSOD, ecCuZnSOD, GPx, lysozyme, and penaeidin 3a. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Antioxidant Effects of Probiotics in Experimentally Induced Peritonitis.

    Science.gov (United States)

    Erginel, Basak; Aydin, Fatih A; Erginel, Turgay; Tanik, Canan; Abbasoglu, Semra D; Soysal, Feryal G; Keskin, Erbug; Celik, Alaaddin; Salman, Tansu

    2016-02-01

    An experimental study was performed to evaluate the protective effects of probiotics on gut mucosa in peritonitis through antioxidant mechanisms. Thirty-two male Wistar albino rats were divided equally into four groups. The rats in Group 1 (control group) underwent laparotomy only. In group 2 (peritonitis group), peritonitis was induced in the rats by the cecal ligation and puncture (CLP) model. In group 3, the rats were treated with probiotics for five days after CLP-induced peritonitis. The last group of rats (group 4) were fed probiotics for five days before the CLP procedure and five days after the surgery. On the fifth day after surgery, all rats were killed, and tissue samples from the terminal ileum were obtained to evaluate the activities of myeloperoxidase (MPO), malondialdehyde (MDA), and glutathione (GSH). Histopathologic examinations were also performed to evaluate the grade of intestinal injury. Myeloperoxidase and MDA activities were increased, GSH concentrations were decreased in group 2, compared with group 1. Intestinal MPO activities in group 4 were decreased compared with group 1 and group 2, indicating a reduction in oxidant activity. Malondialdehyde decreased in group 3 and decreased even more in group 4, compared with the peritonitis group (group 2). Glutathione concentrations were increased in group 4 compared with group 2 and group 3 (p peritonitis, which may be related to antioxidant mechanisms. This antioxidant effect of probiotics might occur when pre-conditioning with probiotics before peritonitis because there is sufficient time to prepare the tissues for oxidative damage.

  14. Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs.

    Science.gov (United States)

    Vizcarra, J A; Kirby, J D; Kim, S K; Galyean, M L

    2007-08-01

    Ghrelin has been implicated in the control of food intake and in the long-term regulation of body weight. We theorize that preventing the ability of ghrelin to interact with its receptors, would eventually lead to decreased appetite and thereby decrease body weight gain. To test our hypothesis, pigs were actively immunized against ghrelin. Ghrelin((1-10)) was conjugated to BSA and emulsified in Freund's incomplete adjuvant and diethylaminoethyl-dextran. Primary immunization was given at 19 weeks of age (WOA), with booster immunizations given 20 and 40 days after primary immunization. Body weight (BW) and plasma samples were collected weekly beginning at 19 WOA, and feed intake was measured daily. Fourteen days after primary immunization, the percentage of bound (125)I-ghrelin in plasma from immunized pigs was increased compared with control animals (Pactively immunized against ghrelin compared with controls. By the end of the experiment, immunized pigs weighed 10% less than control animals (Pimmunized pigs. Apoptosis was not observed in post-mortem samples obtained from the fundic region of the stomach. Our observations suggest that immunization against ghrelin induces mild anorexia. This procedure could potentially be used as a treatment to control caloric intake and obesity.

  15. Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro

    National Research Council Canada - National Science Library

    Jensen GS; Cash HA; Farmer S; Keller D

    2017-01-01

    ...., Landerbrook Drive Suite, Mayfield Heights, OH, USA Objective: The aim of this study was to document the immune activating and anti-inflammatory effects of inactivated probiotic Bacillus coagulans GBI-30, 6086 (Staimune...

  16. Induction of immune tolerance to FIX by intramuscular AAV gene transfer is independent of the activation status of dendritic cells.

    Science.gov (United States)

    Bharadwaj, Arpita S; Kelly, Meagan; Kim, Dongsoo; Chao, Hengjun

    2010-01-21

    The nature of viral vectors is suggested to be a significant contributor to undesirable immune responses subsequent to gene transfer. Such viral vectors, recognized as danger signals by the host immune system, activate dendritic cells (DCs), causing unwanted antivector and/or transgene product immunity. We recently reported efficient induction of immune tolerance to coagulation factor IX (FIX) by direct intramuscular injection of adeno-associated virus (AAV)-FIX. AAV vectors are nonpathogenic and elicit minimal inflammatory response. We hypothesized that the nonpathogenic nature of AAV plays a critical role in induction of tolerance after AAV gene transfer. We observed inefficient recruitment and activation of DCs subsequent to intramuscular injection of AAV. To further validate our hypothesis, we examined immune responses to FIX after intramuscular injection of AAV with simultaneous activation of DCs. We were able to achieve phenotypic and functional activation of DCs after administration of lipopolysaccharide and anti-CD40 antibody. However, we observed efficient induction of FIX tolerance irrespective of DC activation in mice with different genetic and major histocompatibility complex backgrounds. Furthermore, activation of DCs did not exaggerate the immune response induced after intramuscular injection of AAV serotype 2 vector. Our results demonstrate that induction of FIX tolerance after AAV gene transfer is independent of DC activation status.

  17. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins.

    Science.gov (United States)

    Zhao, Baoyu; Shu, Chang; Gao, Xinsheng; Sankaran, Banumathi; Du, Fenglei; Shelton, Catherine L; Herr, Andrew B; Ji, Jun-Yuan; Li, Pingwei

    2016-06-14

    Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)-like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif. Here we show that the pLxIS motif of phosphorylated STING, MAVS, and TRIF binds to IRF-3 in a similar manner, whereas residues upstream of the motif confer specificity. The structure of the IRF-3 phosphomimetic mutant S386/396E bound to the cAMP response element binding protein (CREB)-binding protein reveals that the pLxIS motif also mediates IRF-3 dimerization and activation. Moreover, rotavirus NSP1 (nonstructural protein 1) employs a pLxIS motif to target IRF-3 for degradation, but phosphorylation of NSP1 is not required for its activity. These results suggest a concerted mechanism for the recruitment and activation of IRF-3 that can be subverted by viral proteins to evade innate immune responses.

  18. The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review

    OpenAIRE

    Vassallo Matteo; Mercié Patrick; Cottalorda Jacqueline; Ticchioni Michel; Dellamonica Pierre

    2012-01-01

    Abstract Background Recent observational studies suggest a role for lipopolysaccharide (LPS) as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens. Object A systematic review of LPS as a marker of immune activation in HIV-1 infected patients. Data sources MEDLINE register of articles and international conference proceedings. Review methods Case–control studies comparing the role of plasma LPS as a marker of immu...

  19. A Protective Role of Arecoline Hydrobromide in Experimentally Induced Male Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Indraneel Saha

    2015-01-01

    Full Text Available Objectives. Arecoline, the most potent and abundant alkaloid of betel nut, causes elevation of serum testosterone and androgen receptor expression in rat prostate, in addition to increase in serum insulin levels in rats, leading to insulin resistance and type 2 diabetes-like conditions. This study investigated the role of arecoline on the reproductive status of experimentally induced type 1 diabetic rats. Methods. Changes in the cellular architecture were analyzed by transmission electron microscopy. Blood glucose, serum insulin, testosterone, FSH, and LH were assayed. Fructose content of the coagulating gland and sialic acid content of the seminal vesicles were also analyzed. Results. Arecoline treatment for 10 days at a dose of 10 mg/kg of body weight markedly facilitated β-cell regeneration and reversed testicular and sex accessory dysfunctions by increasing the levels of serum insulin and gonadotropins in type 1 diabetic rats. Critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (pdx-1 and glucose transporter 2 (GLUT-2, were found to be activated by arecoline at the protein level. Conclusion. It can thus be suggested that arecoline is effective in ameliorating the detrimental effects caused by insulin deficiency on gonadal and male sex accessories in rats with type 1 diabetes.

  20. Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats.

    Science.gov (United States)

    Abdel-Fattah, Maha M; Messiha, Basim A S; Salama, Abeer A A

    2015-01-01

    Calcium influx, inflammatory infiltration, cytokine production, immunoglobulin E activation and oxidative stress play coordinated roles in bronchial asthma pathogenesis. We aim to assess the protective effect of cinnarizine against experimentally induced bronchial asthma. Bronchial asthma was induced by ovalbumin sensitization and challenge. Rats were allocated into a normal control, an asthma control, a dexamethasone (standard) treatment, and 2 cinnarizine treatment groups. The respiratory functions tidal volume (TV) and peak expiratory flow rate (PEFR), the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5) in lung tissue, the allergic immunoglobulin IgE in serum, the absolute eosinophil count (AEC) in bronchoalveolar lavage fluid (BALF), as well as the oxidative and nitrosative markers glutathione reduced (GSH) and superoxide dismutase (SOD) in lung tissue and nitric oxide end products (NOx) in BALF were assessed, followed by a histopathological study. Cinnarizine administration significantly restored TV, PEFR, TNF-α, IL-5, IgE, AEC, GSH, SOD and NOx values back to normal levels, and significantly decreased perivascular and peribronchiolar inflammatory scores. Cinnarizine may protect against experimental bronchial asthma. Suppressant effect of cinnarizine on pro-inflammatory cytokines release, IgE antibody production, eosinophil infiltration as well as oxidative and nitrosative stress may explain its anti-asthmatic potential. © 2015 S. Karger AG, Basel.

  1. Body awareness and responses to experimentally Induced pain

    Directory of Open Access Journals (Sweden)

    M. Minev

    2017-09-01

    Full Text Available PURPOSE. The aim of this study is to discuss personal and demographic factors that influence the relationship between physical activity and awareness of one's own body, as well as the pain response (threshold and tolerance of pain, situational anxiety and personality. In the study 38 healthy individual- volunteers, students in Trakia University - Stara Zagora were selected. All participants were divided into two groups: actively involved in individual or team sport (n = 19 and healthy normaly active subjects (non-athletes, n = 19. The age of the study participants ranged between 18 and 39 years, while the gender breakdown was as follows: men - 22 women – 16. Methods: Psychological Questionnaires: Body Awareness Questionnaire that asks subjects to rate, on a 4 point scale, the degree to which they were currently experiencing symptoms of sympathetic arousal, State Trait Anger Scale, and State Trait Anxiety Scale. Objective methods (cold pressure test are used only to determine the pain sensation and pain tolerance thresholds. The results of investigation support significant differences between athletes and non-athletes in pain thershold, body awareness and anxiety. The study conclusions discuss body awareness as an increasing factor for pain resistance in athletes and as an integral part of the learning process among them.

  2. Ticks elicit variable fibrinogenolytic activities upon feeding on hosts with different immune backgrounds.

    Science.gov (United States)

    Vora, Ashish; Taank, Vikas; Dutta, Sucharita M; Anderson, John F; Fish, Durland; Sonenshine, Daniel E; Catravas, John D; Sultana, Hameeda; Neelakanta, Girish

    2017-03-16

    Ticks secrete several anti-hemostatic factors in their saliva to suppress the host innate and acquired immune defenses against infestations. Using Ixodes scapularis ticks and age-matched mice purchased from two independent commercial vendors with two different immune backgrounds as a model, we show that ticks fed on immunodeficient animals demonstrate decreased fibrinogenolytic activity in comparison to ticks fed on immunocompetent animals. Reduced levels of D-dimer (fibrin degradation product) were evident in ticks fed on immunodeficient animals in comparison to ticks fed on immunocompetent animals. Increased engorgement weights were noted for ticks fed on immunodeficient animals in comparison to ticks fed on immunocompetent animals. Furthermore, the LC-MS/MS and quantitative real-time-PCR analysis followed by inhibitor and antibody-blocking assays revealed that the arthropod HSP70-like molecule contributes to differential fibrinogenolysis during tick feeding. Collectively, these results not only indicate that ticks elicit variable fibrinogenolysis upon feeding on hosts with different immune backgrounds but also provide insights for the novel role of arthropod HSP70-like molecule in fibrinogenolysis during blood feeding.

  3. Activation Effects of Polysaccharides of Flammulina velutipes Mycorrhizae on the T Lymphocyte Immune Function

    Directory of Open Access Journals (Sweden)

    Zheng-Fei Yan

    2014-01-01

    Full Text Available Flammulina velutipes mycorrhizae have increasingly been produced with increasing of F. velutipes production. A mouse model was thus used to examine potential effect of F. velutipes mycorrhizae on the immune function. Fifty female Wistar mice (5-weeks-old weighed 15–20 g were randomly allocated into five groups. Polysaccharide of F. velutipes mycorrhizae were treated with mice and mice spleen lymphocytes. The levels of CD3+, CD4+, and CD8+ T lymphocyte, interleukin-2 (IL-2, and tumor necrosis factor-a (TNF-α were determined. The results showed that the proportions of CD3+, and CD4+ T lymphocyte, the ratio of CD4+/CD8+, and the levels of IL-2 and TNF-a were significantly increased in polysaccharide of F. velutipes mycorrhizae, while the proportion of CD8+ T lymphocyte was decreased in polysaccharide of F. velutipes mycorrhizae-dose dependent manner. Our findings indicated that a long term exposure of polysaccharide of F. velutipes mycorrhizae could activate the T lymphocyte immune function. Polysaccharide of F. velutipes mycorrhizae was expected to develop into the immune health products.

  4. Activation effects of polysaccharides of Flammulina velutipes mycorrhizae on the T lymphocyte immune function.

    Science.gov (United States)

    Yan, Zheng-Fei; Liu, Nai-Xu; Mao, Xin-Xin; Li, Yu; Li, Chang-Tian

    2014-01-01

    Flammulina velutipes mycorrhizae have increasingly been produced with increasing of F. velutipes production. A mouse model was thus used to examine potential effect of F. velutipes mycorrhizae on the immune function. Fifty female Wistar mice (5-weeks-old) weighed 15-20 g were randomly allocated into five groups. Polysaccharide of F. velutipes mycorrhizae were treated with mice and mice spleen lymphocytes. The levels of CD3(+), CD4(+), and CD8(+) T lymphocyte, interleukin-2 (IL-2), and tumor necrosis factor-a (TNF-α) were determined. The results showed that the proportions of CD3(+), and CD4(+) T lymphocyte, the ratio of CD4(+)/CD8(+), and the levels of IL-2 and TNF-a were significantly increased in polysaccharide of F. velutipes mycorrhizae, while the proportion of CD8(+) T lymphocyte was decreased in polysaccharide of F. velutipes mycorrhizae-dose dependent manner. Our findings indicated that a long term exposure of polysaccharide of F. velutipes mycorrhizae could activate the T lymphocyte immune function. Polysaccharide of F. velutipes mycorrhizae was expected to develop into the immune health products.

  5. Probiotic activity of Enterococcus faecalis CECT7121: effects on mucosal immunity and intestinal epithelial cells.

    Science.gov (United States)

    Castro, M S; Molina, M A; Azpiroz, M B; Díaz, A M; Ponzio, R; Sparo, M D; Manghi, M A; Canellada, A M

    2016-10-01

    To analyse the effect of Enterococcus faecalis CECT7121 on intestinal epithelial cells (IECs) and its effects on the mucosal immune response. Enterococcus faecalis CECT7121 showed a high adhesion capacity to completely and heterogeneously differentiated human intestinal epithelial cell line (Caco-2 cells). In addition, the contact of this bacterium with Caco-2 cells did not induce inflammatory chemokines (IL-8 and CCL-20). The presence of IgA(+) and IL-6(+) cells in the small intestine, as well as the production of inflammatory cytokines (TNFα, IL-6 and IL-12) in the gut, was determined after intragastric inoculation of Ent. faecalis CECT7121 in BALB/c mice. The administration of Ent. faecalis CECT7121 increased the number of IgA(+) cells in the intestinal lamina propria without modifying the percentage of IL-6(+) cells. No differences were observed in the cytokines measured in the intestinal extracts between probiotic-treated and control mice. Enterococcus faecalis CECT7121 stimulates local mucosal immunity and adheres to IECs without inducing inflammatory signals. Our results indicate that, apart from its already reported systemic immune activity, Ent. faecalis CECT7121 has a modulatory effect at a local level. © 2016 The Society for Applied Microbiology.

  6. Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring.

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    Harvey, Louise; Boksa, Patricia

    2014-08-01

    Both iron deficiency (ID) and infection are common during pregnancy and studies have described altered brain development in offspring as a result of these individual maternal exposures. Given their high global incidence, these two insults may occur simultaneously during pregnancy. We recently described a rat model which pairs dietary ID during pregnancy and prenatal immune activation. Pregnant rats were placed on iron sufficient (IS) or ID diets from embryonic day 2 (E2) until postnatal day 7, and administered the bacterial endotoxin, lipopolysaccharide (LPS) or saline on E15/16. In this model, LPS administration on E15 caused greater induction of the pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α, in ID dams compared to IS dams. This suggested that the combination of prenatal immune activation on a background of maternal ID might have more adverse neurodevelopmental consequences for the offspring than exposure to either insult alone. In this study we used this model to determine whether combined exposure to maternal ID and prenatal immune activation interact to affect juvenile and adult behaviors in the offspring. We assessed behaviors relevant to deficits in humans or animals that have been associated with exposure to either maternal ID or prenatal immune activation alone. Adult offspring from ID dams displayed significant deficits in pre-pulse inhibition of acoustic startle and in passive avoidance learning, together with increases in cytochrome oxidase immunohistochemistry, a marker of metabolic activity, in the ventral hippocampus immediately after passive avoidance testing. Offspring from LPS treated dams showed a significant increase in social behavior with unfamiliar rats, and subtle locomotor changes during exploration in an open field and in response to amphetamine. Surprisingly, there was no interaction between effects of the two insults on the behaviors assessed, and few observed alterations in juvenile behavior. Our findings

  7. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

    Science.gov (United States)

    Demaria, Olivier; De Gassart, Aude; Coso, Sanja; Gestermann, Nicolas; Di Domizio, Jeremy; Flatz, Lukas; Gaide, Olivier; Michielin, Olivier; Hwu, Patrick; Petrova, Tatiana V; Martinon, Fabio; Modlin, Robert L; Speiser, Daniel E; Gilliet, Michel

    2015-12-15

    Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.

  8. The Cost-Effectiveness of Supplementary Immunization Activities for Measles: A Stochastic Model for Uganda

    Science.gov (United States)

    Johns, Benjamin; Nair, Divya; Nabyonga-Orem, Juliet; Fiona-Makmot, Braka; Simons, Emily; Dabbagh, Alya

    2011-01-01

    Supplemental Immunization Activities (SIAs) have become an important adjunct to measles control efforts in countries that endeavor to achieve higher levels of population immunity than can be achieved in a growing routine immunization system. Because SIAs are often supported with funds that have alternative uses, decision makers need to know how cost-effective they are compared with other options. This study integrated a dynamic stochastic model of measles transmission in Uganda (2010–2050) with a cost model to compare a strategy of maintaining Uganda's current (2008) levels of the first dose of routine measles-containing vaccine (MCV1) coverage at 68% with SIAs with a strategy using the same levels of MCV1 coverage without SIAs. The stochastic model was fitted with parameters drawn from district-level measles case reports from Uganda, and the cost model was fitted to administrative data from the Ugandan Expanded Program on Immunization and from the literature. A discount rate of 0.03, time horizon of 2010–2050, and a societal perspective on costs were assumed. Costs expressed in US dollars (2010) included vaccination costs, disease treatment costs including lost productivity of mothers, as well as costs of outbreaks and surveillance. The model estimated that adding on triennial SIAs that covered 95% of children aged 12–59 months to a system that achieved routine coverage rates of 68% would have an incremental cost-effectiveness ratio (ICER) of $1.50 ($US 2010) per disability-adjusted life year averted. The ICER was somewhat higher if the discount rate was set at either 0 or 0.06. The addition of SIAs was found to make outbreaks less frequent and lower in magnitude. The benefit was reduced if routine coverage rates were higher. This cost-effectiveness ratio compares favorably to that of other commonly accepted public health interventions in sub-Saharan Africa. PMID:21666151

  9. Influence of sildenafil and donepezil administration on the serum redox balance in experimentally induced lower limb critical ischemia.

    Science.gov (United States)

    Constantinescu, Mihaela Ioana; Constantinescu, Dan Petru; Andercou, Aurel; Mironiuc, Ion Aurel

    2013-01-01

    Chronic lower limb ischemia (CLLI) leads to endothelial cell dysfunctions and endothelial lesions. The use of substances that release nitric oxide and activate endothelial nitric oxide synthase has proved to be useful in increasing angiogenesis and arteriogenesis under critical ischemia conditions. To investigate the therapeutic effect of Sildenafil and Donepezil with a vasodilating action in experimentally induced CLLI and on serum redox homeostasis. The research was performed in 3 groups of rats (n=10 animals/group) with experimentally induced CLLI: group I - control group; group II - animals treated postoperatively with a therapeutic dose of sildenafil, and group III - animals treated postoperatively with a therapeutic dose of donepezil. Oxidative stress (OS) indicators (malondialdehyde - MDA, protein carbonyls - PC), antioxidant (AO) defense indicators (reduced glutathione - GSH and oxidized glutathione - GSSH), and ceruloplasmin (CP) were determined on days 7, 14, 21 and 30. Statistical processing was performed using the Excel application (Microsoft Office 2007), with the StatsDirect v.2.7.2 software. Changes in OS were evidenced in all groups on account of a decrease in MDA and PC. The greatest OS decrease in all groups was on day 30. AO defence changes were represented by decreased levels of GSH and GSSG in all groups, at the studied moments. Intracellular AO defense in the cytosol, nucleus and mitochondria was similar in all groups, (decreased GSH, GSSG and GSH/GSSG ratio). We found increased extracellular levels of GSH, GSSG, and CP and increased extracellular GSH/GSSG ratio at level compared to values on day 7. 1) The administration of sildenafil (group II) and donepezil (group III) has favorable effects on reducing OS in experimentally induced CLLI. 2) Sildenafil and Donepezil administration stimulates extracellular AO defense on account of CP. 3) Sildenafil and Donepezil administration influences intracellular redox homeostasis on account of the GSH

  10. Autonomic nervous system and hypothalamic-pituitary-adrenal axis response to experimentally induced cold pain in adolescent non-suicidal self-injury--study protocol.

    Science.gov (United States)

    Koenig, Julian; Rinnewitz, Lena; Warth, Marco; Kaess, Michael

    2015-07-07

    Adolescent non-suicidal self-injury (NSSI) is associated with altered sensitivity to experimentally induced pain. Adolescents engaging in NSSI report greater pain threshold and pain tolerance, as well as lower pain intensity and pain unpleasantness compared to healthy controls. The experience of pain is associated with reactivity of both the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. However, previous research has not yet systematically addressed differences in the physiological response to experimentally induced pain comparing adolescents with NSSI and age- and sex-matched healthy controls. Adolescents with NSSI and healthy controls undergo repeated painful stimulation with the cold pressor task. ANS activity is continuously recorded throughout the procedure to assess changes in heart rate and heart rate variability. Blood pressure is monitored and saliva is collected prior to and after nociceptive stimulation to assess levels of saliva cortisol. The study will provide evidence whether lower pain sensitivity in adolescents with NSSI is associated with blunted physiological and endocrinological responses to experimentally induced pain compared to healthy controls. Extending on the existing evidence on altered pain sensitivity in NSSI, measured by self-reports and behavioural assessments, this is the first study to take a systematic approach in evaluating the physiological response to experimentally induced pain in adolescent NSSI. Deutsche Register Klinischer Studien, Study ID: DRKS00007807; Trial Registration Date: 13.02.2015.

  11. Meningococcal Outer Membrane Vesicle Composition-Dependent Activation of the Innate Immune Response.

    Science.gov (United States)

    Zariri, Afshin; Beskers, Joep; van de Waterbeemd, Bas; Hamstra, Hendrik Jan; Bindels, Tim H E; van Riet, Elly; van Putten, Jos P M; van der Ley, Peter

    2016-10-01

    Meningococcal outer membrane vesicles (OMVs) have been extensively investigated and successfully implemented as vaccines. They contain pathogen-associated molecular patterns, including lipopolysaccharide (LPS), capable of triggering innate immunity. However, Neisseria meningitidis contains an extremely potent hexa-acylated LPS, leading to adverse effects when its OMVs are applied as vaccines. To create safe OMV vaccines, detergent treatment is generally used to reduce the LPS content. While effective, this method also leads to loss of protective antigens such as lipoproteins. Alternatively, genetic modification of LPS can reduce its toxicity. In the present study, we have compared the effects of standard OMV isolation methods using detergent or EDTA with those of genetic modifications of LPS to yield a penta-acylated lipid A (lpxL1 and pagL) on the in vitro induction of innate immune responses. The use of detergent decreased both Toll-like receptor 4 (TLR4) and TLR2 activation by OMVs, while the LPS modifications reduced only TLR4 activation. Mutational removal of PorB or lipoprotein factor H binding protein (fHbp), two proteins known to trigger TLR2 signaling, had no effect, indicating that multiple TLR2 ligands are removed by detergent treatment. Detergent-treated OMVs and lpxL1 OMVs showed similar reductions of cytokine profiles in the human monocytic cell line MM6 and human dendritic cells (DCs). OMVs with the alternative penta-acylated LPS structure obtained after PagL-mediated deacylation showed reduced induction of proinflammatory cytokines interleukin-6 (IL-6) and IL-1β but not of IP-10, a typical TRIF-dependent chemokine. Taken together, these data show that lipid A modification can be used to obtain OMVs with reduced activation of innate immunity, similar to what is found after detergent treatment. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  12. Cellular immune responses and phagocytic activity of fishes exposed to pollution of volcano mud.

    Science.gov (United States)

    Risjani, Yenny; Yunianta; Couteau, Jerome; Minier, Christophe

    2014-05-01

    Since May 29, 2006, a mud volcano in the Brantas Delta of the Sidoarjo district has emitted mud that has inundated nearby villages. Pollution in this area has been implicated in detrimental effects on fish health. In fishes, leukocyte and phagocytic cells play a vital role in body defenses. We report for the first time the effect of "LUSI" volcano mud on the immune systems of fish in the Brantas Delta. The aim of this study was to find biomarkers to allow the evaluation of the effects of volcanic mud and anthropogenic pollution on fish health in the Brantas Delta. The study took places at the Brantas Delta, which was polluted by volcano mud, and at reference sites in Karangkates and Pasuruan. Leukocyte numbers were determined using a Neubauer hemocytometer and a light microscope. Differential leukocyte counts were determined using blood smears stained with May Grunwald-Giemsa, providing neutrophil, lymphocyte and monocyte counts. Macrophages were taken from fish kidney, and their phagocytic activity was measured. In vitro analyses revealed that leukocyte and differential leukocyte counts (DLC) were higher in Channa striata and Chanos chanos caught from the polluted area. Macrophage numbers were higher in Oreochromis mossambicus than in the other species, indicating that this species is more sensitive to pollution. In areas close to volcanic mud eruption, all specimens had lower phagocytic activity. Our results show that immune cells were changed and phagocytic activity was reduced in the polluted area indicating cytotoxicity and alteration of the innate immune system in fishes exposed to LUSI volcano mud and anthropogenic pollution. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Effects of Risperidone and Paliperidone Pretreatment on Locomotor Response Following Prenatal Immune Activation

    Science.gov (United States)

    Richtand, Neil M.; Ahlbrand, Rebecca; Horn, Paul; Stanford, Kevin; Bronson, Stefanie L.; McNamara, Robert K.

    2011-01-01

    Aim Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier. We previously described prevention with risperidone of abnormal behavior following neonatal hippocampal lesion. We aimed to extend those findings evaluating risperidone and paliperidone following prenatal immune activation, a developmental model of a schizophrenia risk factor. We evaluated a later developmental time point to determine persistent effects of drug treatment. Methods Pregnant Sprague-Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline treated dams received risperidone (0.45 mg/kg/d), paliperidone (0.05 mg/kg/d), or vehicle from postnatal days 35 to 70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following antipsychotic discontinuation. Results Risperidone and paliperidone had persistent effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Risperidone, but not paliperidone, also exerted persistent effects in offspring of saline-treated dams on locomotor response to saline and amphetamine (5 mg/kg) injection. Conclusions Risperidone and paliperidone pretreatment of poly I:C offspring during peri-pubertal development stabilized response to amphetamine exposure persisting into early adulthood. Prenatal immune activation provides a model for evaluating effects of an environmental risk factor for schizophrenia, and has potential utility for identifying pharmacological approaches to early intervention. PMID:21440257

  14. Antigen display, T-cell activation, and immune evasion during acute and chronic ehrlichiosis.

    Science.gov (United States)

    Nandi, Bisweswar; Chatterjee, Madhumouli; Hogle, Kathryn; McLaughlin, Maura; MacNamara, Katherine; Racine, Rachael; Winslow, Gary M

    2009-10-01

    How spatial and temporal changes in major histocompatibility complex/peptide antigen presentation to CD4 T cells regulate CD4 T-cell responses during intracellular bacterial infections is relatively unexplored. We have shown that immunization with an ehrlichial outer membrane protein, OMP-19, protects mice against fatal ehrlichial challenge infection, and we identified a CD4 T-cell epitope (IA(b)/OMP-19(107-122)) that elicited CD4 T cells following either immunization or infection. Here, we have used an IA(b)/OMP-19(107-122)-specific T-cell line to monitor antigen display ex vivo during acute and chronic infection with Ehrlichia muris, a bacterium that establishes persistent infection in C57BL/6 mice. The display of IA(b)/OMP-19(107-122) by host antigen-presenting cells was detected by measuring intracellular gamma interferon (IFN-gamma) production by the T-cell line. After intravenous infection, antigen presentation was detected in the spleen, peritoneal exudate cells, and lymph nodes, although the kinetics of antigen display differed among the tissues. Antigen presentation and bacterial colonization were closely linked in each anatomical location, and there was a direct relationship between antigen display and CD4 T-cell effector function. Spleen and lymph node dendritic cells (DCs) were efficient presenters of IA(b)/OMP-19(107-122), demonstrating that DCs play an important role in ehrlichial infection and immunity. Chronic infection and antigen presentation occurred within the peritoneal cavity, even in the presence of highly activated CD4 T cells. These data indicated that the ehrlichiae maintain chronic infection not by inhibiting antigen presentation or T-cell activation but, in part, by avoiding signals mediated by activated T cells.

  15. Effects of active and passive gonadotrophin-releasing hormone immunization on recognition and establishment of pregnancy in pigs.

    Science.gov (United States)

    Tast, A; Love, R J; Clarke, I J; Evans, G

    2000-01-01

    This study investigated the effects of a reduction in gonadotrophins, by means of differently timed active and passive gonadotrophin-releasing hormone (GnRH) immunization at various stages, on the maintenance of early pregnancy in pigs. In the first experiment crossbred sows (n = 11) were immunized against GnRH using a commercial vaccine on the day of farrowing, mated at the first oestrus, and a booster immunization was administered 10 days (n = 7) or 20 days (n = 4) after mating. Plasma samples were collected every second day and assayed for GnRH antibodies and progesterone. Pregnancy testing was carried out by real time ultrasound. None of the sows receiving the booster immunization 10 days after mating were pregnant on Day 18 after mating. All sows receiving the booster on Day 20 after mating aborted, with a mean vaccination-to-abortion interval of 10.0 +/- 1.5 days. In the second experiment, crossbred gilts (n = 6) were passively immunized by infusing (i.v.) GnRH immune pig serum on Day 12 after mating. Luteinizing hormone profiles were determined on the day before immunization and one day afterwards. Daily plasma samples were assayed for GnRH antibodies and progesterone. None of the gilts were pregnant 18 days after mating, compared with 5 of 6 non-immunized controls. Booster immunization 10 days after mating resulted in failure of embryonic development and establishment of pregnancy before the corpora lutea (CL) regressed, according to progesterone profiles, whereas immunization 20 days after mating resulted in regression of CL followed by abortion. Passive immunization 12 days after mating had a similar effect to the active immunization 10 days after mating. These results demonstrate two different outcomes of active GnRH immunization depending on the timing of immunization, and indicate that loss of pregnancy between Days 12 and 18 may occur due a reduction in progesterone rather than complete failure of the CL, as occurs at later stages. The findings may

  16. Markers of endothelial cell activation and immune activation are increased in patients with severe leptospirosis and associated with disease severity.

    Science.gov (United States)

    Goeijenbier, Marco; Gasem, M Hussein; Meijers, Joost C M; Hartskeerl, Rudy A; Ahmed, Ahmed; Goris, Marga G A; Isbandrio, Bambang; Schuller, Simone S; Osterhaus, Albert D M E; Martina, Byron E E; van Gorp, Eric C M; Nally, Jarlath E; Wagenaar, Jiri F P

    2015-10-01

    Previous studies concluded that haemorrhage is one of the most accurate prognostic factors of mortality in leptospirosis. Therefore, endothelial cell activation was investigated in relation to disease severity in severe leptospirosis. Prospective cohort study of severe leptospirosis patients. Plasma levels of sE-selectin and Von Willebrand factor (VWF) were determined. Consequently, an in vitro endothelial cell model was used to assess endothelial activation after exposure to virulent Leptospira. Finally, immune activation, as a potential contributing factor to endothelial cell activation, was determined by soluble IL2-receptor (sIL-2r) and soluble Fas-ligand (sFasL) levels. Plasma levels of sE-selectin and VWF strongly increased in patients compared to healthy controls. Furthermore, sE-selectin was significantly elevated (203 ng/ml vs. 157 ng/ml, p leptospirosis patients. Copyright © 2015 The British Infection Association. All rights reserved.

  17. Ganoderma atrum polysaccharide induces anti-tumor activity via the mitochondrial apoptotic pathway related to activation of host immune response.

    Science.gov (United States)

    Li, Wen-Juan; Chen, Yi; Nie, Shao-Ping; Xie, Ming-Yong; He, Ming; Zhang, Shen-Shen; Zhu, Ke-Xue

    2011-03-01

    Ganoderma atrum polysaccharide (PSG-1), the major active ingredient isolated from Ganoderma atrum, has been suggested as a candidate for cancer therapy. The aim of this study was to investigate the anti-tumor effect of PSG-1 using sarcoma 180 (S-180) transplanted mice and further to examine the molecular mechanisms of PSG-1-induced anti-tumor effect. Results showed that PSG-1 significantly inhibited tumor growth in S-180-bearing mice. PSG-1-induced tumor apoptosis was associated with the alteration of Bcl-2 family proteins, increase of reactive oxygen species generation, loss of mitochondrial membrane potential (Δψ(m) ), release of cytochrome c from the mitochondria into cytosol, and activation of caspase-3 and -9. Elevation of immune function was also shown during PSG-1-induced tumor apoptosis, as evidenced by increase of spleen and thymus indexes, lymphocyte proliferation, concentrations of tumor necrosis factor (TNF)-α, and interleukin-2 in serum. Furthermore, the combined treatment of PSG-1 and cyclophosphamide (CTX) results in an enhancement of the anti-tumor effect of CTX alone via increased host immune response. These results suggested that PSG-1 had a potent anti-tumor activity by induction of tumor apoptosis through mitochondrial pathways, and immunoenhancement effect of PSG-1 was related to its anti-tumor effect. In addition, PSG-1 enhanced CTX-induced anti-tumor activity in S-180-bearing mice. Copyright © 2010 Wiley-Liss, Inc.

  18. Antiacrosin antibodies and infertility. II. Gene immunization with human proacrosin to assess the effect of immunity toward proacrosin/acrosin upon protein activities and animal fertility.

    Science.gov (United States)

    Veaute, Carolina; Furlong, Laura I; Cameo, Mónica; Harris, Jeffrey D; Vazquez-Levin, Mónica H

    2009-04-01

    To assess the effect of antiacrosin antibodies upon proacrosin/acrosin activities and animal fertility. Prospective study. Basic research laboratory. A gene immunization (GI) model was developed; mice were injected with the sequence encoding human proacrosin (h-proacrosin), cloned in an expression vector. Subcloning of h-proacrosin in a eukaryotic expression vector (promoter, CMV; leader sequence, alpha-1 antitrypsin; pSF2-Acro); GI of female mice with this plasmid. The following parameters were evaluated: [1] adequate conditions for GI protocols, [2] humoral response to GI with pSF2-Acro, [3] protein regions recognized by the antibodies, and [4] effect of antibodies upon proacrosin/acrosin-ZPA binding and amidase activity, and animal fertility. Conditions of female mice GI with the proacrosin sequence were established (plasmid purification with anion exchange chromatography and 40 microg of pSF2-Acro per dose) to trigger an immune response, reaching maximum levels at week 9 after the first injection. Antibodies produced by GI recognized human and mouse sperm acrosin systems, inhibited human proacrosin/acrosin interaction with recombinant human ZPA and protease activity, and negatively affected mouse IVF and early embryonic development. In addition, mice immunized with SF2-Acro exhibited a significantly lower size of fetuses. Antiacrosin antibodies developed by using GI inhibit human proacrosin/acrosin activities and impair mouse fertility.

  19. Cupping regulates local immunomodulation to activate neural-endocrine-immune worknet.

    Science.gov (United States)

    Guo, Yang; Chen, Bo; Wang, Dong-Qiang; Li, Ming-Yue; Lim, Calista Hui-Min; Guo, Yi; Chen, Zelin

    2017-08-01

    Research on cupping therapy is lacking at home and abroad. However, cupping and acupuncture therapy are both surface stimulation therapies. This paper suggests the mechanism of cupping therapy and proposes that the same mechanism underlies both cupping and acupuncture therapy. The microenvironment is changed when stimulating the surface of the skin, and physical signals transform into biological signals, which also interact with each other in the body. These signalling cascades activate the neuroendocrine-immune system, which produces the therapeutic effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Tumor Necrosis Factor-Mediated Survival of CD169+ Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection

    DEFF Research Database (Denmark)

    Shinde, Prashant V; Xu, Haifeng C; Maney, Sathish Kumar

    2018-01-01

    Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169(+) cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169(+) cells during viral infections remain...... defense against viral pathogens. CD169(+) macrophages are shown to activate innate and adaptive immunity via "enforced virus replication" a controlled amplification of virus particles. However, factors regulating the CD169(+) macrophages remain to be studied. In this paper, we show that after Vesicular...... stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF) which signals via TNFR1 and promote "enforced virus replication" in CD169(+) macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance....

  1. Peroxisome Proliferator-Activated Receptors in the Modulation of the Immune/Inflammatory Response in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Ana Z. Fernandez

    2008-01-01

    Full Text Available Inflammation has been recognized as an important hallmark of atherosclerosis. The pharmacological activation of PPAR- by the thiazolidinediones in diabetes, and of PPAR- by the fibrates in hyperlipidemia has been shown to help to reduce inflammatory markers in preclinical and clinical studies. PPARs are known to modulate immune pathways through at least three different mechanisms: by direct binding to PPRE of anti-inflammatory cytokines genes; by transrepression of transcription factors like NF-B and AP-1; or by corepression. The regulation of the inflammatory pathways by PPARs can be achieved on each one of the cells involved in the atherosclerotic process, that is, monocytes, macrophages, T cells, endothelial cells, and smooth muscle cells. Moreover, as each of these cellular components is interconnected with each other, PPAR activation in one cell type could affect the other ones. As activation of PPARs has clear ant-inflammatory benefits, PPARs ligands should be considered as a new therapeutical approach to ameliorate the exacerbated immune response in atherosclerotic diseases.

  2. Antitumor and immune regulation activities of the extracts of some Chinese marine invertebrates

    Science.gov (United States)

    Zhang, Lixin; Fan, Xiao; Han, Lijun

    2005-03-01

    Extracts of 21 marine invertebrates belonging to Coelenterata, Mollusca, Annelida, Bryozoa, Echiura, Arthropoda, Echinodermata and Urochordata were screened for the studies on their antitumor and immune regulation activities. Antitumor activity was determined by MTT method and immune regulation activity was studied using T- and B-lymphocytes in mice spleen in vitro. It was found that the n-butanol part of Asterina pectinifera, the acetic ether part of Tubuaria marina, 95% ethanol extract of Acanthochiton rubrolineatus have a high inhibition rate of 96.7%, 63.9% and 50.5% respectively on tumor cell line HL-60 at the concentration of 0.063 mg/ml. The inhibition rate of the acetic ether part of Tubuaria marina on the tumor cell line A-549 is 65.4% at concentration of 0.063 mg/mL. The 95% ethanol extract of Meretrix meretrix has so outstanding promoting effect on T-lymphocytes that their multiplication increases 25% when the sample concentration is only 1 μg/ml. On B-lymphocytes, the 95% extract of Rapana venosa, at concentration of 100 μg/ml, has a promotion percentage of 60%. On the other hand, under the condition of no cytotoxic effect, the 95% ethanol extracts of Acanthochiton rubrolineatus and Cellana toreum can reach 92% inhibition rate on T lymphocyte at concentration of 100 μg/ml, while the inhibition rate on B lymphocyte of the 95% extract of Acanthochiton rubrolineatus reaches 92% at the same concentration.

  3. Innate immune activation of NFκB and its antagonism by poxviruses.

    Science.gov (United States)

    Brady, Gareth; Bowie, Andrew G

    2014-10-01

    In recent years there has been an acceleration of discovery in the field of innate anti-viral immunity to the point that many of the key events in early virus sensing and the discrete anti-viral responses they trigger have been elucidated in detail. In particular, pattern recognition receptors (PRRs) that detect viruses at the plasma membrane, in endosomes, and within the cytosol have been characterized. Upon stimulation by viruses, most of these PRRs trigger signal transduction pathways culminating in NFκB activation. NFκB contributes both to type I interferon induction, and to production of pro-inflammatory cytokines from infected cells. Our understanding of host anti-viral innate immunity has been greatly aided by an appreciation of the ways in which poxviruses have evolved strategies to inhibit both innate sensing and effector responses. A recurring feature of poxviral immunomodulation is the apparent necessity for poxviruses to evolve multiple, non-redundant inhibitors of NFκB activation which often appear to act on the same innate signalling pathway. The reason for such apparent over-targeting of one transcription factor is not clear. Here we describe the current understanding of how host cells sense poxvirus infection to trigger signalling pathways leading to NFκB activation and pro-inflammatory cytokine induction, and the ways in which poxviruses have evolved to concisely antagonize these systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Experimental Salmonella typhimurium infections in rats. II. Active and passive immunization as protection against a lethal bacterial dose

    DEFF Research Database (Denmark)

    Hougen, H P; Jensen, E T; Klausen, B

    1990-01-01

    Immunization against a lethal dose of Salmonella typhimurium was studied in athymic and thymus-bearing LEW rats. Active immunization was performed with formalin-killed whole cell vaccine or sublethal infection prior to the lethal infection. After vaccination with killed bacteria the euthymic...... animals produced antibodies against S.typhimurium, but neither the euthymic nor the athymic animals survived the infection. After non-lethal infection euthymic and thymus-grafted nude rats were not affected by the second and otherwise lethal bacterial dose, and had high antibody titres. All the athymic...... nude rats died after the second and lethal bacterial challenge. Passive immunization with plasma from immunized euthymic animals did not protect any of the animals against the lethal bacterial dose. However, all animals survived when treated with large doses of spleen cells from immunized euthymic rats...

  5. Epithelial disruptions, but not immune cell invasion, induced secretory dysfunction following innate immune activation in a novel model of acute salivary gland injury.

    Science.gov (United States)

    Shaalan, Abeer; Carpenter, Guy; Proctor, Gordon

    2017-11-21

    Salivary gland (SG) injurious agents are all translated into loss of salivation (xerostomia). An association has been established between activation of innate immunity and salivary gland injury and dysfunction. However, it remains unclear how the secretory epithelia respond by halting saliva production. C57BL/6 submandibular glands (SMGs) were acutely challenged using a single dose of the innate immune stimulant: polyinosinic-polycytidylic acid (poly (I:C)). Secretory capacity of the infected SMGs was substantiated by assessing the flow rate in response to pilocarpine stimulation. Depletion of the acute inflammatory cells was achieved by pre-treating mice with RB6-8C5 depletion antibody. Flow cytometry, histology and immunohistochemistry were conducted to verify the immune cell depletion. Epithelial expression of saliva-driving molecules: muscarinic 3 receptor (M3R), aquaporin 5 water channel (AQP5), Na-K- CL-Cotransporter 1 (NKCC1) and transmembrane member 16A (TMEM16A), were characterized using RT-qPCR and immunohistochemistry. Tight junction (TJ) protein; zonula occludens (ZO-1) and basement membrane (BM) protein; laminin were assessed by immunohistochemistry. Innate immune challenge prompted dysfunction in the exocrine salivary glands (SGs). Dysregulated gene and protein expression of molecules that drive saliva secretion was substantiated. Aberrant expression of TJ and BM proteins followed innate immune activation. Hyposalivation in the current model was independent of myeloperoxidase (MPO)-positive, acute inflammatory cells. In the present study, we developed a novel injury model of the SGs, featuring acute secretory dysfunction and immediate structural disruptions. Our results ruled out the injurious role of aggressively infiltrating inflammatory cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. Sex Differences in Select Non-communicable HIV-Associated Comorbidities: Exploring the Role of Systemic Immune Activation/Inflammation.

    Science.gov (United States)

    Raghavan, Avanthi; Rimmelin, Dodie E; Fitch, Kathleen V; Zanni, Markella V

    2017-10-27

    The goals of this review are to (1) explore HIV-associated cardiovascular disease (CVD), neurocognitive impairment, and non-AIDS-defining cancers (NADC) as heterogeneous model disease states fuelled in part by systemic immune activation/inflammation; (2) consider sex differences in the epidemiology of these diseases in both high-resource and lower-resource settings; and (3) examine biological and environmental factors which may contribute to heightened systemic immune activation/inflammation specifically among women living with HIV (WLHIV). The observation that WLHIV have higher levels of systemic immune activation/inflammation than men living with HIV (MLHIV) may be relevant to sex differences in select non-communicable HIV-associated comorbidities. Heightened systemic immune activation among WLHIV may be influenced by sex-specific responses to the virus and to immunomodulatory agents, as well as by behavioral choices/comorbid conditions and perturbations in the hypothalamic-pituitary-gonadal axis. Additional research is needed to elucidate region-specific drivers of heightened systemic immune activation/inflammation among WLHIV and to determine whether WLHIV who present with one immune-mediated HIV-associated comorbidity (e.g., cognitive impairment) may be at increased risk for another (e.g., CVD, NADC). This kind of research would facilitate improved risk prediction for non-communicable HIV-associated comorbidities among WLHIV and the development of targeted immunomodulatory prevention strategies.

  7. Variable activation of immune response by quinoa (Chenopodium quinoa Willd.) prolamins in celiac disease.

    Science.gov (United States)

    Zevallos, Victor F; Ellis, H Julia; Suligoj, Tanja; Herencia, L Irene; Ciclitira, Paul J

    2012-08-01

    Celiac disease is an enteropathy triggered by dietary gluten found in wheat, barley, and rye. The current treatment is a strict gluten-free diet. Quinoa is a highly nutritive plant from the Andes, with low concentrations of prolamins, that has been recommended as part of a gluten-free diet; however, few experimental data support this recommendation. We aimed to determine the amount of celiac-toxic prolamin epitopes in quinoa cultivars from different regions of the Andes and the ability of these epitopes to activate immune responses in patients with celiac disease. The concentration of celiac-toxic epitopes was measured by using murine monoclonal antibodies against gliadin and high-molecular-weight glutenin subunits. Immune response was assessed by proliferation assays of celiac small intestinal T cells/interferon-γ (IFN-γ) and production of IFN-γ/IL-15 after organ culture of celiac duodenal biopsy samples. Fifteen quinoa cultivars were tested: 4 cultivars had quantifiable concentrations of celiac-toxic epitopes, but they were below the maximum permitted for a gluten-free food. Cultivars Ayacuchana and Pasankalla stimulated T cell lines at levels similar to those for gliadin and caused secretion of cytokines from cultured biopsy samples at levels comparable with those for gliadin. Most quinoa cultivars do not possess quantifiable amounts of celiac-toxic epitopes. However, 2 cultivars had celiac-toxic epitopes that could activate the adaptive and innate immune responses in some patients with celiac disease. These findings require further investigation in the form of in vivo studies, because quinoa is an important source of nutrients for patients with celiac disease.

  8. Context-specific and immune cell–dependent anti-tumor activities of α1-antitrypsin

    Directory of Open Access Journals (Sweden)

    Ofer Guttman

    2016-12-01

    Full Text Available α1-antitrypsin (AAT, a circulating glycoprotein that rises during acute phase responses and healthy pregnancies, exhibits immunomodulatory properties in several T-cell–dependent immune pathologies. However, AAT does not interfere with isolated T-cell responses; instead, it facilitates polarization of macrophages and dendritic cells towards M2-like and tolerogenic cells, respectively. AAT also allows NK cell responses against tumor cells, while attenuating DC-dependent NK cell activities. Since AAT-treated macrophages bear resemblance to cancer-promoting tumor-associated macrophages (TAMs, it became imperative to examine the possible induction of tumor permissive conditions by AAT. Here, AAT treatment is examined for its effect on tumor development, metastatic spread and selected aspects of tumor immunology. Systemic AAT treatment of mice inoculated with B16-F10 melanoma cells resulted in significant inhibition of tumor growth and metastatic spread. Using NK cell–resistant RMA cells, we show that AAT interferes with tumor development in a CD8+ T-cell–dependent manner. Unexpectedly, upon analysis of tumor cellular composition we identified overly active tumor-infiltrating CD8+ T-cells alongside M1-like TAMs in AAT-treated mice. Based on the ability of AAT to undergo chemical modifications, we emulated conditions of elevated reactive nitrogen and oxygen species. Indeed, macrophages were stimulated by treatment with nitrosylated AAT, and IFN transcripts were significantly elevated in tumors extracted soon after ischemia-reperfusion challenge. These context-specific changes may explain the differential effects of AAT on immune responses towards tumor cells versus benign antigenic targets. These data suggest that systemically elevated levels of AAT may accommodate its physiological function in inflammatory resolution, without compromising tumor-targeting immune responses.

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

    Directory of Open Access Journals (Sweden)

    Philippe Le Bouteiller

    2015-02-01

    Full Text Available 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.

  10. Mucosal permeability and immune activation as potential therapeutic targets of probiotics in irritable bowel syndrome.

    Science.gov (United States)

    Barbara, Giovanni; Zecchi, Lisa; Barbaro, Raffaella; Cremon, Cesare; Bellacosa, Lara; Marcellini, Marco; De Giorgio, Roberto; Corinaldesi, Roberto; Stanghellini, Vincenzo

    2012-10-01

    There is increasingly convincing evidence supporting the participation of the gut microenvironment in the pathophysiology of irritable bowel syndrome (IBS). Studies particularly suggest an interplay between luminal factors (eg, foods and bacteria residing in the intestine), the epithelial barrier, and the mucosal immune system. Decreased expression and structural rearrangement of tight junction proteins in the small bowel and colon leading to increased intestinal permeability have been observed, particularly in postinfectious IBS and in IBS with diarrhea. These abnormalities are thought to contribute to the outflow of antigens through the leaky epithelium, causing overstimulation of the mucosal immune system. Accordingly, subsets of patients with IBS show higher numbers and an increased activation of mucosal immunocytes, particularly mast cells. Immune factors, released by these cells, including proteases, histamine, and prostanoids, participate in the perpetuation of the permeability dysfunction and contribute to the activation of abnormal neural responses involved in abdominal pain perception and changes in bowel habits. All these mechanisms represent new targets for therapeutic approaches in IBS. Probiotics are an attractive therapeutic option in IBS given their recognized safety and by virtue of positive biological effects they can exert on the host. Of importance for the IBS pathophysiology is that preclinical studies have shown that selective probiotic strains exhibit potentially useful properties including anti-inflammatory effects, improvement of mucosal barrier homeostasis, beneficial effects on intestinal microbiota, and a reduction of visceral hypersensitivity. The effect of probiotics on IBS is positive in most randomized, controlled studies, although the gain over the placebo is small. Identifying tailored probiotic approaches for subgroups of IBS patients represents a challenge for the future.

  11. IFNβ produced by TLR4-activated tumor cells is involved in improving the antitumoral immune response.

    Science.gov (United States)

    Núñez, Nicolás Gonzalo; Andreani, Virginia; Crespo, María Inés; Nocera, David Andrés; Breser, María Laura; Morón, Gabriel; Dejager, Lien; Libert, Claude; Rivero, Virginia; Maccioni, Mariana

    2012-02-01

    Toll-like receptor (TLR) ligands may be a valuable tool to promote antitumor responses by reinforcing antitumor immunity. In addition to their expression in immune cells, functional TLRs are also expressed by many cancer cells, but their significance has been controversial. In this study, we examined the action of TLR ligands on tumor pathophysiology as a result of direct tumor cell effects. B16 murine melanoma cells were stimulated in vitro with a TLR4 ligand (LPS-B16) prior to inoculation into TLR4-deficient mice (Tlr4 (lps-del)). Under such conditions, B16 cells yielded smaller tumors than nonstimulated B16 cells. The apoptosis/proliferation balance of the cells was not modified by TLR ligand treatment, nor was this effect compromised in immunocompromised nude mice. Mechanistic investigations revealed that IFNβ was the critical factor produced by TLR4-activated tumor cells in mediating their in vivo outgrowth. Transcriptional analysis showed that TLR4 activation on B16 cells induced changes in the expression of type I IFN and type I IFN-related genes. Most importantly, culture supernatants from LPS-B16 cells improved the maturation of bone marrow-derived dendritic cells (BMDC) from TLR4-deficient mice, upregulating the expression of interleukin-12 and costimulatory molecules on those cells. BMDC maturation was blunted by addition of an IFNβ-neutralizing antibody. Moreover, tumor growth inhibition observed in LPS-B16 tumors was abrogated in IFNAR1-deficient mice lacking a functional type I IFN receptor for binding IFN. Together, our findings show that tumor cells can be induced through the TLR4 pathway to produce IFN and positively contribute to the antitumoral immune response. ©2012 AACR.

  12. The effects of Ethanol Extract of Propolis (EEP on the experimentally induced Candida keratitis in rabbits

    Directory of Open Access Journals (Sweden)

    Ahangari AA

    2011-04-01

    Full Text Available "n 800x600 Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";} Background: Propolis (bee glue is a resinous substance obtained from bee hives living on various plant sources. The purpose of this study was to evaluate the effects of ethanol extract of propolis (EEP on the experimentally induced Candidial keratitis in rabbits."n"nMethods: The alcoholic extract of propolis was prepared by 80% ethyl alcohol. After suppressing the immune system of 24 male rabbits, experimental Candida albicans keratitis was induced in the animals under local anesthesia and sterile conditions. The animals were later divided into four groups including the control or glycerin group and a nystatin and two 500 and 1000µg/ml EEP groups. Treatment continued for 21 days and after sacrificing the animals by humane methods, histopathological samples of the rabbits' eyes were prepared."n"nResults: Keratitis was developed in the eyes of all rabbits a week after the yeast inoculation. In the control group in which animals received glycerin, keratitis persisted until day 21. Clinical signs of keratitis disappeared in the Nystatin and 1000µg/ml EEP groups after 14 and 21 days, respectively. The clinical signs of keratitis partially ameliorated in the animals receiving 500µg/ml EEP. Histopathological examination revealed no differences between groups receiving nystatin or 1000µg/ml EEP."n"nConclusion: It is concluded that, ethanol extract of propolis could completely treat Candida albicans keratitis in 1000µg/ml concentrations. This extract can be used as a safe antifungal agent

  13. CsBAFF, a Teleost B Cell Activating Factor, Promotes Pathogen-Induced Innate Immunity and Vaccine-Induced Adaptive Immunity.

    Directory of Open Access Journals (Sweden)

    Yun Sun

    Full Text Available B cell activating factor (BAFF is a member of the tumor necrosis factor family that is known to play an important role in B cell activation, proliferation, and differentiation in mammals. However, studies of BAFF in teleosts are very limited and its function, in particular that under in vivo conditions, is essentially unknown. In this study, we conducted in vivo as well as in vitro functional analyses of a BAFF homologue (CsBAFF from the teleost fish tongue sole (Cynoglossus semilaevis. CsBAFF is composed of 261 residues and shares moderate sequence identities with known BAFFs of other teleosts. CsBAFF expression was most abundant in immune organs and was upregulated during bacterial infection. Purified recombinant CsBAFF (rCsBAFF bound to tongue sole lymphocytes and promoted cellular proliferation and survival. The results of an in vivo study showed that CsBAFF overexpression in tongue sole significantly enhanced macrophage activation and reduced bacterial infection in fish tissues, whereas knockdown of CsBAFF expression resulted in increased bacterial dissemination and colonization in fish tissues. Furthermore, vaccination studies showed that CsBAFF enhanced the immunoprotection of a DNA vaccine and augmented the production of specific serum antibodies. Taken together, these results provide the first in vivo evidence to indicate that teleost BAFF is an immunostimulator that significantly contributes to the innate antibacterial immune response and vaccine-induced adaptive immune response.

  14. Genome-wide analysis of immune activation in human T and B cells reveals distinct classes of alternatively spliced genes.

    Directory of Open Access Journals (Sweden)

    Yevgeniy A Grigoryev

    2009-11-01

    Full Text Available Alternative splicing of pre-mRNA is a mechanism that increases the protein diversity of a single gene by differential exon inclusion/exclusion during post-transcriptional processing. While alternative splicing is established to occur during lymphocyte activation, little is known about the role it plays during the immune response. Our study is among the first reports of a systematic genome-wide analysis of activated human T and B lymphocytes using whole exon DNA microarrays integrating alternative splicing and differential gene expression. Purified human CD2(+ T or CD19(+ B cells were activated using protocols to model the early events in post-transplant allograft immunity and sampled as a function of time during the process of immune activation. Here we show that 3 distinct classes of alternatively spliced and/or differentially expressed genes change in an ordered manner as a function of immune activation. We mapped our results to function-based canonical pathways and demonstrated that some are populated by only one class of genes, like integrin signaling, while other pathways, such as purine metabolism and T cell receptor signaling, are populated by all three classes of genes. Our studies augment the current view of T and B cell activation in immunity that has been based exclusively upon differential gene expression by providing evidence for a large number of molecular networks populated as a function of time and activation by alternatively spliced genes, many of which are constitutively expressed.

  15. Microbial metalloproteinases mediate sensing of invading pathogens and activate innate immune responses in the lepidopteran model host Galleria mellonella.

    Science.gov (United States)

    Altincicek, Boran; Linder, Monica; Linder, Dietmar; Preissner, Klaus T; Vilcinskas, Andreas

    2007-01-01

    Thermolysin-like metalloproteinases such as aureolysin, pseudolysin, and bacillolysin represent virulence factors of diverse bacterial pathogens. Recently, we discovered that injection of thermolysin into larvae of the greater wax moth, Galleria mellonella, mediated strong immune responses. Thermolysin-mediated proteolysis of hemolymph proteins yielded a variety of small-sized (protein fragments (protfrags) that are potent elicitors of innate immune responses. In this study, we report the activation of a serine proteinase cascade by thermolysin, as described for bacterial lipopolysaccharides (LPS), that results in subsequent prophenoloxidase activation leading to melanization, an elementary immune defense reaction of insects. Quantitative real-time reverse transcription-PCR analyses of the expression of immune-related genes encoding the inducible metalloproteinase inhibitor, gallerimycin, and lysozyme demonstrated increased transcriptional rates after challenge with purified protfrags similar to rates after challenge with LPS. Additionally, we determined the induction of a similar spectrum of immune-responsive proteins that were secreted into the hemolymph by using comparative proteomic analyses of hemolymph proteins from untreated larvae and from larvae that were challenged with either protfrags or LPS. Since G. mellonella was recently established as a valuable pathogenicity model for Cryptococcus neoformans infection, the present results add to our understanding of the mechanisms of immune responses in G. mellonella. The obtained results support the proposed danger model, which suggests that the immune system senses endogenous alarm signals during infection besides recognition of microbial pattern molecules.

  16. Signs of innate immune activation and premature immunosenescence in psoriasis patients.

    Science.gov (United States)

    Šahmatova, Liisi; Sügis, Elena; Šunina, Marina; Hermann, Helen; Prans, Ele; Pihlap, Maire; Abram, Kristi; Rebane, Ana; Peterson, Hedi; Peterson, Pärt; Kingo, Külli; Kisand, Kai

    2017-08-08

    Psoriasis is a chronic inflammatory disease that affects skin and is associated with systemic inflammation and many serious comorbidities ranging from metabolic syndrome to cancer. Important discoveries about psoriasis pathogenesis have enabled the development of effective biological treatments blocking the T helper 17 pathway. However, it has not been settled whether psoriasis is a T cell-mediated autoimmune disease or an autoinflammatory disorder that is driven by exaggerated innate immune signalling. Our comparative gene expression and hierarchical cluster analysis reveal important gene circuits involving innate receptors. Innate immune activation is indicated by increased absent in melanoma 2 (AIM2) inflammasome gene expression and active caspase 1 staining in psoriatic lesional skin. Increased eomesodermin (EOMES) expression in lesional and non-lesional skin is suggestive of innate-like virtual memory CD8+ T cell infiltration. We found that signs of systemic inflammation were present in most of the patients, correlated with the severity of the disease, and pointed to IL-6 involvement in the pathogenesis of psoriatic arthritis. Among the circulating T cell subpopulations, we identified a higher proportion of terminally differentiated or senescent CD8+ T cells, especially in patients with long disease duration, suggesting premature immunosenescence and its possible implications for psoriasis co-morbidities.

  17. Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions.

    Science.gov (United States)

    Lee, Jin; Liao, Rui; Wang, Gaowei; Yang, Bi-Huei; Luo, Xiaolin; Varki, Nissi M; Qiu, Shuang-Jian; Ren, Bing; Fu, Wenxian; Feng, Gen-Sheng

    2017-11-14

    Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutic agents available yet. While dissecting the roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic-polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogens or by Pten loss and associated hepatosteatosis. The immunostimulatory dsRNA inhibited liver cancer initiation, apparently by boosting multiple anti-tumor activities of innate immunity, including induction of immunoregulatory cytokines, activation of NK cells and dendritic cells, and reprogramming of macrophage polarization. This study paves the way for the development of preventive and early interfering strategies for liver cancer to reduce the rapidly increasing incidences of liver cancer in an ever-growing population with chronic liver disorders. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Systemic Immune Activation Leads to Neuroinflammation and Sickness Behavior in Mice

    Directory of Open Access Journals (Sweden)

    Steven Biesmans

    2013-01-01

    Full Text Available Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.

  19. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation

    Science.gov (United States)

    Viswanathan, Kavitha; Dhabhar, Firdaus S.

    2005-04-01

    Effective immunoprotection requires rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. In contrast to immunosuppressive chronic stressors, short-term acute stressors have immunoenhancing effects. Here, we quantify leukocyte infiltration within a surgical sponge to elucidate the kinetics, magnitude, subpopulation, and chemoattractant specificity of an acute stress-induced increase in leukocyte trafficking to a site of immune activation. Mice acutely stressed before sponge implantation showed 200-300% higher neutrophil, macrophage, natural killer cell, and T cell infiltration than did nonstressed animals. We also quantified the effects of acute stress on lymphotactin- (LTN; a predominantly lymphocyte-specific chemokine), and TNF-- (a proinflammatory cytokine) stimulated leukocyte infiltration. An additional stress-induced increase in infiltration was observed for neutrophils, in response to TNF-, macrophages, in response to TNF- and LTN, and natural killer cells and T cells in response to LTN. These results show that acute stress initially increases trafficking of all major leukocyte subpopulations to a site of immune activation. Tissue damage-, antigen-, or pathogen-driven chemoattractants subsequently determine which subpopulations are recruited more vigorously. Such stress-induced increases in leukocyte trafficking may enhance immunoprotection during surgery, vaccination, or infection, but may also exacerbate immunopathology during inflammatory (cardiovascular disease or gingivitis) or autoimmune (psoriasis, arthritis, or multiple sclerosis) diseases. chemokine | psychophysiological stress | surgical sponge | wound healing | lymphotactin

  20. Dendritic cell-induced activation of adaptive and innate antitumor immunity.

    Science.gov (United States)

    van den Broeke, Leon T; Daschbach, Emily; Thomas, Elaine K; Andringa, Gerda; Berzofsky, Jay A

    2003-12-01

    While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.

  1. Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study.

    Science.gov (United States)

    Forton, Daniel M; Hamilton, Gavin; Allsop, Joanna M; Grover, Vijay P; Wesnes, Keith; O'Sullivan, Catherine; Thomas, Howard C; Taylor-Robinson, Simon D

    2008-09-01

    Abnormal cerebral metabolism and cognitive impairments have been reported in patients with chronic hepatitis C (HCV) but studies have failed to demonstrate a relationship between these findings. Twenty-five HCV-positive patients with histologically-mild liver disease were studied with cerebral proton magnetic resonance spectroscopy (MRS), using acquisition parameters to quantify myo-inositol (mI) and other metabolites in frontal white matter (FWM). Patients underwent automated attention and working memory tests (Cognitive Drug Research test system). The mean mI/ creatine ratio in the HCV+ve patients (0.64, SD 0.21) was significantly higher (p=0.02) than in healthy controls (0.52, SD 0.10). On cognitive testing, the HCV+ve patients showed impairments in 2/4 composite scores, reflecting working memory and attention, compared to normative data from healthy volunteers (pcognitive-motor disorder. It is associated with infection and immune activation of microglial cells. The similar findings in this study suggest that cerebral immune activation may also occur in HCV infection. This may underlie the mild neurocognitive impairment and neuropsychological symptoms observed in a proportion of patients.

  2. Allergy-Inducing Chromium Compounds Trigger Potent Innate Immune Stimulation Via ROS-Dependent Inflammasome Activation.

    Science.gov (United States)

    Adam, Christian; Wohlfarth, Jonas; Haußmann, Maike; Sennefelder, Helga; Rodin, Annette; Maler, Mareike; Martin, Stefan F; Goebeler, Matthias; Schmidt, Marc

    2017-02-01

    Chromium allergy is a common occupational skin disease mediated by chromium (VI)-specific T cells that induce delayed-type hypersensitivity in sensitized individuals. Additionally, chromium (VI) can act as an irritant. Both responses critically require innate immune activation, but if and how chromium (VI) elicits this signal is currently unclear. Using human monocytes, primary human keratinocytes, and murine dendritic cells we show that chromium (VI) compounds fail to trigger direct proinflammatory activation but potently induce processing and secretion of IL-1β. IL-1β release required priming by phorbol-ester or toll-like receptor stimulation and was prevented by inhibition of K+ efflux, NLRP3 depletion or caspase-1 inhibition, identifying chromium (VI) as a hapten activator of the NLRP3 inflammasome. Inflammasome activation was initiated by mitochondrial reactive oxygen species production triggered by chromium (VI), as indicated by sensitivity to treatment with the ROS scavenger N-acetyl cysteine and a coinciding failure of K+ efflux, caspase-1, or NLRP3 inhibition to prevent mitochondrial reactive oxygen species accumulation. IL-1β release further correlated with cytotoxicity that was secondary to reactive oxygen species, K+ efflux, and NLRP3 activation. Trivalent chromium was unable to induce mitochondrial reactive oxygen species production, inflammasome activation, and cytotoxicity, suggesting that oxidation state-specific differences in mitochondrial reactivity may determine inflammasome activation and allergic/irritant capacity of different chromium compounds. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Anupa Kamat

    Full Text Available Immune activation is a strong predictor of disease progression in HIV infection. Combinatorial plasma biomarker signatures that represent surrogate markers of immune activation in both viremic and aviremic HIV patients on combination antiretroviral therapy (cART have not been defined. Here, we identify a plasma inflammatory biomarker signature that distinguishes between both viremic and aviremic HIV patients on cART and healthy controls and examine relationships of this signature to markers of disease progression.Multiplex profiling and ELISA were used to detect 15 cytokines/chemokines, soluble IL-2R (sIL-2R, and soluble CD14 (sCD14 in plasma from 57 HIV patients with CD4 nadir <300 cells/µl and 29 healthy controls. Supervised and unsupervised analyses were used to identify biomarkers explaining variance between groups defined by HIV status or drug abuse. Relationships between biomarkers and disease markers were examined by Spearman correlation.The majority (91% of HIV subjects were on cART, with 38% having undetectable viral loads (VL. Hierarchical clustering identified a biomarker cluster in plasma consisting of two interferon-stimulated gene products (CXCL9 and CXCL10, T cell activation marker (sIL-2R, and monocyte activation marker (sCD14 that distinguished both viremic and aviremic HIV patients on cART from controls (p<0.0001 and were top-ranked in variables important in projection plots. IL-12 and CCL4 were also elevated in viremic and aviremic patients compared to controls (p<0.05. IL-12 correlated with IFNα, IFNγ, CXCL9, and sIL-2R (p<0.05. CXCL10 correlated positively with plasma VL and percentage of CD16+ monocytes, and inversely with CD4 count (p = 0.001, <0.0001, and 0.04, respectively.A plasma inflammatory biomarker signature consisting of CXCL9, CXCL10, sIL-2R, and sCD14 may be useful as a surrogate marker to monitor immune activation in both viremic and aviremic HIV patients on cART during disease progression and

  4. Induced prion protein controls immune-activated retroviruses in the mouse spleen.

    Directory of Open Access Journals (Sweden)

    Marius Lötscher

    Full Text Available The prion protein (PrP is crucially involved in transmissible spongiform encephalopathies (TSE, but neither its exact role in disease nor its physiological function are known. Here we show for mice, using histological, immunochemical and PCR-based methods, that stimulation of innate resistance was followed by appearance of numerous endogenous retroviruses and ensuing PrP up-regulation in germinal centers of the spleen. Subsequently, the activated retroviruses disappeared in a PrP-dependent manner. Our results reveal the regular involvement of endogenous retroviruses in murine immune responses and provide evidence for an essential function of PrP in the control of the retroviral activity. The interaction between PrP and ubiquitous endogenous retroviruses may allow new interpretations of TSE pathophysiology and explain the evolutionary conservation of PrP.

  5. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma

    OpenAIRE

    Bonanno Giuseppina; Mariotti Andrea; Procoli Annabella; Folgiero Valentina; Natale Daniela; De Rosa Luca; Majolino Ignazio; Novarese Linda; Rocci Alberto; Gambella Manuela; Ciciarello Marilena; Scambia Giovanni; Palumbo Antonio; Locatelli Franco; De Cristofaro Raimondo

    2012-01-01

    Abstract Background Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment. Methods We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 pat...

  6. Next-generation active immunization approach for synucleinopathies - implications for Parkinson’s Disease clinical trials

    Science.gov (United States)

    Mandler, Markus; Valera, Elvira; Rockenstein, Edward; Weninger, Harald; Patrick, Christina; Adame, Anthony; Santic, Radmila; Meindl, Stefanie; Vigl, Benjamin; Smrzka, Oskar; Schneeberger, Achim; Mattner, Frank; Masliah, Eliezer

    2014-01-01

    Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs® (AFF) that do not elicit a α-syn specific T-cell response. This approach allows the generation of long-term sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies such as Parkinson’s disease (PD). In this context, we screened a large library of peptides that mimic the c-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic mouse models of PD and Dementia with Lewy bodies (DLB), the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses that was accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies. PMID:24525765

  7. Immune Activation, Immunosenescence, and Osteoprotegerin as Markers of Endothelial Dysfunction in Subclinical HIV-Associated Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Alessandra D’Abramo

    2014-01-01

    Full Text Available HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+ and senescence (CD57+ CD28− were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (≥0.9 mm. CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28− CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression.

  8. The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review

    Directory of Open Access Journals (Sweden)

    Vassallo Matteo

    2012-08-01

    Full Text Available Abstract Background Recent observational studies suggest a role for lipopolysaccharide (LPS as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens. Object A systematic review of LPS as a marker of immune activation in HIV-1 infected patients. Data sources MEDLINE register of articles and international conference proceedings. Review methods Case–control studies comparing the role of plasma LPS as a marker of immune activation in HIV-infected patients versus HIV negative subjects. Data synthesis Two hundred and six articles were selected using MEDLINE, plus 51 studies presented at international conferences. Plasma LPS is a marker of immune activation in HIV-infected patients, determining the entry of central memory CD4+ T cells into the replication cycle and finally generating cell death. Plasma LPS probably results from immune-mediated alterations of the intestinal barrier, which can occur soon after HIV seroconversion. LPS is a likely marker of disease progression, as it drives chronic monocyte activation, and some studies suggest that hyperexpression of CCR5 receptors, related to LPS plasma levels, could be responsible for monocyte trafficking in the brain compartment and for the appearance of HIV-associated neurocognitive disorders. Long-term combination antiretroviral therapy (cART generally reduces LPS concentrations, but rarely to the same levels as in the control group. This phenomenon probably depends on ongoing but incomplete repair of the mucosal barrier. Only in patients achieving maximal viral suppression (i.e. viral load  Conclusions LPS is a marker of microbial translocation, responsible for chronic immune activation in HIV-infected patients. Even in successfully treated patients, LPS values are rarely normal. Several studies suggest a role for LPS as a negative predictive marker of immune restoration in patients with blunted CD4 T cell gain.

  9. Resveratrol promotes recovery of immune function of immunosuppressive mice by activating JNK/NF-κB pathway in splenic lymphocytes.

    Science.gov (United States)

    Lai, Xin; Cao, Mei; Song, Xu; Jia, Renyong; Zou, Yuanfeng; Li, Lixia; Liang, Xiaoxia; He, Changliang; Yin, Lizi; Yue, Guizhou; Ye, Gang; Yin, Zhongqiong

    2017-06-01

    Resveratrol, a natural compound found in over 70 plants, is known to possess immunoregulatory effects and anti-inflammatory activity. It has been shown that resveratrol has regulatory effects on different signaling pathways in different diseases. However, few reports have evaluated the effects of resveratrol on reinforcing immunity recovery via activating nuclear factor-κB (NF-κB) pathway and Jun N-terminal kinases (JNK) pathway. The present study aimed to assess immune-enhancing activity and underlying mechanism of resveratrol in immunosuppressive mice. Previously, we reported that resveratrol could promote mouse spleen lymphocyte functions to recover the immune system effectively. In the present study, we show that resveratrol could upregulate the expressions of NF-κB, IκB kinase, JNK, and c-jun in splenic lymphocytes of immunosuppressive mice. Taken together, our results indicate that resveratrol could promote recovery of immunologic function in immunosuppressive mice by activating JNK/NF-κB pathway.

  10. Sex differences matter in the gut: effect on mucosal immune activation and inflammation

    National Research Council Canada - National Science Library

    Sankaran-Walters, Sumathi; Macal, Monica; Grishina, Irina; Nagy, Lauren; Goulart, Larissa; Coolidge, Kathryn; Li, Jay; Fenton, Anne; Williams, Theodore; Miller, Mary K; Flamm, Jason; Prindiville, Thomas; George, Michael; Dandekar, Satya

    2013-01-01

    .... However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system...

  11. Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation

    Science.gov (United States)

    2014-01-01

    Introduction Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer for more than a decade. However, reports on the involvement of HER2 downregulation in trastuzumab’s mechanism of action are inconsistent. The aim of this study is to investigate if the dependence of trastuzumab-mediated cancer cell HER2 downregulation on immune effector cells represents a novel mechanism of action for trastuzumab. Methods HER2 expression was evaluated by Western blotting, flow cytometry, and real-time polymerase chain reaction (PCR) in cell lysates from co-cultures of multiple cancer cell lines with peripheral blood mononuclear cells (PBMCs) in the presence or absence of trastuzumab. The engagement of immune cells by trastuzumab through Fc gamma receptors (FcγRs) was tested using three trastuzumab variants with compromised or no Fc (fragment crystallizable) functions and FcγRs blocking experiments. The engagement of immune cells by trastuzumab in HER2 downregulation was also evaluated in in vivo mouse xenograft tumor models. Results HER2 downregulation of cancer cells by trastuzumab occurred only when trastuzumab was actively engaged with immune cells and cancer cells, as demonstrated consistently in co-cultures of cancer cell lines with PBMCs and in vivo mouse xenograft tumor models. We further demonstrated that HER2 downregulation in cancer cells by immune-cell-engaged trastuzumab was at the transcriptional level, not through the HER2 degradation pathway. Activation of signal transducer and activator of transcription 1 (STAT1) in cancer cells by the increased interferon gamma (IFN-γ) production in immune cells played an important role in downregulating HER2 in cancer cells upon engagement of immune cells by trastuzumab. Furthermore, HER2 downregulation in cancer cells induced by trastuzumab engagement of immune cells was correlated with the antibody’s antitumor efficacy in vivo. Conclusions This

  12. Effects of Pseudoalteromonas sp. BC228 on digestive enzyme activity and immune response of juvenile sea cucumber ( Apostichopus japonicus)

    Science.gov (United States)

    Ma, Yuexin; Sun, Feixue; Zhang, Congyao; Bao, Pengyun; Cao, Shuqing; Zhang, Meiyan

    2014-12-01

    A marine bacterium, Pseudoalteromonas sp. BC228 was supplemented to feed in a feeding experiment aiming to determine its ability of enhancing the digestive enzyme activity and immune response of juvenile Apostichopus japonicus. Sea cucumber individuals were fed with the diets containing 0 (control), 105, 107 and 109 CFU g-1 diet of BC228 for 45 days. Results showed that intestinal trypsin and lipase activities were significantly enhanced by 107 and 109 CFU g-1 diet of BC228 in comparison with control ( P digestive enzyme activity of juvenile sea cucumber, stimulated its immune response and enhanced its resistance to the infection of V. splendidus.

  13. Innate DNA sensing is impaired in HIV patients and IFI16 expression correlates with chronic immune activation.

    Science.gov (United States)

    Nissen, S K; Højen, J F; Andersen, K L D; Kofod-Olsen, E; Berg, R K; Paludan, S R; Østergaard, L; Jakobsen, M R; Tolstrup, M; Mogensen, T H

    2014-07-01

    The innate immune system has been recognized to play a role in the pathogenesis of HIV infection, both by stimulating protective activities and through a contribution to chronic immune activation, the development of immunodeficiency and progression to AIDS. A role for DNA sensors in HIV recognition has been suggested recently, and the aim of the present study was to describe the influence of HIV infection on expression and function of intracellular DNA sensing. Here we demonstrate impaired expression of interferon-stimulated genes in responses to DNA in peripheral blood monuclear cells from HIV-positive individuals, irrespective of whether patients receive anti-retroviral treatment. Furthermore, we show that expression levels of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic guanosine monophosphate-adenosine monophosphate synthase were increased in treatment-naive patients, and for IFI16 expression was correlated with high viral load and low CD4 cell count. Finally, our data demonstrate a correlation between IFI16 and CD38 expression, a marker of immune activation, in CD4(+) central and effector memory T cells, which may indicate that IFI16-mediated DNA sensing and signalling contributes to chronic immune activation. Altogether, the present study demonstrates abnormal expression and function of cytosolic DNA sensors in HIV patients, which may have implications for control of opportunistic infections, chronic immune activation and T cell death. © 2014 British Society for Immunology.

  14. TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis.

    Science.gov (United States)

    Francisco, Ngiambudulu M; Hsu, Nai-Jen; Keeton, Roanne; Randall, Philippa; Sebesho, Boipelo; Allie, Nasiema; Govender, Dhirendra; Quesniaux, Valerie; Ryffel, Bernhard; Kellaway, Lauriston; Jacobs, Muazzam

    2015-06-26

    Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. We generated neuron-specific TNF-deficient (NsTNF(-/-)) mice and compared outcomes of disease against TNF(f/f) control and global TNF(-/-) mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). Intracerebral M. tuberculosis infection of TNF(-/-) mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF(-/-) mice were resistant to infection and presented with a phenotype similar to that in TNF(f/f) control mice. Impaired immunity in TNF(-/-) mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.

  15. The impact of inflammation and immune activation on B cell differentiation during HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Nicolas eRuffin

    2012-01-01

    Full Text Available HIV-1 infection is characterized by continuous antigenic stimulation, chronic immune activation and impaired survival of T and B cells. A decline of resting memory B cells has previously been reported to occur in both children and adults infected with HIV-1; these cells are responsible for mounting and maintaining an adequate serological response to antigens previously encountered in life through natural infection or vaccination. Further understanding of the mechanisms leading to impaired B cell differentiation and germinal center reaction might be essential to design new HIV vaccines and therapies that could improve humoral immune responses in HIV-1 infected individuals. In the present article we summarize the literature and present our view on critical mechanisms of B cell development which are impaired during HIV-1 infection. We also discuss the impact of microbial translocation, a driving force for persistent inflammation during HIV-1 infection, on survival of terminally differentiated B cells and how the altered expression of cytokines/chemokines pivotal for communication between T and B cells in lymphoid tissues may impair formation of memory B cells.

  16. Digital quantification of gene expression in sequential breast cancer biopsies reveals activation of an immune response.

    Directory of Open Access Journals (Sweden)

    Rinath M Jeselsohn

    Full Text Available Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted.

  17. The Ustilago maydis effector Pep1 suppresses plant immunity by inhibition of host peroxidase activity.

    Directory of Open Access Journals (Sweden)

    Christoph Hemetsberger

    Full Text Available The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1 as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of Δpep1 mutant penetrations, H₂O₂ strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the Δpep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

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

    Science.gov (United States)

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

    2015-01-01

    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+CD25HIFOXP3+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. Chronic activation of the innate immune system may underlie the metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Bruce Bartholow Duncan

    2001-05-01

    Full Text Available CONTEXTO: The metabolic syndrome is characterized by a clustering, in free-living populations, of cardiovascular and diabetes risk factors generally linked to insulin resistance, obesity and central obesity. Consonant with the well-established inflammatory pathogenesis of atherosclerotic disease, the metabolic syndrome is now being investigated in relation to its inflammatory nature. OBJETIVO: We present cross-sectional findings demonstrating that markers of inflammation correlate with components of the metabolic syndrome, and prospective findings of the ARIC Study indicating that markers of inflammation and endothelial dysfunction predict the development of diabetes mellitus and weight gain in adults. We present biological evidence to suggest that chronic activation of the innate immune system may underlie the metabolic syndrome, characterizing the common soil for the causality of type 2 diabetes mellitus and cardiovascular disease. CONCLUSIONS: Better understanding of the role of the innate immune system in these diseases may lead to important advances in the prediction and management of diabetes and cardiovascular disease.

  20. Mechanical Stretch Induces Epithelial-Mesenchymal Transition in Alveolar Epithelia via Hyaluronan Activation of Innate Immunity*

    Science.gov (United States)

    Heise, Rebecca L.; Stober, Vandy; Cheluvaraju, Chaitra; Hollingsworth, John W.; Garantziotis, Stavros

    2011-01-01

    Epithelial injury is a central event in the pathogenesis of many inflammatory and fibrotic lung diseases like acute respiratory distress syndrome, pulmonary fibrosis, and iatrogenic lung injury. Mechanical stress is an often underappreciated contributor to lung epithelial injury. Following injury, differentiated epithelia can assume a myofibroblast phenotype in a process termed epithelial to mesenchymal transition (EMT), which contributes to aberrant wound healing and fibrosis. We demonstrate that cyclic mechanical stretch induces EMT in alveolar type II epithelial cells, associated with increased expression of low molecular mass hyaluronan (sHA). We show that sHA is sufficient for induction of EMT in statically cultured alveolar type II epithelial cells and necessary for EMT during cell stretch. Furthermore, stretch-induced EMT requires the innate immune adaptor molecule MyD88. We examined the Wnt/β-catenin pathway, which is known to mediate EMT. The Wnt target gene Wnt-inducible signaling protein 1 (wisp-1) is significantly up-regulated in stretched cells in hyaluronan- and MyD88-dependent fashion, and blockade of WISP-1 prevents EMT in stretched cells. In conclusion, we show for the first time that innate immunity transduces mechanical stress responses through the matrix component hyaluronan, and activation of the Wnt/β-catenin pathway. PMID:21398522

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

    Science.gov (United States)

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

    2015-06-09

    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.

  2. In Vitro Evaluation of Colloidal Silver on Immune Function: Antilymphoproliferative Activity

    Directory of Open Access Journals (Sweden)

    M. A. Franco-Molina

    2016-01-01

    Full Text Available Colloidal silver (AgC is currently used by humans and it can be internalized through inhalation, injection, ingestion, and dermal contact. However, there is limited information about immunological activity; more investigations using colloidal silver are needed. In the present study, the effects of AgC (17.5 ng/mL on immunological parameters (proliferation and immunophenotyping using human peripheral blood mononuclear cells (PBMC and macrophages (phagocytosis and cytotoxicity on leukemia and lymphoma cancer cell lines (1.75 to 17.5 ng/mL were investigated. AgC was observed to significantly (p<0.05 decrease interleukin-2 (IL-2 production and proliferation induced by phytohemagglutinin or concanavalin A in PBMC without affecting its cell viability but with cytotoxic effect on cancer cells. IL-2, IL-4, IL-6, IL-10, INF-γ, and IL-17A cytokines production and CD3+, CD3−CD19+, CD3+CD4+, CD3+CD8+, and CD16+CD56+ PBMC phenotypes were not affected by AgC. The present study demonstrates that colloidal silver is harmless and nontoxic to the immune system cells and its ability to interfere with the immune response by decreasing cell proliferation when stimulated with mitogens demonstrated the antilymphoproliferative potential of AgC.

  3. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation.

    Directory of Open Access Journals (Sweden)

    Sophia Maschalidi

    Full Text Available Intracellular Toll-like receptors (TLRs expressed by dendritic cells recognize nucleic acids derived from pathogens and play an important role in the immune responses against the influenza virus (IAV, a single-stranded RNA sensed by different receptors including TLR7. However, the importance of TLR7 processing in the development of anti-viral immune responses is not known. Here we report that asparagine endopeptidase (AEP deficient mice are unable to generate a strong anti-IAV response, as demonstrated by reduced inflammation, cross presentation of cell-associated antigens and priming of CD8(+ T cells following TLR7-dependent pulmonary infection induced by IAV. Moreover, AEP deficient lung epithelial- or myeloid-cells exhibit impaired TLR7 signaling due to defective processing of this receptor. Indeed, TLR7 requires a proteolytic cleavage by AEP to generate a C-terminal fragment competent for signaling. Thus, AEP activity is critical for TLR7 processing, opening new possibilities for the treatment of influenza and TLR7-dependent inflammatory diseases.

  4. Evaluation of cytotoxicity, immune compatibility and antibacterial activity of biogenic silver nanoparticles.

    Science.gov (United States)

    Składanowski, M; Golinska, P; Rudnicka, K; Dahm, H; Rai, M

    2016-12-01

    The study was focused on assessment of antibacterial activity, cytotoxicity and immune compatibility of biogenic silver nanoparticles (AgNPs) synthesized from Streptomyces sp. NH28 strain. Nanoparticles were biosynthesized and characterized by UV-Vis spectroscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, nanoparticle tracking analysis system and zeta potential. Antibacterial activity was tested against Gram-positive and Gram-negative bacteria; minimal inhibitory concentration was recorded. Cytotoxicity was estimated using L929 mouse fibroblasts via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Biocompatibility of AgNPs was performed using THP1-XBlue™ cells. Biogenic AgNPs presented high antibacterial activity against all tested bacteria. Minimum inhibitory concentration of AgNPs against bacterial cells was found to be in range of 1.25-10 μg/mL. Silver nanoparticles did not show any harmful interaction to mouse fibroblast cell line, and no activation of nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) cells was observed at concentration below 10 µg/mL. The half-maximal inhibitory concentration (IC 50 ) value was established at 64.5 μg/mL. Biological synthesis of silver can be used as an effective system for formation of metal nanoparticles. Biosynthesized AgNPs can be used as an antibacterial agent, which can be safe for eukaryotic cells.

  5. Active immunization with glucose-dependent insulinotropic polypeptide vaccine influences brain function and behaviour in rats.

    Science.gov (United States)

    Tian, J-Q; Wang, Y; Lin, N; Guo, Y-J; Sun, S-H; Zou, D-J

    2010-07-01

    Glucose-dependent insulinotropic polypeptide (GIP) is involved in the aetiology of obesity induced by overnutrition, and blocking GIP activity may be valuable to anti-obesity treatment. However, GIP and GIP receptor are closely related to various brain functions which have caused very little data to be published concerning this cerebral functionality after blocking GIP activity. Here, we showed that active vaccination of mature rats with GIP immunoconjugates [GIP-keyhole limpet haemocyanin (KLH)] was associated with changes in body weight. Furthermore, we also observed significant changes in brain function and behaviour. Data indicated that GIP-KLH-immunized rats showed decreased spontaneous activity in the open field test, decreased cerebral glucose utilization assessed by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT), and increased apoptosis and proliferation of hippocampal granule cells marked by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) or proliferating cell nuclear antigen method. In conclusion, we have shown that vaccine-induced antibodies inhibited GIP activity in vivo and led to significant changes in brain function and behaviour, which underscore the need to address any potential problems GIP-targeted immunotherapy may involve in further research.

  6. Effect of Camel Milk on Oxidative Stresses in Experimentally Induced Diabetic Rabbits

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    Esraa Tantawy

    2010-06-01

    Full Text Available Camel milk has an importance in the treatment of diabetes. It has been shown that the patients who drink camel milk daily, their need to insulin decrease. Therefore, this study aimed to investigate the effect of camel milk in comparison with insulin treatment in experimentally-induced diabetes. This study was carried out on forty male New Zealand rabbits, divided into four groups with ten rabbits in each. The first group G1 was considered as control non-diabetic group and received only normal saline solution. The other animals were injected intravenously with alloxan for induction of diabetes mellitus and then divided into three groups' ten rabbits each as the follows: G2 considered as control diabetic and left untreated, G3 was considered as diabetic and treated with insulin, and G4 was considered as diabetic and received camel milk. At the end of the experiment (4 weeks, blood (whole blood & serum and tissue samples (liver, kidney and pancreas were collected from all the animals for analysis of: enzymatic SOD and catalase, non-enzymatic GSH antioxidant enzyme activities. Serum malondialdeyde, glucose, insulin and lipid profile also were analyzed. The results showed that the camel milk was effective in the treatment of diabetes in comparison to insulin treatment alone. In addition to its hypoglycemic effect, camel milk improved the diabetes-induced oxidative stress. The histopathological evaluations demonstrated that there was a regeneration in β cells and the islets of Langerhans among the pancreatic acini in rabbits receiving camel milk. Our findings suggested that the camel milk administration in case of insulin dependant diabetes mellitus might be recommended as an oral anti-diabetic remedy.

  7. Modulating the innate immune activity in murine tumor microenvironment by a combination of inducer molecules attached to microparticles.

    Science.gov (United States)

    Shahar, Ehud; Gorodetsky, Raphael; Aizenshtein, Elina; Lalush, Lior; Pitcovski, Jacob

    2015-09-01

    Targeted cancer immunotherapy is challenging due to the cellular diversity and imposed immune tolerance in the tumor microenvironment (TME). A promising route to overcome those drawbacks may be by activating innate immune cells (IIC) in the TME, toward tumor destruction. Studies have shown the ability to "re-educate" pro-tumor-activated IIC toward antitumor responses. The current research aims to stimulate such activation using a combination of innate activators loaded onto microparticles (MP). Four inducers of Toll-like receptors 4 and 7, complement C5a receptor (C5aR) and gamma Fc receptor and their combinations were loaded on MP, and their influence on immune cell activation evaluated. MP stimulation of immune cell activation was tested in vitro and in vivo using a subcutaneous B16-F10 melanoma model induced in C57BL6 mice. Exposure to the TLR4 ligand lipopolysaccharide (LPS) bound to MP-induced acute inflammatory cytokine and chemokine activity in vitro and in vivo, with the elevation of CD45(+) leukocytes in particular GR-1(+) neutrophils and F4/80 macrophages in the TME. Nevertheless, LPS alone on MP was insufficient to significantly delay tumor progression. LPS combined with the C5aR ligand C5a-pep on the same MP resulted in a similar inflammation activation pattern. However, interleukin-10 levels were lower, and tumor growth was significantly delayed. Mixtures of these two ligands on separate MP did not yield the same cytokine activation pattern, demonstrating the importance of the cells' dual activation. The results suggest that combining inducers of distinct innate immune activation pathways holds promise for successful redirection of TME-residing IIC toward anti-tumoral activation.

  8. Detection of serum soluble markers of immune activation in rheumatoid arthritis

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    T. Kogure

    1996-01-01

    Full Text Available The mutual correlation among soluble CD4 (sCD4, soluble CD8 (sCD8, and soluble CD23 (sCD23 has not yet been studied in patients with rheumatoid arthritis (RA, although previous studies have demonstrated that certain soluble markers of immune activation are elevated in RA. Thus, we examined this correlation based on the serum levels of sCD4, sCD8 and sCD23, and that of their levels with other serum markers such as immunoglobulin (Ig subtypes (IgG, IgM and IgA, IgM-rheumatoid factor (IgM-RF and C-reactive protein (CRP in 25 RA patients, sCD4 was not elevated, whereas both sCD8 and sCD23 increased in RA patients compared with the healthy controls; a majority of RA patients, in particular, showed a high sCD23 level. The level of sCD23 showed a correlation with that of IgM-RF, but not with those of IgG, IgM, IgA and CRP. Importantly, a high level of sCD23 was not always accompartied with that of sCD8. The independent change between sCD23 and sCD8 levels was also observed in a one-year follow-up study of the two RA patients. These findings indicate that B cells might be generally activated in RA, whereas T-cell activation in variable in each patient with RA, suggesting that sCD23 is a more indicative marker for the immune status of RA patients than sCD8 from the clinical aspects.

  9. Experimentally induced stress in rheumatoid arthritis of recent onset: effects on peripheral blood lymphocytes

    NARCIS (Netherlands)

    Geenen, R.; Godaert, G. L.; Heijnen, C. J.; Vianen, M. E.; Wenting, M. J.; Nederhoff, M. G.; Bijlsma, J. W.

    1998-01-01

    To examine the effects of experimentally-induced stress on the mobilization of peripheral blood lymphocytes (PBL) in patients with rheumatoid arthritis (RA) of recent onset. Twenty-two (16 F, 6 M) patients (mean age 57.6 yrs.) and 23 (15 F, 8 M) healthy subjects (mean age 54.7 yrs.) were subjected

  10. Diet shifts and population dynamics of estuarine foraminifera during ecosystem recovery after experimentally induced hypoxia crises

    NARCIS (Netherlands)

    Brouwer, G.M.; Duijnstee, Ivo; Hazeleger, J.H.; Rossi, F.; Lourens, L.J.; Middelburg, J.J.; Wolthers, M.

    2016-01-01

    This study shows foraminiferal dynamics after experimentally induced hypoxia within the wider context of ecosystem recovery. 13C-labeled bicarbonate and glucose were added to the sediments to examine foraminiferal diet shifts during ecosystem recovery and test-size measurements were used to deduce

  11. A review of the effects of glutamine-enriched diets on experimentally induced enterocolitis.

    Science.gov (United States)

    Rombeau, J L

    1990-01-01

    Studies in animal models of enterocolitis have failed to confirm the purported metabolic and functional benefits of bowel rest induced by use of an elemental diet. Recent reports have demonstrated that glutamine-supplemented diets ameliorate or reverse many of the adverse effects of experimentally induced enterocolitis. Human studies are needed to confirm these findings.

  12. The CSF Immune Response in HIV-1-Associated Cryptococcal Meningitis: Macrophage Activation, Correlates of Disease Severity, and Effect of Antiretroviral Therapy.

    Science.gov (United States)

    Scriven, James E; Graham, Lisa M; Schutz, Charlotte; Scriba, Thomas J; Wilkinson, Katalin A; Wilkinson, Robert J; Boulware, David R; Urban, Britta C; Meintjes, Graeme; Lalloo, David G

    2017-07-01

    Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (immune response at the site of disease.

  13. Intranasal immunization with recombinant HA and mast cell activator C48/80 elicits protective immunity against 2009 pandemic H1N1 influenza in mice.

    Directory of Open Access Journals (Sweden)

    Shu Meng

    Full Text Available BACKGROUND: Pandemic influenza represents a major threat to global health. Vaccination is the most economic and effective strategy to control influenza pandemic. Conventional vaccine approach, despite being effective, has a number of major deficiencies including limited range of protection, total dependence on embryonated eggs for production, and time consuming for vaccine production. There is an urgent need to develop novel vaccine strategies to overcome these deficiencies. METHODOLOGY/PRINCIPAL FINDINGS: The major objective of this work was to develop a novel vaccine strategy combining recombinant haemagglutinin (HA protein and a master cell (MC activator C48/80 for intranasal immunization. We demonstrated in BALB/c mice that MC activator C48/80 had strong adjuvant activity when co-administered with recombinant HA protein intranasally. Vaccination with C48/80 significantly increased the serum IgG and mucosal surface IgA antibody responses against HA protein. Such increases correlated with stronger and durable neutralizing antibody activities, offering protection to vaccinated animals from disease progression after challenge with lethal dose of A/California/04/2009 live virus. Furthermore, protected animals demonstrated significant reduction in lung virus titers, minimal structural alteration in lung tissues as well as higher and balanced production of Th1 and Th2 cytokines in the stimulated splenocytes when compared to those without C48/80. CONCLUSIONS/SIGNIFICANCE: The present study demonstrates that the novel vaccine approach of combining recombinant HA and mucosal adjuvant C48/80 is safe and effective in eliciting protective immunity in mice. Future studies on the mechanism of action of C48/80 and potential combination with other vaccine strategies such as prime and boost approach may help to induce even more potent and broad immune responses against viruses from various clades.

  14. Alphavirus replicon particles expressing TRP-2 provide potent therapeutic effect on melanoma through activation of humoral and cellular immunity.

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    Francesca Avogadri

    2010-09-01

    Full Text Available Malignant melanoma is the deadliest form of skin cancer and is refractory to conventional chemotherapy and radiotherapy. Therefore alternative approaches to treat this disease, such as immunotherapy, are needed. Melanoma vaccine design has mainly focused on targeting CD8+ T cells. Activation of effector CD8+ T cells has been achieved in patients, but provided limited clinical benefit, due to immune-escape mechanisms established by advanced tumors. We have previously shown that alphavirus-based virus-like replicon particles (VRP simultaneously activate strong cellular and humoral immunity against the weakly immunogenic melanoma differentiation antigen (MDA tyrosinase. Here we further investigate the antitumor effect and the immune mechanisms of VRP encoding different MDAs.VRP encoding different MDAs were screened for their ability to prevent the growth of the B16 mouse transplantable melanoma. The immunologic mechanisms of efficacy were investigated for the most effective vaccine identified, focusing on CD8+ T cells and humoral responses. To this end, ex vivo immune assays and transgenic mice lacking specific immune effector functions were used. The studies identified a potent therapeutic VRP vaccine, encoding tyrosinase related protein 2 (TRP-2, which provided a durable anti-tumor effect. The efficacy of VRP-TRP2 relies on a novel immune mechanism of action requiring the activation of both IgG and CD8+ T cell effector responses, and depends on signaling through activating Fcγ receptors.This study identifies a VRP-based vaccine able to elicit humoral immunity against TRP-2, which plays a role in melanoma immunotherapy and synergizes with tumor-specific CD8+ T cell responses. These findings will aid in the rational design of future immunotherapy clinical trials.

  15. Alphavirus replicon particles expressing TRP-2 provide potent therapeutic effect on melanoma through activation of humoral and cellular immunity.

    Science.gov (United States)

    Avogadri, Francesca; Merghoub, Taha; Maughan, Maureen F; Hirschhorn-Cymerman, Daniel; Morris, John; Ritter, Erika; Olmsted, Robert; Houghton, Alan N; Wolchok, Jedd D

    2010-09-10

    Malignant melanoma is the deadliest form of skin cancer and is refractory to conventional chemotherapy and radiotherapy. Therefore alternative approaches to treat this disease, such as immunotherapy, are needed. Melanoma vaccine design has mainly focused on targeting CD8+ T cells. Activation of effector CD8+ T cells has been achieved in patients, but provided limited clinical benefit, due to immune-escape mechanisms established by advanced tumors. We have previously shown that alphavirus-based virus-like replicon particles (VRP) simultaneously activate strong cellular and humoral immunity against the weakly immunogenic melanoma differentiation antigen (MDA) tyrosinase. Here we further investigate the antitumor effect and the immune mechanisms of VRP encoding different MDAs. VRP encoding different MDAs were screened for their ability to prevent the growth of the B16 mouse transplantable melanoma. The immunologic mechanisms of efficacy were investigated for the most effective vaccine identified, focusing on CD8+ T cells and humoral responses. To this end, ex vivo immune assays and transgenic mice lacking specific immune effector functions were used. The studies identified a potent therapeutic VRP vaccine, encoding tyrosinase related protein 2 (TRP-2), which provided a durable anti-tumor effect. The efficacy of VRP-TRP2 relies on a novel immune mechanism of action requiring the activation of both IgG and CD8+ T cell effector responses, and depends on signaling through activating Fcγ receptors. This study identifies a VRP-based vaccine able to elicit humoral immunity against TRP-2, which plays a role in melanoma immunotherapy and synergizes with tumor-specific CD8+ T cell responses. These findings will aid in the rational design of future immunotherapy clinical trials.

  16. Newcastle disease virus mediates pancreatic tumor rejection via NK cell activation and prevents cancer relapse by prompting adaptive immunity.

    Science.gov (United States)

    Schwaiger, Theresa; Knittler, Michael R; Grund, Christian; Roemer-Oberdoerfer, Angela; Kapp, Joachim-Friedrich; Lerch, Markus M; Mettenleiter, Thomas C; Mayerle, Julia; Blohm, Ulrike

    2017-12-15

    Pancreatic cancer is the 8th most common cause of cancer-related deaths worldwide and the tumor with the poorest prognosis of all solid malignancies. In 1957, it was discovered that Newcastle disease virus (NDV) has oncolytic properties on tumor cells. To study the oncolytic properties of NDV in pancreatic cancer a single dose was administered intravenously in a syngeneic orthotopic tumor model using two different murine pancreatic adenocarcinoma cell lines (DT6606PDA, Panc02). Tumor growth was monitored and immune response was analyzed. A single treatment with NDV inhibited DT6606PDA tumor growth in mice and prevented recurrence for a period of three months. Tumor infiltration and systemic activation of NK cells, cytotoxic and helper T-cells was enhanced. NDV-induced melting of Panc02 tumors until d7 pi, but they recurred displaying unrestricted tumor growth, low immunogenicity and inhibition of tumor-specific immune response. Arrest of DT6606PDA tumor growth and rejection was mediated by activation of NK cells and a specific antitumor immune response via T-cells. Panc02 tumors rapidly decreased until d7 pi, but henceforth tumors characterized by the ability to perform immune-regulatory functions reappeared. Our results demonstrated that NDV-activated immune cells are able to reject tumors provided that an adaptive antitumor immune response can be initiated. However, activated NK cells that are abundant in Panc02 tumors lead to outgrowth of nonimmunogenic tumor cells with inhibitory properties. Our study emphasizes the importance of an adaptive immune response, which is initiated by NDV to mediate long-term tumor surveillance in addition to direct oncolysis. © 2017 UICC.

  17. The role of endosomal escape and mitogen-activated protein kinases in adenoviral activation of the innate immune response.

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    Jeffrey S Smith

    Full Text Available Adenoviral vectors (AdV activate multiple signaling pathways associated with innate immune responses, including mitogen-activated protein kinases (MAPKs. In this study, we investigated how systemically-injected AdVs activate two MAPK pathways (p38 and ERK and the contribution of these kinases to AdV-induced cytokine and chemokine responses in mice. Mice were injected intravenously either with a helper-dependent Ad2 vector that does not express viral genes or transgenes, or with the Ad2 mutant ts1, which is defective in endosomal escape. We found that AdV induced rapid phosphorylation of p38 and ERK as well as a significant cytokine response, but ts1 failed to activate p38 or ERK and induced only a limited cytokine response. These results demonstrate that endosomal escape of virions is a critical step in the induction of these innate pathways and responses. We then examined the roles of p38 and ERK pathways in the innate cytokine response by administering specific kinase inhibitors to mice prior to AdV. The cytokine and chemokine response to AdV was only modestly suppressed by a p38 inhibitor, while an ERK inhibitor has mixed effects, lowering some cytokines and elevating others. Thus, even though p38 and ERK are rapidly activated after i.v. injection of AdV, cytokine and chemokine responses are mostly independent of these kinases.

  18. Immunosuppressive activity of ethanolic extract of seeds of Moringa oleifera Lam. in experimental immune inflammation.

    Science.gov (United States)

    Mahajan, Shailaja G; Mehta, Anita A

    2010-07-06

    Traditionally, the plant Moringa oleifera Lam. (Moringaceae) is used for the treatment of ascites and rheumatism, while the dried seeds of the plant are used as an 'anti-allergic' agent. The aim of the study was to assess the efficacy of ethanolic extract of seeds from Moringa oleifera Lam. in experimental immune inflammation. Circulatory and splenic leukocyte counts, delayed-type hypersensitivity reactions and humoral antibody responses were measured in mice using SRBC as the antigen. In addition, macrophage phagocytosis was measured by the carbon clearance test. The extract dose-dependently (50, 100 and 200mg/kg) inhibited spleen weight as well as circulatory leukocyte and splenocyte counts. The delayed-type hypersensitivity reaction was significantly inhibited (PMoringa oleifera have immunosuppressive activity. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Flavored black ginseng exhibited antitumor activity via improving immune function and inducing apoptosis.

    Science.gov (United States)

    Chen, Guilin; Li, Haijun; Gao, Yugang; Zhang, Lianxue; Zhao, Yan

    2017-05-24

    The objective of this project was to examine saponin and carbohydrate conversion, and to evaluate the antitumor activity of a novel ready-to-eat flavored black ginseng (FBG). The results of chemical experiments showed that common saponins in ginseng such as ginsenoside Re, Rg1, Rb1, etc., are almost completely converted to rare saponins and aglycones such as ginsenoside Rg5, protopanaxadiol (PPD), etc., and non-reducing sugars such as starch are almost completely degraded into reducing sugars as affected by garlic juice and high temperature processing. Furthermore, pharmacological experimental results showed that this novel FBG could inhibit the growth of tumors in H22 tumor-bearing mice dose-dependently at the dosage of 250, 500 and 1000 mg kg-1; meanwhile, the results of ELISA, H&E staining, western blotting and qRT-PCR show that FBG could improve immune function and induce tumor cell apoptosis.

  20. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity

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    Kaname Nosaki

    2016-01-01

    Full Text Available Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.

  1. Estrogen receptor signal in regulation of B cell activation during diverse immune responses.

    Science.gov (United States)

    Asaba, Josaine; Bandyopadhyay, Mausumi; Kindy, Mark; Dasgupta, Subhajit

    2015-11-01

    The role of signalling through oestrogen receptors (ERs) in the regulation of B cell activation is an area of growing importance not only in terms protective immunity but also in the determination of the mechanisms of the onset of autoimmune disorders and cancers. The mode of signalling action of this single chain nuclear receptor protein molecule depends on its ability to bind to the promoters of Pax5, HOXC4 and apolipoprotein B RNA-editing enzyme activation-induced cytidine deaminase (AID) genes. ER-mediated transcriptional regulation induces class switch recombination of the immunoglobulin heavy chain variable (VH) to DH-JH genes and somatic hypermutation in developing B cells. The mode of action of ER is associated with BCR-signal pathways that involve the regulator proteins BAFF and APRIL. Additionally, the plasma membrane-bound G protein-coupled oestrogen receptor-1 (GEPR1) directs diverse cell signalling events in B cells that involve the MAPK pathways. These signals are immensely important during progenitor and precursor B cell activation. We have focused our goals on the medicinal aspects of ER-signalling mechanisms and their effects on polyclonal B cell activation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. A lipoprotein family from Mycoplasma fermentans confers host immune activation through Toll-like receptor 2.

    Science.gov (United States)

    Seya, Tsukasa; Matsumoto, Misako

    2002-08-01

    Mycoplasma have been reported to be associated with human diseases. Three forms of a mycoplasma lipopeptide/protein with the ability to modulate the host immune system were independently identified and named macrophage-activating lipopeptide 2 (MALP-2), P48 and M161Ag (identical to MALP-404). Although these molecules had polypeptides of different sizes, they exerted similar immunomodulatory effects on macrophages/dendritic cells, such as cytokine induction, NO production and maturation of antigen-presenting cells (APCs). M161Ag exhibited complement-activating ability and bound macrophages via complement C3b/C3bi and their receptors. The diacylated N-terminal palmitates were involved in these activities. Toll-like receptor 2 (TLR2) was found to be responsible for these functional features of these mycoplasma products, except for complement activation. Here, we summarize the functional properties of this family of proteins, namely pathogen-associated molecular pattern (PAMP) and discuss its relationship to the reported pathogenesis of latent mycoplasma infection.

  3. Invasive Haemophilus influenzae Type b (Hib) Infections in Children with Cancer in the Era of Infant Hib Immunization Programs (1991-2014): A Report from the Canadian Immunization Monitoring Program Active.

    Science.gov (United States)

    McNair, Joanne; Smith, Alyssa; Bettinger, Julie A; Vaudry, Wendy; Tan, Ben; Desai, Shalini; Halperin, Scott A; Top, Karina A

    2017-12-01

    We studied the epidemiology of Haemophilus influenzae type b (Hib) infections among children with cancer admitted to Canadian pediatric hospitals. From 1991-2014, 13 cases among children with cancer were identified through active surveillance. Average age was 6.7 years. Six of 7 cases eligible for infant immunization were age-appropriately immunized (vaccine failures). Children with cancer may benefit from booster Hib immunization.

  4. Th2 biased immune response in cases with active Mycobacterium tuberculosis infection and tuberculin anergy.

    Science.gov (United States)

    Balikó, Z; Szereday, L; Szekeres-Bartho, J

    1998-11-01

    This study was aimed at investigating the immunologic relationship between cytokine production pattern and tuberculin negativity in patients with active Mycobacterium tuberculosis infection. After classifying patients by the extent of pulmonary involvement and the size of the tuberculin reaction, we evaluated the rate of cytokine positivity in peripheral blood to determine whether there is a characteristic cellular immune reaction pattern which could partly explain the tuberculin negativity in some of these cases. The significance of tuberculin anergy occurring in some cases with M. tuberculosis infection is still not clear. We investigated the ratio of IL- 4, IL-10, IL-12, CD-4, CD-8 expressing lymphocytes in the peripheral blood of patients with active M. tuberculosis infection and correlated the percentage of the reactive cells with the positivity or negativity of tuberculin skin reactions. Twenty-eight patients were included in the study, with 11 healthy volunteers serving as controls. 10 ml of venous blood was drawn before starting anti-mycobacterial treatment. A tuberculin skin test was performed, introducing intracutaneously 5 TU PPD on the forearm with results evaluated after 72 h. Consistent with the reactivity or non-reactivity of the tuberculin skin test, we found a significantly higher ratio of IL-4 and IL-10 positive lymphocytes and a significantly lower ratio of IL-12 in the peripheral blood of patients with tuberculin anergy than in that of tuberculin positive patients or healthy donors. There was no difference in the ratio of the CD-4 CD-8 positive lymphocytes among the three groups. To evaluate whether the differences could be explained by the degree of pulmonary tubercular involvement, we classified the patients into three groups according to the extent and type of X-ray findings. Seven out of eight tuberculin negative patients were classified as grade III, whereas in the tuberculin positive group only seven out of 20 fell in this category. There

  5. Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior.

    Science.gov (United States)

    Ronovsky, Marianne; Berger, Stefanie; Zambon, Alice; Reisinger, Sonali N; Horvath, Orsolya; Pollak, Arnold; Lindtner, Claudia; Berger, Angelika; Pollak, Daniela D

    2017-07-01

    Gestational infection is increasingly being recognized for its involvement as causative mechanism in severe developmental brain abnormalities and its contribution to the pathogenesis of psychopathologies later in life. First observations in the widely accepted maternal immune activation (MIA) model based upon the systemic administration of the viral mimetic Polyinosinic:polycytidylic acid (poly(I:C)) have recently suggested a transmission of behavioral and transcriptional traits across generations. Although maternal care behavior (MCB) is known as essential mediator of the transgenerational effects of environmental challenges on offspring brain function and behavior, the possible propagation of alterations of MCB resulting from MIA to following generations has not yet been examined. Here we show that poly(I:C) stimulation at embryonic day 12.5 (E12.5) leads to aberrant MCB and that this effect is transmitted to the female F1 offspring. The transgenerational effects on MCB are paralleled by enhanced depression-like behavior in the second generation F2 offspring with contributions of both maternal and paternal heritages. Examination of offspring hippocampal expression of genes known as targets of MCB and relevant for ensuing non-genetic transmission of altered brain function and behavior revealed transgenerationally conserved and modified expressional patterns in the F1 and F2 generation. Collectively these data firstly demonstrate the transgenerational transmission of the impact of gestational immune activation on the reproductive care behavior of the mother. Behavioral and molecular characteristics of first and second generation offspring suggest transgenerationally imprinted consequences of gestational infection on psychopathological traits related to mood disorders which remain to be examined in future cross-fostering experiments. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  6. The plant virus Tomato Spotted Wilt Tospovirus activates the immune system of its main insect vector, Frankliniella occidentalis.

    Science.gov (United States)

    Medeiros, Ricardo B; Resende, Renato de O; de Avila, Antonio Carlos

    2004-05-01

    Tospoviruses have the ability to infect plants and their insect vectors. Tomato spotted wilt virus (TSWV), the type species in the Tospovirus genus, infects its most important insect vector, Frankliniella occidentalis, the western flower thrips (WFT). However, no detrimental effects on the life cycle or cytopathological changes have been reported in the WFT after TSWV infection, and relatively few viral particles can be observed even several days after infection. We hypothesized that TSWV infection triggers an immune response in the WFT. Using subtractive cDNA libraries to probe WFT DNA macroarrays, we found that the WFT's immune system is activated by TSWV infection. The activated genes included (i) those encoding antimicrobial peptides, such as defensin and cecropin; (ii) genes involved in pathogen recognition, such as those encoding lectins; (iii) those encoding receptors that activate the innate immune response, such as Toll-3; and (iv) those encoding members of signal transduction pathways activated by Toll-like receptors, such as JNK kinase. Transcriptional upregulation of these genes after TSWV infection was confirmed by Northern analysis, and the kinetics of the immune response was measured over time. Several of the detected genes were activated at the same time that viral replication was first detected by reverse transcription-PCR. To our knowledge, this is the first report of the activation of an insect vector immune response by a plant virus. The results may lead to a better understanding of insects' immune responses against viruses and may help in the future development of novel control strategies against plant viruses, as well as human and animal viruses transmitted by insect vectors.

  7. Atividade funcional neutrofílica em cabras com mastite induzida experimentalmente por Staphylococcus aureus e suplementadas com vitamina E (acetato DL-a-tocoferol Neutrophilic function activity in goats with mastitis experimentally induced by Staphylococcus aureus and supplemented with vitamin E (acetate DL-a-tocopherol

    Directory of Open Access Journals (Sweden)

    S.T.A. Lopes

    2003-10-01

    Full Text Available Avaliou-se a função neutrofílica em cabras com mastite por Staphylococcus aureus, induzida experimentalmente, suplementadas com vitamina E (acetato DL-a-tocoferol. Foram utilizadas 14 cabras gestantes da raça Saanen, com idades entre 8 e 12 meses e com cultura bacteriológica do leite negativa. Sete cabras receberam 2000UI de vitamina E, via intramuscular, no dia do parto e no sétimo dia pós-parto. As outras sete não foram medicadas. No 10º dia pós-parto, os dois grupos foram inoculados com 300 unidades formadoras de colônias de Staphylococcus aureus, cepa ATCC 25923, diluídas em 10ml de solução fisiológica, na glândula mamária esquerda. A função de neutrófilos sangüíneos foi medida pelo teste nitroazul tetrazólio (NBT, antes da inoculação, no momento da infecção e 12, 24, 48 e 72 horas pós-infecção, quando foi instituído o tratamento intramamário com antimicrobiano, por três dias consecutivos. A colheita final de sangue foi realizada 48 horas após a última aplicação do medicamento. Amostras de sangue para determinação da vitamina E foram colhidas no dia do parto, no momento da infecção, 48 horas pós-infecção e 48 horas pós-tratamento e analisadas por cromatografia líquida de alta performance. Na prova não estimulada do NBT não foram verificadas diferenças entre grupos e entre momentos. Na prova estimulada do NBT (NBT-E houve diferença entre tratamentos às 12 e 72 horas pós-infecção, com valores mais elevados de NBT-E nos animais sem suplementação. Conclui-se que a suplementação com vitamina E reduz o percentual de neutrófilos NBT-E positivos.Neutrophil function in experimentally induced mastitis in goats, inoculated with Staphylococcus aureus supplemented and not supplemented with vitamin E (acetate DL-a-tocopherol was evaluated. Fourteen pregnant Saanen goats, between 8 and 12 months of age all negative in bacteriological milk cultures, were used. Seven goats were treated with 2,000 IU

  8. Abdominal obesity contributes to neurocognitive impairment in HIV-infected patients with increased inflammation and immune activation.

    Science.gov (United States)

    Sattler, Fred R; He, Jiaxiu; Letendre, Scott; Wilson, Cara; Sanders, Chelsea; Heaton, Robert; Ellis, Ronald; Franklin, Donald; Aldrovandi, Grace; Marra, Christina M; Clifford, David; Morgello, Susan; Grant, Igor; McCutchan, J Allen

    2015-03-01

    We tested our hypothesis that abdominal obesity when associated with increased levels of systemic and central nervous system immunoinflammatory mediators contributes to neurocognitive impairment (NCI). Cross-sectional. Six Academic Centers. One hundred fifty-two patients with plasma HIV RNA obesity, systemic inflammation (high IL-6), and immune activation in plasma (high sCD14) and CSF (high sCD40L). Abdominal obesity, inflammation, and central nervous system immune activation are potential therapeutic targets for NCI in HIV-positive patients.

  9. Ovarian response to pregnant mare serum gonadotropin and porcine pituitary extract in gilts actively immunized against gonadotropin releasing hormone.

    Science.gov (United States)

    Esbenshade, K L

    1987-12-01

    Two experiments were conducted to determine the effect of exogenous gonadotropins on follicular development in gilts actively immunized against gonadotropin releasing hormone (GnRH). Four gilts, which had become acyclic after immunization against GnRH, and four control gilts were given 1,000 IU pregnant mare serum gonadotropin (PMSG), while four additional control gilts were given saline. Control animals were prepuberal crossbred gilts averaging 100 kg body weight. Control gilts given saline had ovaries containing antral follicles (4 to 6 mm in diameter). Control gilts given PMSG exhibited estrus and their ovaries contained corpora hemorrhagica and corpora lutea. PMSG failed to stimulate follicular growth in gilts immunized against GnRH, and ovaries contained regressed corpora albicantia and small antral follicles (less than 1 mm in diameter). Concentrations of luteinizing hormone (LH) and estradiol-17 beta (E2) were non-detectable in gilts immunized against GnRH and given PMSG. In the second experiment, five gilts actively immunized against GnRH were given increasing doses of PMSG every third day until unilateral ovariectomy on d 50. PMSG failed to stimulate follicular growth, and concentrations of follicle stimulating hormone (FSH), E2 and LH were not detectable. Six weeks later, gilts were given a booster immunization and then were given 112 micrograms LH and 15 micrograms FSH intravenously every 6 h for 9 d. The remaining ovary was removed on d 10. Although LH and FSH concentrations were elevated, administration of gonadotropins did not stimulate follicular growth or increase E2 concentrations. These results indicate that neither PMSG or exogenous LH and FSH can induce E2 synthesis or sustain follicular development in gilts actively immunized against GnRH.

  10. Interleukin-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

    Science.gov (United States)

    Liu, Rebecca; Lauridsen, Holly M.; Amezquita, Robert A.; Pierce, Richard W.; Jane-wit, Dan; Fang, Caodi; Pellowe, Amanda S.; Kirkiles-Smith, Nancy C.; Gonzalez, Anjelica L.; Pober, Jordan S.

    2016-01-01

    A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multi-step process that involves sequential cell-cell interactions of circulating leukocytes with interleukin (IL)-1- or tumor necrosis factor-α (TNF)-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a pro-inflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, while neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA-seq analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media (CM) from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and also stimulate neutrophil production of pro-inflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs but not ECs can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondria outer membrane permeabilization and caspase 9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by CM from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space. PMID:27534549

  11. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study.

    Science.gov (United States)

    Cribbs, David H; Berchtold, Nicole C; Perreau, Victoria; Coleman, Paul D; Rogers, Joseph; Tenner, Andrea J; Cotman, Carl W

    2012-07-23

    This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer's disease (AD). In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. Unexpectedly, the extent of

  12. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

    Directory of Open Access Journals (Sweden)

    Cribbs David H

    2012-07-01

    Full Text Available Abstract Background This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD. Methods In a well-powered microarray study of young (20 to 59 years, aged (60 to 99 years, and AD (74 to 95 years cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Results Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%. In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets, with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc receptors and human

  13. Immune-enhancing activities of low molecular weight {beta}-glucan depolymerized by gamma irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Nak-Yun [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Byun, Eui-Hong [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Laboratory of Food Chemistry, Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 (Japan); Kwon, Sun-Kyu; Song, Beom-Seok; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Yoo, Young-Choon [Department of Microbiology, College of Medicine, Konyang University, Daejeon 302-718 (Korea, Republic of); Kim, Mee-Ree [Department of Food and Nutrition, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Lee, Ju-Woon [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of)], E-mail: sjwlee@kaeri.re.kr

    2009-07-15

    {beta}-glucans are structural cell wall polymers of many microorganisms and cereals which possess immunomodulatory properties and have been used in the food, cosmetic and medical industry. In our previous study, {beta}-glucan was depolymerized by gamma irradiation and leads to improve the solubility and viscosity. This study was carried out to evaluate the functional properties, mainly immune-enhancing activities of low molecular weight {beta}-glucan fragmented by gamma irradiation. The results showed that RAW 264.7 macrophage cell stimulation activities of irradiated {beta}-glucan were higher than that of non-irradiated {beta}-glucan. In addition, the oral administration of gamma-irradiated {beta}-glucan significantly increased the proliferation and cytokine (IFN-{gamma} and IL-2) release of spleen and Peyer's patch cells compared with non-irradiated {beta}-glucan. In conclusion, gamma irradiation could be used as an effective method for the production of depolymerized {beta}-glucan improved functional property such as immunomodulatory activity.

  14. Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer.

    Science.gov (United States)

    Parkes, Eileen E; Walker, Steven M; Taggart, Laura E; McCabe, Nuala; Knight, Laura A; Wilkinson, Richard; McCloskey, Karen D; Buckley, Niamh E; Savage, Kienan I; Salto-Tellez, Manuel; McQuaid, Stephen; Harte, Mary T; Mullan, Paul B; Harkin, D Paul; Kennedy, Richard D

    2017-01-01

    Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher's exact test P activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle-specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint-based therapies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. IL-25 Promotes Th2 Immunity Responses in Asthmatic Mice via Nuocytes Activation.

    Directory of Open Access Journals (Sweden)

    Chao Wang

    Full Text Available Interleukin-25 (IL-25 is a potent activator of type-2 immune responses, and is responsible for airway inflammation in asthma. Previous reports have shown that IL-25 expressed hyper-reactivity in an experimental mouse-model of asthma. In addition, the production of IL-13/IL-5 promoted by nuocytes induced airway inflammation. Thus, it has been questioned whether blocking IL-25 against its receptor IL-17BR could inhibit the expression of IL-13 and IL-5 via nuocytes, and further protect against inflammation in ovalbumin (OVA induced mouse-model of asthma.In this study, in order to investigate the correlation among IL-25, IL-5, IL-13 and nuocyte activities, we used OVA-sensitization and -challenging to induce the mouse model of asthma. The murine asthmatic model was validated by histology. The expressions of IL-5, IL-13 and IL-25 were detected by ELISA, quantitative real-time PCR, and western blotting of the lung tissue. Nuocyte activation was identified by the levels of ICOS (clone C398.4A and T1/ST2 (cloneDJ8 (acting as nuocytes surface markers in the bronchoalveolar lavage fluid (BALF. This, in turn, was done by means of flow cytometry. The expressions of IL-25, IL-5 and IL-13 in our murine model were detected in the BALF.The mice sensitized and challenged with OVA showed a high expression of IL-25 in both the mRNA and protein levels in lungs. The expressions of ICOS and T1/ST2 in BALF were increased. A significant correlation between IL-25 mRNA, protein, and other Th2-cell producing cytokines (such as IL-5 and IL-13 moreover were identified. Furthermore, when the asthmatic mice were treated with anti-IL-25, both the inflammatory cells' infiltration and the inflammatory cytokines' secretion were significantly decreased. The present findings indicate that IL-25 might be involved in a series of asthmatic immune responses, playing an important role in the increase of nuocytes, and that its activation is necessary in maintaining Th2 central memory and

  16. Identification of anti-CD98 antibody mimotopes for inducing antibodies with antitumor activity by mimotope immunization.

    Science.gov (United States)

    Saito, Misa; Kondo, Masahiro; Ohshima, Motohiro; Deguchi, Kazuki; Hayashi, Hideki; Inoue, Kazuyuki; Tsuji, Daiki; Masuko, Takashi; Itoh, Kunihiko

    2014-04-01

    A mimotope is an antibody-epitope-mimicking peptide retrieved from a phage display random peptide library. Immunization with antitumor antibody-derived mimotopes is promising for inducing antitumor immunity in hosts. In this study, we isolated linear and constrained mimotopes from HBJ127, a tumor-suppressing anti-CD98 heavy chain mAb, and determined their abilities for induction of antitumor activity equal to that of the parent antibody. We detected elevated levels of antipeptide responses, but failed to detect reactivity against native CD98-expressing HeLa cells in sera of immunized mice. Phage display panning and selection of mimotope-immunized mouse spleen-derived antibody Fab library showed that HeLa cell-reactive Fabs were successfully retrieved from the library. This finding indicates that native antigen-reactive Fab clones represented an undetectable minor population in mimotope-induced antibody repertoire. Functional and structural analysis of retrieved Fab clones revealed that they were almost identical to the parent antibody. From these results, we confirmed that mimotope immunization was promising for retrieving antitumor antibodies equivalent to the parent antibody, although the co-administration of adjuvant compounds such as T-cell epitope peptides and Toll-like receptor 4 agonist peptides is likely to be necessary for inducing stronger antitumor immunity than mimotope injection alone. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  17. Isolation of diploid baker's yeast capable of strongly activating immune cells and analyses of the cell wall structure.

    Science.gov (United States)

    Takada, Yuki; Mizobuchi, Ayano; Kato, Takayuki; Kasahara, Emiko; Ito, Chinatsu; Watanabe, Hajime; Kanzaki, Ken; Kitagawa, Seiichi; Tachibana, Taro; Azuma, Masayuki

    2014-01-01

    Diploid baker's yeast capable of strongly activating a mouse macrophage was constructed based on haploid mutant AQ-37 obtained previously. The obtained strain BQ-55 activated also human immune cells. To clarify a factor for the activation, the cell wall structure, especially the β-glucan structure, was analyzed, suggesting that the length of branching, β-1,6-glucan, may be one of the factors.

  18. Poly(I:C)-Encapsulating Nanoparticles Enhance Innate Immune Responses to the Tuberculosis Vaccine Bacille Calmette-Guérin (BCG) via Synergistic Activation of Innate Immune Receptors.

    Science.gov (United States)

    Speth, Martin T; Repnik, Urska; Müller, Elisabeth; Spanier, Julia; Kalinke, Ulrich; Corthay, Alexandre; Griffiths, Gareth

    2017-11-06

    The attenuated live vaccine strain bacille Calmette-Guérin (BCG) is currently the only available vaccine against tuberculosis (TB), but is largely ineffective against adult pulmonary TB, the most common disease form. This is in part due to BCG's ability to interfere with the host innate immune response, a feature that might be targeted to enhance the potency of this vaccine. Here, we investigated the ability of chitosan-based nanoparticles (pIC-NPs) containing polyinosinic-polycytidylic acid (poly(I:C)), an inducer of innate immunity via Toll-like receptor 3 (TLR3), to enhance the immunogenicity of BCG in mouse bone marrow derived macrophages (BMDM) in vitro. Incorporation of poly(I:C) into NPs protected it against degradation by ribonucleases and increased its uptake by mouse BMDM. Whereas soluble poly(I:C) was ineffective, pIC-NPs strongly enhanced the proinflammatory immune response of BCG-infected macrophages in a synergistic fashion, as evident by increased production of cytokines and induction of nitric oxide synthesis. Using macrophages from mice deficient in key signaling molecules involved in the pathogen recognition response, we identified combined activation of MyD88- and TRIF-dependent TLR signaling pathways to be essential for the synergistic effect between BCG and NP. Moreover, synergy was strongly dependent on the order of the two stimuli, with TLR activation by BCG functioning as the priming event for the subsequent pIC-NP stimulus, which acted through an auto-/paracrine type I interferon (IFN) feedback loop. Our results provide a foundation for a promising new approach to enhance BCG-vaccine immunogenicity by costimulation with NPs. They also contribute to a molecular understanding of the observed synergistic interaction between the pIC-NPs and BCG vaccine.

  19. Innate immunity against molecular mimicry: Examining galectin-mediated antimicrobial activity.

    Science.gov (United States)

    Arthur, Connie M; Patel, Seema R; Mener, Amanda; Kamili, Nourine A; Fasano, Ross M; Meyer, Erin; Winkler, Annie M; Sola-Visner, Martha; Josephson, Cassandra D; Stowell, Sean R

    2015-12-01

    Adaptive immunity provides the unique ability to respond to a nearly infinite range of antigenic determinants. Given the inherent plasticity of the adaptive immune system, a series of tolerance mechanisms exist to reduce reactivity toward self. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity: the ability to recognize microbes that look like self. As a variety of microbes decorate themselves in self-like carbohydrate antigens and tolerance reduces the ability of adaptive immunity to react with self-like structures, protection against molecular mimicry likely resides within the innate arm of immunity. In this review, we will explore the potential consequences of microbial molecular mimicry, including factors within innate immunity that appear to specifically target microbes expressing self-like antigens, and therefore provide protection against molecular mimicry. © 2015 WILEY Periodicals, Inc.

  20. Spatio-temporal regulation of Hsp90-ligand complex leads to immune activation.

    Directory of Open Access Journals (Sweden)

    Yasuaki eTamura

    2016-05-01

    Full Text Available Hsp90 is the most abundant cytosolic HSP and is known to act as a molecular chaperone. We found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived dendritic cells and induced peptide-specific cytotoxic T lymphocytes. Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5+, EEA1+ static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through a endosome-recycling pathway. We also found that extracellular Hsp90 complexed with CpG-A or self-DNA stimulates production of a large amount of IFN-α from pDCs via static early endosome targeting. Thus, extracellular Hsp90 can target the antigen or nucleic acid to a static early endosome by spatio-temporal regulation. Moreover, we showed that Hsp90 associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Hsp90 inhibitor, geldanamycin derivative inhibited the Hsp90 association with TLR7/9, resulting in inhibition IFN-α production, leading to improvement of SLE symptoms. Interstingly, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Thus, Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases. We will discuss how spatio-temporal regulation of Hsp90-ligand complexes within antigen-presenting cells affects the innate immunity and adaptive immunity.

  1. Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder.

    Directory of Open Access Journals (Sweden)

    David N Ruskin

    Full Text Available Prenatal factors influence autism spectrum disorder (ASD incidence in children and can increase ASD symptoms in offspring of animal models. These may include maternal immune activation (MIA due to viral or bacterial infection during the first trimesters. Unfortunately, regardless of ASD etiology, existing drugs are poorly effective against core symptoms. For nearly a century a ketogenic diet (KD has been used to treat seizures, and recent insights into mechanisms of ASD and a growing recognition that immune/inflammatory conditions exacerbate ASD risk has increased interest in KD as a treatment for ASD. Here we studied the effects of KD on core ASD symptoms in offspring exposed to MIA. To produce MIA, pregnant C57Bl/6 mice were injected with the viral mimic polyinosinic-polycytidylic acid; after weaning offspring were fed KD or control diet for three weeks. Consistent with an ASD phenotype of a higher incidence in males, control diet-fed MIA male offspring were not social and exhibited high levels of repetitive self-directed behaviors; female offspring were unaffected. However, KD feeding partially or completely reversed all MIA-induced behavioral abnormalities in males; it had no effect on behavior in females. KD-induced metabolic changes of reduced blood glucose and elevated blood ketones were quantified in offspring of both sexes. Prior work from our laboratory and others demonstrate KDs improve relevant behaviors in several ASD models, and here we demonstrate clear benefits of KD in the MIA model of ASD. Together these studies suggest a broad utility for metabolic therapy in improving core ASD symptoms, and support further research to develop and apply ketogenic and/or metabolic strategies in patients with ASD.

  2. Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II–Induced Hypertension

    Science.gov (United States)

    Xiao, Liang; Kirabo, Annet; Wu, Jing; Saleh, Mohamed A.; Zhu, Linjue; Wang, Feng; Takahashi, Takamune; Loperena, Roxana; Foss, Jason D.; Mernaugh, Raymond L.; Chen, Wei; Roberts, Jackson; Osborn, John W.; Itani, Hana A.; Harrison, David G.

    2015-01-01

    Rationale Inflammation and adaptive immunity plays a crucial role in the development of hypertension. Angiotensin II and likely other hypertensive stimuli activate the central nervous system and promote T cell activation and end-organ damage in peripheral tissues. Objective To determine if renal sympathetic nerves mediate renal inflammation and T cell activation in hypertension. Methods and Results Bilateral renal denervation (RDN) using phenol application to the renal arteries reduced renal norepinephrine (NE) levels and blunted angiotensin II induced hypertension. Bilateral RDN also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells and both CD4+ and CD8+ T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria and nephrinuria. Unilateral RDN, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of IL-1α, IL-1β, and IL-6 from splenic dendritic cells. NE also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II-treated mice primed T cell activation and hypertension in recipient mice. RDN prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. Conclusions Renal sympathetic nerves contribute to dendritic cell activation, subsequent T cell infiltration and end-organ damage in the kidney in the development of hypertension. PMID:26156232

  3. Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Xiao, Liang; Kirabo, Annet; Wu, Jing; Saleh, Mohamed A; Zhu, Linjue; Wang, Feng; Takahashi, Takamune; Loperena, Roxana; Foss, Jason D; Mernaugh, Raymond L; Chen, Wei; Roberts, Jackson; Osborn, John W; Itani, Hana A; Harrison, David G

    2015-08-28

    Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues. To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension. Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II-induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4+ and CD8+ T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1β, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II-treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension. © 2015 American Heart Association, Inc.

  4. Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury.

    Science.gov (United States)

    Yue, Shi; Zhou, Haoming; Wang, Xuehao; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Zhai, Yuan

    2017-05-01

    Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. Copyright © 2017 by The American Association of Immunologists, Inc.

  5. The gateway theory: how regional neural activation creates a gateway for immune cells via an inflammation amplifier.

    Science.gov (United States)

    Ogura, Hideki; Arima, Yasunobu; Kamimura, Daisuke; Murakami, Masaaki

    2013-01-01

    The inflammation amplifier, a nuclear factor-kappa B (NF-kB)feedback loop in non-immune cells including fibroblasts and endothelial cells, describes how NF-kB-mediated transcriptions are enhanced to induce the inflammation in the presence of signal Tranducer and Activator of Transcription 3 (STAT3) activation. It was originally discovered in rheumatoid arthritis and multiple sclerosis mouse models and has since been shown to be associated with various human diseases and disorders including autoimmune diseases, metabolic syndromes, neurodegenerative diseases, and other inflammatory diseases. The amplifier begins with IL-17, which acts as the main signal to express NF-kB-mediated transcriptions, and IL-6, an NF-kB target, which functions as a fuel for the inflammation amplifier. Indeed, other NF-kB targets including various chemokines also act as effector molecules that cause local accumulation of various immune cells and subsequent inflammation. Through extensive studies in the multiple sclerosis model experimental autoimmune encephalomyelitis, we recently demonstrated that regional neural activation induces excess activation of the inflammation amplifier at specific blood vessels in the fifth lumbar cord, creating a gateway for immune cells to enter the central nervous system (CNS). We thus propose the gateway theory to describe how regional neural activation enables immune cells to enter the CNS from the blood and argue that this theory might provide novel therapeutic targets for inflammatory diseases and disorders.

  6. Effects of active immunization against myostatin on carcass quality and expression of the myostatin gene in pigs.

    Science.gov (United States)

    Long, Ding-biao; Zhang, Ke-ying; Chen, Dai-wen; Ding, Xue-mei; Yu, Bing

    2009-10-01

    The study was conducted to investigate the effects of active immunization against myostatin on the titer of myostatin antibody, carcass evaluation, activity of creatine kinase and the expression of the myostatin gene in pigs. Eighteen pigs were allotted into three groups (six pigs per group), and pigs in treatment 1, 2 and 3 were immunized with physiological saline, 1 mg or 4 mg myostatin per pig, respectively. Six pigs were killed by electrical stunning followed by exsanguination at BW of 100 kg. The results indicated that the titer of myostatin antibody was increased in treated groups compared to the control group on day 42 (P activity of pigs treated with 1 mg and 4 mg myostatin was lower than the control group. The immunization of myostatin significantly decreased the myostatin gene expression levels in muscle. It was concluded that optimal active immunization against myostatin could increase the content of myostatin antibody, suppress the activity of creatine kinase and the expression of myostatin gene, and therefore improve the carcass lean percentage for pigs.

  7. Innate and adaptive immune responses both contribute to pathological CD4 T cell activation in HIV-1 infected Ugandans.

    Directory of Open Access Journals (Sweden)

    Michael A Eller

    2011-04-01

    Full Text Available HIV-1 disease progression is associated with persistent immune activation. However, the nature of this association is incompletely understood. Here, we investigated immune activation in the CD4 T cell compartment of chronically HIV-1 infected individuals from Rakai, Uganda. Levels of CD4 T cell activation, assessed as co-expression of PD-1, CD38 and HLA-DR, correlated directly to viral load and inversely to CD4 count. Deeper characterization of these cells indicated an effector memory phenotype with relatively frequent expression of Ki67 despite their PD-1 expression, and levels of these cells were inversely associated with FoxP3+ regulatory T cells. We therefore use the term deregulated effector memory (DEM cells to describe them. CD4 T cells with a DEM phenotype could be generated by antigen stimulation of recall responses in vitro. Responses against HIV-1 and CMV antigens were enriched among the DEM CD4 T cells in patients, and the diverse Vβ repertoire of DEM CD4 T cells suggested they include diverse antigen-specificities. Furthermore, the levels of DEM CD4 T cells correlated directly to soluble CD14 (sCD14 and IL-6, markers of innate immune activation, in plasma. The size of the activated DEM CD4 T cell subset was predictive of the rate of disease progression, whereas IL-6 was only weakly predictive and sCD14 was not predictive. Taken together, these results are consistent with a model where systemic innate immune activation and chronic antigen stimulation of adaptive T cell responses both play important roles in driving pathological CD4 T cell immune activation in HIV-1 disease.

  8. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.

    Directory of Open Access Journals (Sweden)

    Juandy Jo

    2014-06-01

    Full Text Available The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright mucosal-associated invariant T (MAIT and CD56(Bright NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.

  9. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.

    Science.gov (United States)

    Jo, Juandy; Tan, Anthony T; Ussher, James E; Sandalova, Elena; Tang, Xin-Zi; Tan-Garcia, Alfonso; To, Natalie; Hong, Michelle; Chia, Adeline; Gill, Upkar S; Kennedy, Patrick T; Tan, Kai Chah; Lee, Kang Hoe; De Libero, Gennaro; Gehring, Adam J; Willberg, Christian B; Klenerman, Paul; Bertoletti, Antonio

    2014-06-01

    The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.

  10. Structural basis of RNA recognition and activation by innate immune receptor RIG-I

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Fuguo; Ramanathan, Anand; Miller, Matthew T.; Tang, Guo-Qing; Gale, Jr., Michael; Patel, Smita S.; Marcotrigiano, Joseph (Rutgers); (RWJ-Med); (UW-MED)

    2012-05-29

    Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds)RNA with or without a 5'-triphosphate (ppp), by single-stranded RNA marked by a 5'-ppp and by polyuridine sequences. Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer. The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5'-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the RD for RNA binding, and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has a broader impact on other areas of biology, including

  11. Effects of active immunization against growth-hormone releasing factor on puberty and reproductive development in gilts.

    Science.gov (United States)

    Swanchara, K W; Armstrong, J D; Britt, J H

    1999-07-01

    Hormones within the somatotropin cascade influence several physiological traits, including growth and reproduction. Active immunization against growth hormone-releasing factor (GRFi) initiated at 3 or 6 mo of age decreased weight gain, increased deposition of fat, and delayed puberty in heifers. Two experiments were conducted to investigate the effects of GRFi on puberty and subsequent ovulation rate in gilts. Crossbred gilts were actively immunized against GRF-(1-29)-(Gly)2-Cys-NH2 conjugated to human serum albumin (GRFi) or against human serum albumin alone (HSAi). In Exp. 1, gilts were immunized against GRF (n = 12) or HSA (n = 12) at 92 +/- 1 d of age. At 191 d of age, antibody titers against GRF were greater (P gilts. The GRFi decreased (P gilts were immunized against GRF (n = 35) or HSA (n = 35) at 35 +/- 1 d of age. The GRFi at 35 d of age did not alter the number of surface follicles or uterine weight between 93 and 102 d of age, but GRFi decreased (P Immunization against GRF reduced (P gilts, but ovulation rate was lower (P gilts. Thus, GRFi at 92 or 35 d of age decreased serum ST, IGF-I, and BW in prepubertal gilts without altering age of puberty. However, GRFi at 35 d of age, but not 92 d of age, decreased ovulation rate. These results indicate that alterations in the somatotropic axis at 1 mo of age can influence reproductive development in pubertal gilts.

  12. Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis.

    Science.gov (United States)

    Xin, Hong

    2016-01-04

    We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Titanium dioxide nanoparticles stimulate sea urchin immune cell phagocytic activity involving TLR/p38 MAPK-mediated signalling pathway

    Science.gov (United States)

    Pinsino, Annalisa; Russo, Roberta; Bonaventura, Rosa; Brunelli, Andrea; Marcomini, Antonio; Matranga, Valeria

    2015-01-01

    Titanium dioxide nanoparticles (TiO2NPs) are one of the most widespread-engineered particles in use for drug delivery, cosmetics, and electronics. However, TiO2NP safety is still an open issue, even for ethical reasons. In this work, we investigated the sea urchin Paracentrotus lividus immune cell model as a proxy to humans, to elucidate a potential pathway that can be involved in the persistent TiO2NP-immune cell interaction in vivo. Morphology, phagocytic ability, changes in activation/inactivation of a few mitogen-activated protein kinases (p38 MAPK, ERK), variations of other key proteins triggering immune response (Toll-like receptor 4-like, Heat shock protein 70, Interleukin-6) and modifications in the expression of related immune response genes were investigated. Our findings indicate that TiO2NPs influence the signal transduction downstream targets of p38 MAPK without eliciting an inflammatory response or other harmful effects on biological functions. We strongly recommend sea urchin immune cells as a new powerful model for nano-safety/nano-toxicity investigations without the ethical normative issue. PMID:26412401

  14. Effects of aliphatic polyesters on activation of the immune system: studies on macrophages.

    Science.gov (United States)

    Scislowska-Czarnecka, A; Pamula, E; Tlalka, A; Kolaczkowska, E

    2012-01-01

    There is a constant search for biodegradable polymers with biocompatible characteristics. However, the reported materials are rarely tested for their immunostimulatory properties, which is an important issue as immune cells activated by the polymers might cause their rejection and lead to further injury to the host tissues. Therefore, the aim of the present study was to determine if biodegradable polymers are able to activate RAW 264.7 macrophages. Aliphatic polyesters, poly(L-lactide) (PLLA), poly(L-lactide-co-trimethylene carbonate) (PLTMC), poly(glycolide-co-L-lactide) (PGLA), poly(glycolide-co-L-lactide-co-ε-caprolactone) (PGLCap) and poly(glycolide-co-ε-caprolactone) (PGCap), processed into foils by slip-casting, were characterized in terms of their structure ((1)H-NMR, GPC, DSC) and surface properties (chemical composition, water contact angle, surface free energy, topography and roughness). RAW 264.7 cells were cultured on the materials for 3 or 5 days and their adherence, numbers of apoptotic/necrotic cells, as well as production of several cytokines/chemokines and other inflammation-related molecules (matrix metalloproteinases, nitric oxide) was evaluated. The study demonstrated that PLLA and PGLA did not influence macrophage activation and survival. In contrast, PLTMC, PGLCap and PGCap significantly decreased macrophage adherence, increased ratio of apoptosis and up-regulated synthesis/release of numerous inflammatory mediators. Thus, the latter materials might initiate an undesired inflammatory reaction. The above effects of the polymers were attributed to their high hydrophobicity and low polarity due to the presence of ε-caproyl blocks (PGLCap and PGCap), and/or high flexibility and susceptibility to mechanical deformation due to low glasstransition temperature (PLTMC, PGLCap and PGCap). In conclusion, while PLLA and PGLA do not affect macrophage functioning, the other materials (PLTMC, PGLCap, PGCap) up-regulate macrophage activity.

  15. Mutations in FLS2 Ser-938 Dissect Signaling Activation in FLS2-Mediated Arabidopsis Immunity

    Science.gov (United States)

    Cao, Yangrong; Aceti, David J.; Sabat, Grzegorz; Song, Junqi; Makino, Shin-ichi; Fox, Brian G.; Bent, Andrew F.

    2013-01-01

    FLAGELLIN-SENSING 2 (FLS2) is a leucine-rich repeat/transmembrane domain/protein kinase (LRR-RLK) that is the plant receptor for bacterial flagellin or the flagellin-derived flg22 peptide. Previous work has shown that after flg22 binding, FLS2 releases BIK1 kinase and homologs and associates with BAK1 kinase, and that FLS2 kinase activity is critical for FLS2 function. However, the detailed mechanisms for activation of FLS2 signaling remain unclear. The present study initially identified multiple FLS2 in vitro phosphorylation sites and found that Serine-938 is important for FLS2 function in vivo. FLS2-mediated immune responses are abolished in transgenic plants expressing FLS2S938A, while the acidic phosphomimic mutants FLS2S938D and FLS2S938E conferred responses similar to wild-type FLS2. FLS2-BAK1 association and FLS2-BIK1 disassociation after flg22 exposure still occur with FLS2S938A, demonstrating that flg22-induced BIK1 release and BAK1 binding are not sufficient for FLS2 activity, and that Ser-938 controls other aspects of FLS2 activity. Purified BIK1 still phosphorylated purified FLS2S938A and FLS2S938D mutant kinase domains in vitro. Phosphorylation of BIK1 and homologs after flg22 exposure was disrupted in transgenic Arabidopsis thaliana plants expressing FLS2S938A or FLS2D997A (a kinase catalytic site mutant), but was normally induced in FLS2S938D plants. BIK1 association with FLS2 required a kinase-active FLS2, but FLS2-BAK1 association did not. Hence FLS2-BIK1 dissociation and FLS2-BAK1 association are not sufficient for FLS2-mediated defense activation, but the proposed FLS2 phosphorylation site Ser-938 and FLS2 kinase activity are needed both for overall defense activation and for appropriate flg22-stimulated phosphorylation of BIK1 and homologs. PMID:23637603

  16. Detection of Entamoeba histolytica in experimentally induced amoebic liver abscess: comparison of three staining methods

    OpenAIRE

    Tan Zi Ning; Wong Weng Kin; Shaymoli Mustafa; Arefuddin Ahmed; Rahmah Noordin; Tan Gim Cheong; Olivos-Garcia Alfonso; Lim Boon Huat

    2012-01-01

    Objective: To compare the efficacy of three different tissue stains, namely haematoxylin and eosin (H&E), periodic-acid Schiff (PAS) and immunohistochemical (IHC) stains for detection of Entamoeba histolytica (E. histolytica) trophozoites in abscessed liver tissues of hamster. Methods: Amoebic liver abscess was experimentally induced in a hamster by injecting 1 × 106 of axenically cultured virulent E. histolytica trophozoites (HM1-IMSS strain) into the portal vein. After a week post-inocul...

  17. Changes in thermal nociceptive responses in dairy cows following experimentally induced Esherichia coli mastitis

    DEFF Research Database (Denmark)

    Rasmussen, Ditte B.; Fogsgaard, Katrine; Røntved, Christine Maria

    2011-01-01

    Mastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS......) in dairy cows with experimentally induced Escherichia coli mastitis, and correlate behavioral changes in nociceptive responses to clinical and paraclinical variables....

  18. The effect of various drugs on experimentally induced ulcers in immobilized rats

    Science.gov (United States)

    Schramm, H.

    1978-01-01

    Experiments related to the importance of functional disorders in the central nervous system in connection with stomach diseases were performed on Wistar rats. Assuming that severe mental strains may be triggering factors for such disorders, testing of the effects of different drugs on experimentally induced ulcers in these rats was done. The immobilization method described by Bonfils was used. Particular importance was placed on the sex related difference which appeared.

  19. Neuropsychological consequences of experimentally-induced anxiety on working memory performance

    OpenAIRE

    Dunger, Warren

    2016-01-01

    Many theories addressing the complex anxiety-cognition interaction are built upon the notion that working memory is vulnerable to the effects of anxiety. However, most research has utilised studies of trait anxiety which does not allow direct inferences to be made between affect and cognitive performance, or exclude confounds such as pre-existing individual differences. As a result, a systematic review was undertaken to explore the neuropsychological consequences of experimentally-induced sta...

  20. Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice

    Science.gov (United States)

    Sellon, Rance K.; Tonkonogy, Susan; Schultz, Michael; Dieleman, Levinus A.; Grenther, Wetonia; Balish, Ed; Rennick, Donna M.; Sartor, R. Balfour

    1998-01-01

    Mice with targeted deletion of the gene for interleukin-10 (IL-10) spontaneously develop enterocolitis when maintained in conventional conditions but develop only colitis when kept in specific-pathogen-free (SPF) environments. This study tested the hypothesis that enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in IL-10-deficient mice. IL-10-deficient mice were maintained in either SPF conditions or germfree conditions or were populated with bacteria known to cause colitis in other rodent models. IL-10-deficient mice kept in SPF conditions developed colitis in all segments of the colon (cecum and proximal and distal colon). These mice exhibited immune system activation as evidenced by increased expression of CD44 on CD4+ T cells; increased mesenteric lymph node cell numbers; and increased production of immunoglobulin A (IgA), IgG1, and IL-12 p40 from colon fragment cultures. Mice populated with bacterial strains, including Bacteroides vulgatus, known to induce colitis in other rodent models had minimal colitis. Germfree IL-10-deficient mice had no evidence of colitis or immune system activation. We conclude therefore that resident enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in IL-10-deficient mice. PMID:9784526

  1. Female Choice Reveals Terminal Investment in Male Mealworm Beetles, Tenebrio molitor, after a Repeated Activation of the Immune System

    Science.gov (United States)

    Krams, I; Daukšte, J; Kivleniece, I; Krama, T; Rantala, MJ; Ramey, G; Šauša, L

    2011-01-01

    Increasing evidence suggests that secondary sexual traits reflect immunocompetence of males in many animal species. This study experimentally investigated whether a parasite-like immunological challenge via a nylon implant affects sexual attractiveness of males in Tenebrio molitor L. (Coleoptera: Tenebrionidae) Although a single immunological challenge significantly reduced sexual attractiveness and locomotor activity of males, it had no adverse effect on their survival. A second immune challenge of the same males increased their attractiveness. However, it was found that the repeated challenge significantly reduced locomotor activity of males and caused higher mortality. This result indicates terminal investment on sexual signaling, which is supposedly based on a trade-off between pheromone production and energy expenditures needed for such activities as recovery of immune system and locomotor activity. When the third implantation was carried out in the same group of males, melanization of nylon implants was found to be lower in more attractive than in less attractive males. This suggests that males that became sexually attractive after the second immune challenge did not invest in recovery of their immune system. PMID:21864151

  2. Immune activation is inversely related to, but does not cause variation in androgen levels in a cichlid fish species

    NARCIS (Netherlands)

    Ros, Albert F. H.; Oliveira, Rui F.; Dijkstra, Peter D.; Groothuis, Ton G. G.

    Studies on birds and mammals indicate that sexual traits may signal superior health because active immunity, like inflammatory responses to infections, is suppressive to the production of androgens that facilitate the expression of these traits. Here we test this possible pathway for honest

  3. Differing activation status and immune effector molecule expression profiles of neonatal and maternal lymphocytes in an African population.

    NARCIS (Netherlands)

    Engelmann, I.; Moeller, U.; Santamaria, A.; Kremsner, P.G.; Luty, A.J.F.

    2006-01-01

    Higher susceptibility of newborns to infections has been attributed to the hypo-responsiveness of their cellular immune system. Here we compared the activation status and expression of cytokines and cytotoxic molecules of cord versus maternal peripheral blood mononuclear cells in an African

  4. The Serum Complement System: A Simplified Laboratory Exercise to Measure the Activity of an Important Component of the Immune System

    Science.gov (United States)

    Inglis, Jordan E.; Radziwon, Kimberly A.; Maniero, Gregory D.

    2008-01-01

    The immune system is a vital physiological component that affords animals protection from disease and is composed of innate and adaptive mechanisms that rely on cellular and dissolved components. The serum complement system is a series of dissolved proteins that protect against a variety of pathogens. The activity of complement in serum can be…

  5. Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment

    NARCIS (Netherlands)

    Mattei, D.; Ivanov, A.; Ferrai, C.; Jordan, P.; Guneykaya, D.; Buonfiglioli, A.; Schaafsma, W.; Przanowski, P.; Deuther-Conrad, W.; Brust, P.; Hesse, S.; Patt, M.; Sabri, O.; Ross, T. L.; Eggen, B. J. L.; Boddeke, E. W. G. M.; Kaminska, B.; Beule, D.; Pombo, A.; Kettenmann, H.; Wolf, S. A.

    2017-01-01

    Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of

  6. Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae

    Directory of Open Access Journals (Sweden)

    Teufert Karen

    2004-05-01

    Full Text Available Abstract Background Despite its direct connection to the nasopharynx which harbors otitis media pathogens as part of its normal flora, the middle ear cavity is kept free of these bacteria by as yet unknown mechanisms. Respiratory mucosal epithelia, including those of the middle ear and eustachian tube, secrete antimicrobial effectors including lysozyme, lactoferrin and β defensins-1 and -2. To elucidate the role of these innate immune molecules in the normal defense and maintenance of sterility of respiratory mucosa such as that of the middle ear, we assessed their effect on the respiratory pathogens nontypeable Haemophilus influenzae (NTHi 12, Moraxella catarrhalis 035E, and Streptococcus pneumoniae 3, and 6B. Methods Two assay methods, the radial assay and the liquid broth assay, were employed for testing the antimicrobial activity of the molecules. This was done in order to minimize the possibility that the observed effects were artifacts of any single assay system employed. Also, transmission electron microscopy (TEM was employed to evaluate the effect of antimicrobial innate immune molecules on OM pathogens. For the statistical analysis of the data, Student's t-test was performed. Results Results of the radial diffusion assay showed that β defensin-2 was active against all four OM pathogens tested, while treatment with β defensin-1 appeared to only affect M. catarrhalis. The radial assay results also showed that lysozyme was quite effective against S. pneumoniae 3 and 6B and was partially bacteriostatic/bactericidal against M. catarrhalis. Lysozyme however, appeared not to affect the growth of NTHi. Thus, lysozyme seems to have a more pronounced impact on the growth of the Gram-positive S. pneumoniae as compared to that of Gram-negative pathogens. Lactoferrin on the other hand, enhanced the growth of the bacteria tested. The results of the radial assays were confirmed using liquid broth assays for antimicrobial activity, and showed that

  7. Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans.

    Science.gov (United States)

    Cheesman, Hilary K; Feinbaum, Rhonda L; Thekkiniath, Jose; Dowen, Robert H; Conery, Annie L; Pukkila-Worley, Read

    2016-01-27

    Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1. The nsy-1(gf) allele caused hyperinduction of p38 MAPK PMK-1-dependent immune effectors, had greater levels of phosphorylated p38 MAPK, and was more resistant to killing by the bacterial pathogen Pseudomonas aeruginosa compared to wild-type controls. In addition, the nsy-1(gf) mutation was toxic to developing animals. Together, these data suggest that the activity of the MAPKKK NSY-1 is tightly regulated as part of a physiological mechanism to control p38 MAPK-mediated innate immune hyperactivation, and ensure cellular homeostasis in C. elegans. Copyright © 2016 Cheesman et al.

  8. Immune Cell Activation and Co-X-irradiation Effect of Eleutherococcus senticosus Maxim Root

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Hyoung Cheol [Chonbuk National University, Jeonju (Korea, Republic of); Park, Jeong Seob [Iksan National College, Iksan (Korea, Republic of); Choi, Dong Seong [Woosuk University, Samrye (Korea, Republic of)

    2007-09-15

    Purpose: This study was performed to investigate the effects of immune cell activation and the antitumor effect for the combination of treatment with X-irradiation and Eleutherococcus senticosus Maxim Root (ESMR) on mouse tumor cells. Materials and Methods: ESMR (250g) was extracted with 80% methanol, concentrated under decompression and lyophilized. To determine whether ESMR is able to activate the immune cells or not, the proliferation of splenocytes in vitro and the number of B cells and T cells in splenic lymphocytes in ESMR-pretreated mice were evaluated. X-irradiation was given to the mouse fibrosarcoma tumor cells (FSa II) by 250 kv X-irradiation machine. The cytotoxicity of ESMR was evaluated from its ability to reduce the clonogenecity of FSa II cells. In X-irradiation alone group, each 2, 4, 6 and 8 Gy was given to FSa II cells. In X-irradiation with ESMR group, 0.2 mg/ml of ESMR was exposed to FSa II cells for 1 hour before X-irradiation. Results: The proliferation of cultured mouse splenocytes and thymocytes were enhanced by the addition of ESMR in vitro. The number of B cells and T cells in mouse splenic lymphocytes was significantly increased in ESMR pretreated mice in vivo. In FSa II cells that received a combination of 0.2 mg/ml of ESMR with X-irradiation exposure, the survival fraction with a dose of 2, 4 and 6 Gy was 0.39{+-}0.005, 0.22{+-}0.005 and 0.06{+-}0.007, respectively. For FSa II cells treated with X-irradiation alone, the survival fraction with a dose of 2, 4 and 6 Gy was 0.76{+-}0.02, 0.47{+-}0.008 and 0.37{+-}0.01. The difference in the survival fraction of the mouse FSa II cells treated with and without ESMR was statistically significant (p<0.05). Conclusion: Treatment with ESMR increased cell viability of mouse splenocytes in vitro and especially the subpopulation of B cells and T cells in splenocytes in ESMR-pretreated mice. However, treatment with ESMR did not increase the level of Th and Tc subpopulations in the thymocytes

  9. Insensitivity of Astrocytes to Interleukin-10 Signaling following Peripheral Immune Challenge Results in Prolonged Microglial Activation in the Aged Brain

    Science.gov (United States)

    Norden, Diana M.; Trojanowski, Paige J.; Walker, Frederick R.; Godbout, Jonathan P.

    2017-01-01

    Immune-activated microglia from aged mice produce exaggerated levels of cytokines. Despite high levels of microglial IL-10 in the aged brain, neuroinflammation was prolonged and associated with depressive-like deficits. Because astrocytes respond to IL-10 and, in turn, attenuate microglial activation, we investigated if astrocyte-mediated resolution of microglial activation was impaired with age. Here, aged astrocytes had a dysfunctional profile with higher GFAP, lower glutamate transporter expression, and significant cytoskeletal re-arrangement. Moreover, aged astrocytes had reduced expression of growth factors and IL-10 Receptor-1 (IL-10R1). Following in vivo LPS immune challenge, aged astrocytes had a molecular signature associated with reduced responsiveness to IL-10. This IL-10 insensitivity of aged astrocytes resulted in a failure to induce IL-10R1 and TGFβ and resolve microglial activation. Additionally, adult astrocytes reduced microglial activation when co-cultured ex vivo, while aged astrocytes did not. Consistent with the aging studies, IL-10RKO astrocytes did not augment TGFβ after immune challenge and failed to resolve microglial activation. Collectively, a major cytokine-regulatory loop between activated microglia and astrocytes is impaired in the aged brain. PMID:27318131

  10. Ovarian function and hormone secretion of gilts actively immunized against androstenedione.

    Science.gov (United States)

    McKinnie, M R; Britt, J H; Esbenshade, K L

    1988-12-01

    Fifty crossbred gilts immunized against bovine serum albumin (BSA) or androstenedione conjugated to BSA (AD) were used in three experiments. Primary immunizations were given at 120 d of age and boosters at 148 and 176 d. Gilts were moved to pens containing four to five animals each and exposed to boars beginning at 180 d of age. Immunization against AD did not affect age at puberty, percentage of gilts exhibiting estrus or duration of first estrous cycle. Over the three experiments, ovulation rate was 24% greater for AD-immunized gilts than for controls, and the number of corpora lutea was related positively (r = .82) to the log of the antibody titer. Number of ovulations decreased as interval from booster immunization to onset of estrus increased. During diestrus of the first estrous cycle, gilts immunized against AD had more follicles 5 to 10 mm in diameter, more total ovarian follicles and more total ovarian structures (corpora lutea plus follicles) than controls. Immunization against AD increased the frequency of LH pulses on d 16 but not on d 17 or 18, of the estrous cycle. However, average serum concentrations of LH, FSH and estradiol from 5 d before until 2 d after expected estrus were not different between treatment groups. Concentrations of AD in follicles 4 to 6 and greater than 7 mm in diameter were greater in gilts immunized against AD. Mean serum progesterone was higher on d 9 and 12 after mating in AD immunized gilts than in controls. Immunization against AD had no effect on maintenance of pregnancy or embryo survival rate.

  11. The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review.

    Science.gov (United States)

    Vassallo, Matteo; Mercié, Patrick; Cottalorda, Jacqueline; Ticchioni, Michel; Dellamonica, Pierre

    2012-08-27

    Recent observational studies suggest a role for lipopolysaccharide (LPS) as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens. A systematic review of LPS as a marker of immune activation in HIV-1 infected patients. MEDLINE register of articles and international conference proceedings. Case-control studies comparing the role of plasma LPS as a marker of immune activation in HIV-infected patients versus HIV negative subjects. Two hundred and six articles were selected using MEDLINE, plus 51 studies presented at international conferences. Plasma LPS is a marker of immune activation in HIV-infected patients, determining the entry of central memory CD4+ T cells into the replication cycle and finally generating cell death. Plasma LPS probably results from immune-mediated alterations of the intestinal barrier, which can occur soon after HIV seroconversion. LPS is a likely marker of disease progression, as it drives chronic monocyte activation, and some studies suggest that hyperexpression of CCR5 receptors, related to LPS plasma levels, could be responsible for monocyte trafficking in the brain compartment and for the appearance of HIV-associated neurocognitive disorders. Long-term combination antiretroviral