Effects of in utero JP-8 jet fuel exposure on the immune systems of pregnant and newborn mice.

PubMed

Harris, D T; Sakiestewa, D; He, X; Titone, D; Witten, M

2007-10-01

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. In the present study, the effects of in-utero JP-8 jet fuel exposure in mice were examined to ascertain any potential effects of jet fuel exposure on female personnel and their offspring. Exposure by the aerosol route (at 1000 mg/m3 for 1 h/day; similar to exposures incurred by flight line personnel) commencing during the first (d7 to birth) or last (d15 to birth) trimester of pregnancy was analyzed. It was observed that even 6-8 weeks after the last jet fuel exposure that the immune system of the dams (mother of newborn mice) was affected (in accordance with previous reports on normal mice). That is, thymus organ weights and viable cell numbers were decreased, and immune function was depressed. A decrease in viable male offspring was found, notably more pronounced when exposure started during the first trimester of pregnancy. Regardless of when jet fuel exposure started, all newborn mice (at 6-8 weeks after birth) reported significant immunosuppression. That is, newborn pups displayed decreased immune organ weights, decreased viable immune cell numbers and suppressed immune function. When the data were analyzed in relation to the respective mothers of the pups the data were more pronounced. Although all jet fuel-exposed pups were immunosuppressed as compared with control pups, male offspring were more affected by jet fuel exposure than female pups. Furthermore, the immune function of the newborn mice was directly correlated to the immune function of their respective mothers. That is, mothers showing the lowest immune function after JP-8 exposure gave birth to pups displaying the greatest effects of jet fuel exposure on immune function. Mothers who showed the highest levels of immune function after in-utero JP-8 exposure gave birth to pups displaying levels of immune function similar to controls animals that had the lowest levels of immune function. These data indicated that a genetic component might be involved in determining immune responses after jet fuel exposure. Overall, the data showed that in-utero JP-8 jet fuel exposure had long-term detrimental effects on newborn mice, particularly on the viability and immune competence of male offspring.

Characterization of rainbow trout (Oncorhynchus mykiss) spleen transcriptome and identification of immune-related genes

USDA-ARS?s Scientific Manuscript database

Resistance against specific diseases is affecting profitability in fish production systems including rainbow trout. Limited information is known about functions and mechanisms of the immune gene pathways in teleosts. Immunogenomics are powerful tools to determine immune-related genes/gene pathways a...

Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.

PubMed

Voss, Matthias; Bryceson, Yenan T

2017-04-01

Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology. Copyright © 2015. Published by Elsevier Inc.

Correlates of immune defenses in golden eagle nestlings

USGS Publications Warehouse

MacColl, Elisabeth; Vanesky, Kris; Buck, Jeremy A.; Dudek, Benjamin; Eagles-Smith, Collin A.; Heath, Julie A.; Herring, Garth; Vennum, Chris; Downs, Cynthia J.

2017-01-01

An individual's investment in constitutive immune defenses depends on both intrinsic and extrinsic factors. We examined how Leucocytozoon parasite presence, body condition (scaled mass), heterophil-to-lymphocyte (H:L) ratio, sex, and age affected immune defenses in golden eagle (Aquila chrysaetos) nestlings from three regions: California, Oregon, and Idaho. We quantified hemolytic-complement activity and bacterial killing ability, two measures of constitutive immunity. Body condition and age did not affect immune defenses. However, eagles with lower H:L ratios had lower complement activity, corroborating other findings that animals in better condition sometimes invest less in constitutive immunity. In addition, eagles with Leucocytozoon infections had higher concentrations of circulating complement proteins but not elevated opsonizing proteins for all microbes, and eagles from Oregon had significantly higher constitutive immunity than those from California or Idaho. We posit that Oregon eagles might have elevated immune defenses because they are exposed to more endoparasites than eagles from California or Idaho, and our results confirmed that the OR region has the highest rate of Leucocytozoon infections. Our study examined immune function in a free-living, long-lived raptor species, whereas most avian ecoimmunological research focuses on passerines. Thus, our research informs a broad perspective regarding the evolutionary and environmental pressures on immune function in birds.

Prostaglandins modify phosphorylation of specific proteins in the insect cell line BCIRL-HzAM1

USDA-ARS?s Scientific Manuscript database

Prostaglandins (PGs) play crucial roles in vertebrate biology, particularly in immune functions. Because PGs also mediate specific cell functions in insect immunity, we are investigating how these signaling molecules affect insect cells. We reported that PGs, notably PGA1, PGA2, and PGE1, up and/or ...

Cytokines in Drosophila immunity.

PubMed

Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

2016-02-01

Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Effect of a mixture of micronutrients, but not of bovine colostrum concentrate, on immune function parameters in healthy volunteers: a randomized placebo-controlled study

PubMed Central

Wolvers, Danielle AW; van Herpen-Broekmans, Wendy MR; Logman, Margot HGM; van der Wielen, Reggy PJ; Albers, Ruud

2006-01-01

Background Supplementation of nutritional deficiencies helps to improve immune function and resistance to infections in malnourished subjects. However, the suggested benefits of dietary supplementation for immune function in healthy well nourished subjects is less clear. Among the food constituents frequently associated with beneficial effects on immune function are micronutrients such as vitamin C, vitamin E, β-carotene and zinc, and colostrum. This study was designed to investigate the effects these ingredients on immune function markers in healthy volunteers. Methods In a double-blind, randomized, parallel, 2*2, placebo-controlled intervention study one hundred thirty-eight healthy volunteers aged 40–80 y (average 57 ± 10 y) received one of the following treatments: (1) bovine colostrum concentrate 1.2 g/d (equivalent to ~500 mg/d immunoglobulins), (2) micronutrient mix of 288 mg vitamin E, 375 mg vitamin C, 12 mg β-carotene and 15 mg zinc/day, (3) combination of colostrum and micronutrient mix, or (4) placebo. Several immune function parameters were assessed after 6 and 10 weeks. Data were analyzed by analysis of variance. Groups were combined to test micronutrient treatment versus no micronutrient treatment, and colostrum treatment versus no colostrum treatment. Results Overall, consumption of the micronutrient mix significantly enhanced delayed-type hypersensitivity (DTH) responses (p < 0.05). Adjusted covariance analysis showed a positive association between DTH and age. Separate analysis of younger and older age groups indicated that it was the older population that benefited from micronutrient consumption. The other immune function parameters including responses to systemic tetanus and oral typhoid vaccination, phagocytosis, oxidative burst, lymphocyte proliferation and lymphocyte subset distribution were neither affected by the consumption of micronutrients nor by the consumption of bovine colostrum concentrate. Conclusion Consumption of bovine colostrum had no effect on any of the immune parameters assessed. The micronutrient mix enhanced cellular immunity as measured by DTH, with an increased effect by incremental age, but did not affect any of the other immune parameters measured. Although correlations between decreased DTH and enhanced risk of certain infection have been reported, it remains unclear whether and enhanced DTH response actually improves immune defense. The present data suggests that improvement of immune parameters in a population with a generally good immune and nutritional status is limited and that improvement of immune function in this population may be difficult. PMID:17118191

Modeled Microgravity Inhibits Apoptosis in Peripheral Blood Lymphocytes

NASA Technical Reports Server (NTRS)

Risin, Diana; Pellis, Neal R.

1999-01-01

Impairment of the immunity in astronauts and cosmonauts even in short term flights is a recognized risk. Long term orbital space missions and anticipated interplanetary flights increase the concern for more pronounced effects on the immune system with potential clinical consequences. Impairment of the immunity in space may be due tonumerous physiological changes caused by space-related factors, which in turn affect the immune system, or alternatively, it may be due to direct effects of different factors encountered in space on lymphoid cells and their interactions. Indeed, in modeled microgravity (MMG) experiments on Earth we and others showed that microgravity directly affects multiple lymphocyte functions. It interferes with expression of cell surface molecules, causes inhibition of lymphocyte locomotion, suppresses polyclopal and antigen-specific lymphocyte activation, selectively inhibits protein kinase C (PKC) isoforms. Some of these effects were also confirmed in cell culture experiments in real space conditions during Spacelab, Biokosmos and Shuttle Missions. The results of these studies, taken together, strongly indicated that microgravity interferes with fundamental biological processes associated with functional and structural changes in cell surface membranes, cell surface molecules and in their interaction. Based on the data and on their interpretation, we hypothesized that microgravity in addition to observed functional changes affects programmed cell death (PCD) in lymphocyte populations and that this mechanism could contribute to the impairment of the immunity.

mTOR at the Transmitting and Receiving Ends in Tumor Immunity

PubMed Central

Guri, Yakir; Nordmann, Thierry M.; Roszik, Jason

2018-01-01

Cancer is a complex disease and a leading cause of death worldwide. Immunity is critical for cancer control. Cancer cells exhibit high mutational rates and therefore altered self or neo-antigens, eliciting an immune response to promote tumor eradication. Failure to mount a proper immune response leads to cancer progression. mTOR signaling controls cellular metabolism, immune cell differentiation, and effector function. Deregulated mTOR signaling in cancer cells modulates the tumor microenvironment, thereby affecting tumor immunity and possibly promoting carcinogenesis. PMID:29662490

mTOR at the Transmitting and Receiving Ends in Tumor Immunity.

PubMed

Guri, Yakir; Nordmann, Thierry M; Roszik, Jason

2018-01-01

Cancer is a complex disease and a leading cause of death worldwide. Immunity is critical for cancer control. Cancer cells exhibit high mutational rates and therefore altered self or neo-antigens, eliciting an immune response to promote tumor eradication. Failure to mount a proper immune response leads to cancer progression. mTOR signaling controls cellular metabolism, immune cell differentiation, and effector function. Deregulated mTOR signaling in cancer cells modulates the tumor microenvironment, thereby affecting tumor immunity and possibly promoting carcinogenesis.

Are fish immune systems really affected by parasites? an immunoecological study of common carp (Cyprinus carpio)

PubMed Central

2011-01-01

Background The basic function of the immune system is to protect an organism against infection in order to minimize the fitness costs of being infected. According to life-history theory, energy resources are in a trade-off between the costly demands of immunity and other physiological demands. Concerning fish, both physiology and immunity are influenced by seasonal changes (i.e. temporal variation) associated to the changes of abiotic factors (such as primarily water temperature) and interactions with pathogens and parasites. In this study, we investigated the potential associations between the physiology and immunocompetence of common carp (Cyprinus carpio) collected during five different periods of a given year. Our sampling included the periods with temporal variability and thus, it presented a different level in exposure to parasites. We analyzed which of two factors, seasonality or parasitism, had the strongest impact on changes in fish physiology and immunity. Results We found that seasonal changes play a key role in affecting the analyzed measurements of physiology, immunity and parasitism. The correlation analysis revealed the relationships between the measures of overall host physiology, immunity and parasite load when temporal variability effect was removed. When analyzing separately parasite groups with different life-strategies, we found that fish with a worse condition status were infected more by monogeneans, representing the most abundant parasite group. The high infection by cestodes seems to activate the phagocytes. A weak relationship was found between spleen size and abundance of trematodes when taking into account seasonal changes. Conclusions Even if no direct trade-off between the measures of host immunity and physiology was confirmed when taking into account the seasonality, it seems that seasonal variability affects host immunity and physiology through energy allocation in a trade-off between life important functions, especially reproduction and fish condition. Host immunity measures were not found to be in a trade-off with the investigated physiological traits or functions, but we confirmed the immunosuppressive role of 11-ketotestosterone on fish immunity measured by complement activity. We suggest that the different parasite life-strategies influence different aspects of host physiology and activate the different immunity pathways. PMID:21708010

Positive affect and psychobiological processes

PubMed Central

Dockray, Samantha; Steptoe, Andrew

2010-01-01

Positive affect has been associated with favourable health outcomes, and it is likely that several biological processes mediate the effects of positive mood on physical health. There is converging evidence that positive affect activates the neuroendocrine, autonomic and immune systems in distinct and functionally meaningful ways. Cortisol, both total output and the awakening response, has consistently been shown to be lower among individuals with higher levels of positive affect. The beneficial effects of positive mood on cardiovascular function, including heart rate and blood pressure, and the immune system have also been described. The influence of positive affect on these psychobiological processes are independent of negative affect, suggesting that positive affect may have characteristic biological correlates. The duration and conceptualisation of positive affect may be important considerations in understanding how different biological systems are activated in association with positive affect. The association of positive affect and psychobiological processes has been established, and these biological correlates may be partly responsible for the protective effects of positive affect on health outcomes. PMID:20097225

Modulating the function of the immune system by thyroid hormones and thyrotropin.

PubMed

Jara, Evelyn L; Muñoz-Durango, Natalia; Llanos, Carolina; Fardella, Carlos; González, Pablo A; Bueno, Susan M; Kalergis, Alexis M; Riedel, Claudia A

2017-04-01

Accumulating evidence suggests a close bidirectional communication and regulation between the neuroendocrine and immune systems. Thyroid hormones (THs) can exert responses in various immune cells, e.g., monocytes, macrophages, natural killer cells, and lymphocytes, affecting several inflammation-related processes (such as, chemotaxis, phagocytosis, reactive oxygen species generation, and cytokines production). The interactions between the endocrine and immune systems have been shown to contribute to pathophysiological conditions, including sepsis, inflammation, autoimmune diseases and viral infections. Under these conditions, TH therapy could contribute to restoring normal physiological functions. Here we discuss the effects of THs and thyroid stimulating hormone (TSH) on the immune system and the contribution to inflammation and pathogen clearance, as well as the consequences of thyroid pathologies over the function of the immune system. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

The immune system: a target for functional foods?

PubMed

Calder, Philip C; Kew, Samantha

2002-11-01

The immune system acts to protect the host from infectious agents that exist in the environment (bacteria, viruses, fungi, parasites) and from other noxious insults. The immune system is constantly active, acting to discriminate 'non-self' from 'self'. The immune system has two functional divisions: the innate and the acquired. Both components involve various blood-borne factors (complement, antibodies, cytokines) and cells. A number of methodologies exist to assess aspects of immune function; many of these rely upon studying cells in culture ex vivo. There are large inter-individual variations in many immune functions even among the healthy. Genetics, age, gender, smoking habits, habitual levels of exercise, alcohol consumption, diet, stage in the female menstrual cycle, stress, history of infections and vaccinations, and early life experiences are likely to be important contributors to the observed variation. While it is clear that individuals with immune responses significantly below 'normal' are more susceptible to infectious agents and exhibit increased infectious morbidity and mortality, it is not clear how the variation in immune function among healthy individuals relates to variation in susceptibility to infection. Nutrient status is an important factor contributing to immune competence: undernutrition impairs the immune system, suppressing immune functions that are fundamental to host protection. Undernutrition leading to impairment of immune function can be due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients. Often these occur in combination. Nutrients that have been demonstrated (in either animal or human studies) to be required for the immune system to function efficiently include essential amino acids, the essential fatty acid linoleic acid, vitamin A, folic acid, vitamin B6, vitamin B12, vitamin C, vitamin E, Zn, Cu, Fe and Se. Practically all forms of immunity may be affected by deficiencies in one or more of these nutrients. Animal and human studies have demonstrated that adding the deficient nutrient back to the diet can restore immune function and resistance to infection. Among the nutrients studied most in this regard are vitamin E and Zn. Increasing intakes of some nutrients above habitual and recommended levels can enhance some aspects of immune function. However, excess amounts of some nutrients also impair immune function. There is increasing evidence that probiotic bacteria improve host immune function. The effect of enhancing immune function on host resistance to infection in healthy individuals is not clear.

Characterization of the rainbow trout spleen transcriptome and identification of immune-related genes

USDA-ARS?s Scientific Manuscript database

Disease susceptibility affects production efficiency and profitability in rainbow trout aquaculture. There is limited information available regarding the functions and mechanisms of teleost immune pathways. Immunogenomics provides powerful approaches to identify disease resistance genes/gene pathway...

System-Wide Associations between DNA-Methylation, Gene Expression, and Humoral Immune Response to Influenza Vaccination.

PubMed

Zimmermann, Michael T; Oberg, Ann L; Grill, Diane E; Ovsyannikova, Inna G; Haralambieva, Iana H; Kennedy, Richard B; Poland, Gregory A

2016-01-01

Failure to achieve a protected state after influenza vaccination is poorly understood but occurs commonly among aged populations experiencing greater immunosenescence. In order to better understand immune response in the elderly, we studied epigenetic and transcriptomic profiles and humoral immune response outcomes in 50-74 year old healthy participants. Associations between DNA methylation and gene expression reveal a system-wide regulation of immune-relevant functions, likely playing a role in regulating a participant's propensity to respond to vaccination. Our findings show that sites of methylation regulation associated with humoral response to vaccination impact known cellular differentiation signaling and antigen presentation pathways. We performed our analysis using per-site and regionally average methylation levels, in addition to continuous or dichotomized outcome measures. The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation. Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity. Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response. Additionally, CpGs that individually predict humoral immune responses are enriched for polycomb-group and FOXP2 transcription factor binding sites. The most robust associations implicate differential methylation affecting gene expression levels of genes with known roles in immunity (e.g. HLA-B and HLA-DQB2) and immunosenescence. We believe our data and analysis strategy highlight new and interesting epigenetic trends affecting humoral response to vaccination against influenza; one of the most common and impactful viral pathogens.

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

PubMed

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.

Novel Roles for Immune Molecules in Neural Development: Implications for Neurodevelopmental Disorders

PubMed Central

Garay, Paula A.; McAllister, A. Kimberley

2010-01-01

Although the brain has classically been considered “immune-privileged”, current research suggests an extensive communication between the immune and nervous systems in both health and disease. Recent studies demonstrate that immune molecules are present at the right place and time to modulate the development and function of the healthy and diseased central nervous system (CNS). Indeed, immune molecules play integral roles in the CNS throughout neural development, including affecting neurogenesis, neuronal migration, axon guidance, synapse formation, activity-dependent refinement of circuits, and synaptic plasticity. Moreover, the roles of individual immune molecules in the nervous system may change over development. This review focuses on the effects of immune molecules on neuronal connections in the mammalian central nervous system – specifically the roles for MHCI and its receptors, complement, and cytokines on the function, refinement, and plasticity of geniculate, cortical and hippocampal synapses, and their relationship to neurodevelopmental disorders. These functions for immune molecules during neural development suggest that they could also mediate pathological responses to chronic elevations of cytokines in neurodevelopmental disorders, including autism spectrum disorders (ASD) and schizophrenia. PMID:21423522

Immune function and the decision to deploy weapons during fights in the beadlet anemone, Actinia equina.

PubMed

Lane, Sarah M; Briffa, Mark

2018-02-20

The ability to mitigate the costs of engaging in a fight will depend on an individual's physiological state. However, the experience of fighting itself may, in turn, affect an individual's state, especially if the fight results in injury. Previous studies have found a correlation between immune state and fighting success, but the causal direction of this relationship remains unclear. Does immune state determine fighting success? Or does fighting itself influence subsequent immune state? Using the beadlet anemone, Actinia equina , we disentangled the cause and effect of this relationship, measuring immune response once pre-fight and twice post-fight. Contrary to previous findings, pre-fight immune response did not predict fighting success, but rather predicted whether an individual used its weapons during the fight. Furthermore, weapon use and contest outcome significantly affected post-fight immune response. Individuals that used their weapons maintained a stable immune response following the fight, whereas those that fought non-injuriously did not. Furthermore, although winners suffered a reduction in immune response similar to that of losers immediately post-fight, winners began to recover pre-fight levels within 24 h. Our findings indicate that immune state can influence strategic fighting decisions and, moreover, that fight outcome and the agonistic behaviours expressed can significantly affect subsequent immunity. © 2018. Published by The Company of Biologists Ltd.

Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact.

PubMed

Hessel, Ellen V S; Tonk, Elisa C M; Bos, Peter M J; van Loveren, Henk; Piersma, Aldert H

2015-01-01

Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.

Jet fuel-induced immunotoxicity.

PubMed

Harris, D T; Sakiestewa, D; Titone, D; Robledo, R F; Young, R S; Witten, M

2000-09-01

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.

No evidence for parasitism-linked changes in immune function or oxidative physiology over the annual cycle of an avian species.

PubMed

Pap, Péter L; Sesarman, Alina; Vágási, Csongor I; Buehler, Deborah M; Pătraş, Laura; Versteegh, Maaike A; Banciu, Manuela

2014-01-01

Temporally changing environmental conditions occur in most parts of the world and can exert strong pressure on the immune defense of organisms. Seasonality may result in changes in physiological traits over the year, and such changes may be essential for the optimization of defense against infections. Evidence from field and laboratory studies suggest the existence of links between environmental conditions, such as infection risk, and the ability of animals to mount an immune response or to overcome infections; however, the importance of parasites in mediating seasonal change in immune defense is still debated. In this study, we test the hypothesis that seasonal change in immune function and connected physiological traits is related to parasite infection. We sampled captive house sparrows (Passer domesticus) once every 2 mo over 14 mo and compared the annual variation in 12 measures of condition, immune function, antioxidant status, and oxidative damage among birds naturally infested with coccidians or medicated against these parasites. We found significant variation in 10 of 12 traits over the year. However, we found little support for parasite-mediated change in immune function and oxidative status in captive house sparrows. Of the 12 measures, only one was slightly affected by parasite treatment. In support of the absence of any effect of coccidians on the annual profile of the condition and physiological traits, we found no consistent relationships between the intensity of infestation and these response variables over the year. Our results show that chronic coccidian infections have limited effect on the seasonal changing of physiological traits and that the patterns of these measures are probably more affected by acute infection and/or virulent parasite strains.

Effects of experimentally elevated traffic noise on nestling white-crowned sparrow stress physiology, immune function and life history.

PubMed

Crino, Ondi L; Johnson, Erin E; Blickley, Jessica L; Patricelli, Gail L; Breuner, Creagh W

2013-06-01

Roads have been associated with behavioral and physiological changes in wildlife. In birds, roads decrease reproductive success and biodiversity and increase physiological stress. Although the consequences of roads on individuals and communities have been well described, the mechanisms through which roads affect birds remain largely unexplored. Here, we examine one mechanism through which roads could affect birds: traffic noise. We exposed nestling mountain white-crowned sparrows (Zonotrichia leucophrys oriantha) to experimentally elevated traffic noise for 5 days during the nestling period. Following exposure to traffic noise we measured nestling stress physiology, immune function, body size, condition and survival. Based on prior studies, we expected the traffic noise treatment to result in elevated stress hormones (glucocorticoids), and declines in immune function, body size, condition and survival. Surprisingly, nestlings exposed to traffic noise had lower glucocorticoid levels and improved condition relative to control nests. These results indicate that traffic noise does affect physiology and development in white-crowned sparrows, but not at all as predicted. Therefore, when evaluating the mechanisms through which roads affect avian populations, other factors (e.g. edge effects, pollution and mechanical vibration) may be more important than traffic noise in explaining elevated nestling stress responses in this species.

Herbal medicine IMOD suppresses LPS-induced production of proinflammatory cytokines in human dendritic cells

PubMed Central

Mirzaee, Saeedeh; Drewniak, Agata; Sarrami-Forooshani, Ramin; Kaptein, Tanja M.; Gharibdoost, Farhad; Geijtenbeek, Teunis B. H.

2015-01-01

Traditional medicines that stimulate or modulate the immune system can be used as innovative approaches to treat immunological diseases. The herbal medicine IMOD has been shown to strongly modulate immune responses in several animal studies as well as in clinical trials. However, little is known about the mechanisms of IMOD to modulate immunity. Here we have investigated whether IMOD modulates the immunological function of human dendritic cells (DCs). IMOD alone did not induce DC maturation nor production of cytokines. Notably, IMOD decreased the production of pro-inflammatory cytokines IL-6, IL-12 p70, and TNFα by LPS-activated DCs at both mRNA and protein levels in a dose dependent manner. In contrast, treatment with IMOD did not affect LPS induced-production of the anti-inflammatory cytokine IL-10. Furthermore, IMOD inhibited T cell activation/proliferation by LPS-treated DCs and skewed T-cells responses toward the T helper type 2 polarization. These data strongly indicate that IMOD has a potent immunomodulatory ability that affects TLR signaling and thereby modulates DC function. Insight into the immunomodulatory effect of herbal medicine IMOD may provide innovative strategies to affect the immune system and to help combat various diseases. PMID:25870561

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

PubMed Central

Zourdos, Michael C.; Jo, Edward; Ormsbee, Michael J.

2013-01-01

Research examining immune function during obesity suggests that excessive adiposity is linked to impaired immune responses leading to pathology. The deleterious effects of obesity on immunity have been associated with the systemic proinflammatory profile generated by the secretory molecules derived from adipose cells. These include inflammatory peptides, such as TNF-α, CRP, and IL-6. Consequently, obesity is now characterized as a state of chronic low-grade systemic inflammation, a condition considerably linked to the development of comorbidity. Given the critical role of adipose tissue in the inflammatory process, especially in obese individuals, it becomes an important clinical objective to identify lifestyle factors that may affect the obesity-immune system relationship. For instance, stress, physical activity, and nutrition have each shown to be a significant lifestyle factor influencing the inflammatory profile associated with the state of obesity. Therefore, the purpose of this review is to comprehensively evaluate the impact of lifestyle factors, in particular psychological stress, physical activity, and nutrition, on obesity-related immune function with specific focus on inflammation. PMID:24324381

Senescence in immune priming and attractiveness in a beetle.

PubMed

Daukšte, J; Kivleniece, I; Krama, T; Rantala, M J; Krams, I

2012-07-01

Age-related decline in immune activity is referred to as immunosenescence and has been observed for both the adaptive immune response of vertebrates and the innate immune system of invertebrates. Because maintaining a basic level of immune defence and mounting an immune response is costly, optimal investment in immune function should vary over a wide range of individual states such as the individual's age. In this study, we tested whether the immune response and immunological priming within individuals become less efficient with age using mealworm beetles, Tenebrio molitor, as a model organism. We also tested whether ageing and immunological priming affected the odours produced by males. We found that young males of T. molitor were capable of mounting an immune response a sterile nylon monofilament implant with the potential to exhibit a simple form of immune memory through mechanisms of immune priming. Older males did not increase their immune response to a second immune challenge, which negatively affected their sexual attractiveness and remaining life span. Our results indicate that the immune system of older males in T. molitor is less effective, suggesting complex evolutionary trade-offs between ageing, immune response and sexual attractiveness. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

Affective immunology: where emotions and the immune response converge.

PubMed

D'Acquisto, Fulvio

2017-03-01

Affect and emotion are defined as "an essential part of the process of an organism's interaction with stimuli." Similar to affect, the immune response is the "tool" the body uses to interact with the external environment. Thanks to the emotional and immunological response, we learn to distinguish between what we like and what we do not like, to counteract a broad range of challenges, and to adjust to the environment we are living in. Recent compelling evidence has shown that the emotional and immunological systems share more than a similarity of functions. This review article will discuss the crosstalk between these two systems and the need for a new scientific area of research called affective immunology. Research in this field will allow a better understanding and appreciation of the immunological basis of mental disorders and the emotional side of immune diseases.

Review: Interactions between temperament, stress, and immune function in cattle

USDA-ARS?s Scientific Manuscript database

Stressors encountered by animals can pose economic problems for the livestock industry due to increased costs to the producer as well as the consumer. Stress can also adversely affect many physiological systems, including the reproductive and immune systems. In recent years, stress has been associat...

Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis

USDA-ARS?s Scientific Manuscript database

Autoimmune diseases are common, disabling immune disorders affecting millions of people. Recent studies indicate that dysregulated balance of different CD4+ T-cell subpopulations plays a key role in immune pathogenesis of several major autoimmune diseases. Green tea and its active ingredient, epigal...

Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery

NASA Astrophysics Data System (ADS)

Heidegger, Simon; Gößl, Dorothée; Schmidt, Alexandra; Niedermayer, Stefan; Argyo, Christian; Endres, Stefan; Bein, Thomas; Bourquin, Carole

2015-12-01

Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1β. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1β. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06122a

Perinatal stress and early life programming of lung structure and function

PubMed Central

Wright, Rosalind J.

2010-01-01

Exposure to environmental toxins during critical periods of prenatal and/or postnatal development may alter the normal course of lung morphogenesis and maturation, potentially resulting in changes that affect both structure and function of the respiratory system. Moreover, these early effects may persist into adult life magnifying the potential public health impact. Aberrant or excessive pro-inflammatory immune responses, occurring both locally and systemically, that result in inflammatory damage to the airway are a central determinant of lung structure-function changes throughout life. Disruption of neuroendocrine function in early development, specifically the hypothalamic-pituitary-adrenal (HPA) axis, may alter functional status of the immune system. Autonomic nervous system (ANS) function (sympathovagal imbalance) is another integral component of airway function and immunity in childhood. This overview discusses the evidence linking psychological factors to alterations in these interrelated physiological processes that may, in turn, influence childhood lung function and identifies gaps in our understanding. PMID:20080145

Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system

PubMed Central

Lukasch, Barbara; Westerdahl, Helena; Strandh, Maria; Winkler, Hans; Moodley, Yoshan; Knauer, Felix

2017-01-01

Background A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. Methods To do this we used captive house sparrows (Passer domesticus) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Results Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. Discussion We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic. PMID:28875066

Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system.

PubMed

Lukasch, Barbara; Westerdahl, Helena; Strandh, Maria; Winkler, Hans; Moodley, Yoshan; Knauer, Felix; Hoi, Herbert

2017-01-01

A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. To do this we used captive house sparrows ( Passer domesticus ) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.

Invited essay: Cognitive influences on the psychological immune system.

PubMed

Rachman, S J

2016-12-01

The construct of the psychological immune system is described and analysed. The direct and indirect cognitive influences on the system are discussed, and the implications of adding a cognitive construal to the influential model of a behavioural immune system are considered. The psychological immune system has two main properties: defensive and healing. It encompasses a good amount of health-related phenomena that is outside the scope of the behavioural model or the biological immune system. Evidence pertaining to the psychological immune system includes meta-analyses of the associations between psychological variables such as positive affect/wellbeing and diseases and mortality, and associations between wellbeing and positive health. The results of long-term prospective studies are consistent with the conclusions drawn from the meta-analyses. Laboratory investigations of the effects of psychological variables on the biological immune system show that negative affect can slow wound-healing, and positive affect can enhance resistance to infections, for example in experiments involving the introduction of the rhinovirus and the influenza A virus. A number of problems concerning the assessment of the functioning of the psychological immune system are considered, and the need to develop techniques for determining when the system is active or not, is emphasized. This problem is particularly challenging when trying to assess the effects of the psychological immune system during a prolonged psychological intervention, such as a course of resilience training. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hormones and immune function: implications of aging.

PubMed

Arlt, Wiebke; Hewison, Martin

2004-08-01

Aging is associated with a decline in immunity described as immunosenescence. This is paralleled by a decline in the production of several hormones, as typically illustrated by the menopausal loss of ovarian oestrogen production. However, other hormonal changes that occur with aging and that potentially impact on immune function include the release of the pineal gland hormone melatonin and pituitary growth hormone, adrenal production of dehydroepiandrosterone and tissue-specific availability of active vitamin D. It remains to be established whether hormonal changes with aging actually contribute to immunosenescence and this area is at the interface of fact and fiction, clearly inviting systematic research efforts. As a step in this direction, the present review summarizes established facts on the physiology of secretion and function of hormones that, in most cases, decline with aging and that are likely to affect the immune system.

Immunomodulatory effects of Hericium erinaceus derived polysaccharides are mediated by intestinal immunology.

PubMed

Sheng, Xiaotong; Yan, Jingmin; Meng, Yue; Kang, Yuying; Han, Zhen; Tai, Guihua; Zhou, Yifa; Cheng, Hairong

2017-03-22

This study was aimed at investigating the immunomodulating activity of Hericium erinaceus polysaccharide (HEP) in mice, by assessing splenic lymphocyte proliferation (cell-mediated immunity), serum hemolysin levels (humoral immunity), phagocytic capacity of peritoneal cavity phagocytes (macrophage phagocytosis), and NK cell activity. ELISA of immunoglobulin A (SIgA) in the lamina propria, and western blotting of small intestinal proteins were also performed to gain insight into the mechanism by which HEP affects the intestinal immune system. Here, we report that HEP improves immune function by functionally enhancing cell-mediated and humoral immunity, macrophage phagocytosis, and NK cell activity. In addition, HEP was found to upregulate the secretion of SIgA and activate the MAPK and AKT cellular signaling pathways in the intestine. In conclusion, all these results allow us to postulate that the immunomodulatory effects of HEP are most likely attributed to the effective regulation of intestinal mucosal immune activity.

The effect of hydration state and energy balance on innate immunity of a desert reptile.

PubMed

Moeller, Karla T; Butler, Michael W; Denardo, Dale F

2013-05-04

Immune function is a vital physiological process that is often suppressed during times of resource scarcity due to investments in other physiological systems. While energy is the typical currency that has been examined in such trade-offs, limitations of other resources may similarly lead to trade-offs that affect immune function. Specifically, water is a critical resource with profound implications for organismal ecology, yet its availability can fluctuate at local, regional, and even global levels. Despite this, the effect of osmotic state on immune function has received little attention. Using agglutination and lysis assays as measures of an organism's plasma concentration of natural antibodies and capacity for foreign cell destruction, respectively, we tested the independent effects of osmotic state, digestive state, and energy balance on innate immune function in free-ranging and laboratory populations of the Gila monster, Heloderma suspectum. This desert-dwelling lizard experiences dehydration and energy resource fluctuations on a seasonal basis. Dehydration was expected to decrease innate immune function, yet we found that dehydration increased lysis and agglutination abilities in both lab and field studies, a relationship that was not simply an effect of an increased concentration of immune molecules. Laboratory-based differences in digestive state were not associated with lysis or agglutination metrics, although in our field population, a loss of fat stores was correlated with an increase in lysis. Depending on the life history of an organism, osmotic state may have a greater influence on immune function than energy availability. Thus, consideration of osmotic state as a factor influencing immune function will likely improve our understanding of ecoimmunology and the disease dynamics of a wide range of species.

The effect of hydration state and energy balance on innate immunity of a desert reptile

PubMed Central

2013-01-01

Introduction Immune function is a vital physiological process that is often suppressed during times of resource scarcity due to investments in other physiological systems. While energy is the typical currency that has been examined in such trade-offs, limitations of other resources may similarly lead to trade-offs that affect immune function. Specifically, water is a critical resource with profound implications for organismal ecology, yet its availability can fluctuate at local, regional, and even global levels. Despite this, the effect of osmotic state on immune function has received little attention. Results Using agglutination and lysis assays as measures of an organism’s plasma concentration of natural antibodies and capacity for foreign cell destruction, respectively, we tested the independent effects of osmotic state, digestive state, and energy balance on innate immune function in free-ranging and laboratory populations of the Gila monster, Heloderma suspectum. This desert-dwelling lizard experiences dehydration and energy resource fluctuations on a seasonal basis. Dehydration was expected to decrease innate immune function, yet we found that dehydration increased lysis and agglutination abilities in both lab and field studies, a relationship that was not simply an effect of an increased concentration of immune molecules. Laboratory-based differences in digestive state were not associated with lysis or agglutination metrics, although in our field population, a loss of fat stores was correlated with an increase in lysis. Conclusions Depending on the life history of an organism, osmotic state may have a greater influence on immune function than energy availability. Thus, consideration of osmotic state as a factor influencing immune function will likely improve our understanding of ecoimmunology and the disease dynamics of a wide range of species. PMID:23642164

Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome

PubMed Central

Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

2014-01-01

Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting. PMID:24976697

Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome.

PubMed

Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

2014-06-28

Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting.

Osteoimmunology and Beyond

PubMed Central

Ginaldi, Lia; De Martinis, Massimo

2016-01-01

Abstract: Objective Osteoimmunology investigates interactions between skeleton and immune system. In the light of recent discoveries in this field, a new reading register of osteoporosis is actually emerging, in which bone and immune cells are strictly interconnected. Osteoporosis could therefore be considered a chronic immune mediated disease which shares with other age related disorders a common inflammatory background. Here, we highlight these recent discoveries and the new landscape that is emerging. Method Extensive literature search in PubMed central. Results While the inflammatory nature of osteoporosis has been clearly recognized, other interesting aspects of osteoimmunology are currently emerging. In addition, mounting evidence indicates that the immunoskeletal interface is involved in the regulation of important body functions beyond bone remodeling. Bone cells take part with cells of the immune system in various immunological functions, configuring a real expanded immune system, and are therefore variously involved not only as target but also as main actors in various pathological conditions affecting primarily the immune system, such as autoimmunity and immune deficiencies, as well as in aging, menopause and other diseases sharing an inflammatory background. Conclusion The review highlights the complexity of interwoven pathways and shared mechanisms of the crosstalk between the immune and bone systems. More interestingly, the interdisciplinary field of osteoimmunology is now expanding beyond bone and immune cells, defining new homeostatic networks in which other organs and systems are functionally interconnected. Therefore, the correct skeletal integrity maintenance may be also relevant to other functions outside its involvement in bone mineral homeostasis, hemopoiesis and immunity. PMID:27604089

Zinc Signals and Immunity.

PubMed

Maywald, Martina; Wessels, Inga; Rink, Lothar

2017-10-24

Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as "zinc waves", and late homeostatic zinc signals regarding prolonged changes in intracellular zinc.

Immune and genetic gardening of the intestinal microbiome

PubMed Central

Jacobs, Jonathan P.; Braun, Jonathan

2014-01-01

The mucosal immune system – consisting of adaptive and innate immune cells as well as the epithelium – is profoundly influenced by its microbial environment. There is now growing evidence that the converse is also true, that the immune system shapes the composition of the intestinal microbiome. During conditions of health, this bidirectional interaction achieves a homeostasis in which inappropriate immune responses to nonpathogenic microbes are averted and immune activity suppresses blooms of potentially pathogenic microbes (pathobionts). Genetic alteration in immune/epithelial function can affect host gardening of the intestinal microbiome, contributing to the diversity of intestinal microbiota within a population and in some cases allowing for unfavorable microbial ecologies (dysbiosis) that confer disease susceptibility. PMID:24613921

Plasmacytoid DC from Aged Mice Down-Regulate CD8 T Cell Responses by Inhibiting cDC Maturation after Encephalitozoon cuniculi Infection

PubMed Central

Gigley, Jason P.; Khan, Imtiaz A.

2011-01-01

Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations. PMID:21695169

Plasmacytoid DC from aged mice down-regulate CD8 T cell responses by inhibiting cDC maturation after Encephalitozoon cuniculi infection.

PubMed

Gigley, Jason P; Khan, Imtiaz A

2011-01-01

Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations.

Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tonk, Elisa C.M., E-mail: ilse.tonk@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Verhoef, Aart

The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10–50 or PND 50–90 atmore » doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology. -- Highlights: ► In this study we evaluate the relative sensitivities for DEHP induced effects. ► Results of this study demonstrate the age-dependency of DEHP toxicity. ► Functional immune parameters were more sensitive than structural immune parameters. ► Immune parameters were affected at lower dose levels than developmental parameters. ► Findings demonstrate the susceptibility of the developing immune system for DEHP.« less

Variation in sex pheromone emission does not reflect immunocompetence but affects attractiveness of male burying beetles—a combination of laboratory and field experiments

NASA Astrophysics Data System (ADS)

Chemnitz, Johanna; Bagrii, Nadiia; Ayasse, Manfred; Steiger, Sandra

2017-08-01

Life history theory predicts a trade-off between male sexual trait expression and immunocompetence. Using burying beetles, Nicrophorus vespilloides, as a model, we investigated the relationship between male immune function, sex pheromone emission, and attractiveness under field conditions. In the first experiment, we tested whether there is a positive correlation between immune capacity, sex pheromone characteristics (quantity, relative composition, and time invested in pheromone emission), and male attractiveness. As a measurement of immune capacity, we used an individual's encapsulation ability against a novel antigen. In the second experiment, we specifically examined whether a trade-off between chemical trait expression and immune function existed. To this end, we challenged the immune system and measured the subsequent investment in sex pheromone emission and the attractiveness of the male under field conditions. We found that a male's immunocompetence was neither related to the emission of the male's sex pheromone nor to its attractiveness in the field. Furthermore, none of the immune-challenge treatments affected the subsequent investment in pheromone emission or number of females attracted. However, we showed that the same males that emitted a high quantity of their sex pheromone in the laboratory were able to attract more females in the field. Our data suggest that the chemical signal is not a reliable predictor of a male's immunocompetence but rather is a general important fitness-related trait, with a higher emission of the sex pheromone measured in the laboratory directly affecting the attractiveness of a male under field conditions.

Variation in sex pheromone emission does not reflect immunocompetence but affects attractiveness of male burying beetles-a combination of laboratory and field experiments.

PubMed

Chemnitz, Johanna; Bagrii, Nadiia; Ayasse, Manfred; Steiger, Sandra

2017-08-01

Life history theory predicts a trade-off between male sexual trait expression and immunocompetence. Using burying beetles, Nicrophorus vespilloides, as a model, we investigated the relationship between male immune function, sex pheromone emission, and attractiveness under field conditions. In the first experiment, we tested whether there is a positive correlation between immune capacity, sex pheromone characteristics (quantity, relative composition, and time invested in pheromone emission), and male attractiveness. As a measurement of immune capacity, we used an individual's encapsulation ability against a novel antigen. In the second experiment, we specifically examined whether a trade-off between chemical trait expression and immune function existed. To this end, we challenged the immune system and measured the subsequent investment in sex pheromone emission and the attractiveness of the male under field conditions. We found that a male's immunocompetence was neither related to the emission of the male's sex pheromone nor to its attractiveness in the field. Furthermore, none of the immune-challenge treatments affected the subsequent investment in pheromone emission or number of females attracted. However, we showed that the same males that emitted a high quantity of their sex pheromone in the laboratory were able to attract more females in the field. Our data suggest that the chemical signal is not a reliable predictor of a male's immunocompetence but rather is a general important fitness-related trait, with a higher emission of the sex pheromone measured in the laboratory directly affecting the attractiveness of a male under field conditions.

The Hippo Pathway: Immunity and Cancer.

PubMed

Taha, Zaid; J Janse van Rensburg, Helena; Yang, Xiaolong

2018-03-28

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

Maternal nutritional status during pregnancy and infant immune response to routine childhood vaccinations.

PubMed

Obanewa, Olayinka; Newell, Marie-Louise

2017-09-01

To systematically review the association between maternal nutritional status in pregnancy and infant immune response to childhood vaccines. We reviewed literature on maternal nutrition during pregnancy, fetal immune system and vaccines and possible relationships. Thereafter, we undertook a systematic review of the literature of maternal nutritional status and infant vaccine response, extracted relevant information, assessed quality of the nine papers identified and present findings in a narrative format. From limited evidence of average quality, intrauterine nutrition deficiency could lead to functional deficit in the infant's immune function; child vaccine response may thus be negatively affected by maternal malnutrition. Response to childhood vaccination may be associated with fetal and early life environment; evaluation of programs should take this into account.

The Skin Microbiome: Is It Affected by UV-induced Immune Suppression?

PubMed Central

Patra, VijayKumar; Byrne, Scott N.; Wolf, Peter

2016-01-01

Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation (UV-R) from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin’s microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs) that interfere with UV-induced immune suppression. PMID:27559331

HIV enteropathy and aging: gastrointestinal immunity, mucosal epithelial barrier, and microbial translocation.

PubMed

Wang, Hongyin; Kotler, Donald P

2014-07-01

Despite decreases in morbidity and mortality as a result of antiretroviral therapy, gastrointestinal dysfunction remains common in HIV infection. Treated patients are at risk for complications of 'premature' aging, such as cardiovascular disease, osteopenia, neurocognitive decline, malignancies, and frailty. This review summarizes recent observations in this field. Mucosal CD4 lymphocytes, especially Th17 cells, are depleted in acute HIV and simian immune deficiency virus (SIV) infections, although other cell types also are affected. Reconstitution during therapy often is incomplete, especially in mucosa. Mucosal barrier function is affected by both HIV infection and aging and includes paracellular transport via tight junctions and uptake through areas of apoptosis; other factors may affect systemic antigen exposure. The resultant microbial translocation is associated with systemic immune activation in HIV and SIV infections. There is evidence of immune activation and microbial translocation in the elderly. The immune phenotypes of immunosenescence in HIV infection and aging appear similar. There are several targets for intervention; blockage of residual mucosal virus replication, preventing antigen uptake, modulating the microbiome, improving T cell recovery, combining therapies aimed at mucosal integrity, augmenting mucosal immunity, and managing traditional risk factors for premature aging in the general population. Aging may interact with HIV enteropathy to enhance microbial translocation and immune activation.

Effects of small increases in corticosterone levels on morphology, immune function, and feather development.

PubMed

Butler, Michael W; Leppert, Lynda L; Dufty, Alfred M

2010-01-01

Stressors encountered during avian development may affect an individual's phenotype, including immunocompetence, growth, and feather quality. We examined effects of simulated chronic low-level stress on American kestrel (Falco sparverius) nestlings. Continuous release of corticosterone, a hormone involved in the stress response, can model chronic stress in birds. We implanted 13-d-old males with either corticosterone-filled implants or shams and measured their growth, immune function, and feather coloration. We found no significant differences between groups at the end of the weeklong exposure period in morphometrics (mass, tarsus, wing length, and asymmetry), immunocompetence (cutaneous immunity, heterophil/lymphocyte ratio, and humoral immunity), or feather coloration. One week subsequent to implant removal, however, differences were detected. Sham-implanted birds had significantly longer wings and a reduced level of cutaneous immune function compared with those of birds given corticosterone-filled implants. Therefore, increases of only 2 ng/mL in basal corticosterone titer can have small but measurable effects on subsequent avian development.

The effect of pre-laying maternal immunization on offspring growth and immunity differs across experimentally altered postnatal rearing conditions in a wild songbird.

PubMed

Martyka, Rafał; Śliwińska, Ewa B; Martyka, Mirosław; Cichoń, Mariusz; Tryjanowski, Piotr

2018-01-01

Prenatal antibody transfer is an immune-mediated maternal effect by which females can shape postnatal offspring resistance to pathogens and parasites. Maternal antibodies passed on to offspring provide primary protection to neonates against diverse pathogenic antigens, but they may also affect offspring growth and influence the development of an offspring's own immune response. The effects of maternal antibodies on offspring performance commonly require that the disease environment experienced by a mother prior to breeding matches the environment encountered by her offspring after hatching/birth. However, other circumstances, like postnatal rearing conditions that affect offspring food availability, may also determine the effects of maternal antibodies on offspring growth and immunity. To date, knowledge about how prenatal immune-mediated maternal effects interact with various postnatal rearing conditions to affect offspring development and phenotype in wild bird population remains elusive. Here we experimentally studied the interactive effects of pre-laying maternal immunization with a bacterial antigen (lipopolysaccharide) and post-hatching rearing conditions, altered by brood size manipulation, on offspring growth and humoral immunity of wild great tits ( Parus major ). We found that maternal immunization and brood size manipulation interactively affected the growth and specific humoral immune response of avian offspring. Among nestlings reared in enlarged broods, only those that originated from immunized mothers grew better and were heavier at fledging stage compared to those that originated from non-immunized mothers. In contrast, no such effects were observed among nestlings reared in non-manipulated (control) broods. Moreover, offspring of immunized females had a stronger humoral immune response to lipopolysaccharide during postnatal development than offspring of non-immunized females, but only when the nestling was reared in control broods. This study demonstrates that offspring development and their ability to cope with pathogens after hatching are driven by mutual influences of pathogen-induced prenatal maternal effects and post-hatching rearing conditions. Our findings suggest that immune-mediated maternal effects may have context-dependent influences on offspring growth and immune function, related to the postnatal environmental conditions experienced by the progeny.

The zinc pool is involved in the immune-reconstituting effect of melatonin in pinealectomized mice.

PubMed

Mocchegiani, E; Bulian, D; Santarelli, L; Tibaldi, A; Muzzioli, M; Lesnikov, V; Pierpaoli, W; Fabris, N

1996-06-01

Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An involvement of the zinc pool in the immune-reconstituting effect of MEL in old mice has recently been documented. An altered zinc turnover and impaired immune functions are also evident in pinealectomized (px) mice. The present work investigates further the effect of "physiological" doses of MEL on the zinc pool and on thymic and peripheral immune functions in px mice. Daily injections of MEL (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance from negative to positive values. Thymic and peripheral immune functions, including plasma levels of interleukin-2, also recovered. The nontoxic effect of MEL on immune functions was observed in sham-operated mice. Because the half-life of MEL is very short (12 min), interruption of MEL treatment in px mice resulted, after 1 month, in a renewed negative crude zinc balance and a regression of immune functions. Both the zinc pool and immunological parameters were restored by 30 further days of MEL treatment. The existence of a significant correlation between zinc and thymic hormone after both cycles of MEL treatment clearly shows an involvement of the zinc pool in the immunoenhancing effects of MEL and thus suggests an inter-relationship between zinc and MEL in px mice. Moreover, the existence of significant positive correlations between zinc or thymulin and interleukin-2 suggests that interleukin-2 may participate in the action of MEL, via zinc, on thymic functions in px MEL-treated mice.

Immune functions of the garment workers.

PubMed

Sultana, R; Ferdous, K J; Hossain, M; Zahid, M S H; Islam, L N

2012-10-01

Occupational exposure to cotton dust, fibers, metal fumes and different chemicals used in the aparrel manufacturing industries cause a wide range of physical and psychological health problems in the garment workers that may also affect their immune function. To assess the immune system function in garment workers. A total of 45 workers of a garment factory, and 41 control subjects, not exposed to the garment working environment were enrolled in this study. In the study subjects, the complement system function was assessed as bactericidal activity on Escherichia coli DH5α cells using the standard plate count method. Serum complement components C3 and C4 were measured by immunoprecipitation, and IgG was measured by immunonephelometry. The bactericidal activity of serum complement in the garment workers (range: 93.5%-99.9%) was significantly (p<0.01) lower than that in the controls (range: 98.6%-100%). The heat-inactivated serum of the workers showed a significantly enhanced bactericidal activity. In the garment workers, the mean levels of complement C3, and C4 were 1.75 and 0.26 g/L, respectively that were close to those of the controls. The mean IgG level in the garment workers was 13.5 g/L that was significantly (p<0.001) higher than that in the controls. Working in a garment factory may affect the immune system.

A polysaccharide from Dictyophora indusiata inhibits the immunosuppressive function of cancer-associated fibroblasts.

PubMed

Han, Shuyu; Ma, Chaoxiong; Hu, Minghua; Wang, Yuanyuan; Ma, Fangli; Tao, Ning; Qin, Zhihai

2017-10-01

Reversing the function of cancer-associated fibroblasts (CAFs) may improve the efficacy of cancer therapy. Here, we isolated a novel polysaccharide from Dictyophora indusiata (ZSP4) and examined its effects on the function of prostate CAFs. The supernatant of prostate CAFs can stimulate the proliferation of immune cells and inhibit the growth of CD4+/CD8+ T cells. However, after ZSP4 stimulation, the functions of prostate CAFs were inhibited. The mechanism experiment shows that ZSP4 can stimulate prostate CAFs by down-regulating the expression of α-smooth muscle actin. Polysaccharides extracted from Dictyophora indusiata stimulate the proliferation of immune cells and reverse the immune-suppressive functions of prostate CAFs, shedding new light on the development of novel anticancer strategies. The endocrine therapy used to treat prostate cancer aims to eliminate androgenic activity from prostatic tissue; these therapies are painful and of poor therapeutic effect. In this study, we found that polysaccharides extracted from Dictyophora indusiata may affect the micro-environment of tumours and inhibit the growth of the tumours. Our results suggest that polysaccharides may modulate negative immune regulation and enhance antitumour immunity, which is important for clinical therapy. Copyright © 2017 John Wiley & Sons, Ltd.

T cell-B cell interactions in primary immunodeficiencies.

PubMed

Tangye, Stuart G; Deenick, Elissa K; Palendira, Umaimainthan; Ma, Cindy S

2012-02-01

Regulated interactions between cells of the immune system facilitate the generation of successful immune responses, thereby enabling efficient neutralization and clearance of pathogens and the establishment of both cell- and humoral-mediated immunological memory. The corollary of this is that impediments to efficient cell-cell interactions, normally necessary for differentiation and effector functions of immune cells, underly the clinical features and disease pathogenesis of primary immunodeficiencies. In affected individuals, these defects manifest as impaired long-term humoral immunity and susceptibility to infection by specific pathogens. In this review, we discuss the importance of, and requirements for, effective interactions between B cells and T cells during the formation of CD4(+) T follicular helper cells and the elicitation of cytotoxic function of virus-specific CD8(+) T cells, as well as how these processes are abrogated in primary immunodeficiencies due to loss-of-function mutations in defined genes. © 2012 New York Academy of Sciences.

Effects of feed naturally contaminated with Fusarium mycotoxins on metabolism and immunity of dairy cows.

PubMed

Korosteleva, S N; Smith, T K; Boermans, H J

2009-04-01

A previous study in dairy cows showed some effect of feed contaminated with Fusarium mycotoxins on metabolism and immunity. A subsequent experiment investigated the effect of feedborne Fusarium mycotoxins on some immune functions in more detail. A total mixed ration (TMR) containing a blend of feedstuffs naturally contaminated with Fusarium mycotoxins was fed for 63 d to 12 mid-lactation Holstein cows with an average milk production of 36 kg/d in a completely randomized design with repeated measures including 1) control TMR and 2) contaminated TMR. Wheat, corn, hay, and corn silage were the contaminated feedstuffs. Deoxynivalenol was the major contaminant and was found in TMR at 3.5 mg/kg of dry matter. The parameters measured were 1) performance: body weight, body condition score, dry matter intake, milk production, composition and somatic cell count; 2) health: blood serum chemistry, hematology, coagulation profile, and rumen fluid ammonia levels; 3) immune function: total serum immunoglobulins (IgA, IgG, IgM), specific antibody response to ovalbumin, and neutrophil phagocytosis. Dry matter intake, body weight, milk production, and milk composition were not affected by diet. Neutrophil phagocytosis was depressed throughout the experiment in cows fed the contaminated diet. Serum sodium concentrations and osmolality were significantly elevated throughout the experiment in cows fed the contaminated diet. Primary antibody response to ovalbumin immunization was higher in cows fed the contaminated diet compared with controls. It was concluded that feed naturally contaminated with Fusarium mycotoxins can affect metabolic parameters and immune function of dairy cows.

Perinatal inflammation and adult psychopathology: From preclinical models to humans.

PubMed

Depino, Amaicha Mara

2018-05-01

Perinatal environment plays a crucial role in brain development and determines its function through life. Epidemiological studies and clinical reports link perinatal exposure to infection and/or immune activation to various psychiatric disorders. In addition, accumulating evidence from animal models shows that perinatal inflammation can affect various behaviors relevant to psychiatric disorders such as schizophrenia, autism, anxiety and depression. Remarkably, the effects on behavior and brain function do not always depend on the type of inflammatory stimulus or the perinatal age targeted, so diverse inflammatory events can have similar consequences on the brain. Moreover, other perinatal environmental factors that affect behavior (e.g. diet and stress) also elicit inflammatory responses. Understanding the interplay between perinatal environment and inflammation on brain development is required to identify the mechanisms through which perinatal inflammation affect brain function in the adult animal. Evidence for the role of the peripheral immune system and glia on perinatal programming of behavior is discussed in this review, along with recent evidence for the role of epigenetic mechanisms affecting gene expression in the brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Activation of colo-rectal high-threshold afferent nerves by Interleukin-2 is tetrodotoxin-sensitive and upregulated in a mouse model of chronic visceral hypersensitivity.

PubMed

Campaniello, M A; Harrington, A M; Martin, C M; Ashley Blackshaw, L; Brierley, S M; Hughes, P A

2016-01-01

Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS). IBS patients often show alterations in innate and adaptive immune function which may contribute to symptoms. Immune mediators are known to modulate the activity of viscero-sensory afferent nerves, but the focus has been on the innate immune system. Interleukin-2 (IL-2) is primarily associated with adaptive immune responses but its effects on colo-rectal afferent function in health or disease are unknown. Myeloperoxidase (MPO) activity determined the extent of inflammation in health, acute trinitrobenzene-sulfonic acid (TNBS) colitis, and in our post-TNBS colitis model of chronic visceral hypersensitivity (CVH). The functional effects of IL-2 on high-threshold colo-rectal afferents and the expression of IL-2R and NaV 1.7 mRNA in colo-rectal dorsal root ganglia (DRG) neurons were compared between healthy and CVH mice. MPO activity was increased during acute colitis, but subsided to levels comparable to health in CVH mice. IL-2 caused direct excitation of colo-rectal afferents that was blocked by tetrodotoxin. IL-2 did not affect afferent mechanosensitivity in health or CVH. However, an increased proportion of afferents responded directly to IL-2 in CVH mice compared with controls (73% vs 33%; p < 0.05), and the abundance of IL-2R and NaV 1.7 mRNA was increased 3.5- and 2-fold (p < 0.001 for both) in colo-rectal DRG neurons. IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation. © 2015 John Wiley & Sons Ltd.

Eicosanoids: an emerging role in dendritic cell biology.

PubMed

Harizi, Hedi; Gualde, Norbert

2004-01-01

The arachidonic acid (AA)-derived metabolites, termed eicosanoids, are potent lipid mediators with a key role in immune and inflammatory responses. In the immune system, eicosanoids such as prostaglandins (PGs) and leukotrienes (LTs) are produced predominately by antigen-presenting cells (APC), including macrophages and dendritic cells (DC). DC constitute a family of bone marrow-derived professional APC that play a critical role in the induction and modulation of both innate and adaptive immunity. For many years, macrophages were considered as major producers of eicosanoids that are thought to drastically affect their function. Studies concerning the modulation of DC biology by eicosanoids show that PGs and LTs have the potential to affect the maturation, cytokine-producing capacity, Th cell-polarizing ability, and migration of DC. In addition, the development of DC from bone marrow progenitors appears to be under the control of some eicosanoids. Understanding the actions of eicosanoids and their receptors on APC functions is crucial for the generation of efficient DC for therapeutic purposes in patients. In this review, we summarize the current understanding of how DC functions are modulated by eicosanoids.

Plant innate immunity – sunny side up?

PubMed Central

Stael, Simon; Kmiecik, Przemyslaw; Willems, Patrick; Van Der Kelen, Katrien; Coll, Nuria S.; Teige, Markus; Van Breusegem, Frank

2016-01-01

Reactive oxygen species (ROS)- and calcium- dependent signaling pathways play well-established roles during plant innate immunity. Chloroplasts host major biosynthetic pathways and have central roles in energy production, redox homeostasis, and retrograde signaling. However, the organelle’s importance in immunity has been somehow overlooked. Recent findings suggest that the chloroplast also has an unanticipated function as a hub for ROS- and calcium-signaling that affects immunity responses at an early stage after pathogen attack. In this opinion article, we discuss a chloroplastic calcium-ROS signaling branch of plant innate immunity. We propose that this chloroplastic branch acts as a light-dependent rheostat that, through the production of ROS, influences the severity of the immune response. PMID:25457110

Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management.

PubMed

Sznol, Mario; Postow, Michael A; Davies, Marianne J; Pavlick, Anna C; Plimack, Elizabeth R; Shaheen, Montaser; Veloski, Colleen; Robert, Caroline

2017-07-01

Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Complex pattern of immune evasion in MSI colorectal cancer.

PubMed

Ozcan, Mine; Janikovits, Jonas; von Knebel Doeberitz, Magnus; Kloor, Matthias

2018-01-01

Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.

The Hippo Pathway: Immunity and Cancer

PubMed Central

J. Janse van Rensburg, Helena

2018-01-01

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work. PMID:29597279

Spaceflight and immune responses of Rhesus monkeys

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1994-01-01

Evidence from both human and rodent studies indicates that alterations in immunological parameters occur after space flight. The objective of this project is to determine the effects of space flight on immune responses of Rhesus monkeys. The expected significance of the work is a determination of the range of immunological functions of the Rhesus monkey, a primate similar in many ways to man, affected by space flight. Changes in immune responses that could yield alterations in resistance to infection may be determined as well as the duration of alterations in immune responses. Additional information on the nature of cellular interactions for the generation of immune responses may also be obtained.

DEVELOPMENT OF A RISK ASSESSMENT MODEL FOR THE EFFECTS OF ORGANOPHOSPHORUS PESTICIDES ON INFECTIOUS DISEASE SUSCEPTIBILITY AND THE IMMUNE SYSTEM

EPA Science Inventory

There is increased concern about the sublethal effects of organophosphorus (OP) pesticides on human and animal health. This class of chemicals has been shown to affect the immune function of macrophages and lymphocytes. Malathion, an OP compound, is one of the most widely used ...

Investment in constitutive immune function by north American elk experimentally maintained at two different population densities

Treesearch

Cynthia J. Downs; Kelley M. Stewart; Brian L. Dick; Daniel E Crocker

2015-01-01

Natural selection favors individuals that respond with effective and appropriate immune responses to macro or microparasites. Animals living in populations close to ecological carrying capacity experience increased intraspecific competition, and as a result are often in poor nutritional condition. Nutritional condition, in turn, affects the amount of endogenous...

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung.

PubMed

Cheng, Hang; Jin, Chengyan; Wu, Jing; Zhu, Shan; Liu, Yong-Jun; Chen, Jingtao

2017-12-01

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

The effects of electroshock on immune function and disease progression in juvenile spring chinook salmon

USGS Publications Warehouse

VanderKooi, S.P.; Maule, A.G.; Schreck, C.B.

2001-01-01

Although much is known about the effects of electroshock on fish physiology, consequences to the immune system and disease progression have not received attention. Our objectives were to determine the effects of electroshock on selected immune function in juvenile spring chinook salmon Oncorhynchus tshawytscha, the mechanism of any observed alteration, and the effects of electroshock on disease progression. We found that the ability of anterior kidney leukocytes to generate antibody-producing cells (APC) was suppressed 3 h after a pulsed-DC electroshock (300 V, 50 Hz, 8 ms pulse width) but recovered within 24 h. This response was similar in timing and magnitude to that of fish subjected to an acute handling stress. The mechanism of suppression is hypothesized to be via an elevation of plasma cortisol concentrations in response to stress. Other monitored immune functions, skin mucous lysozyme levels, and respiratory burst activity were not affected by exposure to electroshock. The progression of a Renibacterium salmoninarum (RS) infection may have been altered after exposure to an electroshock. The electroshock did not affect infection severity or the number of mortalities, but may have accelerated the time to death. The limited duration of APC suppression and lack of effects on lysozyme and respiratory burst, as well as infection severity and mortality levels in RS-infected fish, led us to conclude that electrofishing under the conditions we tested is a safe procedure in regards to immunity and disease.

EVALUATING THE IMPACTS OF COINFECTION ON IMMUNE SYSTEM FUNCTION OF THE DEER MOUSE ( PEROMYSCUS MANICULATUS) USING SIN NOMBRE VIRUS AND BARTONELLA AS MODEL PATHOGEN SYSTEMS.

PubMed

Lehmer, Erin M; Lavengood, Kathryn; Miller, Mason; Rodgers, Jacob; Fenster, Steven D

2018-01-01

:  Simultaneous infections with multiple pathogens can alter the function of the host's immune system, often resulting in additive or synergistic morbidity. We examined how coinfection with the common pathogens Sin Nombre virus (SNV) and Bartonella sp. affected aspects of the adaptive and innate immune responses of wild deer mice ( Peromyscus maniculatus). Adaptive immunity was assessed by measuring SNV antibody production; innate immunity was determined by measuring levels of C-reactive protein (CRP) in blood and the complement activity of plasma. Coinfected mice had reduced plasma complement activity and higher levels of CRP compared to mice infected with either SNV or Bartonella. However, antibody titers of deer mice infected with SNV were more than double those of coinfected mice. Plasma complement activity and CRP levels did not differ between uninfected deer mice and those infected with only Bartonella, suggesting that comorbid SNV and Bartonella infections act synergistically, altering the innate immune response. Collectively, our results indicated that the immune response of deer mice coinfected with both SNV and Bartonella differed substantially from individuals infected with only one of these pathogens. Results of our study provided unique, albeit preliminary, insight into the impacts of coinfection on immune system function in wild animal hosts and underscore the complexity of the immune pathways that exist in coinfected hosts.

Protein Malnutrition Modifies Innate Immunity and Gene Expression by Intestinal Epithelial Cells and Human Rotavirus Infection in Neonatal Gnotobiotic Pigs

PubMed Central

Paim, Francine C.; Kandasamy, Sukumar; Alhamo, Moyasar A.; Fischer, David D.; Langel, Stephanie N.; Deblais, Loic; Kumar, Anand; Chepngeno, Juliet; Shao, Lulu; Huang, Huang-Chi; Candelero-Rueda, Rosario A.; Rajashekara, Gireesh

2017-01-01

ABSTRACT Malnutrition affects millions of children in developing countries, compromising immunity and contributing to increased rates of death from infectious diseases. Rotavirus is a major etiological agent of childhood diarrhea in developing countries, where malnutrition is prevalent. However, the interactions between the two and their combined effects on immune and intestinal functions are poorly understood. In this study, we used neonatal gnotobiotic (Gn) pigs transplanted with the fecal microbiota of a healthy 2-month-old infant (HIFM) and fed protein-deficient or -sufficient bovine milk diets. Protein deficiency induced hypoproteinemia, hypoalbuminemia, hypoglycemia, stunting, and generalized edema in Gn pigs, as observed in protein-malnourished children. Irrespective of the diet, human rotavirus (HRV) infection early, at HIFM posttransplantation day 3 (PTD3), resulted in adverse health effects and higher mortality rates (45 to 75%) than later HRV infection (PTD10). Protein malnutrition exacerbated HRV infection and affected the morphology and function of the small intestinal epithelial barrier. In pigs infected with HRV at PTD10, there was a uniform decrease in the function and/or frequencies of natural killer cells, plasmacytoid dendritic cells, and CD103+ and apoptotic mononuclear cells and altered gene expression profiles of intestinal epithelial cells (chromogranin A, mucin 2, proliferating cell nuclear antigen, SRY-Box 9, and villin). Thus, we have established the first HIFM-transplanted neonatal pig model that recapitulates major aspects of protein malnutrition in children and can be used to evaluate physiologically relevant interventions. Our findings provide an explanation of why nutrient-rich diets alone may lack efficacy in malnourished children. IMPORTANCE Malnutrition and rotavirus infection, prevalent in developing countries, individually and in combination, affect the health of millions of children, compromising their immunity and increasing the rates of death from infectious diseases. However, the interactions between the two and their combined effects on immune and intestinal functions are poorly understood. We have established the first human infant microbiota-transplanted neonatal pig model of childhood malnutrition that reproduced the impaired immune, intestinal, and other physiological functions seen in malnourished children. This model can be used to evaluate relevant dietary and other health-promoting interventions. Our findings provide an explanation of why adequate nutrition alone may lack efficacy in malnourished children. PMID:28261667

Food supplementation and testosterone interact to influence reproductive behavior and immune function in Sceloporus graciosus.

PubMed

Ruiz, Mayté; French, Susannah S; Demas, Gregory E; Martins, Emília P

2010-02-01

The energetic resources in an organism's environment are essential for executing a wide range of life-history functions, including immunity and reproduction. Most energetic budgets, however, are limited, which can lead to trade-offs among competing functions. Increasing reproductive effort tends to decrease immunity in many cases, and increasing total energy via supplemental feedings can eliminate this effect. Testosterone (T), an important regulator of reproduction, and food availability are thus both potential factors regulating life-history processes, yet they are often tested in isolation of each other. In this study, we considered the effect of both food availability and elevated T on immune function and reproductive behavior in sagebrush lizards, Sceloporus graciosus, to assess how T and energy availability affect these trade-offs. We experimentally manipulated diet (via supplemental feedings) and T (via dermal patches) in males from a natural population. We determined innate immune response by calculating the bacterial killing capability of collected plasma exposed to Escherichia coli ex vivo. We measured reproductive behavior by counting the number of courtship displays produced in a 20-min sampling period. We observed an interactive effect of food availability and T-patch on immune function, with food supplementation increasing immunity in T-patch lizards. Additionally, T increased courtship displays in control food lizards. Lizards with supplemental food had higher circulating T than controls. Collectively, this study shows that the energetic state of the animal plays a critical role in modulating the interactions among T, behavior and immunity in sagebrush lizards and likely other species. Copyright 2009 Elsevier Inc. All rights reserved.

Food supplementation and testosterone interact to influence reproductive behavior and immune function in Sceloporous graciosus

PubMed Central

Ruiz, Mayté; French, Susannah S.; Demas, Gregory E.; Martins, Emília P.

2009-01-01

The energetic resources in an organism’s environment are essential for executing a wide range of life history functions, including immunity and reproduction. Most energetic budgets, however, are limited, which can lead to trade-offs among competing functions. Increasing reproductive effort tends to decrease immunity in many cases; and increasing total energy via supplemental feedings can eliminate this effect. Testosterone (T), an important regulator of reproduction, and food availability are thus both potential factors regulating life-history processes, yet they are often tested in isolation of each other. In this study, we considered the effect of both food availability and elevated T on immune function and reproductive behavior in sagebrush lizards, Sceloporus graciosus, to assess how T and energy availability affect these trade-offs. We experimentally manipulated diet (via supplemental feedings) and T (via dermal patches) in males from a natural population. We determined innate immune response by calculating the bacterial killing capability of collected plasma exposed to E. coli ex vivo. We measured reproductive behavior by counting the number of courtship displays produced in a 20-min sampling period. We observed an interactive effect of food availability and T-patch on immune function, with food supplementation increasing immunity in T-patch lizards. Additionally, T increased courtship displays in control food lizards. Lizards with supplemental food had higher circulating T than controls. Collectively, this study shows that the energetic state of the animal plays a critical role in modulating the interactions among T, behavior and immunity in sagebrush lizards and likely other species. PMID:19800885

The Emerging Role of Epigenetics in Inflammation and Immunometabolism.

PubMed

Raghuraman, Sukanya; Donkin, Ida; Versteyhe, Soetkin; Barrès, Romain; Simar, David

2016-11-01

Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 diabetes mellitus, and these are associated with alterations in the phenotype, function, and trafficking patterns of these cells. The first step in the development of effective therapeutic strategies is the identification of distinct epigenetic signatures associated with metabolic disorders. In this review we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract epigenetically driven metabolic complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of body condition on influenza A virus infection dynamics in mallards following a secondary exposure

PubMed Central

Webb, Colleen T.; Wilson, Kenneth R.; Bentler, Kevin T.; Mooers, Nicole L.; Ellis, Jeremy W.; Root, J. Jeffrey; Franklin, Alan B.; Shriner, Susan A.

2017-01-01

Migratory waterfowl are often viewed as vehicles for the global spread of influenza A viruses (IAVs), with mallards (Anas platyrhynchos) implicated as particularly important reservoir hosts. The physical demands and energetic costs of migration have been shown to influence birds’ body condition; poorer body condition may suppress immune function and affect the course of IAV infection. Our study evaluated the impact of body condition on immune function and viral shedding dynamics in mallards naturally exposed to an H9 IAV, and then secondarily exposed to an H4N6 IAV. Mallards were divided into three treatment groups of 10 birds per group, with each bird’s body condition manipulated as a function of body weight by restricting food availability to achieve either a -10%, -20%, or control body weight class. We found that mallards exhibit moderate heterosubtypic immunity against an H4N6 IAV infection after an infection from an H9 IAV, and that body condition did not have an impact on shedding dynamics in response to a secondary exposure. Furthermore, body condition did not affect aspects of the innate and adaptive immune system, including the acute phase protein haptoglobin, heterophil/lymphocyte ratios, and antibody production. Contrary to recently proposed hypotheses and some experimental evidence, our data do not support relationships between body condition, infection and immunocompetence following a second exposure to IAV in mallards. Consequently, while annual migration may be a driver in the maintenance and spread of IAVs, the energetic demands of migration may not affect susceptibility in mallards. PMID:28423047

Impact of body condition on influenza A virus infection dynamics in mallards following a secondary exposure.

PubMed

Dannemiller, Nicholas G; Webb, Colleen T; Wilson, Kenneth R; Bentler, Kevin T; Mooers, Nicole L; Ellis, Jeremy W; Root, J Jeffrey; Franklin, Alan B; Shriner, Susan A

2017-01-01

Migratory waterfowl are often viewed as vehicles for the global spread of influenza A viruses (IAVs), with mallards (Anas platyrhynchos) implicated as particularly important reservoir hosts. The physical demands and energetic costs of migration have been shown to influence birds' body condition; poorer body condition may suppress immune function and affect the course of IAV infection. Our study evaluated the impact of body condition on immune function and viral shedding dynamics in mallards naturally exposed to an H9 IAV, and then secondarily exposed to an H4N6 IAV. Mallards were divided into three treatment groups of 10 birds per group, with each bird's body condition manipulated as a function of body weight by restricting food availability to achieve either a -10%, -20%, or control body weight class. We found that mallards exhibit moderate heterosubtypic immunity against an H4N6 IAV infection after an infection from an H9 IAV, and that body condition did not have an impact on shedding dynamics in response to a secondary exposure. Furthermore, body condition did not affect aspects of the innate and adaptive immune system, including the acute phase protein haptoglobin, heterophil/lymphocyte ratios, and antibody production. Contrary to recently proposed hypotheses and some experimental evidence, our data do not support relationships between body condition, infection and immunocompetence following a second exposure to IAV in mallards. Consequently, while annual migration may be a driver in the maintenance and spread of IAVs, the energetic demands of migration may not affect susceptibility in mallards.

Abnormal Epigenetic Regulation of Immune System during Aging.

PubMed

Jasiulionis, Miriam G

2018-01-01

Epigenetics refers to the study of mechanisms controlling the chromatin structure, which has fundamental role in the regulation of gene expression and genome stability. Epigenetic marks, such as DNA methylation and histone modifications, are established during embryonic development and epigenetic profiles are stably inherited during mitosis, ensuring cell differentiation and fate. Under the effect of intrinsic and extrinsic factors, such as metabolic profile, hormones, nutrition, drugs, smoke, and stress, epigenetic marks are actively modulated. In this sense, the lifestyle may affect significantly the epigenome, and as a result, the gene expression profile and cell function. Epigenetic alterations are a hallmark of aging and diseases, such as cancer. Among biological systems compromised with aging is the decline of immune response. Different regulators of immune response have their promoters and enhancers susceptible to the modulation by epigenetic marks, which is fundamental to the differentiation and function of immune cells. Consistent evidence has showed the regulation of innate immune cells, and T and B lymphocytes by epigenetic mechanisms. Therefore, age-dependent alterations in epigenetic marks may result in the decline of immune function and this might contribute to the increased incidence of diseases in old people. In order to maintain health, we need to better understand how to avoid epigenetic alterations related to immune aging. In this review, the contribution of epigenetic mechanisms to the loss of immune function during aging will be discussed, and the promise of new means of disease prevention and management will be pointed.

The impact of acute stress on hormones and cytokines, and how their recovery is affected by music-evoked positive mood

PubMed Central

Koelsch, Stefan; Boehlig, Albrecht; Hohenadel, Maximilian; Nitsche, Ines; Bauer, Katrin; Sack, Ulrich

2016-01-01

Stress and recovery from stress significantly affect interactions between the central nervous system, endocrine pathways, and the immune system. However, the influence of acute stress on circulating immune-endocrine mediators in humans is not well known. Using a double-blind, randomized study design, we administered a CO2 stress test to n = 143 participants to identify the effects of acute stress, and recovery from stress, on serum levels of several mediators with immune function (IL-6, TNF-α, leptin, and somatostatin), as well as on noradrenaline, and two hypothalamic–pituitary–adrenal axis hormones (ACTH and cortisol). Moreover, during a 1 h-recovery period, we repeatedly measured these serum parameters, and administered an auditory mood-induction protocol with positive music and a neutral control stimulus. The acute stress elicited increases in noradrenaline, ACTH, cortisol, IL-6, and leptin levels. Noradrenaline and ACTH exhibited the fastest and strongest stress responses, followed by cortisol, IL-6 and leptin. The music intervention was associated with more positive mood, and stronger cortisol responses to the acute stressor in the music group. Our data show that acute (CO2) stress affects endocrine, immune and metabolic functions in humans, and they show that mood plays a causal role in the modulation of responses to acute stress. PMID:27020850

Genome-wide analysis of alternative splicing during dendritic cell response to a bacterial challenge.

PubMed

Rodrigues, Raquel; Grosso, Ana Rita; Moita, Luís

2013-01-01

The immune system relies on the plasticity of its components to produce appropriate responses to frequent environmental challenges. Dendritic cells (DCs) are critical initiators of innate immunity and orchestrate the later and more specific adaptive immunity. The generation of diversity in transcriptional programs is central for effective immune responses. Alternative splicing is widely considered a key generator of transcriptional and proteomic complexity, but its role has been rarely addressed systematically in immune cells. Here we used splicing-sensitive arrays to assess genome-wide gene- and exon-level expression profiles in human DCs in response to a bacterial challenge. We find widespread alternative splicing events and splicing factor transcriptional signatures induced by an E. coli challenge to human DCs. Alternative splicing acts in concert with transcriptional modulation, but these two mechanisms of gene regulation affect primarily distinct functional gene groups. Alternative splicing is likely to have an important role in DC immunobiology because it affects genes known to be involved in DC development, endocytosis, antigen presentation and cell cycle arrest.

Zinc Signals and Immunity

PubMed Central

Maywald, Martina; Wessels, Inga; Rink, Lothar

2017-01-01

Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as “zinc waves”, and late homeostatic zinc signals regarding prolonged changes in intracellular zinc. PMID:29064429

Inborn Errors in Immunity

PubMed Central

Lionakis, M.S.; Hajishengallis, G.

2015-01-01

In recent years, the study of genetic defects arising from inborn errors in immunity has resulted in the discovery of new genes involved in the function of the immune system and in the elucidation of the roles of known genes whose importance was previously unappreciated. With the recent explosion in the field of genomics and the increasing number of genetic defects identified, the study of naturally occurring mutations has become a powerful tool for gaining mechanistic insight into the functions of the human immune system. In this concise perspective, we discuss emerging evidence that inborn errors in immunity constitute real-life models that are indispensable both for the in-depth understanding of human biology and for obtaining critical insights into common diseases, such as those affecting oral health. In the field of oral mucosal immunity, through the study of patients with select gene disruptions, the interleukin-17 (IL-17) pathway has emerged as a critical element in oral immune surveillance and susceptibility to inflammatory disease, with disruptions in the IL-17 axis now strongly linked to mucosal fungal susceptibility, whereas overactivation of the same pathways is linked to inflammatory periodontitis. PMID:25900229

The role of cytokines in immune changes induced by spaceflight

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Miller, E. S.

1993-01-01

It has become apparent that spaceflight alters many immune responses. Among the regulatory components of the immune response that have been shown to be affected by spaceflight is the cytokine network. Spaceflight, as well as model systems of spaceflight, have been shown to affect the production and action of various cytokines including interferons, interleukins, colony stimulating factors, and tumor necrosis factors. These changes have been shown not to involve a general shutdown of the cytokine network but, rather, to involve selective alterations of specific cytokine functions by spaceflight. The full breadth of changes in cytokines induced by spaceflight, as well as mechanisms, duration, adaptation, reversibility, and significance to resistance to infection and neoplastic diseases, remains to be established.

Sex-specific life history responses to nymphal diet quality and immune status in a field cricket.

PubMed

Kelly, C D; Neyer, A A; Gress, B E

2014-02-01

Individual fitness is expected to benefit from earlier maturation at a larger body size and higher body condition. However, poor nutritional quality or high prevalence of disease make this difficult because individuals either cannot acquire sufficient resources or must divert resources to other fitness-related traits such as immunity. Under such conditions, individuals are expected to mature later at a smaller body size and in poorer body condition. Moreover, the juvenile environment can also produce longer-term effects on adult fitness by causing shifts in resource allocation strategies that could alter investment in immune function and affect adult lifespan. We manipulated diet quality and immune status of juvenile Texas field crickets, Gryllus texensis, to investigate how poor developmental conditions affect sex-specific investment in fitness-related traits. As predicted, a poor juvenile diet was related to smaller mass and body size at eclosion in both sexes. However, our results also reveal sexually dimorphic responses to different facets of the rearing environment: female life history decisions are affected more by diet quality, whereas males are affected more by immune status. We suggest that females respond to decreased nutritional income because this threatens their ability to achieve a large adult body size, whereas male fitness is more dependent on reaching adulthood and so they invest in immunity and survival to eclosion. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

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

PubMed Central

Seppälä, Otto; Langeloh, Laura

2016-01-01

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

The trenbolone acetate affects the immune system in rainbow trout, Oncorhynchus mykiss.

PubMed

Massart, Sophie; Redivo, Baptiste; Flamion, Enora; Mandiki, S N M; Falisse, Elodie; Milla, Sylvain; Kestemont, Patrick

2015-06-01

In aquatic systems, the presence of endocrine-disrupting chemicals (EDC) can disrupt the reproductive function but also the immune system of wildlife. Some studies have investigated the effects of androgens on the fish immune parameters but the mechanisms by which the xenoandrogens alter the immunity are not well characterized. In order to test the effects of trenbolone acetate (TbA) on fish immune system, we exposed rainbow trout male juveniles during three weeks to TbA levels at 0.1 and 1μg/L. The present results suggest that TbA impacts, in a tissue-dependent manner, the rainbow trout immunity by affecting primarily the humoral immunity. Indeed, TbA inhibited lysozyme activity in plasma and liver and enhanced the alternative complement pathway activity (ACH50) in kidney. In plasma, the modulation of the complement system was time-dependent. The mRNA expression of genes encoding some cytokines such as renal TGF-β1, TNF-α in skin and hepatic IL-1β was also altered in fish exposed to TbA. Regarding the cellular immunity, no effect was observed on the leucocyte population. However, the expression of genes involved in the development and maturation of lymphoid cells (RAG-1 and RAG-2) was decreased in TbA-treated fish. Among those effects, we suggest that the modulation of RAG-1 and mucus apolipoprotein-A1 gene expression as well as plasma and hepatic lysozyme activities are mediated through the action of the androgen receptor. All combined, we conclude that trenbolone affects the rainbow trout immunity. Copyright © 2015 Elsevier B.V. All rights reserved.

How and why do T cells and their derived cytokines affect the injured and healthy brain?

PubMed Central

Filiano, Anthony J.; Gadani, Sachin P.; Kipnis, Jonathan

2018-01-01

The evolution of adaptive immunity provides enhanced defence against specific pathogens, as well as homeostatic immune surveillance of all tissues. Despite being ‘immune privileged’, the CNS uses the assistance of the immune system in physiological and pathological states. In this Opinion article, we discuss the influence of adaptive immunity on recovery after CNS injury and on cognitive and social brain function. We further extend a hypothesis that the pro-social effects of interferon-regulated genes were initially exploited by pathogens to increase host–host transmission, and that these genes were later recycled by the host to form part of an immune defence programme. In this way, the evolution of adaptive immunity may reflect a host–pathogen ‘arms race’. PMID:28446786

Some basic properties of immune selection.

PubMed

Iwasa, Yoh; Michor, Franziska; Nowak, Martin

2004-07-21

We analyze models for the evolutionary dynamics of viral or other infectious agents within a host. We study how the invasion of a new strain affects the composition and diversity of the viral population. We show that--under strain-specific immunity--the equilibrium abundance of uninfected cells declines during viral evolution. In addition, for cytotoxic immunity the absolute force of infection, and for non-cytotoxic immunity the absolute cellular virulence increases during viral evolution. We prove global stability by means of Lyapunov functions. These unidirectional trends of virus evolution under immune selection do not hold for general cross-reactive immune responses, which introduce frequency-dependent selection among viral strains. Therefore, appropriate cross-reactive immunity can lead to a viral evolution within a host which limits the extent of the disease.

Immunochemistry of Rat Lung Tumorigenesis

DTIC Science & Technology

1981-10-01

immunosuppressive and that both humoral and cell-mediated immune responses are affected (Stjernsward, 1969, 1972 and Prehn , 1963). The relationship of...M.A. and R.T. Prehn , (1972), Immune Status of Autochtonous and Adoptively Protected Mice Toward Spontaneous and Chemically Induced Tumors, Cancer Res...in Human Chromosomes, Hum. Genet. 38:271-278. Prehn , R.T., (1963), Function of Depressed Immunologic Reactivity during Carcinogenesis, J. Natl. Cancer

Psychoneuroimmunology in Pregnancy: Immune Pathways Linking Stress with Maternal Health, Adverse Birth Outcomes, and Fetal Development

PubMed Central

Christian, Lisa M.

2011-01-01

It is well-established that psychological stress promotes immune dysregulation in nonpregnant humans and animals. Stress promotes inflammation, impairs antibody responses to vaccination, slows wound healing, and suppresses cell-mediated immune function. Importantly, the immune system changes substantially to support healthy pregnancy, with attenuation of inflammatory responses and impairment of cell-mediated immunity. This adaptation is postulated to protect the fetus from rejection by the maternal immune system. Thus, stress-induced immune dysregulation during pregnancy has unique implications for both maternal and fetal health, particularly preterm birth. However, very limited research has examined stress-immune relationships in pregnancy. The application of psychoneuroimmunology research models to the perinatal period holds great promise for elucidating biological pathways by which stress may affect adverse pregnancy outcomes, maternal health, and fetal development. PMID:21787802

Equity and immunization supply chain in Madagascar.

PubMed

van den Ent, Maya M V X; Yameogo, Andre; Ribaira, Eric; Hanson, Celina M; Ratoto, Ramiandrasoa; Rasolomanana, Saholy; Foncha, Chrysanthus; Gasse, François

2017-04-19

Vaccination rates have improved in many countries, yet immunization inequities persist within countries and the poorest communities often bear the largest burden of vaccine preventable disease. Madagascar has one of the world's largest equity gaps in immunization rates. Barriers to immunization include immunization supply chain, human resources, and service delivery to reflect the health system building blocks, which affect poor rural communities more than affluent communities. The Reaching Every District (RED) approach was revised to address barriers and bottlenecks. This approach focuses on the provision of regular services, including making cold chain functional. This report describes Madagascar's inequities in immunization, its programmatic causes and the country's plans to address barriers to immunization in the poorest regions in the country. Two cross-sectional health facility surveys conducted in November and December 2013 and in March 2015 were performed in four regions of Madagascar to quantify immunization system barriers. Of the four regions studied, 26-33% of the population live beyond 5km (km) of a health center. By 2015, acceptable (fridges stopped working for less than 6days) cold chains were found in 52-80% of health facilities. Only 10-57% of health centers had at least two qualified health workers. Between 65% and 95% of planned fixed vaccination sessions were conducted and 50-88% of planned outreach sessions were conducted. The proportion of planned outreach sessions that were conducted increased between the two surveys. Madagascar's immunization program faces serious challenges and those affected most are the poorest populations. Major inequities in immunization were found at the subnational level and were mainly geographic in nature. Approaches to improve immunization systems need to be equitable. This may include the replacement of supply chain equipment with those powered by sustainable energy sources, monitoring its functionality at health facility level and vaccination services in all communities. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Infant pain-related negative affect at 12 months of age: early infant and caregiver predictors.

PubMed

Din Osmun, Laila; Pillai Riddell, Rebecca; Flora, David B

2014-01-01

To examine the predictive relationships of early infant and caregiver variables on expressed pain-related negative affect duration at the 12-month immunization. Infants and their caregivers (N = 255) were followed during immunization appointments over the first year of life. Latent growth curve modeling in a structural equation modeling context was used. Higher levels of initial infant pain reactivity at 2 months and caregiver emotional availability averaged across 2, 4, and 6 months of age were related to larger decreases in the duration of infant negative affect over the first 6 months of life. Longer duration of infant negative affect at 2 months and poorer regulation of infant negative affect over the first 6 months of life predicted longer durations of infant negative affect by 12 months. Infant negative affect at 12 months was a function of both infant factors and the quality of caregiver interactive behaviors (emotional availability) in early infancy.

Oxytocin-secreting system: A major part of the neuroendocrine center regulating immunologic activity.

PubMed

Wang, Ping; Yang, Hai-Peng; Tian, Shujun; Wang, Liwei; Wang, Stephani C; Zhang, Fengmin; Wang, Yu-Feng

2015-12-15

Interactions between the nervous system and immune system have been studied extensively. However, the mechanisms underlying the neural regulation of immune activity, particularly the neuroendocrine regulation of immunologic functions, remain elusive. In this review, we provide a comprehensive examination of current evidence on interactions between the immune system and hypothalamic oxytocin-secreting system. We highlight the fact that oxytocin may have significant effects in the body, beyond its classical functions in lactation and parturition. Similar to the hypothalamo-pituitary-adrenal axis, the oxytocin-secreting system closely interacts with classical immune system, integrating both neurochemical and immunologic signals in the central nervous system and in turn affects immunologic defense, homeostasis, and surveillance. Lastly, this review explores therapeutic potentials of oxytocin in treating immunologic disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Immunotoxicological effects of JP-8 jet fuel exposure.

PubMed

Harris, D T; Sakiestewa, D; Robledo, R F; Witten, M

1997-01-01

Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed (3-5). Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.); e.g., the immune system. Significant changes in immune consequences, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long-lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed for 1h/day for 7 days to varying concentrations of aerosolized JP-8 jet fuel to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on their immune systems. It was observed that even at exposure concentrations as low as 100 mg/m3 detrimental effects on the immune system occurred. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in losses of different immune cell subpopulations depending upon the immune organ being examined. Further, JP-8 exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low concentration exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure, as effects were seen at concentrations of jet fuel that did not evidence change in other biological systems. Such changes may have significant effects on the health of the exposed individual.

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3

PubMed Central

Goettel, Jeremy A.; Biswas, Subhabrata; Lexmond, Willem S.; Yeste, Ada; Passerini, Laura; Patel, Bonny; Yang, Siyoung; Sun, Jiusong; Ouahed, Jodie; Shouval, Dror S.; McCann, Katelyn J.; Horwitz, Bruce H.; Mathis, Diane; Milford, Edgar L.; Notarangelo, Luigi D.; Roncarolo, Maria-Grazia; Fiebiger, Edda; Marasco, Wayne A.; Bacchetta, Rosa; Quintana, Francisco J.; Pai, Sung-Yun; Klein, Christoph; Muise, Aleixo M.

2015-01-01

Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific “humanized” mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics. PMID:25833964

Amino acid catabolism: a pivotal regulator of innate and adaptive immunity

PubMed Central

McGaha, Tracy L.; Huang, Lei; Lemos, Henrique; Metz, Richard; Mautino, Mario; Prendergast, George C.; Mellor, Andrew L.

2014-01-01

Summary Enhanced amino acid catabolism is a common response to inflammation, but the immunologic significance of altered amino acid consumption remains unclear. The finding that tryptophan catabolism helped maintain fetal tolerance during pregnancy provided novel insights into the significance of amino acid metabolism in controlling immunity. Recent advances in identifying molecular pathways that enhance amino acid catabolism and downstream mechanisms that affect immune cells in response to inflammatory cues support the notion that amino acid catabolism regulates innate and adaptive immune cells in pathologic settings. Cells expressing enzymes that degrade amino acids modulate antigen-presenting cell and lymphocyte functions and reveal critical roles for amino acid- and catabolite-sensing pathways in controlling gene expression, functions, and survival of immune cells. Basal amino acid catabolism may contribute to immune homeostasis that prevents autoimmunity, whereas elevated amino acid catalytic activity may reinforce immune suppression to promote tumorigenesis and persistence of some pathogens that cause chronic infections. For these reasons, there is considerable interest in generating novel drugs that inhibit or induce amino acid consumption and target downstream molecular pathways that control immunity. In this review, we summarize recent developments and highlight novel concepts and key outstanding questions in this active research field. PMID:22889220

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases

PubMed Central

Xu, Joella; Huang, Guannan; Guo, Tai L.

2016-01-01

Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases. PMID:29051427

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases.

PubMed

Xu, Joella; Huang, Guannan; Guo, Tai L

2016-09-26

Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases.

A randomized controlled crossover trial of the effect of ginseng consumption on the immune response to moderate exercise in healthy sedentary men.

PubMed

Biondo, Patricia D; Robbins, Sarah J; Walsh, Jennifer D; McCargar, Linda J; Harber, Vicki J; Field, Catherine J

2008-10-01

Ginseng is a popular herbal remedy that is reputed to increase resistance to stress and improve immune function. Regular exercise results in acute physiologic stress that affects the immune response. This study was conducted to investigate the effects of daily consumption of a standardized ginsenoside-containing North American ginseng (Panax quinquefolius) extract on immune function before, during, and after a moderate-exercise protocol in healthy sedentary men. Ten healthy males were randomized to receive either ginseng (1125 mg.d-1) or placebo for 35 days. After a 3 month washout period, subjects received the opposite treatment for another 35 days. An exercise test and blood collection were performed at the end of each treatment period. Immune parameters and blood hormone levels were measured before, during, and after the exercise stress protocol. Ginseng treatment reduced the peripheral blood concentration of CD8+ T cells and increased mitogen-stimulated T cell production of interleukin-2 ex vivo. Ginseng had no effect on total white blood cell counts; on concentrations of neutrophils, monocytes, or lymphocytes (CD3+, CD4+, CD16+, CD20+); on lymphocyte proliferation; or on neutrophil oxidative burst. Ginseng did not significantly affect exercise-induced changes in plasma concentrations of lactate, insulin, cortisol, or growth hormone. The consumption of ginseng for 5 weeks had a limited effect on the immune response to an acute exercise protocol.

Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity.

PubMed

Janelsins, Brian M; Mathers, Alicia R; Tkacheva, Olga A; Erdos, Geza; Shufesky, William J; Morelli, Adrian E; Larregina, Adriana T

2009-03-26

Dendritic cells (DCs) are the preferred targets for immunotherapy protocols focused on stimulation of cellular immune responses. However, regardless of initial promising results, ex vivo generated DCs do not always promote immune-stimulatory responses. The outcome of DC-dependent immunity is regulated by proinflammatory cytokines and neuropeptides. Proinflammatory neuropeptides of the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), bind the neurokinin 1 receptor (NK1R) and promote stimulatory immune responses. Nevertheless, the ability of pro-inflammatory tachykinins to affect the immune functions of DCs remains elusive. In the present work, we demonstrate that mouse bone marrow-derived DCs (BMDCs) generated in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), express functional NK1R. Signaling via NK1R with SP, HK-1, or the synthetic agonist [Sar(9)Met(O(2))(11)]-SP rescues DCs from apoptosis induced by deprivation of GM-CSF and IL-4. Mechanistic analysis demonstrates that NK1R agonistic binding promotes DC survival via PI3K-Akt signaling cascade. In adoptive transfer experiments, NK1R-signaled BMDCs loaded with Ag exhibit increased longevity in draining lymph nodes, resulting in enhanced and prolonged effector cellular immunity. Our results contribute to the understanding of the interactions between the immune and nervous systems that control DC function and present a novel approach for ex vivo-generation of potent immune-stimulatory DCs.

Proliferation capacity of T-lymphocytes is affected transiently after a long-term weight gain in Beagle dogs.

PubMed

Van de Velde, H; Janssens, G P J; Rochus, K; Duchateau, L; Scharek-Tedin, L; Zentek, J; Nguyen, P; Cox, E; Buyse, J; Biourge, V; Hesta, M

2013-04-15

Across species obesity is associated with several disorders but in companion animals little information is available on the impact of chronic obesity on immune competence. The aim of the present study was to investigate whether weight gain and stable obese bodyweight affects the immune cell response. Obesity was induced in eight adult healthy beagle dogs (weight gain group; WGG) by a weight gain period (WGP) of 47 weeks, which was immediately followed by a period (stable period: SP) of stable obesity of 26 weeks. Eight adult healthy beagle dogs were included as a control group (CG) and remained at their ideal bodyweight throughout the entire study. Body composition was measured at five intervening time-points. Concentration of serum leptin and inflammatory cytokines, functionality of lymphocytes and phagocytic activity of neutrophils and monocytes were evaluated at ten intervening time-points. Serum leptin concentration was rising during the WGP in the WGG but went to lower concentrations during the SP. At the end of long-term weight gain, a decreased mitogen-induced proliferation of T-lymphocytes was noted but this alteration seemed to be transient after stabilization of bodyweight. This finding may imply an altered immune response for dogs with different energy balances. However, no systemic low grade inflammation or alteration in other immune cell functions was observed. Consequently it is suggested that the change in energy balance during the onset of obesity (becoming obese versus being obese), evokes an additional obesity-related disorder in dogs, i.e. impaired T-lymphocyte immune function. Copyright © 2013 Elsevier B.V. All rights reserved.

Short Term, Low Dose Simvastatin Pretreatment Alters Memory Immune Function Following Secondary Staphylococcus aureus Infection.

PubMed

Smelser, Lisa K; Walker, Callum; Burns, Erin M; Curry, Michael; Black, Nathanael; Metzler, Jennifer A; McDowell, Susan A; Bruns, Heather A

Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function.

Effects of Fenbendazole on Routine Immune Response Parameters of BALB/c Mice

PubMed Central

Cray, Carolyn; Villar, David; Zaias, Julia; Altman, Norman H

2008-01-01

Fenbendazole (FBZ) is an anthelmintic drug widely used to treat and prevent pinworm outbreaks in laboratory rodents. Although data in nonrodent species indicate possible effects of fenbendazole on the bone marrow and lymphocyte proliferation and function, little has been reported regarding possible effects on the rodent immune system. The purpose of the current study was to determine the effects of a therapeutic regimen of FBZ on immune parameters in BALB/c mice. Both 9-wk on–off and 5-wk continuous medicated feed protocols were assessed. No significant differences between normal and FBZ diet treated mice were observed in the following parameters: complete blood count, blood chemistry, quantitation of major T and B cell markers in spleen, quantitation of T cell markers in the thymus, spleen cell proliferation to T and B cell mitogens, bone marrow colony-forming cell assays, skin graft rejection, and primary and secondary humoral immune responses. These data indicate that FBZ treatment does not affect many standard broad measures of immune function. PMID:19049250

Effects of fenbendazole on routine immune response parameters of BALB/c mice.

PubMed

Cray, Carolyn; Villar, David; Zaias, Julia; Altman, Norman H

2008-11-01

Fenbendazole (FBZ) is an anthelmintic drug widely used to treat and prevent pinworm outbreaks in laboratory rodents. Although data in nonrodent species indicate possible effects of fenbendazole on the bone marrow and lymphocyte proliferation and function, little has been reported regarding possible effects on the rodent immune system. The purpose of the current study was to determine the effects of a therapeutic regimen of FBZ on immune parameters in BALB/c mice. Both 9-wk on-off and 5-wk continuous medicated feed protocols were assessed. No significant differences between normal and FBZ diet treated mice were observed in the following parameters: complete blood count, blood chemistry, quantitation of major T and B cell markers in spleen, quantitation of T cell markers in the thymus, spleen cell proliferation to T and B cell mitogens, bone marrow colony-forming cell assays, skin graft rejection, and primary and secondary humoral immune responses. These data indicate that FBZ treatment does not affect many standard broad measures of immune function.

Stem cells and aging from a quasi-immortal point of view.

PubMed

Boehm, Anna-Marei; Rosenstiel, Philip; Bosch, Thomas C G

2013-11-01

Understanding aging and how it affects an organism's lifespan is a fundamental problem in biology. A hallmark of aging is stem cell senescence, the decline of functionality, and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodeling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune-senescence. Yet, what is causing stem cell and immune-senescence? This review discusses experimental studies of potentially immortal Hydra which have made contributions to answering this question. Hydra transcription factor FoxO has been shown to modulate both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate-of-aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging. © 2013 WILEY Periodicals, Inc.

The effect of protective nutrients on mucosal defense in the immature intestine.

PubMed

Forchielli, Maria L; Walker, W Allan

2005-10-01

Oral nutrition plays a dual role in the gut, providing nutrition to the body while affecting the function of the gastrointestinal tract. The exposure of the gut to food antigens, in the form of either beneficial or harmful nutritional substances, contributes to a vast array of physiological and pathologic gastrointestinal responses with secondary systemic implications. The immune system of the gastrointestinal tract is always involved in the first line of defense, and its actions are particularly important in the early period of life as maturation takes place. From maturation, a balance ensues in the regulatory mechanism of host defense, ultimately leading to either tolerance or immune reaction. This paper emphasizes how some nutrients may beneficially affect the gastrointestinal immune system's maturation in both term and especially premature neonates.

Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging.

PubMed

Palmer, Clovis S; Palchaudhuri, Riya; Albargy, Hassan; Abdel-Mohsen, Mohamed; Crowe, Suzanne M

2018-01-01

An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of "inflammaging", a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV + individuals.

The requirement of iron transport for lymphocyte function.

PubMed

Lo, Bernice

2016-01-01

Iron is essential in multiple cellular processes and is especially critical for cellular respiration and division. A new study identified a mutation affecting the iron import receptor TfR1 as the cause of a human primary immunodeficiency, illuminating the importance of iron in immune cell function.

Collaborating with the enemy: function of macrophages in the development of neoplastic disease.

PubMed

Eljaszewicz, Andrzej; Wiese, Małgorzata; Helmin-Basa, Anna; Jankowski, Michal; Gackowska, Lidia; Kubiszewska, Izabela; Kaszewski, Wojciech; Michalkiewicz, Jacek; Zegarski, Wojciech

2013-01-01

Due to the profile of released mediators (such as cytokines, chemokines, growth factors, etc.), neoplastic cells modulate the activity of immune system, directly affecting its components both locally and peripherally. This is reflected by the limited antineoplastic activity of the immune system (immunosuppressive effect), induction of tolerance to neoplastic antigens, and the promotion of processes associated with the proliferation of neoplastic tissue. Most of these responses are macrophages dependent, since these cells show proangiogenic properties, attenuate the adaptive response (anergization of naïve T lymphocytes, induction of Treg cell formation, polarization of immune response towards Th2, etc.), and support invasion and metastases formation. Tumor-associated macrophages (TAMs), a predominant component of leukocytic infiltrate, "cooperate" with the neoplastic tissue, leading to the intensified proliferation and the immune escape of the latter. This paper characterizes the function of macrophages in the development of neoplastic disease.

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

PubMed Central

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

2015-01-01

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

Latent Herpes Viruses Reactivation in Astronauts

NASA Technical Reports Server (NTRS)

Mehta, Satish K.; Pierson, Duane L.

2008-01-01

Space flight has many adverse effects on human physiology. Changes in multiple systems, including the cardiovascular, musculoskeletal, neurovestibular, endocrine, and immune systems have occurred (12, 32, 38, 39). Alterations in drug pharmacokinetics and pharmacodynamics (12), nutritional needs (31), renal stone formation (40), and microbial flora (2) have also been reported. Evidence suggests that the magnitude of some changes may increase with time in space. A variety of changes in immunity have been reported during both short (.16 days) and long (>30 days) space missions. However, it is difficult to determine the medical significance of these immunological changes in astronauts. Astronauts are in excellent health and in superb physical condition. Illnesses in astronauts during space flight are not common, are generally mild, and rarely affect mission objectives. In an attempt to clarify this issue, we identified the latent herpes viruses as medically important indicators of the effects of space flight on immunity. This chapter demonstrates that space flight leads to asymptomatic reactivation of latent herpes viruses, and proposes that this results from marked changes in neuroendocrine function and immunity caused by the inherent stressfullness of human space flight. Astronauts experience uniquely stressful environments during space flight. Potential stressors include confinement in an unfamiliar, crowded environment, isolation, separation from family, anxiety, fear, sleep deprivation, psychosocial issues, physical exertion, noise, variable acceleration forces, increased radiation, and others. Many of these are intermittent and variable in duration and intensity, but variable gravity forces (including transitions from launch acceleration to microgravity and from microgravity to planetary gravity) and variable radiation levels are part of each mission and contribute to a stressful environment that cannot be duplicated on Earth. Radiation outside the Earth's magnetosphere is particularly worrisome because it includes ionizing radiation from cosmic galactic radiation. Increased stress levels appear even before flight, presumably from the rigors of preflight training and the anticipation of the mission (12, 32, 38, 39). Space flight causes significant changes in human immune function (32), but the means by which these changes come about have been difficult to discern. Consistent indicators of stress associated with space flight include increased production of stress hormones, and changes in cells of the immune system. These changes include elevated white blood cell (WBC) and neutrophil counts at landing (15, 16, 35, 37). Activation of generalized stress responses before, during, and after space flight probably affects the function of the immune system. Space flight has been shown to decrease many aspects of immune function, including natural killer (NK) cell activity, interferon production, the blastogenic response of leukocytes to mitogens, cell-mediated immunity, neutrophil function and monocyte function (5, 16, 18, 21, 35-37).

Characterization of Multiple Cytokine Combinations and TGF-β on Differentiation and Functions of Myeloid-Derived Suppressor Cells

PubMed Central

Lee, Cho-Rong; Lee, Wongeun; Cho, Steve K.; Park, Sung-Gyoo

2018-01-01

Myeloid-derived suppressor cells (MDSCs) regulate T cell immunity, and this population is a new therapeutic target for immune regulation. A previous study showed that transforming growth factor-β (TGF-β) is involved in controlling MDSC differentiation and immunoregulatory function in vivo. However, the direct effect of TGF-β on MDSCs with various cytokines has not previously been tested. Thus, we examined the effect of various cytokine combinations with TGF-β on MDSCs derived from bone marrow cells. The data show that different cytokine combinations affect the differentiation and immunosuppressive functions of MDSCs in different ways. In the presence of TGF-β, interleukin-6 (IL-6) was the most potent enhancer of MDSC function, whereas granulocyte colony-stimulating factors (G-CSF) was the most potent in the absence of TGF-β. In addition, IL-4 maintained MDSCs in an immature state with an increased expression of arginase 1 (Arg1). However, regardless of the cytokine combinations, TGF-β increased expansion of the monocytic MDSC (Mo-MDSC) population, expression of immunosuppressive molecules by MDSCs, and the ability of MDSCs to suppress CD4+ T cell proliferation. Thus, although different cytokine combinations affected the MDSCs in different ways, TGF-β directly affects monocytic-MDSCs (Mo-MDSCs) expansion and MDSCs functions. PMID:29543758

Visceral Inflammation and Immune Activation Stress the Brain

PubMed Central

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 to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention. PMID:29213271

Global Regulation of Plant Immunity by Histone Lysine Methyl Transferases

PubMed Central

Lee, Sanghun; Xu, Siming; Lee, Sang Yeol; Yun, Dae-Jin; Mengiste, Tesfaye

2016-01-01

Posttranslational modification of histones modulates gene expression affecting diverse biological functions. We showed that the Arabidopsis thaliana histone methyl transferases SET DOMAIN GROUP8 (SDG8) and SDG25 regulate pep1-, flg22-, and effector-triggered immunity as well as systemic acquired resistance. Genome-wide basal and induced transcriptome changes regulated by SDG8 and/or SDG25 showed that two genes of the SDG-dependent transcriptome, CAROTENOID ISOMERASE2 (CCR2) and ECERIFERUM3 (CER3), were also required for plant immunity, establishing mechanisms in defense functions for SDG8 and SDG25. CCR2 catalyzes the biosynthesis of carotenoids, whereas CER3 is involved in the biosynthesis of cuticular wax. SDG8 and SDG25 affected distinct and overlapping global and locus-specific histone H3 lysine 4 (H3K4) and histone H3 lysine 36 (H3K36) methylations. Loss of immunity in sdg mutants was attributed to altered global and CCR2- and CER3-specific histone lysine methylation (HLM). Loss of immunity in sdg, ccr2, and cer3 mutants was also associated with diminished accumulation of lipids and loss of cuticle integrity. In addition, sdg8 and sdg25 mutants were impaired in H2B ubiquitination (H2Bubn) at CCR2, CER3, and H2Bubn regulated R gene, SNC1, revealing crosstalk between the two types of histone modifications. In summary, SDG8 and SDG25 contribute to plant immunity directly through HLM or indirectly through H2Bubn and by regulating expression of plant immunity genes, accumulation of lipids, biosynthesis of carotenoids, and maintenance of cuticle integrity. PMID:27354553

Global Regulation of Plant Immunity by Histone Lysine Methyl Transferases.

PubMed

Lee, Sanghun; Fu, Fuyou; Xu, Siming; Lee, Sang Yeol; Yun, Dae-Jin; Mengiste, Tesfaye

2016-07-01

Posttranslational modification of histones modulates gene expression affecting diverse biological functions. We showed that the Arabidopsis thaliana histone methyl transferases SET DOMAIN GROUP8 (SDG8) and SDG25 regulate pep1-, flg22-, and effector-triggered immunity as well as systemic acquired resistance. Genome-wide basal and induced transcriptome changes regulated by SDG8 and/or SDG25 showed that two genes of the SDG-dependent transcriptome, CAROTENOID ISOMERASE2 (CCR2) and ECERIFERUM3 (CER3), were also required for plant immunity, establishing mechanisms in defense functions for SDG8 and SDG25. CCR2 catalyzes the biosynthesis of carotenoids, whereas CER3 is involved in the biosynthesis of cuticular wax. SDG8 and SDG25 affected distinct and overlapping global and locus-specific histone H3 lysine 4 (H3K4) and histone H3 lysine 36 (H3K36) methylations. Loss of immunity in sdg mutants was attributed to altered global and CCR2- and CER3-specific histone lysine methylation (HLM). Loss of immunity in sdg, ccr2, and cer3 mutants was also associated with diminished accumulation of lipids and loss of cuticle integrity. In addition, sdg8 and sdg25 mutants were impaired in H2B ubiquitination (H2Bubn) at CCR2, CER3, and H2Bubn regulated R gene, SNC1, revealing crosstalk between the two types of histone modifications. In summary, SDG8 and SDG25 contribute to plant immunity directly through HLM or indirectly through H2Bubn and by regulating expression of plant immunity genes, accumulation of lipids, biosynthesis of carotenoids, and maintenance of cuticle integrity. © 2016 American Society of Plant Biologists. All rights reserved.

Effects of aquatic exercise on health-related physical fitness, blood fat, and immune functions of children with disabilities

PubMed Central

Kim, Ki-Hyeon; Lee, Bo-Ae; Oh, Deuk-Ja

2018-01-01

The purpose of this study is to verify the effects of aquatic exercise on the health-related physical fitness, blood fat, and immune functions of children with disabilities. To achieve the aforementioned purpose, the researchers studied 10 children with grade 1 or grade 2 disabilities who do not exercise regularly. The researchers used SPSS 21.0 to calculate the averages and standard deviations of the data and performed a paired t-test to verify the differences in averages before and after an exercise. The study showed significant differences in lean body weight, muscular strength, cardiovascular endurance, flexibility, and muscular endurance. The researchers found statistically significant differences in triglyceride as well as in immunoglobulin G. The findings suggest that aquatic exercise affects the health-related physical fitness, blood fat, and immune functions of children with disabilities. PMID:29740565

Family Structure and Functions Identified by Persons Living with HIV/AIDS.

ERIC Educational Resources Information Center

Wong-Wylie, Gina; Doherty-Poirier, Maryanne; Kieren, Dianne

1999-01-01

A study looked at the structural and functional aspects of family from the perspective of six people living with acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV). Results showing how HIV/AIDS affects all members of the sufferer's family have implications for family practitioners. (Author/JOW)

HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes

PubMed Central

Núñez-Andrade, Norman; Iborra, Salvador; Trullo, Antonio; Moreno-Gonzalo, Olga; Calvo, Enrique; Catalán, Elena; Menasche, Gaël; Sancho, David; Vázquez, Jesús; Yao, Tso-Pang

2016-01-01

HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4+ T cell activation. In this study, we show that HDAC6 contributes to the cytotoxic function of CD8+ T cells. Immunization studies revealed defective cytotoxic activity in vivo in the absence of HDAC6. Adoptive transfer of wild-type or Hdac6-/- CD8+ T cells to Rag1-/- mice demonstrated specific impairment in CD8+ T cell responses against vaccinia infection. Mechanistically, HDAC6-deficient cytotoxic T lymphocytes (CTLs) showed defective in vitro cytolytic activity related to altered dynamics of lytic granules, inhibited kinesin 1 – dynactin mediated terminal transport of lytic granules to the immune synapse and deficient exocytosis, but not to target cell recognition, T cell receptor (TCR) activation or interferon (IFNγ) production. Our results establish HDAC6 as an effector of the immune cytotoxic response that acts by affecting the dynamics, transport and secretion of lytic granules by CTLs. PMID:26869226

Retinoic Acid Modulates Interferon-γ Production by Hepatic Natural Killer T Cells via Phosphatase 2A and the Extracellular Signal-Regulated Kinase Pathway

PubMed Central

Chang, Heng-Kwei

2015-01-01

Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune function, such as defending against infections and immune regulation. Although RA affects various types of immune cells, including antigen-presenting cells, B lymphocytes, and T lymphocytes, whether it affects natural killer T (NKT) cells remain unknown. In this study, we found that RA decreased interferon (IFN)-γ production by activated NKT cells through T-cell receptor (TCR) and CD28. We also found that RA reduced extracellular signal-regulated kinase (ERK) phosphorylation, but increased phosphatase 2A (PP2A) activity in TCR/CD28-stimulated NKT cells. The increased PP2A activity, at least partly, contributed to the reduction of ERK phosphorylation. Since inhibition of ERK activation decreases IFN-γ production by TCR/CD28-stimulated NKT cells, RA may downregulate IFN-γ production by TCR/CD28-stimulated NKT cells through the PP2A-ERK pathway. Our results demonstrated a novel function of RA in modulating the IFN-γ expression by activated NKT cells. PMID:25343668

Maternal and fetal response to fetal persistent infection with bovine viral diarrhea virus.

PubMed

Hansen, Thomas R; Smirnova, Natalia P; Van Campen, Hana; Shoemaker, Megan L; Ptitsyn, Andrey A; Bielefeldt-Ohmann, Helle

2010-10-01

Infection of naïve pregnant cows with non-cytopathic (ncp) bovine viral diarrhea virus (BVDV) results in transplacental infection of the fetus. Infection of the pregnant cow with ncp BVDV late in gestation (after day 150) results in transient infection (TI), as both the dam and fetus can mount an immune response to the virus. In contrast, if the fetus is infected with ncp BVDV early in gestation (before day 150), the fetal immune system is undeveloped and unable to recognize the virus as foreign. This results in induction of immune tolerance to the infecting BVDV strain and persistent infection (PI). Infection of naïve pregnant heifers with ncp BVDV2 on day 75 was hypothesized to induce differential gene expression in white blood cells of the dams and their fetuses, adversely affecting development and antiviral immune responses in PI fetuses. Gene expression differed in maternal blood cells in the presence of PI versus uninfected fetuses. PI adversely affected fetal development and antiviral responses, despite protective immune responses in the dam. Fetal PI with BVDV alters maternal immune function, compromises fetal growth and immune responses, and results in expression of maternal blood biomarkers that can be used to identify cows carrying PI fetuses.

Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke.

PubMed

Singh, Vikramjeet; Roth, Stefan; Llovera, Gemma; Sadler, Rebecca; Garzetti, Debora; Stecher, Bärbel; Dichgans, Martin; Liesz, Arthur

2016-07-13

Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome. We have identified a bidirectional communication along the brain-gut microbiota-immune axis and show that the gut microbiota is a central regulator of immune homeostasis. Acute brain lesions induced dysbiosis of the microbiome and, in turn, changes in the gut microbiota affected neuroinflammatory and functional outcome after brain injury. The microbiota impact on immunity and stroke outcome was transmissible by microbiota transplantation. Our findings support an emerging concept in which the gut microbiota is a key regulator in priming the neuroinflammatory response to brain injury. These findings highlight the key role of microbiota as a potential therapeutic target to protect brain function after injury. Copyright © 2016 the authors 0270-6474/16/367428-13$15.00/0.

Cats are not small dogs: is there an immunological explanation for why cats are less affected by arthropod-borne disease than dogs?

PubMed

Day, Michael J

2016-09-20

It is widely recognized that cats appear to be less frequently affected by arthropod-borne infectious diseases than dogs and share fewer zoonotic pathogens with man. This impression is supported by the relative lack of scientific publications related to feline vector-borne infections. This review explores the possible reasons for the difference between the two most common small companion animal species, including the hypothesis that cats might have a genetically-determined immunological resistance to arthropod vectors or the microparasites they transmit. A number of simple possibilities might account for the lower prevalence of these diseases in cats, including factors related to the lifestyle and behaviour of the cat, lesser spend on preventative healthcare for cats and reduced opportunities for research funding for these animals. The dog and cat have substantially similar immune system components, but differences in immune function might in part account for the markedly distinct prevalence and clinicopathological appearance of autoimmune, allergic, idiopathic inflammatory, immunodeficiency, neoplastic and infectious diseases in the two species. Cats have greater genetic diversity than dogs with much lower linkage disequilibrium in feline compared with canine breed groups. Immune function is intrinsically related to the nature of the intestinal microbiome and subtle differences between the canine and feline microbial populations might also impact on immune function and disease resistance. The reasons for the apparent lesser susceptibility of cats to arthropod-borne infectious diseases are likely to be complex, but warrant further investigation.

Beneficial immune modulatory effects of a specific nutritional combination in a murine model for cancer cachexia

PubMed Central

Faber, J; Vos, P; Kegler, D; van Norren, K; Argilés, J M; Laviano, A; Garssen, J; van Helvoort, A

2008-01-01

The majority of patients with advanced cancer are recognised by impaired immune competence influenced by several factors, including the type and stage of the tumour and the presence of cachexia. Recently, a specific nutritional combination containing fish oil, specific oligosaccharide mixture, high protein content and leucine has been developed aimed to support the immune system of cancer patients in order to reduce the frequency and severity of (infectious) complications. In a recently modified animal model cachexia is induced by inoculation of C26 tumour cells in mice. In a pre-cachectic state, no effect was observed on contact hypersensitivity, a validated in vivo method to measure Th1-mediated immune function, after adding the individual nutritional ingredients to the diet of tumour-bearing mice. However, the complete mixture resulted in significantly improved Th1 immunity. Moreover, in a cachectic state, the complete mixture reduced plasma levels of pro-inflammatory cytokines and beneficially affected ex vivo immune function. Accordingly, the combination of the nutritional ingredients is required to obtain a synergistic effect, leading to a reduced inflammatory state and improved immune competence. From this, it can be concluded that the specific nutritional combination has potential as immune-supporting nutritional intervention to reduce the risk of (infectious) complications in cancer patients. PMID:19018259

How the microbiota shapes rheumatic diseases.

PubMed

Van de Wiele, Tom; Van Praet, Jens T; Marzorati, Massimo; Drennan, Michael B; Elewaut, Dirk

2016-07-01

The human gut harbours a tremendously diverse and abundant microbial community that correlates with, and even modulates, many health-related processes. The mucosal interfaces are particularly active sites of microorganism-host interplay. Growing insight into the characteristic composition and functionality of the mucosal microbiota has revealed that the microbiota is involved in mucosal barrier integrity and immune function. This involvement affects proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local and systemic immune responses and how disturbances in the host-microorganism interplay can potentially affect the development and progression of rheumatic diseases. Increasing our understanding of how to promote host-microorganism homeostasis could therefore reveal novel strategies for the prevention or alleviation of rheumatic disease.

Phenoloxidase activity among developmental stages and pupal cell types of the ground beetle Carabus (Chaetocarabus) lefebvrei (Coleoptera, Carabidae).

PubMed

Giglio, Anita; Giulianini, Piero Giulio

2013-04-01

In ecological immunology is of great importance the study of the immune defense plasticity as response to a variable environment. In holometabolous insects the fitness of each developmental stage depends on the capacity to mount a response (i.e. physiological, behavioral) under environmental pressure. The immune response is a highly dynamic trait closely related to the ecology of organism and the variation in the expression of an immune system component may affect another fitness relevant trait of organism (i.e. growth, reproduction). The present research quantified immune function (total and differential number of hemocytes, phagocytosis in vivo and activity of phenoloxidase) in the pupal stage of Carabus (Chaetocarabus) lefebvrei. Moreover, the cellular and humoral immune function was compared across the larval, pupal and adult stages to evaluate the changes in immunocompetence across the developmental stages. Four types of circulating hemocytes were characterized via transmission electron microscopy in the pupal stage: prohemocytes, plasmatocytes, granulocytes and oenocytoids. The artificial non-self-challenge treatments performed in vivo have shown that plasmatocytes and granulocytes are responsible for phagocytosis. The level of active phenoloxidase increases with the degree of pigmentation of the cuticle in each stage. In C. lefebvrei, there are different strategies in term of immune response to enhance the fitness of each life stage. The results have shown that the variation in speed and specificity of immune function across the developmental stages is correlated with differences in infection risk, life expectancy and biological function of the life cycle. Copyright © 2013 Elsevier Ltd. All rights reserved.

Metabolic regulation of inflammation.

PubMed

Gaber, Timo; Strehl, Cindy; Buttgereit, Frank

2017-05-01

Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. As an evolutionary response, immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. In the past 5 years, it has become clear that cellular metabolism affects immune cell function and differentiation, and that disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases. This Review outlines the metabolic challenges faced by immune cells in states of homeostasis and inflammation, as well as the variety of metabolic configurations utilized by immune cells during differentiation and activation. Changes in cellular metabolism that contribute towards the dysfunctional immune responses seen in rheumatic diseases are also briefly discussed.

Chronobiology of the neuroimmunoendocrine system and aging.

PubMed

Mate, Ianire; Madrid, Juan Antonio; De la Fuente, Mónica

2014-01-01

The health maintenance depends on the preservation of the homeostatic systems, such as nervous, endocrine and immune system, and a proper communication between them. In this regard, the circadian system, which promotes a better physiological system functions and thus well being, could be considered part of that homeostatic complex, since the neuroimmunoendocrine system possesses circadian patterns in most variables, as well as circannual or seasonal variations. With aging, an impairment of the homeostatic systems occurs and an alteration of circadian system regulation has been demonstrated. In the immune system, several function parameters, which are good markers of health and of the rate of aging, change not only with age (immunosenescence) but also throughout the day and year. Indeed, with advancing age there is a modification of immune cell circadian function especially in lymphocytes. Moreover, immune functions at early afternoon correspond to more aged values than at morning, especially in mature subjects (60-79 years of age). In addition, these mature men and women showed a significant impaired immune cell function, which is especially remarkable in the winter. It is noteworthy the role of immunomodulatory hormones, such as melatonin, in the regulation of biological rhythms and their involvement in the aging process. Furthermore, the evidence of a neuroimmune regulation of the circadian system and its disturbance with aging, highlights the importance of proinflammatory cytokines in this complex cross-talk. The biological rhythms disruption with age and some diseases (jet lag, cancer and seasonal affective disorder), could contribute increasing the immune system impairment and consequently the loss of health.

Effects of Simulated Microgravity on Functions of Neutrophil-like HL-60 Cells

NASA Astrophysics Data System (ADS)

Wang, Chengzhi; Li, Ning; Zhang, Chen; Sun, Shujin; Gao, Yuxin; Long, Mian

2015-11-01

Altered gravity, especially microgravity affects cellular functions of immune cells and can result in immune dysfunction for long-term, manned spaceflight and space exploration. The underlying mechanism, however, of sensing and responding to the gravity alteration is poorly understood. Here, a rotary cell culture system (RCCS) bioreactor was used to elucidate the effects of simulated microgravity on polymorphonuclear neutrophils (PMN)-like HL-60 cells. Alteration of cell morphology, up-regulation of (nitric oxide) NO production, enhancement of interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein 1 (MCP-1) secretion, and diversity of cellular adhesion molecule expression were observed for the cells cultured in RCCS, leading to the up-regulated inflammatory immune responses and host defense. It was also indicated that such alterations in biological responses of PMNs mediated the reduced rolling velocity and decreased adhesion of PMN-like HL-60 cells on endothelial cells under shear flow. This work furthers the understandings in the effects and mechanism of microgravity on PMN functions, which are potentially helpful for optimizing the countermeasures to immune suppression in the future long-term, manned spaceflight.

The role of juvenile hormone in immune function and pheromone production trade-offs: a test of the immunocompetence handicap principle.

PubMed Central

Rantala, Markus J; Vainikka, Anssi; Kortet, Raine

2003-01-01

The immunocompetence handicap hypothesis postulates that secondary sexual traits are honest signals of mate quality because the hormones (e.g. testosterone) needed to develop secondary sexual traits have immunosuppressive effects. The best support for predictions arising from the immunocompetence handicap hypothesis so far comes from studies of insects, although they lack male-specific hormones such as testosterone. In our previous studies, we found that female mealworm beetles prefer pheromones of immunocompetent males. Here, we tested how juvenile hormone (JH) affects male investment in secondary sexual characteristics and immune functions in the mealworm beetle, Tenebrio molitor. We injected male mealworm beetles with JH (type III) and found that injection increased the attractiveness of male pheromones but simultaneously suppressed immune functions (phenoloxidase activity and encapsulation). Our results suggest that JH, which is involved in the control of reproduction and morphogenesis, also plays a central role in the regulation of a trade-off between the immune system and sexual advertisement in insects. Thus, the results reflect a general mechanism by which the immunocompetence handicap hypothesis may work in insects. PMID:14613612

A gut feeling: Microbiome-brain-immune interactions modulate social and affective behaviors.

PubMed

Sylvia, Kristyn E; Demas, Gregory E

2018-03-01

The expression of a wide range of social and affective behaviors, including aggression and investigation, as well as anxiety- and depressive-like behaviors, involves interactions among many different physiological systems, including the neuroendocrine and immune systems. Recent work suggests that the gut microbiome may also play a critical role in modulating behavior and likely functions as an important integrator across physiological systems. Microbes within the gut may communicate with the brain via both neural and humoral pathways, providing numerous avenues of research in the area of the gut-brain axis. We are now just beginning to understand the intricate relationships among the brain, microbiome, and immune system and how they work in concert to influence behavior. The effects of different forms of experience (e.g., changes in diet, immune challenge, and psychological stress) on the brain, gut microbiome, and the immune system have often been studied independently. Though because these systems do not work in isolation, it is essential to shift our focus to the connections among them as we move forward in our investigations of the gut-brain axis, the shaping of behavioral phenotypes, and the possible clinical implications of these interactions. This review summarizes the recent progress the field has made in understanding the important role the gut microbiome plays in the modulation of social and affective behaviors, as well as some of the intricate mechanisms by which the microbiome may be communicating with the brain and immune system. Copyright © 2018 Elsevier Inc. All rights reserved.

Control of body temperature and immune function in patients undergoing open surgery for gastric cancer.

PubMed

Shao, Li; Pang, Nannan; Yan, Ping; Jia, Fengju; Sun, Qi; Ma, Wenjuan; Yang, Yi

2018-04-09

The influence of mild perioperative hypothermia on the immune function and incidence of postoperative wound infections has been suggested, but the specific mechanism is unclear. This study aimed to analyze the body temperature, immune function, and wound infection rates in patients receiving open surgery for gastric cancer. Body temperature was controlled in each patient using one of four different methods: wrapping limbs, head and neck; insulated blankets; warming infusion fluids and insulated blankets; and warming fluids without insulated blankets. One hundred patients were randomly divided into four groups of 25 patients each, and every group received a different intraoperative treatment for maintaining normal body temperature. Nasopharyngeal and rectal temperatures, transforming growth factor beta (TGF-β), interleukin 10 (IL-10) levels, and cluster of differentiation (CD)3+ and CD4+/CD25+ regulatory T cell (Treg) counts were measured before surgery and at 2 and 4 hours postoperatively. Patients were evaluated at one week after surgery for signs of infection. Intraoperative body temperature and measures of immune function varied significantly between the four groups, with the largest temperature changes observed in the group in which only the limbs were wrapped in cotton pads to control the body temperature. The group in which infusion fluids and transfused blood (if needed) were heated to 37℃, peritoneal irrigation fluid was heated to 37℃, and an insulation blanket was heated to 39℃ and placed under the patient, showed the lowest temperature change (i.e., close to normal temperature) and cytokine response after surgery. No intergroup differences were found in the infection rates at one week after surgery. In conclusion, body temperature variation during surgery affects the immune function of patients, and maintaining body temperature close to normal results in the least variation of immune function.

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

PubMed Central

McCarthy, Cameron G.; Webb, R. Clinton

2016-01-01

Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study. PMID:26721702

Effects of space flight conditions on the function of the immune system and catecholamine production simulated in a rodent model of hindlimb unloading

NASA Technical Reports Server (NTRS)

Aviles, Hernan; Belay, Tesfaye; Vance, Monique; Sonnenfeld, Gerald

2005-01-01

The rodent model of hindlimb unloading has been successfully used to simulate some of the effects of space flight conditions. Previous studies have indicated that mice exposed to hindlimb-unloading conditions have decreased resistance to infections compared to restrained and normally housed control mice. OBJECTIVE: The purpose of this study was to clarify the mechanisms involved in resistance to infection in this model by examining the effects of hindlimb unloading on the function of the immune system and its impact on the production of catecholamines. METHODS: Female Swiss Webster mice were hindlimb-unloaded during 48 h and the function of the immune system was assessed in spleen and peritoneal cells immediately after this period. In addition, the kinetics of catecholamine production was measured throughout the hindlimb-unloading period. RESULTS: The function of the immune system was significantly suppressed in the hindlimb-unloaded group compared to restrained and normally housed control mice. Levels of catecholamines were increased in the hindlimb-unloaded group and peaked at 12 h following the commencement of unloading. CONCLUSION: These results suggest that physiological responses of mice are altered early after hindlimb unloading and that catecholamines may play a critical role in the modulation of the immune system. These changes may affect the ability of mice to resist infections. Copyright (c) 2005 S. Karger AG, Basel.

Neutrophils are immune cells preferentially targeted by retinoic acid in elderly subjects

PubMed Central

2010-01-01

Background The immune system gradually deteriorates with age and nutritional status is a major factor in immunosenescence. Of the many nutritional factors implicated in age-related immune dysfunction, vitamin A may be a good candidate, since vitamin A concentrations classically decrease during aging whereas it may possess important immunomodulatory properties via its active metabolites, the retinoic acids. This prompted us to investigate the immune response induced by retinoids in adults and elderly healthy subjects. Before and after oral supplementation with 13cis retinoic acid (0.5 mg/kg/day during 28 days), whole blood cells were phenotyped, and functions of peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were investigated by flow cytometry and ELISA tests. Results In both young adults (n = 20, 25 ± 4 years) and older subjects (n = 20, 65 ± 4 years), retinoic acid supplementation had no effect on the distribution of leukocyte subpopulations or on the functions of PBMC (Il-2 and sIl-2R production, membrane expression of CD25). Concerning PMN, retinoic acid induced an increase in both spontaneous migration and cell surface expression of CD11b in the two different age populations, whereas bactericidal activity and phagocytosis remained unchanged. Conclusions We demonstrated that retinoic acid induces the same intensity of immune response between adult and older subjects, and more specifically affects PMN functions, i.e. adhesion and migration, than PBMC functions. PMID:20727130

Functional Similarities between Pigeon ‘Milk’ and Mammalian Milk: Induction of Immune Gene Expression and Modification of the Microbiota

PubMed Central

Gillespie, Meagan J.; Stanley, Dragana; Chen, Honglei; Donald, John A.; Nicholas, Kevin R.; Moore, Robert J.; Crowley, Tamsyn M.

2012-01-01

Pigeon ‘milk’ and mammalian milk have functional similarities in terms of nutritional benefit and delivery of immunoglobulins to the young. Mammalian milk has been clearly shown to aid in the development of the immune system and microbiota of the young, but similar effects have not yet been attributed to pigeon ‘milk’. Therefore, using a chicken model, we investigated the effect of pigeon ‘milk’ on immune gene expression in the Gut Associated Lymphoid Tissue (GALT) and on the composition of the caecal microbiota. Chickens fed pigeon ‘milk’ had a faster rate of growth and a better feed conversion ratio than control chickens. There was significantly enhanced expression of immune-related gene pathways and interferon-stimulated genes in the GALT of pigeon ‘milk’-fed chickens. These pathways include the innate immune response, regulation of cytokine production and regulation of B cell activation and proliferation. The caecal microbiota of pigeon ‘milk’-fed chickens was significantly more diverse than control chickens, and appears to be affected by prebiotics in pigeon ‘milk’, as well as being directly seeded by bacteria present in pigeon ‘milk’. Our results demonstrate that pigeon ‘milk’ has further modes of action which make it functionally similar to mammalian milk. We hypothesise that pigeon ‘lactation’ and mammalian lactation evolved independently but resulted in similarly functional products. PMID:23110233

"Immune TOR-opathies," a Novel Disease Entity in Clinical Immunology.

PubMed

Jung, Sophie; Gámez-Díaz, Laura; Proietti, Michele; Grimbacher, Bodo

2018-01-01

Primary immunodeficiencies (PIDs) represent a group of mostly monogenic disorders caused by loss- or gain-of-function mutations in over 340 known genes that lead to abnormalities in the development and/or the function of the immune system. However, mutations in different genes can affect the same cell-signaling pathway and result in overlapping clinical phenotypes. In particular, mutations in the genes encoding for members of the phosphoinositide3-kinase (PI3K)/AKT/mTOR/S6 kinase (S6K) signaling cascade or for molecules interacting with this pathway have been associated with different PIDs that are often characterized by the coexistence of both immune deficiency and autoimmunity. The serine/threonine kinase mechanistic/mammalian target of rapamycin (mTOR), which acts downstream of PI3K and AKT, is emerging as a key regulator of immune responses. It integrates a variety of signals from the microenvironment to control cell growth, proliferation, and metabolism. mTOR plays therefore a central role in the regulation of immune cells' differentiation and functions. Here, we review the different PIDs that share an impairment of the PI3K/AKT/mTOR/S6K pathway and we propose to name them "immune TOR-opathies" by analogy with a group of neurological disorders that has been originally defined by PB Crino and that are due to aberrant mTOR signaling (1). A better understanding of the role played by this complex intracellular cascade in the pathophysiology of "immune TOR-opathies" is crucial to develop targeted therapies.

Alterations in dendritic cell function in aged mice: potential implications for immunotherapy design.

PubMed

Paula, Carine; Motta, Adriana; Schmitz, Carla; Nunes, Claudia P; Souza, Ana Paula; Bonorino, Cristina

2009-02-01

It is known that immune system functions decrease with age, and that adaptive immune responses, especially CD4+ T cell function, seem to be the main affected point in immunity with aging. Dendritic cells (DC) are the major antigen presenting cell (APC), and at least part of the defects observed in adaptive immunity of aged individuals could be due to diminished potential of bone marrow to generate new DC, or defects in DC function. In this study, we investigated if the ability of aged bone marrow (BM) to generate new DC in vitro, as well as aged BM-derived DC responses to lypopolysaccharide (LPS). Because DC are important tools in newly developing anti-tumor therapies, we also studied the ability of aged DC to phagocytose and present antigen from necrotic tumor cells. We found that aged BM generated fewer DC in vitro compared to young BM. While LPS-induced DC maturation is reduced in DC of aged mice, a high TNF-alpha production is observed in aged DC even without LPS stimulation. While phagocytosis of tumor cells is not affected by age, and DC derived from aged BM show a higher TNF-alpha production in response to phagocytosis, presentation of tumor antigens was decreased in aged DC. Because class II upregulation in response to phagocytosis was similar between aged and young DC, this could indicate an age associated processing defect in the exogenous pathway. These findings suggest that age of BM used to generate DC does not impair their phagocytic ability or TNF-alpha production, however leads to a decreased yield in mature DC, reduced response to LPS, and diminished antigen processing/presentation potential. Our results are relevant to optimization DC-based vaccine design for aged populations.

Human milk oligosaccharides: The role in the fine-tuning of innate immune responses.

PubMed

Kulinich, Anna; Liu, Li

2016-09-02

In order to secure the health of newborns over the period of immune immaturity during the first months of life, a mother provides her offspring with passive protection: bioactive molecules transferred through the placenta and breast milk. It is well known that human milk contains immunoglobulins (Ig), immune cells and diverse cytokines, which affect newborn directly or indirectly and contribute to the maturation of the immune system. However, in addition to the above-stated molecules, human milk oligosaccharides (HMOs), a complex mixture of free indigestible carbohydrates with multiple functions, play exceptional roles in the functioning of the infants' immune system. These biological molecules have been studied over decades, however, interest in HMOs does not seem to have abated. Although biological activities of oligosaccharides from human milk have been explicitly reviewed, information regarding the role of HMOs in inflammation remains rather fragmented. The purpose of this review is to compile existing knowledge about the role of certain species of HMOs, including fucosylated, galactosylated and sialylated oligosaccharides, and their signaling pathways in immunity and inflammation. The advances in applying this information to the treatment of diseases in infants as well as adults were also reviewed here. Copyright © 2016 Elsevier Ltd. All rights reserved.

Thermal sensitivity of immune function: evidence against a generalist-specialist trade-off among endothermic and ectothermic vertebrates

USGS Publications Warehouse

Butler, Michael W.; Stahlschmidt, Zachary R.; Ardia, Daniel R.; Davies, Scott; Davis, Jon; Guillette, Louis J.; Johnson, Nicholas; McCormick, Stephen D.; McGraw, Kevin J.; DeNardo, Dale F.

2013-01-01

Animal body temperature (Tbody) varies over daily and annual cycles, affecting multiple aspects of biological performance in both endothermic and ectothermic animals. Yet a comprehensive comparison of thermal performance among animals varying in Tbody (mean and variance) and heat production is lacking. Thus, we examined the thermal sensitivity of immune function (a crucial fitness determinant) in Vertebrata, a group encompassing species of varying thermal biology. Specifically, we investigated temperature-related variation in two innate immune performance metrics, hemagglutination and hemolysis, for 13 species across all seven major vertebrate clades. Agglutination and lysis were temperature dependent and were more strongly related to the thermal biology of species (e.g., mean Tbody) than to the phylogenetic relatedness of species, although these relationships were complex and frequently surprising (e.g., heterotherms did not exhibit broader thermal performance curves than homeotherms). Agglutination and lysis performance were positively correlated within species, except in taxa that produce squalamine, a steroidal antibiotic that does not lyse red blood cells. Interestingly, we found the antithesis of a generalist-specialist trade-off: species with broader temperature ranges of immune performance also had higher peak performance levels. In sum, we have uncovered thermal sensitivity of immune performance in both endotherms and ectotherms, highlighting the role that temperature and life history play in immune function across Vertebrata.

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

PubMed

Hardcastle, Sharni Lee; Brenu, Ekua Weba; Johnston, Samantha; Nguyen, Thao; Huth, Teilah; Wong, Naomi; Ramos, Sandra; Staines, Donald; Marshall-Gradisnik, Sonya

2015-06-02

Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors. CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naïve CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells. This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.

Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12

PubMed Central

Janelsins, Brian M.; Sumpter, Tina L.; Tkacheva, Olga A.; Rojas-Canales, Darling M.; Erdos, Geza; Mathers, Alicia R.; Shufesky, William J.; Storkus, Walter J.; Falo, Louis D.; Morelli, Adrian E.; Larregina, Adriana T.

2013-01-01

Substance-P and hemokinin-1 are proinflammatory neuropeptides with potential to promote type 1 immunity through agonistic binding to neurokinin-1 receptor (NK1R). Dendritic cells (DCs) are professional antigen-presenting cells that initiate and regulate the outcome of innate and adaptive immune responses. Immunostimulatory DCs are highly desired for the development of positive immunization techniques. DCs express functional NK1R; however, regardless of their potential DC-stimulatory function, the ability of NK1R agonists to promote immunostimulatory DCs remains unexplored. Here, we demonstrate that NK1R signaling activates therapeutic DCs capable of biasing type 1 immunity by inhibition of interleukin-10 (IL-10) synthesis and secretion, without affecting their low levels of IL-12 production. The potent type 1 effector immune response observed following cutaneous administration of NK1R-signaled DCs required their homing in skin-draining lymph nodes (sDLNs) where they induced inflammation and licensed endogenous-conventional sDLN-resident and -recruited inflammatory DCs to secrete IL-12. Our data demonstrate that NK1R signaling promotes immunostimulatory DCs, and provide relevant insight into the mechanisms used by neuromediators to regulate innate and adaptive immune responses. PMID:23365459

Effects of Lactobacillus plantarum Strain OLL2712 Culture Conditions on the Anti-inflammatory Activities for Murine Immune Cells and Obese and Type 2 Diabetic Mice.

PubMed

Toshimitsu, T; Ozaki, S; Mochizuki, J; Furuichi, K; Asami, Y

2017-04-01

Studies on the health-promoting effects of lactic acid bacteria (LAB) are numerous, but few provide examples of the relationship between LAB function and culture conditions. We verified the effect of differences in culture conditions on Lactobacillus plantarum OLL2712 functionality; this strain exhibits anti-inflammatory activity and preventive effects against metabolic disorders. We measured interleukin-10 (IL-10) and IL-12 production in murine immune cells treated with OLL2712 cells prepared under various culture conditions. The results showed that the IL-10-inducing activities of OLL2712 cells on murine immune cells differed dramatically between OLL2712 groups at different culture phases and using different culture medium components, temperatures, and neutralizing pHs. In particular, exponential-phase cells had much more IL-10-inducing activity than stationary-phase cells. We confirmed that the Toll-like receptor 2 (TLR2) stimulation activity of OLL2712 cells depended on culture conditions in conjunction with IL-10-inducing activity. We also demonstrated functional differences by culture phases in vivo ; OLL2712 cells at exponential phase had more anti-inflammatory activity and anti-metabolic-disorder effects on obese and diabetic mice than those by their stationary-phase counterparts. These results suggest that culture conditions affect the functionality of anti-inflammatory LAB. IMPORTANCE While previous studies demonstrated that culture conditions affected the immunomodulatory properties of lactic acid bacteria (LAB), few have comprehensively investigated the relationship between culture conditions and LAB functionality. In this study, we demonstrated several culture conditions of Lactobacillus plantarum OLL2712 for higher anti-inflammatory activity. We also showed that culture conditions concretely influenced the health-promoting functions of OLL2712 in vivo , particularly against metabolic disorders. Further, we characterized a novel mechanism by which changing LAB culture conditions affected immunomodulatory properties. Our results suggest that culture condition optimization is important for the production of LAB with anti-inflammatory activity. Copyright © 2017 American Society for Microbiology.

Gut microbiota and obesity.

PubMed

Scarpellini, Emidio; Campanale, Mariachiara; Leone, Diana; Purchiaroni, Flaminia; Vitale, Giovanna; Lauritano, Ernesto Cristiano; Gasbarrini, Antonio

2010-10-01

Intestinal epithelium, mucosal immune system, and bacterial flora represent a morpho-functional system on dynamic balance responsible for the intestinal metabolic and trophic functions, and the regulation of mucosal and systemic host's immunity. Obesity is a pathological condition affecting a growing number of people especially in the Western countries resulting from the failure of the organism's energetic balance based on the perfect equality of income, waste, and storage. Recent evidences explain the mechanisms for the microbial regulation of the host's metabolism both in health and disease. In particular, animal studies have explained how quali-/quantitative changes in microflora composition are able to affect the absorption of the nutrients and the energy distribution. Antibiotics, prebiotics, probiotics, and symbiotics are the instruments utilized in the current clinical practice to modulate the intestinal bacterial flora in man both in health and pathologic conditions with promising preliminary results on prevention and therapy of obesity and related metabolic diseases.

Modulation of Toll-like receptor signaling in innate immunity by natural products.

PubMed

Chen, Luxi; Yu, Jianhua

2016-08-01

For centuries, natural products and their derivatives have provided a rich source of compounds for the development of new immunotherapies in the treatment of human disease. Many of these compounds are currently undergoing clinical trials, particularly as anti-oxidative, anti-microbial, and anti-cancer agents. However, the function and mechanism of natural products in how they interact with our immune system has yet to be extensively explored. Natural immune modulators may provide the key to control and ultimately defeat disorders affecting the immune system. They can either up- or down-regulate the immune response with few undesired adverse effects. In this review, we summarize the recent advancements made in utilizing natural products for immunomodulation and their important molecular targets, members of the Toll-like receptor (TLR) family, in the innate immune system. Copyright © 2016 Elsevier B.V. All rights reserved.

Early CMV Viremia Is Associated with Impaired Viral Control following Nonmyeloablative Hematopoietic Cell Transplantation with a Total Lymphoid Irradiation and Antithymocyte Globulin Preparative Regimen

PubMed Central

Schaenman, Joanna M.; Shashidhar, Sumana; Rhee, Chanu; Wong, Jonathan; Navato, Shelly; Wong, Ruby M.; Ho, Dora Y.; Arai, Sally; Johnston, Laura; Brown, Janice M.

2017-01-01

The reconstitution of immune function after hematopoietic cell transplant (HCT) plays an important role in the control of viral infections. Both donor and recipient cytomegalovirus (CMV) serostatus has been shown to contribute to effective immune function; however, the influence of a nonmyeloablative preparative (NMA) regimen using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) on antiviral immune reconstitution has not yet been described. In 117 recipients of NMA HCT patients following ATG and TLI, not unexpectedly, CMV viremia was seen in approximately 60% of the seropositive patients regardless of donor serostatus, and recipient seropositivity significantly increased the odds of CMV viremia after transplant in a multivariate analysis. The administration of ATG and TLI resulted in a strikingly earlier viremia in the posttransplant period when compared to the previously reported timing of viremia following myeloablative preparative regimens, especially for transplant recipients who were seropositive for CMV with seronegative donors. Furthermore, early viremia in the setting of a CMV naïve donor was associated with a delay in functional antiviral control. These observations demonstrate the dynamic nature of immunity in relation to CMV antigen exposure in the complex environment resulting from NMA conditions where both donor and residual recipient immune response affect viral control. PMID:20736077

Role of antioxidants and trace elements in health and immunity of transition dairy cows.

PubMed

Spears, Jerry W; Weiss, William P

2008-04-01

A number of antioxidants and trace minerals have important roles in immune function and may affect health in transition dairy cows. Vitamin E and beta-carotene are important cellular antioxidants. Selenium (Se) is involved in the antioxidant system via its role in the enzyme glutathione peroxidase. Inadequate dietary vitamin E or Se decreases neutrophil function during the perpariturient period. Supplementation of vitamin E and/or Se has reduced the incidence of mastitis and retained placenta, and reduced duration of clinical symptoms of mastitis in some experiments. Research has indicated that beta-carotene supplementation may enhance immunity and reduce the incidence of retained placenta and metritis in dairy cows. Marginal copper deficiency resulted in reduced neutrophil killing and decreased interferon production by mononuclear cells. Copper supplementation of a diet marginal in copper reduced the peak clinical response during experimental Escherichia coli mastitis. Limited research indicated that chromium supplementation during the transition period may increase immunity and reduce the incidence of retained placenta.

Aged Garlic Extract Modifies Human Immunity.

PubMed

Percival, Susan S

2016-02-01

Garlic contains numerous compounds that have the potential to influence immunity. Immune cells, especially innate immune cells, are responsible for the inflammation necessary to kill pathogens. Two innate lymphocytes, γδ-T and natural killer (NK) cells, appear to be susceptible to diet modification. The purpose of this review was to summarize the influence of aged garlic extract (AGE) on the immune system. The author's laboratory is interested in AGE's effects on cell proliferation and activation and inflammation and to learn whether those changes might affect the occurrence and severity of colds and flu. Healthy human participants (n = 120), between 21 and 50 y of age, were recruited for a randomized, double-blind, placebo-controlled parallel-intervention study to consume 2.56 g AGE/d or placebo supplements for 90 d during the cold and flu season. Peripheral blood mononuclear cells were isolated before and after consumption, and γδ-T and NK cell function was assessed by flow cytometry. The effect on cold and flu symptoms was determined by using daily diary records of self-reported illnesses. After 45 d of AGE consumption, γδ-T and NK cells proliferated better and were more activated than cells from the placebo group. After 90 d, although the number of illnesses was not significantly different, the AGE group showed reduced cold and flu severity, with a reduction in the number of symptoms, the number of days participants functioned suboptimally, and the number of work/school days missed. These results suggest that AGE supplementation may enhance immune cell function and may be partly responsible for the reduced severity of colds and flu reported. The results also suggest that the immune system functions well with AGE supplementation, perhaps with less accompanying inflammation. This trial was registered at clinicaltrials.gov as NCT01390116. © 2016 American Society for Nutrition.

The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

PubMed Central

Krstić, Jelena; Djordjević, Ivana Okić; Jauković, Aleksandra

2016-01-01

State of tumor microenvironment (TME) is closely linked to regulation of tumor growth and progression affecting the final outcome, refractoriness, and relapse of disease. Interactions of tumor, immune, and mesenchymal stromal/stem cells (MSCs) have been recognized as crucial for understanding tumorigenesis. Due to their outstanding features, stem cell-like properties, capacity to regulate immune response, and dynamic functional phenotype dependent on microenvironmental stimuli, MSCs have been perceived as important players in TME. Signals provided by tumor-associated chronic inflammation educate MSCs to alter their phenotype and immunomodulatory potential in favor of tumor-biased state of MSCs. Adjustment of phenotype to TME and acquisition of tumor-promoting ability by MSCs help tumor cells in maintenance of permissive TME and suppression of antitumor immune response. Potential utilization of MSCs in treatment of tumor is based on their inherent ability to home tumor tissue that makes them suitable delivery vehicles for immune-stimulating factors and vectors for targeted antitumor therapy. Here, we review data regarding intrusive effects of inflammatory TME on MSCs capacity to affect tumor development through modification of their phenotype and interactions with immune system. PMID:27630452

Immune cell functions in iron overload.

PubMed Central

de Sousa, M

1989-01-01

A number of studies done in the last 10 years demonstrate the importance of iron in regulating the expression of T lymphoid cell surface markers, in influencing the expansion of different T cell subsets and in affecting different immune cell functions in vitro. It has been argued that some of the results obtained could be explained by the formation of iron polymers in the experimental conditions used in vitro (Soyano Fernandez & Romano, 1985). In this review the results of studies of immunological function in clinical situations of iron overload are analysed. From this analysis, it is concluded that the majority of the observations made in vitro have a counterpart in vivo, thus providing additional compelling evidence for the importance of iron as an immunoregulator. PMID:2649280

Acute dermal abscesses caused by Serratia marcescens.

PubMed

Soria, Xavier; Bielsa, Isabel; Ribera, Miquel; Herrero, María José; Domingo, Helena; Carrascosa, José Manuel; Ferrándiz, Carlos

2008-05-01

Primary acute cutaneous infections caused by Serratia marcescens are extremely unusual. Nevertheless, Serratia infections are especially frequent in chronic granulomatous disease, which is a primary immunodeficiency that affects phagocytic cells of the innate immune system. We report a young man without history of infections, who developed multiple dermal abscesses on a leg with chronic lymphoedema attributed to S marcescens. Laboratory investigations showed a delayed partial neutrophilic oxidative function. It is remarkable that the patient did not have any other infections during childhood, when most of the innate immune deficiencies are diagnosed, and he had no history of granulomatous lesions. We hypothesize that the delayed neutrophilic oxidative function could be explained by a partial neutrophilic oxidative function, which could be enough to maintain the patient asymptomatic until this infection.

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs.

PubMed

Friedenberg, Steven G; Buhrman, Greg; Chdid, Lhoucine; Olby, Natasha J; Olivry, Thierry; Guillaumin, Julien; O'Toole, Theresa; Goggs, Robert; Kennedy, Lorna J; Rose, Robert B; Meurs, Kathryn M

2016-03-01

Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher's exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12) and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared with the reference allele, DLA-79*001:01), resulting in F33L and N37D amino acid changes. These mutations occur in the peptide-binding pocket of the protein, and based upon our computational modeling studies, are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly and to determine the specific mechanism by which the identified variants alter canine immune system function.

Immunomodulatory effects of linomide in animals immunized with immunopathogenic retinal antigens: dissociation between different immune functions.

PubMed

Shirkey, B L; Slavin, S; Vistica, B P; Podgor, M J; Gery, I

1997-06-01

Linomide (LS-2616, quinoline-3-carboxamide) has been reported to exert a diverse range of effects on the immune system. On one hand, this drug was found to stimulate the immune system and to enhance activities such as DTH or allograft rejection. On the other hand, linomide was shown to inhibit the induction of experimental autoimmune encephalomyelitis and myasthenia gravis, as well as the development of diabetes in non-obese diabetic (NOD) mice. Here we report the effects of linomide in animals immunized with uveitogenic retinal antigens. Treatment with linomide completely inhibited the development of experimental autoimmune uveoretinitis (EAU) in mice immunized with interphotoreceptor retinoid-binding protein and markedly suppressed EAU in rats immunized with S-antigen (S-Ag). In addition, linomide-treated rats exhibited reduced antibody production and lymphocyte proliferative response to S-Ag. In contrast to these suppressive activities, linomide treatment did not affect the development of adoptively transferred EAU in rats and moderately enhanced the DTH reactions to S-Ag in immunized rats in which EAU and other immune responses to this antigen were suppressed.

Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders.

PubMed

Jaiswal, Preeti; Mohanakumar, Kochupurackal P; Rajamma, Usha

2015-08-01

Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits. Copyright © 2015 Elsevier Ltd. All rights reserved.

Taste Receptors Mediate Sinonasal Immunity and Respiratory Disease

PubMed Central

Douglas, Jennifer E.; Cohen, Noam A.

2017-01-01

The bitter taste receptor T2R38 has been shown to play a role in the pathogenesis of chronic rhinosinusitis (CRS), where the receptor functions to enhance upper respiratory innate immunity through a triad of beneficial immune responses. Individuals with a functional version of T2R38 are tasters for the bitter compound phenylthiocarbamide (PTC) and exhibit an anti-microbial response in the upper airway to certain invading pathogens, while those individuals with a non-functional version of the receptor are PTC non-tasters and lack this beneficial response. The clinical ramifications are significant, with the non-taster genotype being an independent risk factor for CRS requiring surgery, poor quality-of-life (QOL) improvements post-operatively, and decreased rhinologic QOL in patients with cystic fibrosis. Furthermore, indirect evidence suggests that non-tasters also have a larger burden of biofilm formation. This new data may influence the clinical management of patients with infectious conditions affecting the upper respiratory tract and possibly at other mucosal sites throughout the body. PMID:28218655

Change in the immune function of porcine iliac artery endothelial cells infected with porcine circovirus type 2 and its inhibition on monocyte derived dendritic cells maturation

PubMed Central

Liu, Shiyu; Zou, Zhanming; Zhu, Linlin; Liu, Xinyu; Zhou, Shuanghai

2017-01-01

Porcine circovirus-associated disease is caused by porcine circovirus type 2 (PCV2) infection, which targets iliac artery endothelial cells (PIECs); it leads to severe immunopathologies and is associated with major economic losses in the porcine industry. Here, we report that in vitro PCV2 infection of PIECs causes cell injury, which affects DC function as well as adaptive immunity. Specifically, PCV2 infection downregulated PIEC antigen-presenting molecule expression, upregulated cytokines involved in the immune and inflammatory response causing cell damage and repair, and altered the migratory capacity of PIECs. In addition, PCV2-infected PIECs inhibited DC maturation, enhanced the endocytic ability of DCs, and weakened the stimulatory effect of DCs on T lymphocytes. Together, these findings indicate that profound functional impairment of DCs in the presence of PCV2-infected PIECs may be a potential pathogenic mechanism associated with PCV2-induced porcine disease. PMID:29073194

Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities

PubMed Central

Hohl, Tobias M.

2017-01-01

Purpose of review Invasive aspergillosis is a worldwide disease that primarily affects immune-compromised patients, agricultural workers with corneal abrasions, individuals with structural lung disease, and patients with primary immune deficiency. The critical function of the immune system is to prevent the germination of airborne conidia into tissue-invasive hyphae. This review covers recent advances that shape our understanding of anti-Aspergillus immunity at the molecular and cellular level. Recent findings Host defense against conidia and hyphae occurs via distinct molecular mechanisms that involve intracellular and extracellular killing pathways, as well as cooperation between different myeloid cell subsets. The strength and efficacy of the host response is shaped by the tissue microenvironment. In preclinical models of disease, host immune augmentation strategies have yielded benefits, yet translating these insights into therapeutic strategies in humans remains challenging. Summary Although advances in early diagnostic strategies and in antifungal drugs have ameliorated clinical outcomes of invasive aspergillosis, further improvements depend on gaining deeper insight into and translating advances in anti-Aspergillus immunity. PMID:28509673

Aging of the Immune System. Mechanisms and Therapeutic Targets.

PubMed

Weyand, Cornelia M; Goronzy, Jörg J

2016-12-01

Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.

Geographical and temporal variation in environmental conditions affects nestling growth but not immune function in a year-round breeding equatorial lark.

PubMed

Ndithia, Henry K; Bakari, Samuel N; Matson, Kevin D; Muchai, Muchane; Tieleman, B Irene

2017-01-01

Variation in growth and immune function within and among populations is often associated with specific environmental conditions. We compared growth and immune function in nestlings of year-round breeding equatorial Red - capped Lark Calandrella cinerea from South Kinangop, North Kinangop and Kedong (Kenya), three locations that are geographically close but climatically distinct. In addition, we studied growth and immune function of lark nestlings as a function of year - round variation in breeding intensity and rain within one location. We monitored mass, wing, and tarsus at hatching (day 1) and at 4, 7, and 10 days post - hatch, and we quantified four indices of immune function (haptoglobin, agglutination, lysis and nitric oxide) using blood samples collected on day 10. Nestling body mass and size at hatching, which presumably reflect the resources that females allocated to their eggs, were lowest in the most arid location, Kedong. Contrary to our predictions, nestlings in Kedong grew faster than nestlings in the two other cooler and wetter locations of South and North Kinangop. During periods of peak reproduction within Kedong, nestlings were heavier at hatching, but they did not grow faster over the first 10 days post - hatch. In contrast, rainfall, which did not relate to timing of breeding, had no effect on hatching mass, but more rain did coincide with faster growth post - hatch. Finally, we found no significant differences in nestling immune function, neither among locations nor with the year - round variation within Kedong. Based on these results, we hypothesize that female body condition determines nestling mass and size at hatching, but other independent environmental conditions subsequently shape nestling growth. Overall, our results suggest that environmental conditions related to food availability for nestlings are relatively unimportant to the timing of breeding in equatorial regions, while these same conditions do have consequences for nestling size and growth.

Flight performance of western sandpipers, Calidris mauri, remains uncompromised when mounting an acute phase immune response.

PubMed

Nebel, Silke; Buehler, Deborah M; MacMillan, Alexander; Guglielmo, Christopher G

2013-07-15

Migratory birds have been implicated in the spread of some zoonotic diseases, but how well infected individuals can fly remains poorly understood. We used western sandpipers, Calidris mauri, to experimentally test whether flight is affected when long-distance migrants are mounting an immune response and whether migrants maintain immune defences during a flight in a wind tunnel. We measured five indicators of innate immunity in 'flown-healthy' birds (flying in a wind tunnel without mounting an immune response), 'flown-sick' birds (flying while mounting an acute phase response, which is part of induced innate immunity), and a non-flying control group ('not-flown'). Voluntary flight duration did not differ between flown-healthy and flown-sick birds, indicating that mounting an acute phase response to simulated infection did not hamper an individual's ability to fly for up to 3 h. However, in comparison to not-flown birds, bacterial killing ability of plasma was significantly reduced after flight in flown-sick birds. In flown-healthy birds, voluntary flight duration was positively correlated with bacterial killing ability and baseline haptoglobin concentration of the blood plasma measured 1-3 weeks before experimental flights, suggesting that high quality birds had strong immune systems and greater flight capacity. Our findings indicate that flight performance is not diminished by prior immune challenge, but that flight while mounting an acute phase response negatively affects other aspects of immune function. These findings have important implications for our understanding of the transmission of avian diseases, as they suggest that birds can still migrate while fighting an infection.

CMV-Specific CD8 T Cell Differentiation and Localization: Implications for Adoptive Therapies.

PubMed

Smith, Corinne J; Quinn, Michael; Snyder, Christopher M

2016-01-01

Human cytomegalovirus (HCMV) is a ubiquitous virus that causes chronic infection and, thus, is one of the most common infectious complications of immune suppression. Adoptive transfer of HCMV-specific T cells has emerged as an effective method to reduce the risk for HCMV infection and/or reactivation by restoring immunity in transplant recipients. However, the CMV-specific CD8 + T cell response is comprised of a heterogenous mixture of subsets with distinct functions and localization, and it is not clear if current adoptive immunotherapy protocols can reconstitute the full spectrum of CD8 + T cell immunity. The aim of this review is to briefly summarize the role of these T cell subsets in CMV immunity and to describe how current adoptive immunotherapy practices might affect their reconstitution in patients. The bulk of the CMV-specific CD8 + T cell population is made up of terminally differentiated effector T cells with immediate effector function and a short life span. Self-renewing memory T cells within the CMV-specific population retain the capacity to expand and differentiate upon challenge and are important for the long-term persistence of the CD8 + T cell response. Finally, mucosal organs, which are frequent sites of CMV reactivation, are primarily inhabited by tissue-resident memory T cells, which do not recirculate. Future work on adoptive transfer strategies may need to focus on striking a balance between the formation of these subsets to ensure the development of long lasting and protective immune responses that can access the organs affected by CMV disease.

Cytokines and immune surveillance in humans

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1993-01-01

Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to further explore the effects of space flight on cytokines and cytokine-directed immunological function.

The role of the thymus in allogeneic hematopoietic stem cell transplantation.

PubMed

Krenger, Werner; Holländer, Georg A

2010-07-19

Allogeneic haematopoietic stem cell transplantation (HSCT) is used to treat an increasing number of congenital and acquired disorders of the haematopoietic system. Even though cytoreductive conditioning regimens vary in intensity, all clinically used protocols invariably cause side effects that compromise transiently or long-term the response of the natural and the adaptive immune systems. However, in the context of the reconstruction of immunity, the generation of naïve T cells constitutes a slow process, and requires a functionally competent thymus. Unfortunately, regular thymic function is frequently suppressed by transplant-related toxicities. Most notably, graft-versus-host disease (GVHD) causes a state of posttransplantation immune deficiency. Here we discuss preclinical allogeneic HSCT models and clinical observations that have contributed to a detailed understanding of the cellular and molecular mechanisms responsible for the thymic dysfunction caused by acute GVHD. An in-depth knowledge of the mechanisms that control regular thymopoiesis and, conversely, affect thymus function is expected to provide the factual basis for the design of innovative therapies to recover T-cell numbers and function following allogeneic HSCT.

Transcriptional Regulation of T-Cell Lipid Metabolism: Implications for Plasma Membrane Lipid Rafts and T-Cell Function.

PubMed

Robinson, George A; Waddington, Kirsty E; Pineda-Torra, Ines; Jury, Elizabeth C

2017-01-01

It is well established that cholesterol and glycosphingolipids are enriched in the plasma membrane (PM) and form signaling platforms called lipid rafts, essential for T-cell activation and function. Moreover, changes in PM lipid composition affect the biophysical properties of lipid rafts and have a role in defining functional T-cell phenotypes. Here, we review the role of transcriptional regulators of lipid metabolism including liver X receptors α/β, peroxisome proliferator-activated receptor γ, estrogen receptors α/β (ERα/β), and sterol regulatory element-binding proteins in T-cells. These receptors lie at the interface between lipid metabolism and immune cell function and are endogenously activated by lipids and/or hormones. Importantly, they regulate cellular cholesterol, fatty acid, glycosphingolipid, and phospholipid levels but are also known to modulate a broad spectrum of immune responses. The current evidence supporting a role for lipid metabolism pathways in controlling immune cell activation by influencing PM lipid raft composition in health and disease, and the potential for targeting lipid biosynthesis pathways to control unwanted T-cell activation in autoimmunity is reviewed.

Transcriptional Regulation of T-Cell Lipid Metabolism: Implications for Plasma Membrane Lipid Rafts and T-Cell Function

PubMed Central

Robinson, George A.; Waddington, Kirsty E.; Pineda-Torra, Ines; Jury, Elizabeth C.

2017-01-01

It is well established that cholesterol and glycosphingolipids are enriched in the plasma membrane (PM) and form signaling platforms called lipid rafts, essential for T-cell activation and function. Moreover, changes in PM lipid composition affect the biophysical properties of lipid rafts and have a role in defining functional T-cell phenotypes. Here, we review the role of transcriptional regulators of lipid metabolism including liver X receptors α/β, peroxisome proliferator-activated receptor γ, estrogen receptors α/β (ERα/β), and sterol regulatory element-binding proteins in T-cells. These receptors lie at the interface between lipid metabolism and immune cell function and are endogenously activated by lipids and/or hormones. Importantly, they regulate cellular cholesterol, fatty acid, glycosphingolipid, and phospholipid levels but are also known to modulate a broad spectrum of immune responses. The current evidence supporting a role for lipid metabolism pathways in controlling immune cell activation by influencing PM lipid raft composition in health and disease, and the potential for targeting lipid biosynthesis pathways to control unwanted T-cell activation in autoimmunity is reviewed. PMID:29225604

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

PubMed Central

Danese, Andrea; J Lewis, Stephanie

2017-01-01

The brain and the immune system are not fully formed at birth, but rather continue to mature in response to the postnatal environment. The two-way interaction between the brain and the immune system makes it possible for childhood psychosocial stressors to affect immune system development, which in turn can affect brain development and its long-term functioning. Drawing from experimental animal models and observational human studies, we propose that the psychoneuroimmunology of early-life stress can offer an innovative framework to understand and treat psychopathology linked to childhood trauma. Early-life stress predicts later inflammation, and there are striking analogies between the neurobiological correlates of early-life stress and of inflammation. Furthermore, there are overlapping trans-diagnostic patterns of association of childhood trauma and inflammation with clinical outcomes. These findings suggest new strategies to remediate the effect of childhood trauma before the onset of clinical symptoms, such as anti-inflammatory interventions and potentiation of adaptive immunity. Similar strategies might be used to ameliorate the unfavorable treatment response described in psychiatric patients with a history of childhood trauma. PMID:27629365

A T-cell-dependent humoral immune response is preserved during the administration of the nerve agent pre-treatment pyridostigmine bromide in a murine model.

PubMed

Griffiths, Gareth D; Telford, Gary; Hooi, Doreen S W; Cook, David L; Wilkinson, Lucy J; Green, Christopher A; Pritchard, David I

2005-03-01

Immune regulation, either via the autonomic nervous system or by a proposed "non-neuronal" cholinergic system, suggests that the immune system may be susceptible to perturbation by compounds affecting cholinergic function. Here, the current UK and US nerve agent pre-treatment, pyridostigmine bromide (PB) and the related anti-acetylcholinesterase (AChE) compounds physostigmine (PHY) and BW284c51 were tested for their ability to affect mouse splenocyte function in vitro. In addition, PB, at a dose equivalent to that received during pre-treatment for nerve agent poisoning, was tested for its effect on a T-cell-dependent humoral response to antigen in vivo in the mouse. None of the anti-AChEs tested affected concanavalin A (Con A)-, anti-CD3- or lipopolysaccharide LPS-driven splenocyte proliferation, in vitro, at concentrations expected to give effective nerve agent pre-treatment. However, higher concentrations (>100 microM) particularly of PHY caused some inhibition of the proliferative responses. In vivo, PB or saline was administered via 28-day mini-osmotic pumps to give a 25-40% inhibition of whole blood AChE in the PB-treated animals. During PB or saline administration, primary and secondary doses (i.p.) of sheep red blood cells (SRBC) were given and the humoral response determined by monitoring anti-SRBC IgM and IgG levels. Splenocytes isolated from the experimental animals were also examined for their proliferative and cytokine responses to stimulation. No remarkable effects of PB were seen during the period of AChE inhibition on the humoral immune response. However, a modest elevation in IL-2 and IFN(gamma) in Con A-stimulated lymphocytes was seen in PB-treated animals following pump removal. Overall these data suggest that, in vivo, the SRBC stimulated T-cell-dependent immune response is unaffected by the administration of PB at pre-treatment doses.

Immunization against lysozyme-like proteins affect sperm function and fertility in the rat.

PubMed

Narmadha, Ganapathy; Yenugu, Suresh

2016-11-01

Proteins of the epididymal and testicular mileu contribute to sperm maturation and a vast majority of them remain uncharacterised. In this study, the role of three Lysozyme-like (LYZL) proteins, namely LYZL1, LYZL4 and LYZL6 in sperm function was assessed using in vitro neutralization and auto antibodies generation model. Rats immunized with LYZL1, LYZL4 and LYZL6 proteins had a litter size of 5.93, 8.47 and 2.10 respectively compared to 9.96 in the control rats. The litter size was further reduced to 4.53, 7.67 and 1.23 for the corresponding proteins in the second mating conducted 14 weeks after immunization. Epididymal and testicular fluids obtained from the immunized rats displayed a very high antibody titre against all the three proteins. Sperm count was significantly reduced in rats immunized with LYZL1 or LYZL6 and to a lower extent in LYZL4 group. Acrosome reaction associated calcium release was inhibited in spermatozoa obtained from LYZL1 or LYZL4 or LYZL6 immunized rats as well as in spermatozoa incubated with antiserum against the three proteins. Impairment in path velocity, progressive velocity and track speed were observed in spermatozoa obtained from LYZL6 immunized rats. Treatment of spermatozoa with LYZL6 recombinant protein did not potentiate calcium release and acrosome reaction. Results of this study indicate a role for LYZL proteins in sperm function and further studies are warranted to explore them as potential contraceptive agents. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Differential Regulation of Two-Tiered Plant Immunity and Sexual Reproduction by ANXUR Receptor-Like Kinases.

PubMed

Mang, Hyunggon; Feng, Baomin; Hu, Zhangjian; Boisson-Dernier, Aurélien; Franck, Christina M; Meng, Xiangzong; Huang, Yanyan; Zhou, Jinggeng; Xu, Guangyuan; Wang, Taotao; Shan, Libo; He, Ping

2017-12-01

Plants have evolved two tiers of immune receptors to detect infections: cell surface-resident pattern recognition receptors (PRRs) that sense microbial signatures and intracellular nucleotide binding domain leucine-rich repeat (NLR) proteins that recognize pathogen effectors. How PRRs and NLRs interconnect and activate the specific and overlapping plant immune responses remains elusive. A genetic screen for components controlling plant immunity identified ANXUR1 (ANX1), a malectin-like domain-containing receptor-like kinase, together with its homolog ANX2, as important negative regulators of both PRR- and NLR-mediated immunity in Arabidopsis thaliana ANX1 constitutively associates with the bacterial flagellin receptor FLAGELLIN-SENSING2 (FLS2) and its coreceptor BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1). Perception of flagellin by FLS2 promotes ANX1 association with BAK1, thereby interfering with FLS2-BAK1 complex formation to attenuate PRR signaling. In addition, ANX1 complexes with the NLR proteins RESISTANT TO PSEUDOMONAS SYRINGAE2 (RPS2) and RESISTANCE TO P. SYRINGAE PV MACULICOLA1. ANX1 promotes RPS2 degradation and attenuates RPS2-mediated cell death. Surprisingly, a mutation that affects ANX1 function in plant immunity does not disrupt its function in controlling pollen tube growth during fertilization. Our study thus reveals a molecular link between PRR and NLR protein complexes that both associate with cell surface-resident ANX1 and uncovers uncoupled functions of ANX1 and ANX2 during plant immunity and sexual reproduction. © 2017 American Society of Plant Biologists. All rights reserved.

A Simulated Heat Wave Has Diverse Effects on Immune Function and Oxidative Physiology in the Corn Snake (Pantherophis guttatus).

PubMed

Stahlschmidt, Z R; French, S S; Ahn, A; Webb, A; Butler, M W

Animals will continue to encounter increasingly warm environments, including more frequent and intense heat waves. Yet the physiological consequences of heat waves remain equivocal, potentially because of variation in adaptive plasticity (reversible acclimation) and/or aspects of experimental design. Thus, we measured a suite of physiological variables in the corn snake (Pantherophis guttatus) after exposure to field-parameterized, fluctuating temperature regimes (moderate temperature and heat wave treatments) to address two hypotheses: (1) a heat wave causes physiological stress, and (2) thermal performance of immune function exhibits adaptive plasticity in response to a heat wave. We found little support for our first hypothesis because a simulated heat wave had a negative effect on body mass, but it also reduced oxidative damage and did not affect peak performance of three immune metrics. Likewise, we found only partial support for our second hypothesis. After exposure to a simulated heat wave, P. guttatus exhibited greater performance breadth and reduced temperature specialization (the standardized difference between peak performance and performance breadth) for only one of three immune metrics and did so in a sex-dependent manner. Further, a simulated heat wave did not elicit greater performance of any immune metric at higher temperatures. Yet a heat wave likely reduced innate immune function in P. guttatus because each metric of innate immune performance in this species (as in most vertebrates) was lower at elevated temperatures. Together with previous research, our study indicates that a heat wave may have complex, modest, and even positive physiological effects in some taxa.

Starvation stress affects the interplay among shrimp gut microbiota, digestion and immune activities.

PubMed

Dai, Wen-Fang; Zhang, Jin-Jie; Qiu, Qiong-Fen; Chen, Jiong; Yang, Wen; Ni, Sui; Xiong, Jin-Bo

2018-05-24

Aquatic animals are frequently suffered from starvation due to restricted food availability or deprivation. It is currently known that gut microbiota assists host in nutrient acquisition. Thus, exploring the gut microbiota responses would improve our understanding on physiological adaptation to starvation. To achieve this, we investigated how the gut microbiota and shrimp digestion and immune activities were affected under starvation stress. The results showed that the measured digestion activities in starved shrimp were significantly lower than in normal cohorts; while the measured immune activities exhibited an opposite trend. A structural equation modeling (SEM) revealed that changes in the gut bacterial community were directly related to digestive and immune enzyme activities, which in turn markedly affected shrimp growth traits. Notably, several gut bacterial indicators that characterized the shrimp nutrient status were identified, with more abundant opportunistic pathogens in starved shrimp, although there were no statistical differences in the overall diversity and the structures of gut bacterial communities between starved and normal shrimp. Starved shrimp exhibited less connected and cooperative interspecies interaction as compared with normal cohorts. Additionally, the functional pathways involved in carbohydrate and protein digestion, glycan biosynthesis, lipid and enzyme metabolism remarkably decreased in starved shrimp. These attenuations could increase the susceptibility of starved shrimp to pathogens infection. In summary, this study provides novel insights into the interplay among shrimp digestion, immune activities and gut microbiota in response to starvation stress. Copyright © 2018 Elsevier Ltd. All rights reserved.

Early adaption to the antarctic environment at dome C: consequences on stress-sensitive innate immune functions.

PubMed

Feuerecker, Matthias; Crucian, Brian; Salam, Alex P; Rybka, Ales; Kaufmann, Ines; Moreels, Marjan; Quintens, Roel; Schelling, Gustav; Thiel, Manfred; Baatout, Sarah; Sams, Clarence; Choukèr, Alexander

2014-09-01

Abstract Feuerecker, Matthias, Brian Crucian, Alex P. Salam, Ales Rybka, Ines Kaufmann, Marjan Moreels, Roel Quintens, Gustav Schelling, Manfred Thiel, Sarah Baatout, Clarence Sams, and Alexander Choukèr. Early adaption in the Antarctic environment at Dome C: Consequences on stress-sensitive innate immune functions. High Alt Med Biol 15:341-348, 2014.-Purpose/Aims: Medical reports of Antarctic expeditions indicate that health is affected under these extreme conditions. The present study at CONCORDIA-Station (Dome C, 3233 m) seeks to investigate the early consequences of confinement and hypobaric hypoxia on the human organism. Nine healthy male participants were included in this study. Data collection occurred before traveling to Antarctica (baseline), and at 1 week and 1 month upon arrival. Investigated parameters included basic physiological variables, psychological stress tests, cell blood count, stress hormones, and markers of innate immune functions in resting and stimulated immune cells. By testing for the hydrogen peroxide (H2O2) production of stimulated polymorphonuclear leukocytes (PMNs), the effects of the hypoxia-adenosine-sensitive immune modulatory pathways were examined. As compared to baseline data, reduced oxygen saturation, hemoconcentration, and an increase of secreted catecholamines was observed, whereas no psychological stress was seen. Upon stimulation, the activity of PMNs and L-selectin shedding was mitigated after 1 week. Endogenous adenosine concentration was elevated during the early phase. In summary, living conditions at high altitude influence the innate immune system's response. After 1 month, some of the early effects on the human organism were restored. As this early adaptation is not related to psychological stress, the changes observed are likely to be induced by environmental stressors, especially hypoxia. As hypoxia is triggering ATP-catabolism, leading to elevated endogenous adenosine concentrations, this and the increased catecholamine concentration might contribute to the early, but reversible downregulation of innate immune functions. This indicates the slope of innate immune adaptation to hypoxia.

Impact of Chronic Viral Infection on T-Cell Dependent Humoral Immune Response.

PubMed

Rodriguez, Stéphane; Roussel, Mikaël; Tarte, Karin; Amé-Thomas, Patricia

2017-01-01

During the last decades, considerable efforts have been done to decipher mechanisms supported by microorganisms or viruses involved in the development, differentiation, and function of immune cells. Pathogens and their associated secretome as well as the continuous inflammation observed in chronic infection are shaping both innate and adaptive immunity. Secondary lymphoid organs are functional structures ensuring the mounting of adaptive immune response against microorganisms and viruses. Inside these organs, germinal centers (GCs) are the specialized sites where mature B-cell differentiation occurs leading to the release of high-affinity immunoglobulin (Ig)-secreting cells. Different steps are critical to complete B-cell differentiation process, including proliferation, somatic hypermutations in Ig variable genes, affinity-based selection, and class switch recombination. All these steps require intense interactions with cognate CD4 + helper T cells belonging to follicular helper lineage. Interestingly, pathogens can disturb this subtle machinery affecting the classical adaptive immune response. In this review, we describe how viruses could act directly on GC B cells, either through B-cell infection or by their contribution to B-cell cancer development and maintenance. In addition, we depict the indirect impact of viruses on B-cell response through infection of GC T cells and stromal cells, leading to immune response modulation.

Role of selenium-containing proteins in T cell and macrophage function

PubMed Central

Carlson, Bradley A.; Yoo, Min-Hyuk; Shrimali, Rajeev K.; Irons, Robert; Gladyshev, Vadim N.; Hatfield, Dolph L.; Park, Jin Mo

2011-01-01

Synopsis Selenium has been known for many years to have a role in boosting immune function, but the manner in which this element acts at the molecular level in host defense and inflammatory diseases is poorly understood. To elucidate the role of selenium-containing proteins in immune function, we knocked out the expression of this protein class in T cells or macrophages of mice by targeting the removal of the selenocysteine tRNA gene using loxP-Cre technology. Mice with selenoprotein-less T cells manifested reduced pools of mature and functional T cells in lymphoid tissues and an impairment in T cell-dependent antibody responses. Furthermore, selenoprotein deficiency in T cells led to an inability of these cells to suppress reactive oxygen species (ROS) production, which in turn affected their ability to proliferate in response to T cell receptor stimulation. Selenoprotein-less macrophages, on the other hand, manifested mostly normal inflammatory responses, but this deficiency resulted in an altered regulation in extracellular matrix-related gene expression and a diminished migration of macrophages in a protein gel matrix. These observations provided novel insights into the role of selenoproteins in immune function and tissue homeostasis. PMID:20576203

Using Proteomics to Identify Viral microRNA-Regulated Genes | Center for Cancer Research

Cancer.gov

Kaposi sarcoma is a soft tissue malignancy that affects the skin, the mucous membranes, the lymph nodes and other organs of individuals with compromised immune systems. It is caused by infection with human herpesvirus-8 also known as Kaposi sarcoma-associated herpesvirus or KSHV. The herpesvirus family is unique in that it is the only viral family currently known to express multiple microRNAs (miRNAs); KSHV produces 12 pre-miRNAs, which are processed into at least 25 mature miRNAs. While their functions are not well understood, these miRNAs may be a way for the virus to alter the host immune response without producing proteins that could be recognized and targeted by the immune system. Joseph Ziegelbauer, Ph.D., in CCR’s HIV and AIDS Malignancy Branch, and his colleagues set out to identify human targets of KSHV miRNAs and to understand their functional importance.

[Functional analysis of Grp and Iris, the gag and env domesticated errantivirus genes, in the Drosophila melanogaster genome].

PubMed

Makhnovskii, P A; Kuzmin, I V; Nefedova, L N; Kima, A I

2016-01-01

Drosophila melanogaster is the only invertebrate that contains endogenous retroviruses, which are called errantiviruses. Two domesticated genes, Grp and Iris, which originate from errantivirus gag and env, respectively, have been found in the D. melanogaster genome. The functions performed by the genes in Drosophila are still unclear. To identify the functions of domesticated gag and env in the D. melanogaster genome, expression of Iris and Grp was studied in strains differing by the presence or absence of the functional gypsy errantivirus. In addition, the expression levels were measured after injection of gram-positive and gram-negative bacteria, which activate different immune response pathways, and exposure to various abiotic stress factors. The presence of functional D. melanogaster retrovirus gypsy was found to increase the Grp expression level in somatic tissues of the carcass, while exerting no effect on the Iris expression level. Activation of the immune response in D. melanogaster by bacteria Bacillus cereus increased the Grp expression level and did not affect Iris expression. As for the effects of abiotic stress factors (oxidative stress, starvation, and heat and cold stress), the Grp expression level increased in response to starvation in D. melanogaster females, and the Iris expression level was downregulated in heat shock and oxidative stress. Based on the findings, Grp was assumed to play a direct role in the immune response in D. melanogaster; Iris is not involved in immune responses, but and apparently performs a cell function that is inhibited in stress.

Robustness trade-offs and host–microbial symbiosis in the immune system

PubMed Central

Kitano, Hiroaki; Oda, Kanae

2006-01-01

The immune system provides organisms with robustness against pathogen threats, yet it also often adversely affects the organism as in autoimmune diseases. Recently, the molecular interactions involved in the immune system have been uncovered. At the same time, the role of the bacterial flora and its interactions with the host immune system have been identified. In this article, we try to reconcile these findings to draw a consistent picture of the host defense system. Specifically, we first argue that the network of molecular interactions involved in immune functions has a bow-tie architecture that entails inherent trade-offs among robustness, fragility, resource limitation, and performance. Second, we discuss the possibility that commensal bacteria and the host immune system constitute an integrated defense system. This symbiotic association has evolved to optimize its robustness against pathogen attacks and nutrient perturbations by harboring a broad range of microorganisms. Owing to the inherent propensity of a host immune system toward hyperactivity, maintenance of bacterial flora homeostasis might be particularly important in the development of preventive strategies against immune disorders such as autoimmune diseases. PMID:16738567

Long noncoding RNA in hematopoiesis and immunity.

PubMed

Satpathy, Ansuman T; Chang, Howard Y

2015-05-19

Dynamic gene expression during cellular differentiation is tightly coordinated by transcriptional and post-transcriptional mechanisms. An emerging theme is the central role of long noncoding RNAs (lncRNAs) in the regulation of this specificity. Recent advances demonstrate that lncRNAs are expressed in a lineage-specific manner and control the development of several cell types in the hematopoietic system. Moreover, specific lncRNAs are induced to modulate innate and adaptive immune responses. lncRNAs can function via RNA-DNA, RNA-RNA, and RNA-protein target interactions. As a result, they affect several stages of gene regulation, including chromatin modification, mRNA biogenesis, and protein signaling. We discuss recent advances, future prospects, and challenges in understanding the roles of lncRNAs in immunity and immune-mediated diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of the Microbiota in Immunity and inflammation

PubMed Central

Belkaid, Yasmine; Hand, Timothy

2014-01-01

The microbiota plays a fundamental role on the induction, training and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes. When operating optimally this immune system–microbiota alliance allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. However, in high-income countries overuse of antibiotics, changes in diet, and elimination of constitutive partners such as nematodes has selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected. PMID:24679531

Kidney dendritic cells in acute and chronic renal disease.

PubMed

Hochheiser, Katharina; Tittel, André; Kurts, Christian

2011-06-01

Dendritic cells are not only the master regulators of adaptive immunity, but also participate profoundly in innate immune responses. Much has been learned about their basic immunological functions and their roles in various diseases. Comparatively little is still known about their role in renal disease, despite their obvious potential to affect immune responses in the kidney, and immune responses that are directed against renal components. Kidney dendritic cells form an abundant network in the renal tubulointerstitium and constantly survey the environment for signs of injury or infection, in order to alert the immune system to the need to initiate defensive action. Recent studies have identified a role for dendritic cells in several murine models of acute renal injury and chronic nephritis. Here we summarize the current knowledge on the role of kidney dendritic cells that has been obtained from the study of murine models of renal disease. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.

Immune and hemorheological changes in Chronic Fatigue Syndrome

PubMed Central

2010-01-01

Background Chronic Fatigue Syndrome (CFS) is a multifactorial disorder that affects various physiological systems including immune and neurological systems. The immune system has been substantially examined in CFS with equivocal results, however, little is known about the role of neutrophils and natural killer (NK) phenotypes in the pathomechanism of this disorder. Additionally the role of erythrocyte rheological characteristics in CFS has not been fully expounded. The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in CFS patients. Methods Flow cytometric measurements were performed for neutrophil function, lymphocyte numbers, NK phenotypes (CD56dimCD16+ and CD56brightCD16-) and NK cytotoxic activity. Erythrocyte aggregation, deformability and fibrinogen levels were also assessed. Results CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56brightCD16- NK phenotypes in comparison to healthy controls (n = 10). However, hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56dimCD16+ NK cells were similar between the two groups. Conclusion These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients. PMID:20064266

Expression and Regulation of Cholecystokinin Receptor in the Chicken's Immune Organs and Cells.

PubMed

El-Kassas, Seham; Odemuyiwa, Solomon; Hajishengallis, George; Connell, Terry D; Nashar, Toufic O

2016-12-01

Cholecystokinin (CCK) is a neuropeptide that affects growth rate in chickens by regulating appetite. CCK peptides exert their function by binding to two identified receptors, CCKAR and CCKBR in the GI tract and the brain, respectively, as well as in other organs. In mammals, CCK/CCKAR interactions affect a number of immunological parameters, including regulation of lymphocytes and functioning of monocytes. Thus, food intake and growth can potentially be altered by infection and the resulting inflammatory immune response. It is uncertain, however, whether chicken express CCKAR in immune organs and cells, and, if so, whether CCKAR expression is regulated by pathogen derived inflammatory stimuli. Herein, we identify expression of CCKAR protein in chicken peripheral blood mononuclear cells (PBMC) including monocytes, and expression of the CCKAR gene in PBMC, thymus, bursa, and spleen, in selected commercial and pure chicken breeds. Further, stimulation with various types of E. coli heat-labile enterotoxins or lipopolysaccharide significantly regulated expression of CCKAR on monocytes in the different breeds. Ligation of CCKAR with antibodies in PBMC induced mobilization of Ca 2+ , indicating that CCKAR is signal competent. Injection with polyinosinic: polycytidylic acid (poly I:C), a synthetic analogue of double stranded viral RNA that binds Toll-Like Receptor-3 (TLR3), also regulated gene expressions of CCKAR and proinflammatory cytokines, in the different breeds. Interestingly, variations in the expression levels of proinflammatory cytokines in the different breeds were highly correlated with CCKAR expression levels. Taken together, these findings indicate that the physiological function of CCKAR in the chicken is tightly regulated in immune organs and cells by external inflammatory stimuli, which in turn regulate growth. This is the first report CCKAR expression in immune organs and cells, in any species, and the initial observation that CCKAR is regulated by inflammatory stimuli associated with bacterial and viral infection.

Expression and Regulation of Cholecystokinin Receptor in the Chicken's Immune Organs and Cells

PubMed Central

El-Kassas, Seham; Odemuyiwa, Solomon; Hajishengallis, George; Connell, Terry D; Nashar, Toufic O

2017-01-01

Cholecystokinin (CCK) is a neuropeptide that affects growth rate in chickens by regulating appetite. CCK peptides exert their function by binding to two identified receptors, CCKAR and CCKBR in the GI tract and the brain, respectively, as well as in other organs. In mammals, CCK/CCKAR interactions affect a number of immunological parameters, including regulation of lymphocytes and functioning of monocytes. Thus, food intake and growth can potentially be altered by infection and the resulting inflammatory immune response. It is uncertain, however, whether chicken express CCKAR in immune organs and cells, and, if so, whether CCKAR expression is regulated by pathogen derived inflammatory stimuli. Herein, we identify expression of CCKAR protein in chicken peripheral blood mononuclear cells (PBMC) including monocytes, and expression of the CCKAR gene in PBMC, thymus, bursa, and spleen, in selected commercial and pure chicken breeds. Further, stimulation with various types of E. coli heat-labile enterotoxins or lipopolysaccharide significantly regulated expression of CCKAR on monocytes in the different breeds. Ligation of CCKAR with antibodies in PBMC induced mobilization of Ca2+, indicating that CCKAR is signal competent. Injection with polyinosinic: polycytidylic acid (poly I:C), a synthetic analogue of double stranded viral RNA that binds Toll-Like Receptor-3 (TLR3), also regulated gene expressions of CCKAR and proinflammatory cytokines, in the different breeds. Interestingly, variations in the expression levels of proinflammatory cytokines in the different breeds were highly correlated with CCKAR expression levels. Taken together, these findings indicate that the physiological function of CCKAR in the chicken is tightly regulated in immune organs and cells by external inflammatory stimuli, which in turn regulate growth. This is the first report CCKAR expression in immune organs and cells, in any species, and the initial observation that CCKAR is regulated by inflammatory stimuli associated with bacterial and viral infection. PMID:28149670

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation, function and EBV immunity.

PubMed

Edwards, Emily S J; Bier, Julia; Cole, Theresa S; Wong, Melanie; Hsu, Peter; Berglund, Lucinda J; Boztug, Kaan; Lau, Anthony; Gostick, Emma; Price, David A; O'Sullivan, Michael; Meyts, Isabelle; Choo, Sharon; Gray, Paul; Holland, Steven M; Deenick, Elissa K; Uzel, Gulbu; Tangye, Stuart G

2018-05-22

Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphatidylinositol-3 kinase, result in hyperactivation of the PI3K-AKT-mTOR pathway and underlie a novel inborn error of immunity. Affected individuals exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or CMV infection, and an increased incidence of B-cell lymphoproliferation and/or lymphoma. Mechanisms underlying disease pathogenesis remain unknown. Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in individuals with PIK3CD GOF mutations, identify key molecules required for cell mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this as well as other EBV-opathies. We studied the consequences of PIK3CD GOF mutations on the generation, differentiation and function of CD8 + T cells and NK cells, which are implicated in host defense against infection with herpesviruses including EBV. PIK3CD GOF total and EBV-specific CD8 + T cells were skewed towards an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion, and increased susceptibility to re-activation induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF. NK cells in PIK3CD GOF individuals also exhibited perturbed expression of differentiation-associated molecules. Both CD8 + T cells and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, PDL-1/2 and CD70. PIK3CD GOF mutations aberrantly induce exhaustion and/or senescence and impair cytotoxicity of CD8+ T and NK cells. These defects may contribute to clinical features of affected individuals, such as impaired immunity to herpesviruses and tumor surveillance. Copyright © 2018. Published by Elsevier Inc.

Ontogeny of the cortisol stress response in channel catfish (Ictalurus punctatus)

USDA-ARS?s Scientific Manuscript database

Cortisol is a glucocorticoid hormone which is an endocrine signaling molecule in all vertebrates and acts through intracellular glucocorticoid receptors (GR). Cortisol affects many biological functions including immunity, stress, growth, ion homeostasis, and reproduction. The objective of this stu...

Photoperiodic adjustments in immune function protect Siberian hamsters from lethal endotoxemia.

PubMed

Prendergast, Brian J; Hotchkiss, Andrew K; Bilbo, Staci D; Kinsey, Steven G; Nelson, Randy J

2003-02-01

Seasonal changes in day length enhance or suppress components of immune function in individuals of several mammalian species. Siberian hamsters (Phodopus sungorus) exhibit multiple changes in neuroendocrine, reproductive, and immune function after exposure to short days. The manner in which these changes are integrated into the host response to pathogens is not well understood. The present experiments tested the hypothesis that short-day changes in immune function alter the pathogenesis of septic shock and survival after challenge with endotoxin. Male and female Siberian hamsters raised in long-day photoperiods were transferred as adults to short days or remained in their natal photoperiod. Six to 8 weeks later, hamsters were injected i.p. with 0, 1, 2.5, 10, 25, or 50 mg/kg bacterial lipopolysaccharide (LPS) (the biologically active constituent of endotoxin), and survival was monitored for 96 h. Short days significantly improved survival of male hamsters treated with 10 or 25 mg/kg LPS and improved survival in females treated with 50 mg/kg LPS. Transfer from long to short days shifted the LD50 in males by approximately 90%, from 5.3 to 9.9 mg/kg, and in females from 11.1 to 15.0 mg/kg (+35%). Long-day females were more resistant than were males to lethal endotoxemia. In vitro production of the proinflammatory cytokine TNFalpha in response to LPS stimulation was significantly lower in macrophages extracted from short-day relative to long-day hamsters, as were circulating concentrations of TNFalpha in vivo after i.p. administration of LPS, suggesting that diminished cytokine responses to LPS in short days may mitigate the lethality of endotoxemia. Adaptation to short days induces changes in immune parameters that affect survival in the face of immune challenges.

Effects of ration level on immune functions in chinook salmon (Oncorhynchus tshawytscha)

USGS Publications Warehouse

Alcorn, S.W.; Pascho, R.J.; Murray, A.L.; Shearer, K.D.

2003-01-01

The relationship between nutritional status and disease resistance in cultured salmonids can be affected by dietary manipulations. Careful attention to feeding levels may be important to avoid imbalances in nutrient levels that could ultimately impair a fish's ability to resist infectious microorganisms. In the current study, fish in three feed-level groups were fed an experimental diet either to satiation, 64% of satiation or 40% of satiation. A fourth group of fish were fed a commercial diet at the 64% of satiation level and served as controls. To evaluate certain indices of disease resistance in the test and control fish, a panel of assays was employed to measure humoral and cellular immune functions 30, 39 and 54 weeks after starting the dietary treatments. The panel included measures of blood hematocrit and leucocrit levels, plasma protein concentration and serum lysozyme and complement activity. Cellular analyses included differential blood leucocyte counts, NBT reduction and phagocytosis by pronephros macrophages and myeloperoxidase activity of pronephros neutrophils. No differences were observed in those indices between fish tested from the control-diet group (commercial diet fed at the 64% rate) and fish tested from the 64% feed-level group, except that fish fed the commercial diet had a greater concentration of plasma protein. Leucocrit values and plasma protein concentrations tended to increase among the experimental feed groups as the ration increased from 40% to satiation. More importantly, phagocytic activity by anterior kidney leucocytes was found to be inversely proportional to the feed level. Whereas the results of this study provide evidence that the salmonid immune system may be fairly robust with regard to available metabolic energy, the significant changes observed in phagocytic cell activity suggest that some cellular immune functions may be affected by the feed level.

Steroidogenesis in the skin: implications for local immune functions

PubMed Central

Slominski, Andrzej; Zbytek, Bazej; Nikolakis, Georgios; Manna, Pulak R.; Skobowiat, Cezary; Zmijewski, Michal; Li, Wei; Janjetovic, Zorica; Postlethwaite, Arnold; Zouboulis, Christos C.; Tuckey, Robert C.

2013-01-01

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7 -steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. PMID:23435015

Allatotropin: A pleiotropic neuropeptide that elicits mosquito immune responses.

PubMed

Hernández-Martínez, Salvador; Sánchez-Zavaleta, Minerva; Brito, Kevin; Herrera-Ortiz, Antonia; Ons, Sheila; Noriega, Fernando G

2017-01-01

Allatotropins (AT) are neuropeptides with pleotropic functions on a variety of insect tissues. They affect processes such as juvenile hormone biosynthesis, cardiac rhythm, oviduct and hindgut contractions, nutrient absorption and circadian cycle. The present work provides experimental evidence that AT elicits immune responses in two important mosquito disease vectors, Anopheles albimanus and Aedes aegypti. Hemocytes and an immune-competent mosquito cell line responded to AT by showing strong morphological changes and increasing bacterial phagocytic activity. Phenoloxidase activity in hemolymph was also increased in Ae. aegypti mosquitoes treated with AT but not in An. albimanus, suggesting differences in the AT-dependent immune activation in the two species. In addition, two important insect immune markers, nitric oxide levels and expression of antimicrobial peptide genes, were increased in An. albimanus guts after AT treatment. AT conjugated to quantum dot nanocrystals (QDots) specifically labeled hemocytes in vivo in both mosquito species, implying molecular interactions between AT and hemocytes. The results of our studies suggest a new role for AT in the modulation of the immune response in mosquitoes.

Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.

PubMed

Luck, Helen; Tsai, Sue; Chung, Jason; Clemente-Casares, Xavier; Ghazarian, Magar; Revelo, Xavier S; Lei, Helena; Luk, Cynthia T; Shi, Sally Yu; Surendra, Anuradha; Copeland, Julia K; Ahn, Jennifer; Prescott, David; Rasmussen, Brittany A; Chng, Melissa Hui Yen; Engleman, Edgar G; Girardin, Stephen E; Lam, Tony K T; Croitoru, Kenneth; Dunn, Shannon; Philpott, Dana J; Guttman, David S; Woo, Minna; Winer, Shawn; Winer, Daniel A

2015-04-07

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Immune status influences fear and anxiety responses in mice after acute stress exposure

PubMed Central

Clark, Sarah M.; Sand, Joseph; Francis, T. Chase; Nagaraju, Anitha; Michael, Kerry C.; Keegan, Achsah D.; Kusnecov, Alexander; Gould, Todd D.; Tonelli, Leonardo H.

2014-01-01

Significant evidence suggests that exposure to traumatic and/or acute stress in both mice and humans results in compromised immune function that in turn may affect associated brain processes. Additionally, recent studies in mouse models of immune deficiency have suggested that adaptive immunity may play a role during traumatic stress exposure and that impairments in lymphocyte function may contribute to increased susceptibility to various psychogenic stressors. However, rodent studies on the relationship between maladaptive stress responses and lymphocyte deficiency have been complicated by the fact that genetic manipulations in these models may also result in changes in CNS function due to the expression of targeted genes in tissues other than lymphocytes, including the brain. To address these issues we utilized mice with a deletion of recombination-activating gene 2 (Rag2), which has no confirmed expression in the CNS; thus, its loss should result in the absence of mature lymphocytes without altering CNS function directly. Stress responsiveness of immune deficient Rag2−/− mice on a BALB/c background was evaluated in three different paradigms: predator odor exposure (POE), fear conditioning (FC) and learned helplessness (LH). These models are often used to study different aspects of stress responsiveness after the exposure to an acute stressor. In addition, immunoblot analysis was used to assess hippocampal BDNF expression under both stressed and non-stressed conditions. Subsequent to POE, Rag2−/− mice exhibited a reduced acoustic startle response compared to BALB/c mice; no significant differences in behavior were observed in either FC or LH. Furthermore, analysis of hippocampal BDNF indicated that Rag2−/− mice have elevated levels of the mature form of BDNF compared to BALB/c mice. Results from our studies suggest that the absence of mature lymphocytes is associated with increased resilience to stress exposure in the POE and does not affect behavioral responses in the FC and LH paradigms. These findings indicate that lymphocytes play a specific role in stress responsiveness dependent upon the type, nature and intensity of the stressor. PMID:24524915

Impact of Helminth Infections and Nutritional Constraints on the Small Intestine Microbiota

PubMed Central

Cattadori, Isabella M.; Albert, Istvan; Eilertson, Kirsten E.; Kapur, Vivek; Pathak, Ashutosh; Mitchell, Susan

2016-01-01

Helminth infections and nutrition can independently alter the composition and abundance of the gastrointestinal microbiota, however, their combined effect is poorly understood. Here, we used the T. retortaeformis-rabbit system to examine how the helminth infection and host restriction from coprophagy/ready-to-absorb nutrients affected the duodenal microbiota, and how these changes related to the acquired immune response at the site of infection. A factorial experiment was performed where the bacterial community, its functionality and the immune response were examined in four treatments (Infect, Infect+Collar, Control+Collar and Control). Helminths reduced the diversity and abundance of the microbiota while the combination of parasites and coprophagic restriction led to a more diversified and abundant microbiota than infected cases, without significantly affecting the intensity of infection. Animals restricted from coprophagy and free from parasites exhibited the richest and most abundant bacterial community. By forcing the individuals to absorb nutrients from less digested food, the coprophagic restriction appears to have facilitated the diversity and proliferation of bacteria in the duodenum. Changes in the microbiota were more clearly associated with changes in the immune response for the infected than the nutrient restricted animals. The functional and metabolic characteristics of the duodenal microbiota were not significantly different between treatments. Overall, infection and diet affect the gut microbiota but their interactions and outcome can be complex. These findings can have important implications for the development of control measures to helminth infections where poor nutrition/malnutrition can also be a concern. PMID:27438701

Impact of Helminth Infections and Nutritional Constraints on the Small Intestine Microbiota.

PubMed

Cattadori, Isabella M; Sebastian, Aswathy; Hao, Han; Katani, Robab; Albert, Istvan; Eilertson, Kirsten E; Kapur, Vivek; Pathak, Ashutosh; Mitchell, Susan

2016-01-01

Helminth infections and nutrition can independently alter the composition and abundance of the gastrointestinal microbiota, however, their combined effect is poorly understood. Here, we used the T. retortaeformis-rabbit system to examine how the helminth infection and host restriction from coprophagy/ready-to-absorb nutrients affected the duodenal microbiota, and how these changes related to the acquired immune response at the site of infection. A factorial experiment was performed where the bacterial community, its functionality and the immune response were examined in four treatments (Infect, Infect+Collar, Control+Collar and Control). Helminths reduced the diversity and abundance of the microbiota while the combination of parasites and coprophagic restriction led to a more diversified and abundant microbiota than infected cases, without significantly affecting the intensity of infection. Animals restricted from coprophagy and free from parasites exhibited the richest and most abundant bacterial community. By forcing the individuals to absorb nutrients from less digested food, the coprophagic restriction appears to have facilitated the diversity and proliferation of bacteria in the duodenum. Changes in the microbiota were more clearly associated with changes in the immune response for the infected than the nutrient restricted animals. The functional and metabolic characteristics of the duodenal microbiota were not significantly different between treatments. Overall, infection and diet affect the gut microbiota but their interactions and outcome can be complex. These findings can have important implications for the development of control measures to helminth infections where poor nutrition/malnutrition can also be a concern.

High-Concentrate Diet-Induced Change of Cellular Metabolism Leads to Decreases of Immunity and Imbalance of Cellular Activities in Rumen Epithelium.

PubMed

Lu, Zhongyan; Shen, Hong; Shen, Zanming

2018-01-01

In animals, the immune and cellular processes of tissue largely depend on the status of local metabolism. However, in the rumen epithelium, how the cellular metabolism affects epithelial immunity, and cellular processes, when the diet is switched from energy-rich to energy-excess status, with regard to animal production and health, have not as yet been reported. RNA-seq was applied to compare the biological processes altered by an increase of dietary concentration from 10% to 35% with those altered by an increase of dietary concentration from 35% to 65% (dietary concentrate: the non-grass component in diet, including corn, soya bean meal and additive. High concentrate diet composed of 35% grass, 55% corn, 8% soya bean meal and 2% additive). In addition to the functional analysis of enriched genes in terms of metabolism, the immune system, and cellular process, the highly correlated genes to the enriched metabolism genes were identified, and the function and signaling pathways related to the differentially expressed neighbors were compared among the groups. The variation trends of molar proportions of ruminal SCFAs and those of enriched pathways belonging to metabolism, immune system, and cellular process were altered with the change of diets. With regard to metabolism, lipid metabolism and amino acid metabolism were most affected. According to the correlation analysis, both innate and adaptive immune responses were promoted by the metabolism genes enriched under the 65% concentrate diet. However, the majority of immune responses were suppressed under the 35% concentrate diet. Moreover, the exclusive upregulation of cell growth and dysfunction of cellular transport and catabolism were induced by the metabolism genes enriched under the 65% concentrate diet. On the contrary, a balanced regulation of cellular processes was detected under the 35% concentrate diet. These results indicated that the alterations of cellular metabolism promote the alterations in cellular immunity, repair, and homeostasis in the rumen epithelium, thereby leading to the switch of concentrate effects from positive to negative with regard to animal production and health. © 2018 The Author(s). Published by S. Karger AG, Basel.

Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis.

PubMed

Leppkes, Moritz; Neurath, Markus F; Herrmann, Martin; Becker, Christoph

2016-01-01

Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT". © Society for Leukocyte Biology.

Regulation of immune cells in the uterus during pregnancy in ruminants.

PubMed

Hansen, P J

2007-03-01

Pregnancy results in a change in number and function of immune cells in utero that potentially affects fetal survival and uterine defense mechanisms postpartum. These changes are driven by local signals from the conceptus as well as from hormonal changes mediated by the placenta or maternal system. In sheep, for example, macrophages accumulate in the uterine endometrium during pregnancy (Tekin and Hansen, 2004). Use of a unilaterally pregnant model, in which pregnancy is surgically confined to 1 uterine horn, has revealed that accumulation of macrophages is due to systemic signals (numbers of cells in the nonpregnant uterine horn of the unilaterally pregnant ewe higher than amounts in uteri of nonpregnant ewes) and locally produced signals (number of cells in the uterus of unilaterally ligated ewes higher in the pregnant horn than in the nonpregnant horn; Tekin and Hansen, 2004). Gamma-delta T cells also accumulate in uterine epithelium during pregnancy as a result of unidentified systemic signals (Lee et al., 1992; Majewski et al., 2001). These cells may participate in growth of the conceptus, immunosuppression, or placental detachment at parturition. One of the key regulators of uterine immune function is progesterone. In sheep, progesterone can block tissue graft rejection in utero when injected to achieve concentrations too low to directly inhibit lymphocyte proliferation (Majewski and Hansen, 2002; Padua et al., 2005). Progesterone probably inhibits uterine immune responses in sheep indirectly by inducing secretion of a member of the serine proteinase inhibitor family called uterine serpin from the endometrial epithelium. Uterine serpin can block lymphocyte proliferation in vitro in sheep (Peltier et al., 2000) and natural killer cell-mediated abortion in vivo in mice (Liu and Hansen, 1993). Uterine serpin is also present in cattle, goats, and pigs, but its role in immune function in these species has not been documented. The relevance of changes in uterine immune function to the reproductive and immune status of ruminants has not been fully established. There is evidence for immunological causes of pregnancy loss associated with cloned fetuses (Hill et al., 2002) and with mastitis (Hansen et al., 2004), but it is not known whether inappropriate recognition of alloantigens on the conceptus is an important cause of pregnancy loss. It is also possible that downregulation of uterine immune function during pregnancy can lead to a postpartum uterus with a compromised capacity for preventing establishment of infectious disease. Thus, optimal immune function in utero requires a balance between the need to maintain effective immune surveillance and effector mechanisms with the requirement that immunological responses leading to conceptus demise are minimized.

Nutrition, diet and immunosenescence.

PubMed

Maijó, Mònica; Clements, Sarah J; Ivory, Kamal; Nicoletti, Claudio; Carding, Simon R

2014-01-01

Ageing is characterized by immunosenescence and the progressive decline in immunity in association with an increased frequency of infections and chronic disease. This complex process affects both the innate and adaptive immune systems with a progressive decline in most immune cell populations and defects in activation resulting in loss of function. Although host genetics and environmental factors, such as stress, exercise and diet can impact on the onset or course of immunosenescence, the mechanisms involved are largely unknown. This review focusses on identifying the most significant aspects of immunosenescence and on the evidence that nutritional intervention might delay this process, and consequently improve the quality of life of the elderly. Copyright © 2014. Published by Elsevier Ireland Ltd.

Genome-Wide Gene Expression in relation to Age in Large Laboratory Cohorts of Drosophila melanogaster

PubMed Central

Carlson, Kimberly A.; Gardner, Kylee; Pashaj, Anjeza; Carlson, Darby J.; Yu, Fang; Eudy, James D.; Zhang, Chi; Harshman, Lawrence G.

2015-01-01

Aging is a complex process characterized by a steady decline in an organism's ability to perform life-sustaining tasks. In the present study, two cages of approximately 12,000 mated Drosophila melanogaster females were used as a source of RNA from individuals sampled frequently as a function of age. A linear model for microarray data method was used for the microarray analysis to adjust for the box effect; it identified 1,581 candidate aging genes. Cluster analyses using a self-organizing map algorithm on the 1,581 significant genes identified gene expression patterns across different ages. Genes involved in immune system function and regulation, chorion assembly and function, and metabolism were all significantly differentially expressed as a function of age. The temporal pattern of data indicated that gene expression related to aging is affected relatively early in life span. In addition, the temporal variance in gene expression in immune function genes was compared to a random set of genes. There was an increase in the variance of gene expression within each cohort, which was not observed in the set of random genes. This observation is compatible with the hypothesis that D. melanogaster immune function genes lose control of gene expression as flies age. PMID:26090231

Honey Bee Antiviral Immune Barriers as Affected by Multiple Stress Factors: A Novel Paradigm to Interpret Colony Health Decline and Collapse.

PubMed

Nazzi, Francesco; Pennacchio, Francesco

2018-03-30

Any attempt to outline a logical framework in which to interpret the honey bee health decline and its contribution to elevated colony losses should recognize the importance of the multifactorial nature of the responsible syndrome and provide a functional model as a basis for defining and testing working hypotheses. We propose that covert infections by deformed wing virus (DWV) represent a sword of Damocles permanently threatening the survival of honey bee colonies and suggest that any factor affecting the honey bee’s antiviral defenses can turn this pathogen into a killer. Here we discuss the available experimental evidence in the framework of a model based on honey bee immune competence as affected by multiple stress factors that is proposed as a conceptual tool for analyzing bee mortality and its underlying mechanisms.

Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner.

PubMed

Doerflinger, Sylvie Y; Throop, Andrea L; Herbst-Kralovetz, Melissa M

2014-06-15

Bacterial vaginosis increases the susceptibility to sexually transmitted infections and negatively affects women's reproductive health. To investigate host-vaginal microbiota interactions and the impact on immune barrier function, we colonized 3-dimensional (3-D) human vaginal epithelial cells with 2 predominant species of vaginal microbiota (Lactobacillus iners and Lactobacillus crispatus) or 2 prevalent bacteria associated with bacterial vaginosis (Atopobium vaginae and Prevotella bivia). Colonization of 3-D vaginal epithelial cell aggregates with vaginal microbiota was observed with direct attachment to host cell surface with no cytotoxicity. A. vaginae infection yielded increased expression membrane-associated mucins and evoked a robust proinflammatory, immune response in 3-D vaginal epithelial cells (ie, expression of CCL20, hBD-2, interleukin 1β, interleukin 6, interleukin 8, and tumor necrosis factor α) that can negatively affect barrier function. However, P. bivia and L. crispatus did not significantly upregulate pattern-recognition receptor-signaling, mucin expression, antimicrobial peptides/defensins, or proinflammatory cytokines in 3-D vaginal epithelial cell aggregates. Notably, L. iners induced pattern-recognition receptor-signaling activity, but no change was observed in mucin expression or secretion of interleukin 6 and interleukin 8. We identified unique species-specific immune signatures from vaginal epithelial cells elicited by colonization with commensal and bacterial vaginosis-associated bacteria. A. vaginae elicited a signature that is consistent with significant disruption of immune barrier properties, potentially resulting in enhanced susceptibility to sexually transmitted infections during bacterial vaginosis. © 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.

Tomato Prenylated RAB Acceptor Protein 1 Modulates Trafficking and Degradation of the Pattern Recognition Receptor LeEIX2, Affecting the Innate Immune Response

PubMed Central

Pizarro, Lorena; Leibman-Markus, Meirav; Schuster, Silvia; Bar, Maya; Meltz, Tal; Avni, Adi

2018-01-01

Plants recognize microbial/pathogen associated molecular patterns (MAMP/PAMP) through pattern recognition receptors (PRRs) triggering an immune response against pathogen progression. MAMP/PAMP triggered immune response requires PRR endocytosis and trafficking for proper deployment. LeEIX2 is a well-known Solanum lycopersicum RLP-PRR, able to recognize and respond to the fungal MAMP/PAMP ethylene-inducing xylanase (EIX), and its function is highly dependent on intracellular trafficking. Identifying protein machinery components regulating LeEIX2 intracellular trafficking is crucial to our understanding of LeEIX2 mediated immune responses. In this work, we identified a novel trafficking protein, SlPRA1A, a predicted regulator of RAB, as an interactor of LeEIX2. Overexpression of SlPRA1A strongly decreases LeEIX2 endosomal localization, as well as LeEIX2 protein levels. Accordingly, the innate immune responses to EIX are markedly reduced by SlPRA1A overexpression, presumably due to a decreased LeEIX2 availability. Studies into the role of SlPRA1A in LeEIX2 trafficking revealed that LeEIX2 localization in multivesicular bodies/late endosomes is augmented by SlPRA1A. Furthermore, inhibiting vacuolar function prevents the LeEIX2 protein level reduction mediated by SlPRA1A, suggesting that SlPRA1A may redirect LeEIX2 trafficking to the vacuole for degradation. Interestingly, SlPRA1A overexpression reduces the amount of several RLP-PRRs, but does not affect the protein level of receptor-like kinase PRRs, suggesting a specific role of SlPRA1A in RLP-PRR trafficking and degradation. PMID:29545816

Macrophages and depression - a misalliance or well-arranged marriage?

PubMed

Roman, Adam; Kreiner, Grzegorz; Nalepa, Irena

2013-01-01

Depression is a severe medical condition with multiple manifestations and diverse, largely unknown etiologies. The immune system, particularly macrophages, plays an important role in the pathology of the illness. Macrophages represent a heterogeneous population of immune cells that is dispersed throughout the body. The central nervous system is populated by several types of macrophages, including microglia, perivascular cells, meningeal and choroid plexus macrophages and pericytes. These cells occupy different brain compartments and have various functions. Under basal conditions, brain macrophages support the proper function of neural cells, organize and preserve the neuronal network and maintain homeostasis. As cells of the innate immune system, they recognize and react to any disturbances in homeostasis, eliminating pathogens or damaged cells, terminating inflammation and proceeding to initiate tissue reconstruction. Disturbances in these processes result in diverse pathologies. In particular, tissue stress or malfunction, both in the brain and in the periphery, produce sustained inflammatory states, which may cause depression. Excessive release of proinflammatory mediators is responsible for alterations of neurotransmitter systems and the occurrence of depressive symptoms. Almost all antidepressive drugs target monoamine or serotonin neurotransmission and also have anti-inflammatory or immunosuppressive properties. In addition, non-pharmacological treatments, such as electroconvulsive shock, can also exert anti-inflammatory effects. Recent studies have shown that antidepressive therapies can affect the functional properties of peripheral and brain macrophages and skew them toward the anti-inflammatory M2 phenotype. Because macrophages can affect outcome of inflammatory diseases, alleviate sickness behavior and improve cognitive function, it is possible that the effects of antidepressive treatments may be, at least in part, mediated by changes in macrophage activity.

Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome.

PubMed

Zapata, Luis; Pich, Oriol; Serrano, Luis; Kondrashov, Fyodor A; Ossowski, Stephan; Schaefer, Martin H

2018-05-31

Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic. Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes. In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.

Dim light at night increases immune function in Nile grass rats, a diurnal rodent.

PubMed

Fonken, Laura K; Haim, Achikam; Nelson, Randy J

2012-02-01

With the widespread adoption of electrical lighting during the 20th century, human and nonhuman animals became exposed to high levels of light at night for the first time in evolutionary history. This divergence from the natural environment may have significant implications for certain ecological niches because of the important influence light exerts on the circadian system. For example, circadian disruption and nighttime light exposure are linked to changes in immune function. The majority of studies investigating the effects of light exposure and circadian disruption on the immune system use nocturnal rodents. In diurnal species, many hormones and immune parameters vary with secretion patterns 180° out of phase to those of nocturnal rodents. Thus, the authors investigated the effects of nighttime light exposure on immunocompetence in diurnal Nile grass rats (Arvicanthis niloticus). Rats were housed in either standard 14-h light (L):10-h dark (D) cycles with L ∼150 lux and D 0 lux or dim light at night (dLAN) cycles of LD 14:10 with L ∼150 lux and D 5 lux for 3 wks, then tested for plasma bactericidal capacity, as well as humoral and cell-mediated immune responses. Rats exposed to dLAN showed increased delayed-type hypersensitivity pinna swelling, which is consistent with enhanced cell-mediated immune function. dLAN rats similarly showed increased antibody production following inoculation with keyhole lymphocyte hemocyanin (KLH) and increased bactericidal capacity. Daytime corticosterone concentrations were elevated in grass rats exposed to nighttime dim light, which may have influenced immunological measures. Overall, these results indicate nighttime light affects immune parameters in a diurnal rodent.

A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4

PubMed Central

Alsina, L; Israelsson, E; Altman, MC; Dang, KK; Ghandil, P; Israel, L; von Bernuth, H; Baldwin, N; Qin, H; Jin, Z; Banchereau, R; Anguiano, E; Ionan, A; Abel, L; Puel, A; Picard, C; Pascual, V; Casanova, JL; Chaussabel, D

2014-01-01

Loss of function in the kinase IRAK-4 or the adapter MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. Yet patients with loss of function mutations are surprisingly only susceptible to a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients’ blood to Toll-like receptor and interleukin-1 receptor agonists, and whole pathogens. Responses to purified agonists were globally abolished but variable residual responses were present following exposure to whole pathogens. Further dissection of the latter responses identified a narrow repertoire of immune transcriptional programs affected by loss of MyD88 or IRAK-4 function. This work introduces the use of a systems approach for the global assessment of innate immune responses, and the characterization of human primary immunodeficiencies. PMID:25344726

Hospital For Special Surgery/Immune System REgulation In Musculoskeletal Disorders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eric Meffre; Lionel Ivashkiv

2007-08-20

Inflammation on musculoskeletal disorders such as rheumatoid arthritis (RA) is the result of dysregulation of the immune system. When the immune system, which maintains the integrity of the organism in an environment rich in infectious microbes, becomes misdirected toward components of one’s own tissue, autoimmune disease can result with autoantibodies contributing to the inflammation and tissue damage. RA is a chronic autoimmune disease marked by severe inflammation that causes pain, swelling, stiffness and loss of function in the joints, which is estimated to affect 1 percent of the US adult population. Furthermore, autoimmune diseases, which affect women at a highermore » rate, are the fourth largest cause of disability among women in the US and among the top ten causes of death. The long range goal of this study is to elucidate the mechanisms that regulate the generation of autoantibodies by B cells in normal individuals and in patients with autoimmune diseases and provide insights into potential therapeutic interventions.« less

DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice.

PubMed

Cox, Nehemiah; Pilling, Darrell; Gomer, Richard H

2015-07-07

Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcγ receptors (FcγR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcγR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti-DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics.

Exosomes and their roles in immune regulation and cancer.

PubMed

Greening, David W; Gopal, Shashi K; Xu, Rong; Simpson, Richard J; Chen, Weisan

2015-04-01

Exosomes, a subset of extracellular vesicles (EVs), function as a mode of intercellular communication and molecular transfer. Exosomes facilitate the direct extracellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells in vitro and in vivo. The immunological activities of exosomes affect immunoregulation mechanisms including modulating antigen presentation, immune activation, immune suppression, immune surveillance, and intercellular communication. Besides immune cells, cancer cells secrete immunologically active exosomes that influence both physiological and pathological processes. The observation that exosomes isolated from immune cells such as dendritic cells (DCs) modulate the immune response has enforced the way these membranous vesicles are being considered as potential immunotherapeutic reagents. Indeed, tumour- and immune cell-derived exosomes have been shown to carry tumour antigens and promote immunity, leading to eradication of established tumours by CD8(+) T cells and CD4(+) T cells, as well as directly suppressing tumour growth and resistance to malignant tumour development. Further understanding of these areas of exosome biology, and especially of molecular mechanisms involved in immune cell targeting, interaction and manipulation, is likely to provide significant insights into immunorecognition and therapeutic intervention. Here, we review the emerging roles of exosomes in immune regulation and the therapeutic potential in cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunomodulation of enteric neural function in irritable bowel syndrome.

PubMed

O'Malley, Dervla

2015-06-28

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which is characterised by symptoms such as bloating, altered bowel habit and visceral pain. It's generally accepted that miscommunication between the brain and gut underlies the changes in motility, absorpto-secretory function and pain sensitivity associated with IBS. However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. Anecdotally, IBS patients have noted that periods of stress can result in symptom flares and many patients exhibit co-morbid stress-related mood disorders such as anxiety and depression. However, in addition to psychosocial stressors, infection-related stress has also been linked with the initiation, persistence and severity of symptom flares. Indeed, prior gastrointestinal infection is one of the strongest predictors of developing IBS. Despite a lack of overt morphological inflammation, the importance of immune factors in the pathophysiology of IBS is gaining acceptance. Subtle changes in the numbers of mucosal immune cell infiltrates and elevated levels of circulating pro-inflammatory cytokines have been reproducibly demonstrated in IBS populations. Moreover, these immune mediators directly affect neural signalling. An exciting new area of research is the role of luminal microbiota in the modulation of neuro-immune signalling, resulting in local changes in gastrointestinal function and alterations in central neural functioning. Progress in this area has begun to unravel some of the complexities of neuroimmune and neuroendocrine interactions and how these molecular exchanges contribute to GI dysfunction.

Arabidopsis glycosylphosphatidylinositol-anchored protein LLG1 associates with and modulates FLS2 to regulate innate immunity.

PubMed

Shen, Qiujing; Bourdais, Gildas; Pan, Huairong; Robatzek, Silke; Tang, Dingzhong

2017-05-30

Plants detect and respond to pathogen invasion with membrane-localized pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and activate downstream immune responses. Here we report that Arabidopsis thaliana LORELEI-LIKE GPI-ANCHORED PROTEIN 1 (LLG1), a coreceptor of the receptor-like kinase FERONIA, regulates PRR signaling. In a forward genetic screen for suppressors of enhanced disease resistance 1 ( edr1 ), we identified the point mutation llg1-3 , which suppresses edr1 disease resistance but does not affect plant growth and development. The llg1 mutants show enhanced susceptibility to various virulent pathogens, indicating that LLG1 has an important role in plant immunity. LLG1 constitutively associates with the PAMP receptor FLAGELLIN SENSING 2 (FLS2) and the elongation factor-Tu receptor, and forms a complex with BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1 in a ligand-dependent manner, indicating that LLG1 functions as a key component of PAMP-recognition immune complexes. Moreover, LLG1 contributes to accumulation and ligand-induced degradation of FLS2, and is required for downstream innate immunity responses, including ligand-induced phosphorylation of BOTRYTIS-INDUCED KINASE 1 and production of reactive oxygen species. Taken together, our findings reveal that LLG1 associates with PAMP receptors and modulates their function to regulate disease responses. As LLG1 functions as a coreceptor of FERONIA and plays central roles in plant growth and development, our findings indicate that LLG1 participates in separate pathways, and may suggest a potential connection between development and innate immunity in plants.

Arabidopsis glycosylphosphatidylinositol-anchored protein LLG1 associates with and modulates FLS2 to regulate innate immunity

PubMed Central

Shen, Qiujing; Pan, Huairong; Robatzek, Silke; Tang, Dingzhong

2017-01-01

Plants detect and respond to pathogen invasion with membrane-localized pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and activate downstream immune responses. Here we report that Arabidopsis thaliana LORELEI-LIKE GPI-ANCHORED PROTEIN 1 (LLG1), a coreceptor of the receptor-like kinase FERONIA, regulates PRR signaling. In a forward genetic screen for suppressors of enhanced disease resistance 1 (edr1), we identified the point mutation llg1-3, which suppresses edr1 disease resistance but does not affect plant growth and development. The llg1 mutants show enhanced susceptibility to various virulent pathogens, indicating that LLG1 has an important role in plant immunity. LLG1 constitutively associates with the PAMP receptor FLAGELLIN SENSING 2 (FLS2) and the elongation factor-Tu receptor, and forms a complex with BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1 in a ligand-dependent manner, indicating that LLG1 functions as a key component of PAMP-recognition immune complexes. Moreover, LLG1 contributes to accumulation and ligand-induced degradation of FLS2, and is required for downstream innate immunity responses, including ligand-induced phosphorylation of BOTRYTIS-INDUCED KINASE 1 and production of reactive oxygen species. Taken together, our findings reveal that LLG1 associates with PAMP receptors and modulates their function to regulate disease responses. As LLG1 functions as a coreceptor of FERONIA and plays central roles in plant growth and development, our findings indicate that LLG1 participates in separate pathways, and may suggest a potential connection between development and innate immunity in plants. PMID:28507137

Effect of lead acetate on the in vitro engulfment and killing capability of toad (Bufo arenarum) neutrophils.

PubMed

Rosenberg, Carolina E; Fink, Nilda E; Arrieta, Marcos A; Salibián, Alfredo

2003-11-01

Lead is an element of risk for the environment and human health and has harmful effects that may exceed those of other inorganic toxicants. The immune system is one of the targets of lead. Its immunomodulatory actions depend on the level of exposure, and it has been demonstrated that environmental amounts of the metal alter immune function. Very little information is available regarding the effect of the metal on different aspects of the immune system of lower vertebrates, in particular of amphibians. The aim of this study was to investigate the effect of sublethal lead (as acetate) on the function of polymorphonuclear cells of Bufo arenarum. The results revealed that phagocytic and lytic functions of the adherent blood cells collected from sublethal lead-injected toads and incubated with suspensions of Candida pseudotropicalis were affected negatively. The decrease of the phagocytic activity was correlated with increased blood lead levels (P < 0.0001). Additional information referred to the total and differential leukocyte counts was presented; the only difference found was in the number of blast-like cells that resulted augmented in the samples of lead-injected toads. It was concluded that the evaluation of these parameters might be a reliable tool for the biological monitoring of the immune status of amphibians.

Nervous temperament in infant monkeys is associated with reduced sensitivity of leukocytes to cortisol's influence on trafficking.

PubMed

Capitanio, John P; Mendoza, Sally P; Cole, Steve W

2011-01-01

There is growing evidence that temperament/personality factors are associated with immune function and health-related outcomes. Neuroticism, in particular, is a risk-factor for several diseases, many with a strong inflammatory component. We propose that neuroticism (or nervous temperament in monkeys) is related to dysregulation of immune function by glucocorticoids. The present study tested the hypothesis that animals with a nervous temperament would show no relationship between cortisol concentrations and leukocyte numbers in peripheral blood (an easily obtainable measure of glucocorticoid-mediated immune function), while animals low on this factor would show expected relationships. Infant rhesus monkeys (n=1507) experienced a standardized testing procedure involving blood sampling, behavioral tests, and temperament ratings. Results confirmed the hypothesis: low-nervous animals showed the expected positive relationship between cortisol levels and neutrophil numbers, while high-nervous animals showed no relationship. High-nervous animals also showed elevated cortisol concentrations at most sample points, and responded to a human challenge with more negative emotional behavior. These data suggest that individuals with a nervous temperament show evidence of glucocorticoid desensitization of immune cells. Differences with other studies, including the specific types of leukocytes that are affected, are discussed, and implications for disease processes are suggested. Copyright © 2010 Elsevier Inc. All rights reserved.

Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells

PubMed Central

Marca, Valeria La; Gianchecchi, Elena

2018-01-01

Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among all the different immunocytes involved in T1D etiopathogenesis, a relevant role of natural killer cells (NKs) is currently emerging. NKs represent the interface between innate and adaptive immunity; they intervene in the defense against infections and present, at the same time, typical features of the adaptive immune cells, such as expansion and generation of memory cells. Several recent studies, performed both in animal models and in human diabetic patients, revealed aberrations in NK cell frequency and functionality in the peripheral blood and in damaged tissues, suggesting their possible redirection towards affected tissues. NKs oscillate from a quiescent to an activated state through a delicate balance of activating and inhibitory signals transduced via surface receptors. Further accurate investigations are needed to elucidate the exact role of NKs in T1D, in order to develop novel immune-based therapies able to reduce the disease risk or delay its onset. PMID:29534427

Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells.

PubMed

Marca, Valeria La; Gianchecchi, Elena; Fierabracci, Alessandra

2018-03-10

Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among all the different immunocytes involved in T1D etiopathogenesis, a relevant role of natural killer cells (NKs) is currently emerging. NKs represent the interface between innate and adaptive immunity; they intervene in the defense against infections and present, at the same time, typical features of the adaptive immune cells, such as expansion and generation of memory cells. Several recent studies, performed both in animal models and in human diabetic patients, revealed aberrations in NK cell frequency and functionality in the peripheral blood and in damaged tissues, suggesting their possible redirection towards affected tissues. NKs oscillate from a quiescent to an activated state through a delicate balance of activating and inhibitory signals transduced via surface receptors. Further accurate investigations are needed to elucidate the exact role of NKs in T1D, in order to develop novel immune-based therapies able to reduce the disease risk or delay its onset.

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

PubMed Central

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

2015-01-01

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

Effects of supplementation with higher levels of manganese and magnesium on immune function.

PubMed

Son, Eun-Wha; Lee, Sung-Ryul; Choi, Hye-Sook; Koo, Hyun-Jung; Huh, Jung-Eun; Kim, Mi-Hyun; Pyo, Suhkneung

2007-06-01

The magnesium (Mg) and manganese (Mn) were evaluated for its effectiveness as an immunomodulator in rats. The treatments were as follows: Group 1, AIN-93M diet (0.05% Mg, 0.001% Mn); Group 2, high-dose Mg (0.1% Mg, 0.001% Mn); and Group 3, high dose Mn (0.05% Mg, 0.01% Mn) (n-12/group). After 12 weeks of supplementation, rats were sacrificed to assess the effect on a range of innate responses (tumoricidal activity, oxidative burst and nitric oxide) and the mitogen-stimulated lymphoproliferative response. Immune function was significantly affected in both the high dose Mg and the Mn group. Lymphocyte proliferative responses and NK cell activity were measured in pooled spleen from each group. The mitogen response of lymphocytes to LPS in the spleen was significantly reduced in high dose Mg-treated groups, whereas the response to ConA was not affected in both high dose minerals-treated groups. The reactive oxygen species level of macrophages was decreased in both groups. These effects were more pronounced in high dose Mg-treated group. Nitric oxide production was also decreased in high dose minerals-treated group. In addition, tumoricidal activities of splenic NK cell and peritoneal macrophage in mineral exposed rats were significantly increased. Moreover, percent death of macrophage was reduced in two groups receiving high dose mineral supplements. Taken together, the present data suggest that high dose trace min erals exert a differential effect on the function of immune cells.

Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.

PubMed

Ramírez-Alejo, Noé; Alcántara-Montiel, Julio C; Yamazaki-Nakashimada, Marco; Duran-McKinster, Carola; Valenzuela-León, Paola; Rivas-Larrauri, Francisco; Cedillo-Barrón, Leticia; Hernández-Rivas, Rosaura; Santos-Argumedo, Leopoldo

2015-10-01

NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females. Copyright © 2015 Elsevier Inc. All rights reserved.

Gain in Brain Immunity in the Oldest-Old Differentiates Cognitively Normal from Demented Individuals

PubMed Central

Katsel, Pavel; Tan, Weilun; Haroutunian, Vahram

2009-01-01

Background Recent findings suggest that Alzheimer's disease (AD) neuropathological features (neuritic plaques and NFTs) are not strongly associated with dementia in extreme old (over 90 years of age) and compel a search for neurobiological indices of dementia in this rapidly growing segment of the elderly population. We sought to characterize transcriptional and protein profiles of dementia in the oldest-old. Methods and Findings Gene and protein expression changes relative to non-demented age-matched controls were assessed by two microarray platforms, qPCR and Western blot in different regions of the brains of oldest-old and younger old persons who died at mild or severe stages of dementia. Our results indicate that: i) consistent with recent neuropathological findings, gene expression changes associated with cognitive impairment in oldest-old persons are distinct from those in cognitively impaired youngest-old persons; ii) transcripts affected in young-old subjects with dementia participate in biological pathways related to synaptic function and neurotransmission while transcripts affected in oldest-old subjects with dementia are associated with immune/inflammatory function; iii) upregulation of immune response genes in cognitively intact oldest-old subjects and their subsequent downregulation in dementia suggests a potential protective role of the brain immune-associated system against dementia in the oldest-old; iv) consistent with gene expression profiles, protein expression of several selected genes associated with the inflammatory/immune system in inferior temporal cortex is significantly increased in cognitively intact oldest-old persons relative to cognitively intact young-old persons, but impaired in cognitively compromised oldest-old persons relative to cognitively intact oldest-old controls. Conclusions These results suggest that disruption of the robust immune homeostasis that is characteristic of oldest-old individuals who avoided dementia may be directly associated with dementia in the oldest-old and contrast with the synaptic and neurotransmitter system failures that typify dementia in younger old persons. PMID:19865478

Immunological function of vitamin D during human pregnancy.

PubMed

Ji, Jin-Lu; Muyayalo, Kahinho P; Zhang, Yong-Hong; Hu, Xiao-Hui; Liao, Ai-Hua

2017-08-01

The well-established classic role of vitamin D is implicated in the regulation of the balance between calcium and phosphorus. Furthermore, vitamin D is also involved in many non-classic physiological processes, mainly including the regulation of cell proliferation, differentiation, apoptosis and immune function, participation in the inflammatory response and maintenance of genome stability function. During pregnancy, vitamin D receptor and its metabolic enzymes are expressed at the placenta and decidua, indicating the potential role in the mechanism of immunomodulation at the maternal-fetal interface. The insufficiency or deficiency of vitamin D may affect the mother directly and is related to specific pregnancy outcomes, such as preeclampsia, gestational diabetes, and recurrent miscarriage. This article reviews the effects of vitamin D on immune regulation during pregnancy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Elongator subunit 3 positively regulates plant immunity through its histone acetyltransferase and radical S-adenosylmethionine domains

PubMed Central

2013-01-01

Background Pathogen infection triggers a large-scale transcriptional reprogramming in plants, and the speed of this reprogramming affects the outcome of the infection. Our understanding of this process has significantly benefited from mutants that display either delayed or accelerated defense gene induction. In our previous work we demonstrated that the Arabidopsis Elongator complex subunit 2 (AtELP2) plays an important role in both basal immunity and effector-triggered immunity (ETI), and more recently showed that AtELP2 is involved in dynamic changes in histone acetylation and DNA methylation at several defense genes. However, the function of other Elongator subunits in plant immunity has not been characterized. Results In the same genetic screen used to identify Atelp2, we found another Elongator mutant, Atelp3-10, which mimics Atelp2 in that it exhibits a delay in defense gene induction following salicylic acid treatment or pathogen infection. Similarly to AtELP2, AtELP3 is required for basal immunity and ETI, but not for systemic acquired resistance (SAR). Furthermore, we demonstrate that both the histone acetyltransferase and radical S-adenosylmethionine domains of AtELP3 are essential for its function in plant immunity. Conclusion Our results indicate that the entire Elongator complex is involved in basal immunity and ETI, but not in SAR, and support that Elongator may play a role in facilitating the transcriptional induction of defense genes through alterations to their chromatin. PMID:23856002

Assessment of the innate immune response in the periparturient cow.

PubMed

Trevisi, Erminio; Minuti, Andrea

2018-02-01

The transition period is the most critical phase in the life of high yielding dairy cows. Within a few weeks, cows are submitted to many challenges (physiological, nutritional, psychological, management) that require prompt and effective adaptive responses. The immune system is involved in this process, and many changes of the cow's immune system components have been observed around calving. Cows are considered to be immunosuppressed in late lactation, and available data suggest that the immune system is dysregulated around parturition. Significant attention has been focused on modification of cellular functions (e.g. the reduction of phagocytosis and diapedesis), but growing interest concerns the components of the innate immune system, which often exhibits increased responses such as susceptibility to inflammatory events and the related acute phase response (APR). Systemic inflammation plays a significant role in early lactation, affects many liver functions and has been associated with the impairment of cow performance (i.e. reduced feed intake, milk yield, fertility, welfare). The assessment of variations in immune-metabolic indices offers opportunities to predict the onset of the health troubles and to anticipate the proper therapies needed to guarantee health, good welfare and fertility in the following lactation. The frequency of diseases (metabolic and infectious) before calving is rare, but several clues suggest that various metabolic and immune variations can begin during the dry period. Interesting preliminary results encourage this perspective and possible candidates are suggested. Copyright © 2017 Elsevier Ltd. All rights reserved.

Elongator subunit 3 positively regulates plant immunity through its histone acetyltransferase and radical S-adenosylmethionine domains.

PubMed

Defraia, Christopher T; Wang, Yongsheng; Yao, Jiqiang; Mou, Zhonglin

2013-07-16

Pathogen infection triggers a large-scale transcriptional reprogramming in plants, and the speed of this reprogramming affects the outcome of the infection. Our understanding of this process has significantly benefited from mutants that display either delayed or accelerated defense gene induction. In our previous work we demonstrated that the Arabidopsis Elongator complex subunit 2 (AtELP2) plays an important role in both basal immunity and effector-triggered immunity (ETI), and more recently showed that AtELP2 is involved in dynamic changes in histone acetylation and DNA methylation at several defense genes. However, the function of other Elongator subunits in plant immunity has not been characterized. In the same genetic screen used to identify Atelp2, we found another Elongator mutant, Atelp3-10, which mimics Atelp2 in that it exhibits a delay in defense gene induction following salicylic acid treatment or pathogen infection. Similarly to AtELP2, AtELP3 is required for basal immunity and ETI, but not for systemic acquired resistance (SAR). Furthermore, we demonstrate that both the histone acetyltransferase and radical S-adenosylmethionine domains of AtELP3 are essential for its function in plant immunity. Our results indicate that the entire Elongator complex is involved in basal immunity and ETI, but not in SAR, and support that Elongator may play a role in facilitating the transcriptional induction of defense genes through alterations to their chromatin.

How Does Optimism Suppress Immunity? Evaluation of Three Affective Pathways

PubMed Central

Segerstrom, Suzanne C.

2005-01-01

Studies have linked optimism to poorer immunity during difficult stressors. In the present report, when first-year law students (N = 46) relocated to attend law school, reducing conflict among curricular and extracurricular goals, optimism predicted larger delayed type hypersensitivity responses, indicating more robust in vivo cellular immunity. However, when students did not relocate, increasing goal conflict, optimism predicted smaller responses. Although this effect has been attributed to negative affect when difficult stressors violate optimistic expectancies, distress did not mediate optimism’s effects on immunity. Alternative affective mediators related to engagement – engaged affect and fatigue – likewise failed to mediate optimism’s effects, although all three types of affect independently influenced in vivo immunity. Alternative pathways include effort or self-regulatory depletion. PMID:17014284

B cell biology: implications for treatment of systemic lupus erythematosus.

PubMed

Anolik, J H

2013-04-01

B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread utilization of B cell depletion therapy in autoimmune diseases and the need for new therapeutic approaches in SLE, a better understanding of human B cell subsets and the balance of pathogenic and regulatory functions is of the essence.

Adsorption of surfactant protein D from human respiratory secretions by carbon nanotubes and polystyrene nanoparticles depends on nanomaterial surface modification and size

PubMed Central

Marchetti, Magda; Shaffer, Milo S. P.; Zambianchi, Martina; Chen, Shu; Superti, Fabiana; Schwander, Stephan; Gow, Andrew; Zhang, Junfeng (Jim); Chung, Kian Fan; Ryan, Mary P.; Porter, Alexandra E.; Tetley, Teresa D.

2015-01-01

The alveolar respiratory unit constitutes one of the main targets of inhaled nanoparticles; the effect of engineered nanomaterials (NMs) on human health is largely unknown. Surfactant protein D (SP-D) is synthesized by alveolar type II epithelial cells and released into respiratory secretions; its main function is in immune defence, notably against inhaled microbes. SP-D also plays an important role in modulating an appropriate inflammatory response in the lung, and reduced SP-D is associated with a number of inflammatory lung diseases. Adsorption of SP-D to inhaled NMs may facilitate their removal via macrophage phagocytosis. This study addresses the hypothesis that the chemistry, size and surface modification of engineered NMs will impact on their interaction with, and adsorption of, SP-D. To this purpose, we have examined the interactions between SP-D in human lung lavage and two NMs, carbon nanotubes and polystyrene nanoparticles, with different surface functionalization. We have demonstrated that particle size, functionalization and concentration affect the adsorption of SP-D from human lung lavage. Functionalization with negatively charged groups enhanced the amount of SP-D binding. While SP-D binding would be expected to enhance macrophage phagocytosis, these results suggest that the degree of binding is markedly affected by the physicochemistry of the NM and that deposition of high levels of some nanoparticles within the alveolar unit might deplete SP-D levels and affect alveolar immune defence mechanisms. PMID:25533095

Immune Priming, Fat Reserves, Muscle Mass and Body Weight of the House Cricket is Affected by Diet Composition.

PubMed

Córdoba-Aguilar, A; Nava-Sánchez, A; González-Tokman, D M; Munguía-Steyer, R; Gutiérrez-Cabrera, A E

2016-08-01

Some insect species are capable of producing an enhanced immune response after a first pathogenic encounter, a process called immune priming. However, whether and how such ability is driven by particular diet components (protein/carbohydrate) have not been explored. Such questions are sound given that, in general, immune response is dietary dependent. We have used adults of the house cricket Acheta domesticus L. (Orthoptera: Gryllidae) and exposed them to the bacteria Serratia marcescens. We first addressed whether survival rate after priming and nonpriming treatments is dietary dependent based on access/no access to proteins and carbohydrates. Second, we investigated how these dietary components affected fat reserves, muscle mass, and body weight, three key traits in insect fitness. Thus, we exposed adult house crickets to either a protein or a carbohydrate diet and measured the three traits. After being provided with protein, primed animals survived longer compared to the other diet treatments. Interestingly, this effect was also sex dependent with primed males having a higher survival than primed females when protein was supplemented. For the second experiment, protein-fed animals had more fat, muscle mass, and body weight than carbohydrate-fed animals. Although we are not aware of the immune component underlying immune priming, our results suggest that its energetic demand for its functioning and/or consequent survival requires a higher demand of protein with respect to carbohydrate. Thus, protein shortage can impair key survival-related traits related to immune and energetic condition. Further studies varying nutrient ratios should verify our results.

Differential transcriptomic responses of Biomphalaria glabrata (Gastropoda, Mollusca) to bacteria and metazoan parasites, Schistosoma mansoni and Echinostoma paraensei (Digenea, Platyhelminthes)

PubMed Central

Adema, Coen M; Hanington, Patrick C.; Lun, Cheng-Man; Rosenberg, George H.; Aragon, Anthony D; Stout, Barbara A; Richard, Mara L. Lennard; Gross, Paul S.; Loker, Eric S

2009-01-01

A 70-mer oligonucleotide-based microarray (1152 features) that emphasizes stress and immune responses factors was constructed to study transcriptomic responses of the snail Biomphalaria glabrata to different immune challenges. In addition to sequences with relevant putative ID and Gene Ontology (GO) annotation, the array features non-immune factors and unknown B. glabrata ESTs for functional gene discovery. The transcription profiles of B. glabrata (3 biological replicates, each a pool of 5 snails) were recorded at 12 hours post wounding, exposure to Gram negative or Gram positive bacteria (Escherichia coli and Micrococcus luteus, respectively), or infection with compatible trematode parasites (S. mansoni or E. paraensei, 20 miracidia/snail), relative to controls, using universal reference RNA. The data were subjected to Significance Analysis for Microarrays (SAM), with a false positive rate (FPR) ≤10%. Wounding yielded a modest differential expression profile (27 up/21 down) with affected features mostly dissimilar from other treatments. Partially overlapping, yet distinct expression profiles were recorded from snails challenged with E. coli (83 up/20 down) or M. luteus (120 up/42 down), mostly showing up-regulation of defense and stress-related features. Significantly altered expression of selected immune features indicates that B. glabrata detects and responds differently to compatible trematodes. Echinostoma paraensei infection was associated mostly with down regulation of many (immune-) transcripts (42 up/68 down), whereas S. mansoni exposure yielded a preponderance of up-regulated features (140 up/23 down), with only few known immune genes affected. These observations may reflect the divergent strategies developed by trematodes during their evolution as specialized pathogens of snails to negate host defense responses. Clearly, the immune defenses of B. glabrata distinguish and respond differently to various immune challenges. PMID:19962194

Mitigation of Inflammatory Immune Responses with Hydrophilic Nanoparticles.

PubMed

Li, Bowen; Xie, Jingyi; Yuan, Zhefan; Jain, Priyesh; Lin, Xiaojie; Wu, Kan; Jiang, Shaoyi

2018-04-16

While hydrophobic nanoparticles (NPs) have been long recognized to boost the immune activation, whether hydrophilic NPs modulate an immune system challenged by immune stimulators and how their hydrophilic properties may affect the immune response is still unclear. To answer this question, three polymers, poly(ethylene glycol) (PEG), poly(sulfobetaine) (PSB) and poly(carboxybetaine) (PCB), which are commonly considered hydrophilic, are studied in this work. For comparison, nanogels with uniform size and homogeneous surface functionalities were made from these polymers. Peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) and an LPS-induced lung inflammation murine model were used to investigate the influence of nanogels on the immune system. Results show that the treatment of hydrophilic nanogels attenuated the immune responses elicited by LPS both in vitro and in vivo. Moreover, we found that PCB nanogels, which have the strongest hydration and the lowest non-specific protein binding, manifested the best performance in alleviating the immune activation, followed by PSB and PEG nanogels. This reveals that the immunomodulatory effect of hydrophilic materials is closely related to their hydration characteristics and their ability to resist non-specific binding in complex media. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Induction of innate immunity in control of mucosal transmission of HIV.

PubMed

Wang, Yufei; Lehner, Thomas

2011-09-01

To present evidence of the role of innate mucosal immunity and to harness this arm of immunity in protection against HIV infection. Dendritic cells, monocytes, natural killer (NK) cells and γδ T cells are critical in innate immunity, which is mediated by Toll-like receptor (TLR) and recently identified stress pathways. Complement factors, cytokines and chemokines have diverse functions usually affecting HIV infection indirectly. A novel group of innate intracellular HIV restriction factors has been identified - APOBEC3G, TRIM5α and tetherin - all of which are upregulated by type I interferons and some by vaccination and TLR agonists. Whereas innate immunity conventionally lacks memory, recent evidence suggests that some of the cells and intracellular factors may express immunological memory-like features. Innate mucosal immunity may provide early effective control of HIV transmission and replication. Some vaccines can enhance innate immune factors, such as APOBEC3G and control HIV during the eclipse period, allowing full weight of neutralizing and/or cytotoxic T cells to develop and prevent mucosal HIV infection. The next generation of vaccines should be designed to target both innate and adaptive immune memory responses.

Nuclear localization of metabolic enzymes in immunity and metastasis.

PubMed

He, Yuchen; Gao, Menghui; Cao, Yiqu; Tang, Haosheng; Liu, Shuang; Tao, Yongguang

2017-12-01

Metabolism is essential to all living organisms that provide cells with energy, regulators, building blocks, enzyme cofactors and signaling molecules, and is in tune with nutritional conditions and the function of cells to make the appropriate developmental decisions or maintain homeostasis. As a fundamental biological process, metabolism state affects the production of multiple metabolites and the activation of various enzymes that participate in regulating gene expression, cell apoptosis, cancer progression and immunoreactions. Previous studies generally focus on the function played by the metabolic enzymes in the cytoplasm and mitochondrion. In this review, we conclude the role of them in the nucleus and their implications for cancer progression, immunity and metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Indispensable Role of Proteases in Plant Innate Immunity.

PubMed

Balakireva, Anastasia V; Zamyatnin, Andrey A

2018-02-23

Plant defense is achieved mainly through the induction of microbe-associated molecular patterns (MAMP)-triggered immunity (MTI), effector-triggered immunity (ETI), systemic acquired resistance (SAR), induced systemic resistance (ISR), and RNA silencing. Plant immunity is a highly complex phenomenon with its own unique features that have emerged as a result of the arms race between plants and pathogens. However, the regulation of these processes is the same for all living organisms, including plants, and is controlled by proteases. Different families of plant proteases are involved in every type of immunity: some of the proteases that are covered in this review participate in MTI, affecting stomatal closure and callose deposition. A large number of proteases act in the apoplast, contributing to ETI by managing extracellular defense. A vast majority of the endogenous proteases discussed in this review are associated with the programmed cell death (PCD) of the infected cells and exhibit caspase-like activities. The synthesis of signal molecules, such as salicylic acid, jasmonic acid, and ethylene, and their signaling pathways, are regulated by endogenous proteases that affect the induction of pathogenesis-related genes and SAR or ISR establishment. A number of proteases are associated with herbivore defense. In this review, we summarize the data concerning identified plant endogenous proteases, their effect on plant-pathogen interactions, their subcellular localization, and their functional properties, if available, and we attribute a role in the different types and stages of innate immunity for each of the proteases covered.

Sex hormones and the genesis of autoimmunity.

PubMed

Ackerman, Lindsay S

2006-03-01

The sexually dimorphic prevalence of autoimmune disease remains one of the most intriguing clinical observations among this group of disorders. While sex hormones have long been recognized for their roles in reproductive functions, within the past 2 decades scientists have found that sex hormones are integral signaling modulators of the mammalian immune system. Sex hormones have definitive roles in lymphocyte maturation, activation, and synthesis of antibodies and cytokines. Sex hormone expression is altered among patients with autoimmune disease, and this variation of expression contributes to immune dysregulation. English-language literature from the last 10 years was reviewed to examine the relationship between sex hormones and the function of the mammalian immune system. Approximately 50 publications were included in this review, and the majority were controlled trials with investigator blinding that compared both male and female diseased and normal subjects. The review provided basic knowledge regarding the broad impact of sex hormones on the immune system and how abnormal sex hormone expression contributes to the development and maintenance of autoimmune phenomena, with a focus on systemic lupus erythematosus, as models of "lupus-prone" mice are readily available. Sex hormones affect the function of the mammalian immune system, and sex hormone expression is different in patients with systemic lupus erythematosus than in healthy subjects. Sex hormones play a role in the genesis of autoimmunity. Future research may provide a therapeutic approach that is capable of altering disease pathogenesis, rather than targeting disease sequelae.

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling.

PubMed

Jensen, Liselotte E

2017-08-15

Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36α, IL-36β and IL-36γ, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1α, IL-1β, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1α, IL-1β, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Differential Gender Effects in the Relationship between Perceived Immune Functioning and Autistic Traits.

PubMed

Mackus, Marlou; Kruijff, Deborah de; Otten, Leila S; Kraneveld, Aletta D; Garssen, Johan; Verster, Joris C

2017-04-12

Altered immune functioning has been demonstrated in individuals with autism spectrum disorder (ASD). The current study explores the relationship between perceived immune functioning and experiencing ASD traits in healthy young adults. N = 410 students from Utrecht University completed a survey on immune functioning and autistic traits. In addition to a 1-item perceived immune functioning rating, the Immune Function Questionnaire (IFQ) was completed to assess perceived immune functioning. The Dutch translation of the Autism-Spectrum Quotient (AQ) was completed to examine variation in autistic traits, including the domains "social insights and behavior", "difficulties with change", "communication", "phantasy and imagination", and "detail orientation". The 1-item perceived immune functioning score did not significantly correlate with the total AQ score. However, a significant negative correlation was found between perceived immune functioning and the AQ subscale "difficulties with change" (r = -0.119, p = 0.019). In women, 1-item perceived immune functioning correlated significantly with the AQ subscales "difficulties with change" (r = -0.149, p = 0.029) and "communication" (r = -0.145, p = 0.032). In men, none of the AQ subscales significantly correlated with 1-item perceived immune functioning. In conclusion, a modest relationship between perceived immune functioning and several autistic traits was found.

Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor

PubMed Central

Farooqi, I. Sadaf; Wangensteen, Teresia; Collins, Stephan; Kimber, Wendy; Matarese, Giuseppe; Keogh, Julia M.; Lank, Emma; Bottomley, Bill; Lopez-Fernandez, Judith; Ferraz-Amaro, Ivan; Dattani, Mehul T.; Ercan, Oya; Myhre, Anne Grethe; Retterstol, Lars; Stanhope, Richard; Edge, Julie A.; McKenzie, Sheila; Lessan, Nader; Ghodsi, Maryam; De Rosa, Veronica; Perna, Francesco; Fontana, Silvia; Barroso, Inês; Undlien, Dag E.; O'Rahilly, Stephen

2009-01-01

BACKGROUND A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations — 7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism. PMID:17229951

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

PubMed

Farooqi, I Sadaf; Wangensteen, Teresia; Collins, Stephan; Kimber, Wendy; Matarese, Giuseppe; Keogh, Julia M; Lank, Emma; Bottomley, Bill; Lopez-Fernandez, Judith; Ferraz-Amaro, Ivan; Dattani, Mehul T; Ercan, Oya; Myhre, Anne Grethe; Retterstol, Lars; Stanhope, Richard; Edge, Julie A; McKenzie, Sheila; Lessan, Nader; Ghodsi, Maryam; De Rosa, Veronica; Perna, Francesco; Fontana, Silvia; Barroso, Inês; Undlien, Dag E; O'Rahilly, Stephen

2007-01-18

A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism. Copyright 2007 Massachusetts Medical Society.

DEVELOPMENT OF RISK ASSESSMENT TECHNIQUES FOR SOIL BIOAVAILABILITY AND BIOACCUMULATION OF AN ORGANOPHOSPHORUS PESTICIDE

EPA Science Inventory

There is increased concern about the effects of organophosphorus (OP) pesticides on human and animal health. This class of chemicals has been shown to affect the immune function of macrophages and lymphocytes. Malathion, an OP compound, is one of the most widely used pesticides...

Feed withdrawal and transportation effects on Salmonella enterica levels in market weight pigs

USDA-ARS?s Scientific Manuscript database

Feed withdrawal and transport commonly occur together in pigs. Objectives were to determine if these pre-slaughter stressors, feed withdrawal and transportation, affect the levels of Salmonella, stress hormone concentrations, and immune functions in infected market pigs. A 2 x 2 factorial analysis ...

Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein.

PubMed

Qi, Hangfei; Chu, Virginia; Wu, Nicholas C; Chen, Zugen; Truong, Shawna; Brar, Gurpreet; Su, Sheng-Yao; Du, Yushen; Arumugaswami, Vaithilingaraja; Olson, C Anders; Chen, Shu-Hua; Lin, Chung-Yen; Wu, Ting-Ting; Sun, Ren

2017-02-21

Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.

Hibernating Little Brown Myotis (Myotis lucifugus) Show Variable Immunological Responses to White-Nose Syndrome

PubMed Central

Moore, Marianne S.; Reichard, Jonathan D.; Murtha, Timothy D.; Nabhan, Morgan L.; Pian, Rachel E.; Ferreira, Jennifer S.; Kunz, Thomas H.

2013-01-01

White-nose syndrome (WNS) is an emerging infectious disease devastating hibernating North American bat populations that is caused by the psychrophilic fungus Geomyces destructans. Previous histopathological analysis demonstrated little evidence of inflammatory responses in infected bats, however few studies have compared other aspects of immune function between WNS-affected and unaffected bats. We collected bats from confirmed WNS-affected and unaffected sites during the winter of 2008–2009 and compared estimates of their circulating levels of total leukocytes, total immunoglobulins, cytokines and total antioxidants. Bats from affected and unaffected sites did not differ in their total circulating immunoglobulin levels, but significantly higher leukocyte counts were observed in bats from affected sites and particularly in affected bats with elevated body temperatures (above 20°C). Bats from WNS-affected sites exhibited significantly lower antioxidant activity and levels of interleukin-4 (IL-4), a cytokine that induces T cell differentiation. Within affected sites only, bats exhibiting visible fungal infections had significantly lower antioxidant activity and levels of IL-4 compared to bats without visible fungal infections. Overall, bats hibernating in WNS-affected sites showed immunological changes that may be evident of attempted defense against G. destructans. Observed changes, specifically elevated circulating leukocytes, may also be related to the documented changes in thermoregulatory behaviors of affected bats (i.e. increased frequencies in arousal from torpor). Alterations in immune function may reflect expensive energetic costs associated with these processes and intrinsic qualities of the immunocapability of hibernating bats to clear fungal infections. Additionally, lowered antioxidant activity indicates a possible imbalance in the pro- versus antioxidant system, may reflect oxidative tissue damage, and should be investigated as a contributor to WNS-associated morbidity and mortality. PMID:23527062

Immune and regulatory functions of neutrophils in inflammatory bone loss

PubMed Central

Hajishengallis, George; Moutsopoulos, Niki M.; Hajishengallis, Evlambia; Chavakis, Triantafyllos

2016-01-01

Although historically viewed as merely anti-microbial effectors in acute infection or injury, neutrophils are now appreciated to be functionally versatile with critical roles also in chronic inflammation. Periodontitis, a chronic inflammatory disease that destroys the tooth-supporting gums and bone, is particularly affected by alterations in neutrophil numbers or function, as revealed by observations in monogenic disorders and relevant mouse models. Besides being a significant debilitating disease and health burden in its own right, periodontitis is thus an attractive model to dissect uncharted neutrophil-associated (patho)physiological pathways. Here, we summarize recent evidence that neutrophils can contribute to inflammatory bone loss not only through the typical bystander injury dogma but intriguingly also through their absence from the affected tissue, where they normally perform important immunomodulatory functions. Moreover, we discuss recent advances in the interactions of neutrophils with the vascular endothelium and – upon extravasation – with bacteria, and how the dysregulation of these interactions leads to inflammatory tissue damage. Overall, neutrophils have both protective and destructive roles in periodontitis, as they are involved in both the maintenance of periodontal tissue homeostasis and the induction of inflammatory bone loss. This highlights the importance of developing approaches that promote or sustain a fine balance between homeostatic immunity and inflammatory pathology. PMID:26936034

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

PubMed

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.

Effect of hen age and maternal vitamin D source on performance, hatchability, bone mineral density, and progeny in vitro early innate immune function.

PubMed

Saunders-Blades, J L; Korver, D R

2015-06-01

The metabolite 25-hydroxy vitamin D3 (25-OHD) can complement or replace vitamin D3 in poultry rations, and may influence broiler production and immune function traits. The effect of broiler breeder dietary 25-OHD on egg production, hatchability, and chick early innate immune function was studied. We hypothesized that maternal dietary 25-OHD would support normal broiler breeder production and a more mature innate immune system of young chicks. Twenty-three-week-old Ross 308 hens (n=98) were placed in 4 floor pens and fed either 2,760 IU vitamin D3 (D) or 69 μg 25-OHD/kg feed. Hen weights were managed according to the primary breeder management guide. At 29 to 31 wk (Early), 46 to 48 wk (Mid), and 61 to 63 wk (Late), hens were artificially inseminated and fertile eggs incubated and hatched. Chicks were placed in cages based on maternal treatment and grown to 7 d age. Innate immune function and plasma 25-OHD were assessed at 1 and 4 d post-hatch on 15 chicks/treatment. Egg production, hen BW, and chick hatch weight were not affected by diet (P>0.05). Total in vitro Escherichia coli (E. coli) killing by 25-OHD chicks was greater than the D chicks at 4 d for the Early and Mid hatches, and 1 and 4 d for the Late hatch. This can be partly explained by the 25-OHD chicks from the Late hatch also having a greater E. coli phagocytic capability. No consistent pattern of oxidative burst response was observed. Chicks from the Mid hatch had greater percent phagocytosis, phagocytic capability, and E. coli killing than chicks from Early and Late hatches. Overall, maternal 25-OHD increased hatchability and in vitro chick innate immunity towards E. coli. Regardless of treatment, chicks from Late and Early hens had weaker early innate immune responses than chicks from Mid hens. The hen age effect tended to be the greatest factor influencing early chick innate immunity, but maternal 25-OHD also increased several measures relative to D. © 2015 Poultry Science Association Inc.

Revealing phenotype-associated functional differences by genome-wide scan of ancient haplotype blocks

PubMed Central

Onuki, Ritsuko; Yamaguchi, Rui; Shibuya, Tetsuo; Kanehisa, Minoru; Goto, Susumu

2017-01-01

Genome-wide scans for positive selection have become important for genomic medicine, and many studies aim to find genomic regions affected by positive selection that are associated with risk allele variations among populations. Most such studies are designed to detect recent positive selection. However, we hypothesize that ancient positive selection is also important for adaptation to pathogens, and has affected current immune-mediated common diseases. Based on this hypothesis, we developed a novel linkage disequilibrium-based pipeline, which aims to detect regions associated with ancient positive selection across populations from single nucleotide polymorphism (SNP) data. By applying this pipeline to the genotypes in the International HapMap project database, we show that genes in the detected regions are enriched in pathways related to the immune system and infectious diseases. The detected regions also contain SNPs reported to be associated with cancers and metabolic diseases, obesity-related traits, type 2 diabetes, and allergic sensitization. These SNPs were further mapped to biological pathways to determine the associations between phenotypes and molecular functions. Assessments of candidate regions to identify functions associated with variations in incidence rates of these diseases are needed in the future. PMID:28445522

Genetic Causes of Human NK Cell Deficiency and Their Effect on NK Cell Subsets

PubMed Central

Mace, Emily M.; Orange, Jordan S.

2016-01-01

Human NK cells play critical roles in human host defense, particularly the control of viral infection and malignancy, and patients with congenital immunodeficiency affecting NK cell function or number can suffer from severe illness. The importance of NK cell function is particularly underscored in patients with primary immunodeficiency in which NK cells are the primary or sole affected population (NK cell deficiency, NKD). While NKD may lead to the absence of NK cells, we are also gaining an increasing appreciation of the effect that NKD may have on the generation of specific NK cell subsets. In turn, this leads to improved insights into the requirements for human NK cell subset generation, as well as their importance in immune homeostasis. The presence of inherently abnormally developed or functionally impaired NK cells, in particular, appears to be problematic in the way of interfering with normal human host defense and may be more impactful than low numbers of NK cells alone. Here, we review the known genetic causes of NKD and the insight that is derived by these into the requirements for human subset generation and, by extension, for NK cell-mediated immunity. PMID:27994588

The effect of dermal benzophenone-2 administration on immune system activity, hypothalamic-pituitary-thyroid axis activity and hematological parameters in male Wistar rats.

PubMed

Broniowska, Żaneta; Ślusarczyk, Joanna; Starek-Świechowicz, Beata; Trojan, Ewa; Pomierny, Bartosz; Krzyżanowska, Weronika; Basta-Kaim, Agnieszka; Budziszewska, Bogusława

2018-04-13

Benzophenones used as UV filters, in addition to the effects on the skin, can be absorbed into the blood and affect the function of certain organs. So far, their effects on the sex hormone receptors and gonadal function have been studied, but not much is known about their potential action on other systems. The aim of the present study was to determine the effect of benzophenone-2 (BP-2) on immune system activity, hypothalamic-pituitary-thyroid (HPT) axis activity and hematological parameters. BP-2 was administered dermally, twice daily at a dose of 100 mg/kg for 4-weeks to male Wistar rats. Immunological and hematological parameters and HPT axis activity were assayed 24 h after the last administration. It was found that BP-2 did not change relative weights of the thymus and spleen and did not exert toxic effect on tymocytes and splenocytes. However, this compound increased proliferative activity of splenocytes, enhanced metabolic activity of splenocytes and thymocytes and nitric oxide production of these cells. In animals exposed to BP-2, the HPT axis activity was increased, as evidenced by reduction in the thyroid stimulating hormone (TRH) level and increase in free fraction of triiodothyronine (fT3) and thyroxin (fT4) in blood. BP-2 had no effect on leukocyte, erythrocyte and platelet counts or on morphology and hemoglobin content in erythrocytes. The conducted research showed that dermal, sub-chronic BP-2 administration evoked hyperthyroidism, increased activity or function of the immune cells but did not affect hematological parameters. We suggest that topical administration of BP-2 leading to a prolonged elevated BP-2 level in blood causes hyperthyroidism, which in turn may be responsible for the increased immune cell activity or function. However, only future research can explain the mechanism and functional importance of the changes in thyroid hormones and immunological parameters observed after exposure to BP-2. Copyright © 2018 Elsevier B.V. All rights reserved.

Immunology of intraocular tumors.

PubMed

Niederkorn, Jerry Y; Wang, Shixuan

2005-02-01

The immune surveillance hypothesis was introduced over 30 years ago and proposed that neoplasms express novel antigens that subjected them to immune detection and elimination. In order for immune surveillance to be effective in controlling neoplasms, two requirements must be satisfied: 1) the tumor must arise in a body site that permits the induction the full array of immune responses and 2) the immune elements generated must have unfettered access to the tumor and be able to express their entire range of effector functions at the tumor site. The unique immunologic and anatomic features of the eye prevent the induction and expression of conventional immunity--a phenomenon known as 'immune privilege'. Although ocular immune privilege represents a theoretical obstacle to immune surveillance, some highly immunogenic intraocular tumors can circumvent immune privilege and undergo immune rejection. Uveal melanoma is the most common intraocular malignancy in adults, yet it occurs with a frequency that is no higher than neoplasms arising in conventional bodies. The presence of either tumor-infiltrating lymphocytes (TIL) or tumor-infiltrating macrophages (TIM) is associated with poor prognosis in uveal melanoma patients and suggests that some immune responses to intraocular tumors might exacerbate, rather than mitigate, tumor progression. Although counterintuitive, this proposition is consistent with the 'immune stimulation' hypothesis of tumor progression offered by Richmond Prehn over thirty years ago. It remains to be ascertained if immune stimulation affects the malignancy of ocular tumors, but it represents an intriguing explanation for the paradoxes of uveal melanoma.

Spontaneous Pneumocystis carinii pneumonia in immunodeficient mutant scid mice. Natural history and pathobiology.

PubMed Central

Roths, J. B.; Marshall, J. D.; Allen, R. D.; Carlson, G. A.; Sidman, C. L.

1990-01-01

The opportunistic pathogen Pneumocystis carinii (Pc) poses a major clinical health problem in individuals with immune deficiency, including those patients with human immunodeficiency (HIV)-associated acquired immune deficiency disease (AIDS). Heretofore, in vivo investigations of the biology of Pc and pathogenesis of pneumocystosis have generally employed steroid-induced immune suppression with antibiotic prophylaxis and protein deprivation. This approach has many drawbacks, chief among them being the widespread, multiple interacting effects caused by the inducing agents. Athymic (nude) mice and rats have been used, but are less than ideal, as the immune defect primarily affects T lymphocytes. This article describes the natural history, pathobiology, and environmental effects on Pc pneumonitis in nonaxenically housed mice homozygous for the autosomal recessive mutation 'severe combined immunodeficiency' (scid), which almost totally lack both cell-mediated and antibody-mediated immune functions. The predictability, unequivocal expression, high morbidity, and well-defined genetic basis make scid/scid mutant mice the model of choice for in vivo studies of spontaneous pneumocystosis. Images Figure 3 Figure 6 PMID:2349968

Immune response and immunopathology during toxoplasmosis1

PubMed Central

Dupont, Christopher D.; Christian, David A.; Hunter, Christopher A.

2012-01-01

Toxoplasma gondii is a protozoan parasite of medical and veterinary significance that is able to infect any warm-blooded vertebrate host. In addition to its importance to public health, several inherent features of the biology of T. gondii have made it an important model organism to study host-pathogen interactions. One factor is the genetic tractability of the parasite, which allows studies on the microbial factors that affect virulence and allows the development of tools that facilitate immune studies. Additionally, mice are natural hosts for T. gondii, and the availability of numerous reagents to study the murine immune system makes this an ideal experimental system to understand the functions of cytokines and effector mechanisms involved in immunity to intracellular microorganisms. In this article, we will review current knowledge of the innate and adaptive immune responses required for resistance to toxoplasmosis, the events that lead to the development of immunopathology, and the natural regulatory mechanisms that limit excessive inflammation during this infection. PMID:22955326

Conserved hypothetical protein Rv1977 in Mycobacterium tuberculosis strains contains sequence polymorphisms and might be involved in ongoing immune evasion.

PubMed

Jiang, Yi; Liu, Haican; Wang, Xuezhi; Li, Guilian; Qiu, Yan; Dou, Xiangfeng; Wan, Kanglin

2015-01-01

Host immune pressure and associated parasite immune evasion are key features of host-pathogen co-evolution. A previous study showed that human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved and thus it was deduced that M. tuberculosis lacks antigenic variation and immune evasion. Here, we selected 151 clinical Mycobacterium tuberculosis isolates from China, amplified gene encoding Rv1977 and compared the sequences. The results showed that Rv1977, a conserved hypothetical protein, is not conserved in M. tuberculosis strains and there are polymorphisms existed in the protein. Some mutations, especially one frameshift mutation, occurred in the antigen Rv1977, which is uncommon in M.tb strains and may lead to the protein function altering. Mutations and deletion in the gene all affect one of three T cell epitopes and the changed T cell epitope contained more than one variable position, which may suggest ongoing immune evasion.

XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.

PubMed

Li, Feng-Yen; Chaigne-Delalande, Benjamin; Su, Helen; Uzel, Gulbu; Matthews, Helen; Lenardo, Michael J

2014-04-03

Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and has led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.

Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder.

PubMed

Sheikine, Yuri; Woda, Craig B; Lee, Pui Y; Chatila, Talal A; Keles, Sevgi; Charbonnier, Louis-Marie; Schmidt, Birgitta; Rosen, Seymour; Rodig, Nancy M

2015-07-01

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder is an autoimmune disease caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. These mutations affect the normal function of circulating regulatory T cells. IPEX is characterized by profound immune dysregulation leading to dermatitis, enteropathy, multiple endocrinopathies and failure to thrive. Different forms of renal injury have also been noted in these patients but these have been described to a very limited extent. Three patients with IPEX with characteristic renal findings and mutations in FOXP3, including one novel mutation, are described. Case presentations are followed by a review of the renal manifestations noted in IPEX and the range of therapeutic options for this disorder. We recommend that IPEX be considered in the differential diagnosis of young children who present with signs of immune dysregulation with a concomitant renal biopsy demonstrating immune complex deposition in a membranous-like pattern and/or interstitial nephritis.

Body height affects the strength of immune response in young men, but not young women.

PubMed

Krams, Indrikis A; Skrinda, Ilona; Kecko, Sanita; Moore, Fhionna R; Krama, Tatjana; Kaasik, Ants; Meija, Laila; Lietuvietis, Vilnis; Rantala, Markus J

2014-08-28

Body height and other body attributes of humans may be associated with a diverse range of social outcomes such as attractiveness to potential mates. Despite evidence that each parameter plays a role in mate choice, we have little understanding of the relative role of each, and relationships between indices of physical appearance and general health. In this study we tested relationships between immune function and body height of young men and women. In men, we report a non-linear relationship between antibody response to a hepatitis-B vaccine and body height, with a positive relationship up to a height of 185 cm, but an inverse relationship in taller men. We did not find any significant relationship between body height and immune function in women. Our results demonstrate the potential of vaccination research to reveal costly traits that govern evolution of mate choice in humans and the importance of trade-offs among these traits.

Body height affects the strength of immune response in young men, but not young women

PubMed Central

Krams, Indrikis A.; Skrinda, Ilona; Kecko, Sanita; Moore, Fhionna R.; Krama, Tatjana; Kaasik, Ants; Meija, Laila; Lietuvietis, Vilnis; Rantala, Markus J.

2014-01-01

Body height and other body attributes of humans may be associated with a diverse range of social outcomes such as attractiveness to potential mates. Despite evidence that each parameter plays a role in mate choice, we have little understanding of the relative role of each, and relationships between indices of physical appearance and general health. In this study we tested relationships between immune function and body height of young men and women. In men, we report a non-linear relationship between antibody response to a hepatitis-B vaccine and body height, with a positive relationship up to a height of 185 cm, but an inverse relationship in taller men. We did not find any significant relationship between body height and immune function in women. Our results demonstrate the potential of vaccination research to reveal costly traits that govern evolution of mate choice in humans and the importance of trade-offs among these traits. PMID:25164474

Secretory IgA reactivity to social threat in youth: Relations with HPA, ANS, and behavior.

PubMed

Laurent, Heidemarie K; Stroud, Laura R; Brush, Bridget; D'Angelo, Christina; Granger, Douglas A

2015-09-01

Although the role of immune marker secretory immunoglobulin A (SIgA) in stress-related health outcomes is gaining recognition, SIgA responsiveness to acute stress has rarely been assessed in adults, and not at all in children. This study was designed to clarify developmental origins of differential immune function-related health risks by investigating youth SIgA responses to psychosocial stressors, including both normative responses and variability related to behavioral problems. Children and adolescents from a larger study (n=82) gave 6 saliva samples during a laboratory session in which they were exposed to a series of performance or interpersonal stressors. Samples were assayed for SIgA, as well as cortisol (representing hypothalamic-pituitary-adrenal axis activity) and alpha-amylase (sAA; representing autonomic nervous system activity). Behavioral problems were assessed with parent-report measures of youth internalizing and externalizing. Youth SIgA trajectories followed a normative pattern of reactivity and recovery around the stressors; however, these responses were blunted in youth with higher externalizing scores. SIgA showed differential associations with cortisol and sAA, and with positive and negative affect; whereas overall levels of SIgA related to cortisol output and positive affect, changes in SIgA over time synchronized with changes in sAA and negative affect. In contrast to SIgA, neither cortisol nor sAA related significantly to behavioral problems. Implications for the role of SIgA during psychosocial stress in the development of immune function-related health risks are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: Epidermal H2O2/ONOO(-)-mediated stress abrogates tryptophan hydroxylase and dopa decarboxylase activities, leading to low serotonin and melatonin levels.

PubMed

Schallreuter, Karin U; Salem, Mohamed A E L; Gibbons, Nick C J; Martinez, Aurora; Slominski, Radomir; Lüdemann, Jürgen; Rokos, Hartmut

2012-06-01

Vitiligo is characterized by a progressive loss of inherited skin color. The cause of the disease is still unknown. To date, there is accumulating in vivo and in vitro evidence for massive oxidative stress via hydrogen peroxide (H(2)O(2)) and peroxynitrite (ONOO(-)) in the skin of affected individuals. Autoimmune etiology is the favored theory. Since depletion of the essential amino acid L-tryptophan (Trp) affects immune response mechanisms, we here looked at epidermal Trp metabolism via tryptophan hydroxylase (TPH) with its downstream cascade, including serotonin and melatonin. Our in situ immunofluorescence and Western blot data reveal significantly lower TPH1 expression in patients with vitiligo. Expression is also low in melanocytes and keratinocytes under in vitro conditions. Although in vivo Fourier transform-Raman spectroscopy proves the presence of 5-hydroxytryptophan, epidermal TPH activity is completely absent. Regulation of TPH via microphthalmia-associated transcription factor and L-type calcium channels is severely affected. Moreover, dopa decarboxylase (DDC) expression is significantly lower, in association with decreased serotonin and melatonin levels. Computer simulation supports H(2)O(2)/ONOO(-)-mediated oxidation/nitration of TPH1 and DDC, affecting, in turn, enzyme functionality. Taken together, our data point to depletion of epidermal Trp by Fenton chemistry and exclude melatonin as a relevant contributor to epidermal redox balance and immune response in vitiligo.

Regulatory role of periodontal ligament fibroblasts for innate immune cell function and differentiation.

PubMed

Konermann, Anna; Stabenow, Dirk; Knolle, Percy A; Held, Stefanie A E; Deschner, James; Jäger, Andreas

2012-10-01

Innate immunity is crucial for an effective host defense against pathogenic microorganisms in periodontal tissues. As periodontal ligament (PDL) cells synthesize immunomodulatory cytokines, the aim of this in vitro study was to investigate whether these cells can interact with innate immune cells. Resting and inflammatory primed (IL-1β, TNF-α, HMGB1) human PDL cells were co-cultured with human monocyte-derived dendritic cells or macrophages. Migration, phenotypic maturation and modulation of phagocytosis of Porphyromonas gingivalis by immune cells were investigated upon co-culture with PDL cells and/or their released soluble factors. PDL cells interacted with immune cells under both non-inflammatory and inflammatory conditions. Immune cell migration was significantly enhanced by co-culture with PDL cells, which also affected their phenotypic maturation both through cell-cell contact and through released soluble mediators. The dendritic cell maturation markers CD83 and CD86 were upregulated as much as both 'alternatively activated' M2 macrophage maturation markers CD23 and CD163. In contrast, the 'classically activated' M1 macrophage maturation marker CD64 was downregulated. Finally, PDL cells significantly enhanced the phagocytosis of Porphyromonas gingivalis by immune cells. Our experiments revealed that PDL cells are not only structural elements of the periodontium, but actively influence immune responses by interaction with innate immune cells.

The Bidirectional Relationship between Sleep and Immunity against Infections

PubMed Central

Ibarra-Coronado, Elizabeth G.; Pantaleón-Martínez, Ana Ma.; Velazquéz-Moctezuma, Javier; Prospéro-García, Oscar; Méndez-Díaz, Mónica; Pérez-Tapia, Mayra; Pavón, Lenin; Morales-Montor, Jorge

2015-01-01

Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed. PMID:26417606

The Bidirectional Relationship between Sleep and Immunity against Infections.

PubMed

Ibarra-Coronado, Elizabeth G; Pantaleón-Martínez, Ana Ma; Velazquéz-Moctezuma, Javier; Prospéro-García, Oscar; Méndez-Díaz, Mónica; Pérez-Tapia, Mayra; Pavón, Lenin; Morales-Montor, Jorge

2015-01-01

Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed.

Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms

PubMed Central

Tsave, Olga; Petanidis, Savvas; Kioseoglou, Efrosini; Yavropoulou, Maria P.; Yovos, John G.; Anestakis, Doxakis; Tsepa, Androniki; Salifoglou, Athanasios

2016-01-01

Over the last decade, a diverse spectrum of vanadium compounds has arisen as anti-inflammatory therapeutic metallodrugs targeting various diseases. Recent studies have demonstrated that select well-defined vanadium species are involved in many immune-driven molecular mechanisms that regulate and influence immune responses. In addition, advances in cell immunotherapy have relied on the use of metallodrugs to create a “safe,” highly regulated, environment for optimal control of immune response. Emerging findings include optimal regulation of B/T cell signaling and expression of immune suppressive or anti-inflammatory cytokines, critical for immune cell effector functions. Furthermore, in-depth perusals have explored NF-κB and Toll-like receptor signaling mechanisms in order to enhance adaptive immune responses and promote recruitment or conversion of inflammatory cells to immunodeficient tissues. Consequently, well-defined vanadium metallodrugs, poised to access and resensitize the immune microenvironment, interact with various biomolecular targets, such as B cells, T cells, interleukin markers, and transcription factors, thereby influencing and affecting immune signaling. A synthetically formulated and structure-based (bio)chemical reactivity account of vanadoforms emerges as a plausible strategy for designing drugs characterized by selectivity and specificity, with respect to the cellular molecular targets intimately linked to immune responses, thereby giving rise to a challenging field linked to the development of immune system vanadodrugs. PMID:27190573

Immunity to fish rhabdoviruses

USGS Publications Warehouse

Purcell, Maureen K.; Laing, Kerry J.; Winton, James R.

2012-01-01

Members of the family Rhabdoviridae are single-stranded RNA viruses and globally important pathogens of wild and cultured fish and thus relatively well studied in their respective hosts or other model systems. Here, we review the protective immune mechanisms that fish mount in response to rhabdovirus infections. Teleost fish possess the principal components of innate and adaptive immunity found in other vertebrates. Neutralizing antibodies are critical for long-term protection from fish rhabdoviruses, but several studies also indicate a role for cell-mediated immunity. Survival of acute rhabdoviral infection is also dependent on innate immunity, particularly the interferon (IFN) system that is rapidly induced in response to infection. Paradoxically, rhabdoviruses are sensitive to the effects of IFN but virulent rhabdoviruses can continue to replicate owing to the abilities of the matrix (M) protein to mediate host-cell shutoff and the non-virion (NV) protein to subvert programmed cell death and suppress functional IFN. While many basic features of the fish immune response to rhabdovirus infections are becoming better understood, much less is known about how factors in the environment affect the ecology of rhabdovirus infections in natural populations of aquatic animals.

Immunity to fish rhabdoviruses.

PubMed

Purcell, Maureen K; Laing, Kerry J; Winton, James R

2012-01-01

Members of the family Rhabdoviridae are single-stranded RNA viruses and globally important pathogens of wild and cultured fish and thus relatively well studied in their respective hosts or other model systems. Here, we review the protective immune mechanisms that fish mount in response to rhabdovirus infections. Teleost fish possess the principal components of innate and adaptive immunity found in other vertebrates. Neutralizing antibodies are critical for long-term protection from fish rhabdoviruses, but several studies also indicate a role for cell-mediated immunity. Survival of acute rhabdoviral infection is also dependent on innate immunity, particularly the interferon (IFN) system that is rapidly induced in response to infection. Paradoxically, rhabdoviruses are sensitive to the effects of IFN but virulent rhabdoviruses can continue to replicate owing to the abilities of the matrix (M) protein to mediate host-cell shutoff and the non‑virion (NV) protein to subvert programmed cell death and suppress functional IFN. While many basic features of the fish immune response to rhabdovirus infections are becoming better understood, much less is known about how factors in the environment affect the ecology of rhabdovirus infections in natural populations of aquatic animals.

Allatotropin: A pleiotropic neuropeptide that elicits mosquito immune responses

PubMed Central

Sánchez-Zavaleta, Minerva; Brito, Kevin; Herrera-Ortiz, Antonia; Ons, Sheila; Noriega, Fernando G.

2017-01-01

Allatotropins (AT) are neuropeptides with pleotropic functions on a variety of insect tissues. They affect processes such as juvenile hormone biosynthesis, cardiac rhythm, oviduct and hindgut contractions, nutrient absorption and circadian cycle. The present work provides experimental evidence that AT elicits immune responses in two important mosquito disease vectors, Anopheles albimanus and Aedes aegypti. Hemocytes and an immune-competent mosquito cell line responded to AT by showing strong morphological changes and increasing bacterial phagocytic activity. Phenoloxidase activity in hemolymph was also increased in Ae. aegypti mosquitoes treated with AT but not in An. albimanus, suggesting differences in the AT-dependent immune activation in the two species. In addition, two important insect immune markers, nitric oxide levels and expression of antimicrobial peptide genes, were increased in An. albimanus guts after AT treatment. AT conjugated to quantum dot nanocrystals (QDots) specifically labeled hemocytes in vivo in both mosquito species, implying molecular interactions between AT and hemocytes. The results of our studies suggest a new role for AT in the modulation of the immune response in mosquitoes. PMID:28426765

Complement factor H in host defense and immune evasion.

PubMed

Parente, Raffaella; Clark, Simon J; Inforzato, Antonio; Day, Anthony J

2017-05-01

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

Cigarette Smoke Modulates Repair and Innate Immunity following Injury to Airway Epithelial Cells.

PubMed

Amatngalim, Gimano D; Broekman, Winifred; Daniel, Nadia M; van der Vlugt, Luciën E P M; van Schadewijk, Annemarie; Taube, Christian; Hiemstra, Pieter S

2016-01-01

Cigarette smoking is the main risk factor associated with chronic obstructive pulmonary disease (COPD), and contributes to COPD development and progression by causing epithelial injury and inflammation. Whereas it is known that cigarette smoke (CS) may affect the innate immune function of airway epithelial cells and epithelial repair, this has so far not been explored in an integrated design using mucociliary differentiated airway epithelial cells. In this study, we examined the effect of whole CS exposure on wound repair and the innate immune activity of mucociliary differentiated primary bronchial epithelial cells, upon injury induced by disruption of epithelial barrier integrity or by mechanical wounding. Upon mechanical injury CS caused a delayed recovery in the epithelial barrier integrity and wound closure. Furthermore CS enhanced innate immune responses, as demonstrated by increased expression of the antimicrobial protein RNase 7. These differential effects on epithelial repair and innate immunity were both mediated by CS-induced oxidative stress. Overall, our findings demonstrate modulation of wound repair and innate immune responses of injured airway epithelial cells that may contribute to COPD development and progression.

Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates

PubMed Central

Sunyer, Oriol J.

2016-01-01

Fishes (i.e., teleost fishes) are the largest group of vertebrates. Although their immune system is based on the fundamental receptors, pathways, and cell types found in all groups of vertebrates, fishes show a diversity of particular features that challenge some classical concepts of immunology. In this chapter, we discuss the particularities of fish immune repertoires from a comparative perspective. We examine how allelic exclusion can be achieved when multiple Ig loci are present, how isotypic diversity and functional specificity impact clonal complexity, how loss of the MHC class II molecules affects the cooperation between T and B cells, and how deep sequencing technologies bring new insights about somatic hypermutation in the absence of germinal centers. The unique coexistence of two distinct B-cell lineages respectively specialized in systemic and mucosal responses is also discussed. Finally, we try to show that the diverse adaptations of immune repertoires in teleosts can help in understanding how somatic adaptive mechanisms of immunity evolved in parallel in different lineages across vertebrates. PMID:26537384

Hair follicle is a target of stress hormone and autoimmune reactions.

PubMed

Ito, Taisuke

2010-11-01

Interest in the hair follicle (HF) has recently increased, yet the detailed mechanisms of HF function and immune privilege (IP) have not yet been elucidated. This review discusses the critical points of immunobiology and hormonal aspects of HFs. The HF is a unique mini-organ because it has its own immune system and hormonal milieu. In addition, the HF immune and hormonal systems may greatly affect skin immunobiology. Therefore, knowledge of HF immunobiology and hormonal aspects will lead to a better understanding of skin biology. The HF has a unique hair cycle (anagen, catagen and telogen) and contains stem cells in the bulge area. The HF is closely related to sebaceous glands and the nervous system. This article reviews the interaction between the endocrine/immune system and HFs, including the pathogenesis of alopecia areata associated with stress. Copyright © 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Activation of VIP signaling enhances immunosuppressive effect of MDSCs on CMV-induced adaptive immunity.

PubMed

Forghani, Parvin; Petersen, Christopher T; Waller, Edmund K

2017-10-10

Vasoactive intestinal peptide (VIP) is recognized as a potent anti-inflammatory factor which affects both the innate and adaptive arms of the immune system. These effects include, but are not limited to, inhibition of T cell proliferation and disruption of immune homeostasis. Myeloid-derived suppressor cells (MDSC) are an immune regulatory cell type that has been described in settings of cancer and infectious disease._Here we demonstrate a reduced circulating monocytic MDSCs in the VIP -/- vs. wild type MCMV. VIP-/- MDSCs secretes less NO upon stimulation with LPS and interferon that relatively lose the ability to suppress T cells activation in vitro compared to wild type MDSCs._Considering the importance of VIP in immunomodulation, the possible effect of VIP in the suppressive function of MDSC populations following CMV infection remains unknown. We describe the possible role of VIP in the regulation of anti-CMV activity of T cells through the activation of MDSCs.

Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

NASA Astrophysics Data System (ADS)

Mitchell, Michael J.; Webster, Jamie; Chung, Amanda; Guimarães, Pedro P. G.; Khan, Omar F.; Langer, Robert

2017-03-01

Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces.

Practical applications of trace minerals for dairy cattle.

PubMed

Overton, T R; Yasui, T

2014-02-01

Trace minerals have critical roles in the key interrelated systems of immune function, oxidative metabolism, and energy metabolism in ruminants. To date, the primary trace elements of interest in diets for dairy cattle have included Zn, Cu, Mn, and Se although data also support potentially important roles of Cr, Co, and Fe in diets. Trace minerals such as Zn, Cu, Mn, and Se are essential with classically defined roles as components of key antioxidant enzymes and proteins. Available evidence indicates that these trace minerals can modulate aspects of oxidative metabolism and immune function in dairy cattle, particularly during the transition period and early lactation. Chromium has been shown to influence both immune function and energy metabolism of cattle; dairy cows fed Cr during the transition period and early lactation have evidence of improved immune function, increased milk production, and decreased cytological endometritis. Factors that complicate trace mineral nutrition at the farm level include the existence of a large number of antagonisms affecting bioavailability of individual trace minerals and uncertainty in terms of requirements under all physiological and management conditions; therefore, determining the optimum level and source of trace minerals under each specific situation continues to be a challenge. Typical factorial approaches to determine requirements for dairy cattle do not account for nuances in biological function observed with supplementation with various forms and amounts of trace minerals. Trace mineral nutrition modulates production, health, and reproduction in cattle although both formal meta-analysis and informal survey of the literature reveal substantial heterogeneity of response in these outcome variables. The industry has largely moved away from oxide-based programs toward sulfate-based programs; however, some evidence favors shifting supplementation strategies further toward more bioavailable forms of inorganic and organic trace minerals. Furthermore, opportunities for specific modulation of aspects of health, milk production, and reproduction through supplementation strategies for diets of transition dairy cows are attractive because of the known dynamics of energy metabolism, immune function, and oxidative metabolism during this timeframe.

Antibiotics in 16-day-old broilers temporarily affect microbial and immune parameters in the gut.

PubMed

Wisselink, H J; Cornelissen, J B W J; Mevius, D J; Smits, M A; Smidt, H; Rebel, J M J

2017-09-01

Animal health benefits from a stable intestinal homeostasis, for which proper development and functioning of the intestinal microbiota and immune system are essential. It has been established that changes in microbial colonization in early life (the first 2 wk post hatch) impacts the functioning of the adult gut and the associated crosstalk between microbiota and intestinal mucosal cells. The aim of the present study was to study the effect of the administration of antibiotics later in life (d 15 to 20 post hatch) on microbiota and immune parameters. For this purpose, chickens received from 15 d post hatch during 5 d amoxicillin or enrofloxacin through their drinking water. Before and at 6, 16, and 27 d after start of the administration of antibiotics, the composition of the microbiota in the jejunum was determined using a 16S ribosomal RNA gene-targeted DNA microarray, the CHICKChip. At 6 d after the start of the administration of the antibiotics, the composition and diversity of the microbiota were affected significantly (P < 0.05), but this change was small and observed only temporarily since differences disappeared at 16 d after initiating treatment with amoxillin and at 27 d after starting treatment with enrofloxacin. Intestinal morphology and development were not visibly affected since there were no differences between villus/crypt ratios and numbers of PAS+ and PCNA+ cells in the duodenum and jejunum at any time point. At 16 d after the start of antibiotic administration, the number of CD4+ T-cells and CD8+ T-cells in the duodenum was lower compared to the control animals; however, this difference was not significant. At some time points, significant differences (P < 0.05) were observed among the groups to locally expressed IL-8, IL-1β, IFN-γ, IL-2, and IL-4 mRNA. However, this effect was not long lasting, as differences that were observed at 16 d after starting the treatment had disappeared at 27 d after treatment was started. The results of this study indicate that later in the broiler's life, antibiotics only temporarily affect intestinal microbial and immune parameters. © 2017 Poultry Science Association Inc.

Acute brief heat stress in late gestation alters neonatal calf innate immune functions.

PubMed

Strong, R A; Silva, E B; Cheng, H W; Eicher, S D

2015-11-01

Heat stress, as one of the environmental stressors affecting the dairy industry, compromises the cow milk production, immune function, and reproductive system. However, few studies have looked at how prenatal heat stress (HS) affects the offspring. The objective of this study was to evaluate the effect of HS during late gestation on calf immunity. Calves were born to cows exposed to evaporative cooling (CT) or HS (cyclic 23-35°C) for 1 wk at 3 wk before calving. Both bull and heifer calves (CT, n=10; HS, n=10) were housed in similar environmental temperatures after birth. Both CT and HS calves received 3.78 L of pooled colostrum within 12 h after birth and were fed the same diet throughout the study. In addition to tumor necrosis factor α, IL-1β, IL-1 receptor antagonist (IL-1RA), and toll-like receptor (TLR)2, and TLR4 mRNA expression, the expression of CD14(+) and CD18(+) cells, and DEC205(+) dendritic cells were determined in whole blood samples at d 0, 3, 7, 14, 21, and 28. The neutrophil to lymphocyte ratio, differential cell counts, and the hematocrit were also determined. During late gestation, the HS cows had greater respiration rates, rectal temperatures, and tended to spend more time standing compared with the CT cows. The HS calves had less expression of tumor necrosis factor-α and TLR2 and greater levels of IL-1β, IL-1RA, and TLR4 compared with CT calves. The HS calves also had a greater percentage of CD18(+) cells compared with the CT calves. Additionally, a greater percentage of neutrophils and lesser percentage of lymphocytes were in the HS calves compared with the CT calves. The results indicate that biomarkers of calves' immunity are affected in the first several weeks after birth by HS in the dam during late gestation. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice

PubMed Central

Cox, Nehemiah; Pilling, Darrell; Gomer, Richard H.

2015-01-01

Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcγ receptors (FcγR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcγR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti–DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics. PMID:26106150

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

PubMed Central

Downey, Luke A.; Loftis, Jennifer M.

2014-01-01

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes – increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID:24485894

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes.

PubMed

Semenkovich, Nicholas P; Planer, Joseph D; Ahern, Philip P; Griffin, Nicholas W; Lin, Charles Y; Gordon, Jeffrey I

2016-12-20

The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ + and γδ + intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.

Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine.

PubMed

Downey, Luke A; Loftis, Jennifer M

2014-03-15

Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes - increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. Published by Elsevier B.V.

TCR and IL-7 Signaling Are Altered in the Absence of Functional GTPase of the Immune Associated Nucleotide Binding Protein 5 (GIMAP5)

PubMed Central

Chen, Xi-Lin; Serrano, Daniel; Ghobadi, Farnaz; Mayhue, Marian; Hoebe, Kasper; Ilangumaran, Subburaj; Ramanathan, Sheela

2016-01-01

GTPase of the immune associated nucleotide binding protein (GIMAP) family of proteins are expressed essentially in cells of the hematopoietic system. Mutation in the founding member of this gene family, Gimap5, results in the lymphopenic phenotype in Bio-Breeding diabetes prone rats. In mice, deletion of functional Gimap5 gene affects the survival and renewal of hematopoietic stem cells in addition to the defects observed in T cells. Here we show that T cells from OTII TCR-transgenic Gimap5sph/sph mice do not proliferate in response to its cognate antigen. Furthermore, T cells from Gimap5 mutant rats and mice show decreased phosphorylation of STAT5 following stimulation with IL-7. Our results suggest that functional Gimap5 is required for optimal signaling through TCR and IL-7R in T cells. PMID:27023180

CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

PubMed

Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

2016-03-01

The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

Can the big five factors of personality predict lymphocyte counts?

PubMed

Ožura, Ana; Ihan, Alojz; Musek, Janek

2012-03-01

Psychological stress is known to affect the immune system. The Limbic Hypothalamic Pituitary Adrenal (LHPA) axis has been identified as the principal path of the bidirectional communication between the immune system and the central nervous system with significant psychological activators. Personality traits acted as moderators of the relationship between life conflicts and psychological distress. This study focuses on the relationship between the Big Five factors of personality and immune regulation as indicated by Lymphocyte counts. Our study included 32 professional soldiers from the Slovenian Army that completed the Big Five questionnaire (Goldberg IPIP-300). We also assessed their white blood cell counts with a detailed lymphocyte analysis using flow cytometry. The correlations between personality variables and immune system parameters were calculated. Furthermore, regression analyses were performed using personality variables as predictors and immune parameters as criteria. The results demonstrated that the model using the Big Five factors as predictors of Lymphocyte counts is significant in predicting the variance in NK and B cell counts. Agreeableness showed the strongest predictive function. The results offer support for the theoretical models that stressed the essential links between personality and immune regulation. Further studies with larger samples examining the Big five factors and immune system parameters are needed.

Studying brain-regulation of immunity with optogenetics and chemogenetics; A new experimental platform.

PubMed

Ben-Shaanan, Tamar; Schiller, Maya; Rolls, Asya

2017-10-01

The interactions between the brain and the immune system are bidirectional. Nevertheless, we have far greater understanding of how the immune system affects the brain than how the brain affects immunity. New technological developments such as optogenetics and chemogenetics (using DREADDs; Designer Receptors Exclusively Activated by Designer Drugs) can bridge this gap in our understanding, as they enable an unprecedented mechanistic and systemic analysis of the communication between the brain and the immune system. In this review, we discuss new experimental approaches for revealing neuronal circuits that can participate in regulation of immunity. In addition, we discuss methods, specifically optogenetics and chemogenetics, that enable targeted neuronal manipulation to reveal how different brain regions affect immunity. We describe how these techniques can be used as an experimental platform to address fundamental questions in psychoneuroimmunology and to understand how neuronal circuits associate with different psychological states can affect physiology. Copyright © 2016 Elsevier Inc. All rights reserved.

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression.

PubMed

Patsoukis, Nikolaos; Bardhan, Kankana; Weaver, Jessica D; Sari, Duygu; Torres-Gomez, Alvaro; Li, Lequn; Strauss, Laura; Lafuente, Esther M; Boussiotis, Vassiliki A

2017-08-22

Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1-interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM-lamellipodin (MRL) class of adaptor molecules. Through its various domains, RIAM is a critical node of signal integration for activation of T cells, recruits monomeric and polymerized actin to drive actin remodeling and cytoskeletal reorganization, and promotes inside-out integrin signaling in T cells. As a regulator of inside-out integrin activation, RIAM affects multiple functions of innate and adaptive immunity. The effects of RIAM on cytoskeletal reorganization and integrin activation have implications in cell migration and trafficking of cancer cells. We provide an overview of the structure and interactions of RIAM, and we discuss the implications of RIAM functions in innate and adaptive immunity and cancer. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Early Nutrition as a Major Determinant of 'Immune Health': Implications for Allergy, Obesity and Other Noncommunicable Diseases.

PubMed

Prescott, Susan L

2016-01-01

Early-life nutritional exposures are significant determinants of the development and future health of all organ systems. The dramatic rise in infant immune diseases, most notably allergy, indicates the specific vulnerability of the immune system to early environmental changes. Dietary changes are at the center of the emerging epigenetic paradigms that underpin the rise in many modern inflammatory and metabolic diseases. There is growing evidence that exposures in pregnancy and the early postnatal period can modify gene expression and disease susceptibility. Although modern dietary changes are complex and involve changing patterns of many nutrients, there is also interest in the developmental effects of specific nutrients. Oligosaccharides (soluble fiber), antioxidants, polyunsaturated fatty acids, folate and other vitamins have documented effects on immune function as well as metabolism. Some have also been implicated in modified risk of allergic diseases in observational studies. Intervention studies are largely limited to trials with polyunsaturated fatty acids and oligosaccharides, showing preliminary but yet unconfirmed benefits in allergy prevention. Understanding how environmental influences disrupt the finely balanced development of immune and metabolic programming is of critical importance. Diet-sensitive pathways are likely to be crucial in these processes. While an epigenetic mechanism provides a strong explanation of how nutritional exposures can affect fetal gene expression and subsequent disease risk, other diet-induced tissue compositional changes may also contribute directly to altered immune and metabolic function--including diet-induced changes in the microbiome. A better understanding of nutritional programming of immune health, nutritional epigenetics and the biological processes sensitive to nutritional exposures early in life may lead to dietary strategies that provide more tolerogenic conditions during early immune programming and reduce the burden of many inflammatory diseases--not just allergy. © 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.

Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function.

PubMed

Thompson, Matthew G; Navarro, Flor; Chitsike, Lennox; Ramirez, Luis; Kovacs, Elizabeth J; Watkins, Stephanie K

2016-12-01

Dendritic cells (DCs) are a critical component of anti-tumor immunity due to their ability to induce a robust immune response to antigen (Ag). Alcohol was previously shown to reduce DC ability to present foreign Ag and promote pro-inflammatory responses in situations of infection and trauma. However the impact of alcohol exposure on generation of an anti-tumor response, especially in the context of generation of an immune vaccine has not been examined. In the clinic, DC vaccines are typically generated from autologous blood, therefore prior exposure to substances such as alcohol may be a critical factor to consider regarding the effectiveness in generating an immune response. In this study, we demonstrate for the first time that ethanol differentially affects DC and tumor Ag-specific T cell responses depending on sex. Signaling pathways were found to be differentially regulated in DC in females compared to males and these differences were exacerbated by ethanol treatment. DC from female mice treated with ethanol were unable to activate Ag-specific cytotoxic T cells (CTL) as shown by reduced expression of CD44, CD69, and decreased production of granzyme B and IFNγ. Furthermore, although FOXO3, an immune suppressive mediator of DC function, was found to be upregulated in DC from female mice, ethanol related suppression was independent of FOXO3. These findings demonstrate for the first time differential impacts of alcohol on the immune system of females compared to males and may be a critical consideration for determining the effectiveness of an immune based therapy for cancer in patients that consume alcohol. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Lipid accumulation, oxidative stress and immune-related molecules affected by tributyltin exposure in muscle tissues of rare minnow (Gobiocypris rarus).

PubMed

Zhang, Jiliang; Zhang, Chunnuan; Ma, Dongdong; Liu, Min; Huang, Shuntao

2017-12-01

Tributyltin (TBT) is reported to induce adipogenesis in fish, which might affect nutritional qualities and health status. Muscle tissues account for the majority of body mass, and have been described as a major site of fat deposition and an immunologically active organ. Therefore, the present study aims to evaluate whether chronic exposures of TBT, at environmental concentrations of 1, 10 and 100 ng/L, affects lipid accumulation, oxidative stress and immune status in muscle tissues of rare minnow (Gobiocypris rarus). After 60 d of exposure, TBT increased contents of total lipid, total cholesterol, triglyceride and fatty acids in muscle tissues. Interestingly, TBT exposure disrupted fatty acid composition and increased contents of unsaturated fatty acids (such as eicosapentaenoic acid and docosahexaenoic acid) in muscle tissues, which might be a response to preserve membrane functions from TBT exposure. Meanwhile, the concentrations of hepatic fatty acid desaturase 2 (Δ6-desaturase) and stearoyl-CoA desaturase (Δ9-desaturase) were increased after TBT exposure, which might contribute the increase of unsaturated fatty acids. Furthermore, TBT increased muscle lipid peroxidation products, antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase), and the expression of immune-related molecules (tumor necrosis factor alpha, interleukin 1 beta and nuclear factor kappa B) in muscle tissues. The disruption of TBT on the lipid accumulation, oxidative stress and immune-toxic effects in muscle tissues of fish might reduce nutritional qualities, and affect growth and health status, which might pose a constant and serious threat to fish and result in economic loss in aquaculture. Copyright © 2017 Elsevier Ltd. All rights reserved.

Human genetic variation and the gut microbiome in disease.

PubMed

Hall, Andrew Brantley; Tolonen, Andrew C; Xavier, Ramnik J

2017-11-01

Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

Soy lecithin supplementation alters macrophage phagocytosis and lymphocyte response to concanavalin A: a study in alloxan-induced diabetic rats.

PubMed

Miranda, Dalva T S Z; Batista, Vanessa G; Grando, Fernanda C C; Paula, Fernanda M; Felício, Caroline A; Rubbo, Gabriella F S; Fernandes, Luiz C; Curi, Rui; Nishiyama, Anita

2008-12-01

Dietary soy lecithin supplementation decreases hyperlipidemia and influences lipid metabolism. Although this product is used by diabetic patients, there are no data about the effect of soy lecithin supplementation on the immune system. The addition of phosphatidylcholine, the main component of lecithin, to a culture of lymphocytes has been reported to alter their function. If phosphatidylcholine changes lymphocyte functions in vitro as previously shown, then it could also affect immune cells in vivo. In the present study, the effect of dietary soy lecithin on macrophage phagocytic capacity and on lymphocyte number in response to concanavalin A (ConA) stimulation was investigated in non-diabetic and alloxan-induced diabetic rats. Supplementation was carried out daily with 2 g kg(-1) b.w. lecithin during 7 days. After that, blood was drawn from fasting rats and peritoneal macrophages and mesenteric lymph node lymphocytes were collected to determine the phospholipid content. Plasma triacylglycerol (TAG), total and HDL cholesterol and glucose levels were also determined. Lymphocytes were stimulated by ConA. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye reduction method and flow cytometry were employed to evaluate lymphocyte metabolism and cell number, respectively. Soy lecithin supplementation significantly increased both macrophage phagocytic capacity (+29%) in non-diabetic rats and the lymphocyte number in diabetic rats (+92%). It is unlikely that plasma lipid levels indirectly affect immune cells, since plasma cholesterol, TAG, or phospholipid content was not modified by lecithin supplementation. In conclusion, lymphocyte and macrophage function were altered by lecithin supplementation, indicating an immunomodulatory effect of phosphatidylcholine.

New activity of yamamarin, an insect pentapeptide, on immune system of mealworm, Tenebrio molitor.

PubMed

Walkowiak-Nowicka, K; Nowicki, G; Kuczer, M; Rosiński, G

2017-09-12

In insects, two types of the immune responses, cellular and humoral, constitute a defensive barrier against various parasites and pathogens. In response to pathogens, insects produce a wide range of immune agents that act on pathogens directly, such as cecropins or lysozyme, or indirectly by the stimulation of hemocyte migration or by increasing phenoloxidase (PO) activity. Recently, many new immunologically active substances from insects, such as peptides and polypeptides, have been identified. Nevertheless, in the most cases, their physiological functions are not fully known. One such substance is yamamarin - a pentapeptide isolated from the silk moth Antheraea yamamai. This yamamarin possesses strong antiproliferative properties and is probably involved in diapause regulation. Here, we examined the immunotropic activity of yamamarin by testing its impact on selected functions of the immune system in heterologous bioassays with the beetle Tenebrio molitor, commonly known as a stored grains pest. Our results indicate that the pentapeptide affects the activity of immune processes in the beetle. We show that yamamarin induces changes in both humoral and cellular responses. The yamamarin increases the activity of PO, as well as causes changes in the hemocyte cytoskeleton and stimulates phagocytic activity. We detected an increased number of apoptotic hemocytes, however after the yamamarin injection, no significant variations in the antibacterial activity in the hemolymph were observed. The obtained data suggest that yamamarin could be an important controller of the immune system in T. molitor.

Blood Vessels in Allotransplantation.

PubMed

Abrahimi, P; Liu, R; Pober, J S

2015-07-01

Human vascularized allografts are perfused through blood vessels composed of cells (endothelium, pericytes, and smooth muscle cells) that remain largely of graft origin and are thus subject to host alloimmune responses. Graft vessels must be healthy to maintain homeostatic functions including control of perfusion, maintenance of permselectivity, prevention of thrombosis, and participation in immune surveillance. Vascular cell injury can cause dysfunction that interferes with these processes. Graft vascular cells can be activated by mediators of innate and adaptive immunity to participate in graft inflammation contributing to both ischemia/reperfusion injury and allograft rejection. Different forms of rejection may affect graft vessels in different ways, ranging from thrombosis and neutrophilic inflammation in hyperacute rejection, to endothelialitis/intimal arteritis and fibrinoid necrosis in acute cell-mediated or antibody-mediated rejection, respectively, and to diffuse luminal stenosis in chronic rejection. While some current therapies targeting the host immune system do affect graft vascular cells, direct targeting of the graft vasculature may create new opportunities for preventing allograft injury and loss. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Does dietary insect meal affect the fish immune system? The case of mealworm, Tenebrio molitor on European sea bass, Dicentrarchus labrax.

PubMed

Henry, M A; Gasco, L; Chatzifotis, S; Piccolo, G

2018-04-01

Feeding small European sea bass, Dicentrarchus labrax, for 6 weeks with Tenebrio molitor larval meal showed significant anti-inflammatory responses (ceruloplasmin, myeloperoxidase and nitric oxide). Serum bacteriolytic activity against a Gram negative bacterium was not significantly affected by dietary Tenebrio, while both lysozyme antibacterial activity and serum trypsin inhibition usually linked to the anti-parasite activity of the fish, were significantly enhanced. The latter may be due to the similarities in the composition of the exoskeleton of parasites and insects that may therefore act as an immunostimulant potentially increasing the anti-parasitic activity. The addition of exogenous proteases significantly decreased both trypsin-inhibition and serum bacteriolytic activity probably through direct inhibition of the proteins responsible for these immune functions. Further investigation involving bacterial or parasitic challenges will be necessary to assess if the effects of dietary mealworm meal on the immune system observed in the present study are translated into an improved resistance to diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunity to Popular Stereotypes of Aging? Seniors and Stereotype Threat

ERIC Educational Resources Information Center

Horton, Sean; Baker, Joseph; Pearce, William; Deakin, Janice M.

2010-01-01

Previous research suggests that seniors' short-term performance is affected by stereotype threat--defined as a situation in which an individual is at risk of confirming a negative characterization about one's group. The current study attempted to replicate and extend these findings to areas of cognitive and physical functioning considered…

Transcriptome analysis reveals persistent effects of neonatal diet on small intestine gene expression profile in a porcine model

USDA-ARS?s Scientific Manuscript database

Breastfeeding is associated with several benefits affecting gut development and immune function. Compared to breast feeding, infant formula feeding is linked to a greater risk for gut dysfunction, ear and respiratory tract infections, and allergies. The beneficial effects appear to last at least thr...

Global Deletion of TSPO Does Not Affect the Viability and Gene Expression Profile

PubMed Central

Wang, Huaishan; Yang, Jia; Yang, Qi; Fu, Yi; Hu, Yu; Liu, Fang; Wang, Weiqing; Cui, Lianxian; Chen, Hui; Zhang, Jianmin; He, Wei

2016-01-01

Translocator Protein (18kDa, TSPO) is a mitochondrial outer membrane transmembrane protein. Its expression is elevated during inflammation and injury. However, the function of TSPO in vivo is still controversial. Here, we constructed a TSPO global knockout (KO) mouse with a Cre-LoxP system that abolished TSPO protein expression in all tissues and showed normal phenotypes in the physiological condition. The birth rates of TSPO heterozygote (Het) x Het or KO x KO breeding were consistent with Mendel’s Law, suggesting a normal viability of TSPO KO mice at birth. RNA-seq analysis showed no significant difference in the gene expression profile of lung tissues from TSPO KO mice compared with wild type mice, including the genes associated with bronchial alveoli immune homeostasis. The alveolar macrophage population was not affected by TSPO deletion in the physiological condition. Our findings contradict the results of Papadopoulos, but confirmed Selvaraj’s findings. This study confirms TSPO deficiency does not affect viability and bronchial alveolar immune homeostasis. PMID:27907096

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

PubMed

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

2016-07-01

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

Vaccinia virus decreases major histocompatibility complex (MHC) class II antigen presentation, T-cell priming, and peptide association with MHC class II

PubMed Central

Rehm, Kristina E; Connor, Ramsey F; Jones, Gwendolyn J B; Yimbu, Kenneth; Mannie, Mark D; Roper, Rachel L

2009-01-01

Vaccinia virus (VACV) is the current live virus vaccine used to protect humans against smallpox and monkeypox, but its use is contraindicated in several populations because of its virulence. It is therefore important to elucidate the immune evasion mechanisms of VACV. We found that VACV infection of antigen-presenting cells (APCs) significantly decreased major histocompatibility complex (MHC) II antigen presentation and decreased synthesis of 13 chemokines and cytokines, suggesting a potent viral mechanism for immune evasion. In these model systems, responding T cells were not directly affected by virus, indicating that VACV directly affects the APC. VACV significantly decreased nitric oxide production by peritoneal exudate cells and the RAW macrophage cell line in response to lipopolysaccharide (LPS) and interferon (IFN)-γ, decreased class II MHC expression on APCs, and induced apoptosis in macrophages and dendritic cells. However, VACV decreased antigen presentation by 1153 B cells without apparent apoptosis induction, indicating that VACV differentially affects B lymphocytes and other APCs. We show that the key mechanism of VACV inhibition of antigen presentation may be its reduction of antigenic peptide loaded into the cleft of MHC class II molecules. These data indicate that VACV evades the host immune response by impairing critical functions of the APC. PMID:20067538

Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells

PubMed Central

Boddupalli, Chandra Sekhar; Bar, Noffar; Kadaveru, Krishna; Krauthammer, Michael; Pornputtapong, Natopol; Ariyan, Stephan; Narayan, Deepak; Kluger, Harriet; Deng, Yanhong; Verma, Rakesh; Das, Rituparna; Bacchiocchi, Antonella; Halaban, Ruth; Sznol, Mario; Dhodapkar, Madhav V.; Dhodapkar, Kavita M.

2016-01-01

Heterogeneity of tumor cells and their microenvironment can affect outcome in cancer. Blockade of immune checkpoints (ICPs) expressed only on a subset of immune cells leads to durable responses in advanced melanoma. Tissue-resident memory T (TRM) cells have recently emerged as a distinct subset of memory T cells in nonlymphoid tissues. Here, we show that functional properties and expression of ICPs within tumor-infiltrating lymphocytes (TILs) differ from those of blood T cells. TILs secrete less IL-2, IFN-γ, and TNF-α compared with circulating counterparts, and expression of VEGF correlated with reduced TIL infiltration. Within tumors, ICPs are particularly enriched within T cells with phenotype and genomic features of TRM cells and the CD16+ subset of myeloid cells. Concurrent T cell receptor (TCR) and tumor exome sequencing of individual metastases in the same patient revealed that interlesional diversity of TCRs exceeded differences in mutation/neoantigen load in tumor cells. These findings suggest that the TRM subset of TILs may be the major target of ICP blockade and illustrate interlesional diversity of tissue-resident TCRs within individual metastases, which did not equilibrate between metastases and may differentially affect the outcome of immune therapy at each site. PMID:28018970

The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro.

PubMed

Krusch, Matthias; Salih, Julia; Schlicke, Manuela; Baessler, Tina; Kampa, Kerstin Maria; Mayer, Frank; Salih, Helmut Rainer

2009-12-15

Sunitinib and Sorafenib are protein kinase inhibitors (PKI) approved for treatment of patients with advanced renal cell cancer (RCC). However, long-term remissions of advanced RCC have only been observed after IL-2 treatment, which underlines the importance of antitumor immune responses in RCC patients. Because PKI, besides affecting tumor cells, also may inhibit signaling in immune effector cells, we determined how Sunitinib and Sorafenib influence antitumor immunity. We found that cytotoxicity and cytokine production of resting and IL-2-activated PBMC are inhibited by pharmacological concentrations of Sorafenib but not Sunitinib. Analysis of granule-mobilization within PBMC revealed that this was due to impaired reactivity of NK cells, which substantially contribute to antitumor immunity by directly killing target cells and shaping adaptive immune responses by secreting cytokines like IFN-gamma. Analyses with resting and IL-2-activated NK cells revealed that both PKI concentration dependently inhibit cytotoxicity and IFN-gamma production of NK cells in response to tumor targets. This was due to impaired PI3K and ERK phosphorylation which directly controls NK cell reactivity. However, while Sorafenib inhibited NK cell effector functions and signaling at levels achieved upon recommended dosing, pharmacological concentrations of Sunitinib had no effect, and this was observed upon stimulation of NK cell reactivity by tumor target cells and upon IL-2 treatment. In light of the important role of NK cells in antitumor immunity, and because multiple approaches presently aim to combine PKI treatment with immunotherapeutic strategies, our data demonstrate that choice and dosing of the most suitable PKI in cancer treatment requires careful consideration.

The effects of an instant haw beverage on lipid levels, antioxidant enzyme and immune function in hyperlipidemia patients.

PubMed

Chen, Jidi; Xue, Bin; Li, Keji; Shi, Jingda; Krempin, D; Zhu, M; Garland, C

2002-05-01

To determine the effectiveness of an instant haw beverage in regulating lipid disturbance, enhancing antioxidant enzyme activity and immune function. Data was collected from 60 hyperlipidemic subjects. In this crossover design, each subject randomly received either the instant haw beverage (100 ml corresponding to 3 g of haw powder or 30 g of fresh haw fruit plus the carrier-guar gum plus some starch) or placebo (guar gum 1.5 g plus some starch as the carrier of the beverage) twice daily. Each supplementation lasted 31 days with a 28-day washout period between treatments. The instant haw beverage significantly reduced total serum cholesterol (9.6%), triglyceride (12.1%), LDLC (18%) while significantly increased SOD activities (7.5%). The placebo was shown to have positive results in some of the lipid profiles, though the effects of the instant haw beverage demonstrated greater significance. Serum triglyceride levels were significantly decreased and SOD activity significantly increased only as subjects were supplemented with the instant haw beverage while no significant changes were seen with placebo. Supplementation with the instant haw beverage positively affects blood lipid profile, antioxidant status and immune function in individuals with hyperlipidemia.

Circadian rhythms accelerate wound healing in female Siberian hamsters

PubMed Central

Cable, Erin J.; Onishi, Kenneth G.; Prendergast, Brian J.

2017-01-01

Circadian rhythms (CRs) provide temporal regulation and coordination of numerous physiological traits, including immune function. CRs in multiple aspects of immune function are absent in rodents that have been rendered circadian-arrhythmic through various methods. In Siberian hamsters, circadian arrhythmia can be induced by disruptive light treatments (DPS). Here we examined CRs in wound healing, and the effects of circadian disruption on wound healing in DPS-arrhythmic hamsters. Circadian entrained/rhythmic (RHYTH) and behaviorally-arrhythmic (ARR) female hamsters were administered a cutaneous wound either 3 h after light onset (ZT03) or 2 h after dark onset (ZT18); wound size was quantified daily using image analyses. Among RHYTH hamsters, ZT03 wounds healed faster than ZT18 wounds, whereas in ARR hamsters, circadian phase did not affect wound healing. In addition, wounds healed slower in ARR hamsters. The results document a clear CR in wound healing, and indicate that the mere presence of organismal circadian organization enhances this aspect of immune function. Faster wound healing in CR-competent hamsters may be mediated by CR-driven coordination of the temporal order of mechanisms (inflammation, leukocyte trafficking, tissue remodeling) underlying cutaneous wound healing. PMID:27998755

The relative abundance of hemocyte types in a polyphagous moth larva depends on diet.

PubMed

Vogelweith, Fanny; Moret, Yannick; Monceau, Karine; Thiéry, Denis; Moreau, Jérôme

2016-05-01

Hemocytes are crucial cells of the insect immune system because of their involvement in multiple immune responses including coagulation, phagocytosis and encapsulation. There are various types of hemocytes, each having a particular role in immunity, such that variation in their relative abundance affects the outcome of the immune response. This study aims to characterize these various types of hemocytes in larvae of the grapevine pest insect Eupoecilia ambiguella, and to assess variation in their concentration as a function of larval diet and immune challenge. Four types of hemocytes were found in the hemolymph of 5th instar larvae: granulocytes, oenocytoids, plasmatocytes and spherulocytes. We found that the total concentration of hemocytes and the concentration of each hemocyte type varied among diets and in response to the immune challenge. Irrespective of the diet, the concentration of granulocytes increased following a bacterial immune challenge, while the concentration of plasmatocytes and spherulocytes differentially varied between larval diets. The concentration of oenocytoids did not vary among diets before the immune challenge but varied between larval diets in response to the challenge. These results suggest that the resistance of insect larvae to different natural enemies critically depends on the effect of larval diet on the larvae's investment into the different types of hemocytes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Air Pollution and Epigenetics: Effects on SP-A and Innate Host Defense in the Lung

PubMed Central

Silveyra, Patricia; Floros, Joanna

2013-01-01

Summary An appropriate immune and inflammatory response is key to defend against harmful agents present in the environment such as pathogens, allergens, and inhaled pollutants, including ozone and particulate matter. Air pollution is a serious public health concern worldwide, and cumulative evidence revealed that air pollutants contribute to epigenetic variation in several genes, and this in turn can contribute to disease susceptibility. Several groups of experts have recently reviewed findings on epigenetics and air pollution [1–6]. Surfactant proteins play a central role in pulmonary host defense by mediating pathogen clearance, modulating allergic responses and facilitating the resolution of lung inflammation. Recent evidence indicates that surfactant proteins are subject to epigenetic regulation under hypoxia and other conditions. Oxidative stress caused by ozone, and exposure to particulate matter have been shown to affect the expression of surfactant protein A (SP-A), an important lung host defense molecule, as well as alter its functions. In this review, we discuss recent findings in the fields of epigenetics and air pollution effects on innate immunity, with focus on SP-A, and the human SP-A variants in particular. Their function may be differentially affected by pollutants and specifically by ozone-induced oxidative stress, and this in turn may differentially affect susceptibility to lung disease. PMID:22553125

Immunotoxic effects of environmental pollutants in marine mammals.

PubMed

Desforges, Jean-Pierre W; Sonne, Christian; Levin, Milton; Siebert, Ursula; De Guise, Sylvain; Dietz, Rune

2016-01-01

Due to their marine ecology and life-history, marine mammals accumulate some of the highest levels of environmental contaminants of all wildlife. Given the increasing prevalence and severity of diseases in marine wildlife, it is imperative to understand how pollutants affect the immune system and consequently disease susceptibility. Advancements and adaptations of analytical techniques have facilitated marine mammal immunotoxicology research. Field studies, captive-feeding experiments and in vitro laboratory studies with marine mammals have associated exposure to environmental pollutants, most notable polychlorinated biphenyls (PCBs), organochlorine pesticides and heavy metals, to alterations of both the innate and adaptive arms of immune systems, which include aspects of cellular and humoral immunity. For marine mammals, reported immunotoxicology endpoints fell into several major categories: immune tissue histopathology, haematology/circulating immune cell populations, functional immune assays (lymphocyte proliferation, phagocytosis, respiratory burst, and natural killer cell activity), immunoglobulin production, and cytokine gene expression. Lymphocyte proliferation is by far the most commonly used immune assay, with studies using different organic pollutants and metals predominantly reporting immunosuppressive effects despite the many differences in study design and animal life history. Using combined field and laboratory data, we determined effect threshold levels for suppression of lymphocyte proliferation to be between b0.001-10 ppm for PCBs, 0.002-1.3 ppm for Hg, 0.009-0.06 for MeHg, and 0.1-2.4 for cadmium in polar bears and several pinniped and cetacean species. Similarly, thresholds for suppression of phagocytosis were 0.6-1.4 and 0.08-1.9 ppm for PCBs and mercury, respectively. Although data are lacking for many important immune endpoints and mechanisms of specific immune alterations are not well understood, this review revealed a systemic suppression of immune function in marine mammals exposed to environmental contaminants. Exposure to immunotoxic contaminants may have significant population level consequences as a contributing factor to increasing anthropogenic stress in wildlife and infectious disease outbreaks.

Toxic effects of dietary methylmercury on immune system development in nestling American kestrels (Falco sparverius)

USGS Publications Warehouse

Fallacara, Dawn M.; Halbrook, Richard S.; French, John B.

2011-01-01

This study evaluated the effects of dietary methylmercury (MeHg) on immune system development in captive-reared nestling American kestrels (Falco sparverius) to determine whether T cell–mediated and antibody-mediated adaptive immunity are targets for MeHg toxicity at environmentally relevant concentrations. Nestlings received various diets, including 0 (control), 0.6, and 3.9 μg/g (dry wt) MeHg for up to 18 d posthatch. Immunotoxicity endpoints included cell-mediated immunity (CMI) using the phytohemagglutinin (PHA) skin-swelling assay and antibody-mediated immune response via the sheep red blood cell (SRBC) hemagglutination assay. T cell– and B cell–dependent histological parameters in the spleen, thymus, and bursa of Fabricius were correlated with the functional assays. For nestlings in the 0.6 and 3.9 μg/g MeHg groups, CMI was suppressed by 73 and 62%, respectively, at 11 d of age. Results of this functional assay were correlated with T cell–dependent components of the spleen and thymus. Dose-dependent lymphoid depletion in spleen tissue directly affected the proliferation of T-lymphocyte populations, insofar as lower stimulation indexes from the PHA assay occurred in nestlings with lower proportions of splenic white pulp and higher THg concentrations. Nestlings in the 3.9 μg/g group also exhibited lymphoid depletion and a lack of macrophage activity in the thymus. Methylmercury did not have a noticeable effect on antibody-mediated immune function or B cell–dependent histological correlates. We conclude that T cell–mediated immunosuppression is the primary target of MeHg toward adaptive immunity in developing kestrels. This study provides evidence that environmentally relevant concentrations of MeHg may compromise immunocompetence in a developing terrestrial predator and raises concern regarding the long-term health effects of kestrels that were exposed to dietary MeHg during early avian development.

TET1 and TET3 are essential in induction of Th2-type immunity partly through regulation of IL-4/13A expression in zebrafish model.

PubMed

Yang, Chao; Li, Zhuo; Kang, Wei; Tian, Yu; Yan, Yuzhu; Chen, Wei

2016-10-10

It has been considered that epigenetic modulation can affect a diverse array of cellular activities, in which ten eleven translocation (TET) methylcytosine dioxygenase family members refer to a group of fundamental components involved in catalyzation of 5-hydroxymethylcytosine and modification of gene expression. Even though the function of TET proteins has been gradually revealed, their roles in immune regulation are still largely unknown. Recent studies provided clues that TET2 could regulate several innate immune-related inflammatory mediators in mammals. This study sought to explore the function of TET family members in potential T-helper (Th) cell differentiation involved in adaptive immunity by utilizing a zebrafish model. As shown by results, soluble antigens could induce expression of zebrafish IL-4/13A (i.e. a pivotal Th2-type cytokine essential in Th2 cell differentiation and functions), and further trigger the expression of Th1- and Th2-related genes. It is noteworthy that this response was accompanied by the up-regulation of two TET family members (TET1 and TET3) both in immune organs (spleen and kidney) and cells (peripheral lymphocytes). Knocking-down of TET1 and TET3 will give rise to the decreased responses of IL-4/13A induction against exogenous soluble antigen stimulation, and further restrain the expression of Th2-related genes, which indicates a restrained Th2 cell differentiation. Nonetheless, TET2 did not exhibit effect on the modification of Th1/Th2 related gene expression. Hence, these data showed that TET1 and TET3 might be two significant epigenetic regulators involved in Th2 differentiation through regulation of IL-4/13A expression. This is the first report to show that TET family members play indispensable roles in Th2-type immunity, indicating an epigenetic modulation manner involved in adaptive immune regulations and responses. Copyright © 2016 Elsevier B.V. All rights reserved.

Critical disease windows shaped by stress exposure alter allocation trade-offs between development and immunity.

PubMed

Kirschman, Lucas J; Crespi, Erica J; Warne, Robin W

2018-01-01

Ubiquitous environmental stressors are often thought to alter animal susceptibility to pathogens and contribute to disease emergence. However, duration of exposure to a stressor is likely critical, because while chronic stress is often immunosuppressive, acute stress can temporarily enhance immune function. Furthermore, host susceptibility to stress and disease often varies with ontogeny; increasing during critical developmental windows. How the duration and timing of exposure to stressors interact to shape critical windows and influence disease processes is not well tested. We used ranavirus and larval amphibians as a model system to investigate how physiological stress and pathogenic infection shape development and disease dynamics in vertebrates. Based on a resource allocation model, we designed experiments to test how exposure to stressors may induce resource trade-offs that shape critical windows and disease processes because the neuroendocrine stress axis coordinates developmental remodelling, immune function and energy allocation in larval amphibians. We used wood frog larvae (Lithobates sylvaticus) to investigate how chronic and acute exposure to corticosterone, the dominant amphibian glucocorticoid hormone, mediates development and immune function via splenocyte immunohistochemistry analysis in association with ranavirus infection. Corticosterone treatments affected immune function, as both chronic and acute exposure suppressed splenocyte proliferation, although viral replication rate increased only in the chronic corticosterone treatment. Time to metamorphosis and survival depended on both corticosterone treatment and infection status. In the control and chronic corticosterone treatments, ranavirus infection decreased survival and delayed metamorphosis, although chronic corticosterone exposure accelerated rate of metamorphosis in uninfected larvae. Acute corticosterone exposure accelerated metamorphosis increased survival in infected larvae. Interactions between stress exposure (via glucocorticoid actions) and infection impose resource trade-offs that shape optimal allocation between development and somatic function. As a result, critical disease windows are likely shaped by stress exposure because any conditions that induce changes in differentiation rates will alter the duration and susceptibility of organisms to stressors or disease. © 2017 The Authors. Journal of Animal Ecology © 2017 British Ecological Society.

Effects of functional feeds on the lipid composition, transcriptomic responses and pathology in heart of Atlantic salmon (Salmo salar L.) before and after experimental challenge with Piscine Myocarditis Virus (PMCV).

PubMed

Martinez-Rubio, Laura; Evensen, Øystein; Krasnov, Aleksei; Jørgensen, Sven Martin; Wadsworth, Simon; Ruohonen, Kari; Vecino, Jose L G; Tocher, Douglas R

2014-06-11

Cardiomyopathy syndrome (CMS) is a severe cardiac disease of Atlantic salmon (Salmo salar) recently associated with a double-stranded RNA virus, Piscine Myocarditis Virus (PMCV). The disease has been diagnosed in 75-85 farms in Norway each year over the last decade resulting in annual economic losses estimated at up to €9 million. Recently, we demonstrated that functional feeds led to a milder inflammatory response and reduced severity of heart lesions in salmon experimentally infected with Atlantic salmon reovirus, the causal agent of heart and skeletal muscle inflammation (HSMI). In the present study we employed a similar strategy to investigate the effects of functional feeds, with reduced lipid content and increased eicosapentaenoic acid levels, in controlling CMS in salmon after experimental infection with PMCV. Hepatic steatosis associated with CMS was significantly reduced over the time course of the infection in fish fed the functional feeds. Significant differences in immune and inflammatory responses and pathology in heart tissue were found in fish fed the different dietary treatments over the course of the infection. Specifically, fish fed the functional feeds showed a milder and delayed inflammatory response and, consequently, less severity of heart lesions at earlier and later stages after infection with PMCV. Decreasing levels of phosphatidylinositol in cell membranes combined with the increased expression of genes related with T-cell signalling pathways revealed new interactions between dietary lipid composition and the immune response in fish during viral infection. Dietary histidine supplementation did not significantly affect immune responses or levels of heart lesions. Combined with the previous findings on HSMI, the results of the present study highlight the potential role of clinical nutrition in controlling inflammatory diseases in Atlantic salmon. In particular, dietary lipid content and fatty acid composition may have important immune-modulatory effects in Atlantic salmon that could be potentially beneficial in fish balancing the immune and tissue responses to viral infections.

Next-Generation Immune Repertoire Sequencing as a Clue to Elucidate the Landscape of Immune Modulation by Host-Gut Microbiome Interactions.

PubMed

Ichinohe, Tatsuo; Miyama, Takahiko; Kawase, Takakazu; Honjo, Yasuko; Kitaura, Kazutaka; Sato, Hiroyuki; Shin-I, Tadasu; Suzuki, Ryuji

2018-01-01

The human immune system is a fine network consisted of the innumerable numbers of functional cells that balance the immunity and tolerance against various endogenous and environmental challenges. Although advances in modern immunology have revealed a role of many unique immune cell subsets, technologies that enable us to capture the whole landscape of immune responses against specific antigens have been not available to date. Acquired immunity against various microorganisms including host microbiome is principally founded on T cell and B cell populations, each of which expresses antigen-specific receptors that define a unique clonotype. Over the past several years, high-throughput next-generation sequencing has been developed as a powerful tool to profile T- and B-cell receptor repertoires in a given individual at the single-cell level. Sophisticated immuno-bioinformatic analyses by use of this innovative methodology have been already implemented in clinical development of antibody engineering, vaccine design, and cellular immunotherapy. In this article, we aim to discuss the possible application of high-throughput immune receptor sequencing in the field of nutritional and intestinal immunology. Although there are still unsolved caveats, this emerging technology combined with single-cell transcriptomics/proteomics provides a critical tool to unveil the previously unrecognized principle of host-microbiome immune homeostasis. Accumulation of such knowledge will lead to the development of effective ways for personalized immune modulation through deeper understanding of the mechanisms by which the intestinal environment affects our immune ecosystem.

Reproductive Toxicity of T Cells in Early Life: Abnormal Immune Development and Postnatal Diseases.

PubMed

Liu, Han-Xiao; Jiang, Aifang; Chen, Ting; Qu, Wen; Yan, Hui-Yi; Ping, Jie

2017-01-01

Immunity is a balanced status with adequate biological defenses to recognize and fight "non-self", as well as adequate tolerance to recognize "self". To maintain this immune homeostasis, a well-organized T cell immune network is required, which in part depends on the well-controlled development of alternative effector T cells, with different cytokine repertoires. Recent researches have pointed that developing fetal T cells network is a remarkably sensitive toxicological target for adverse factors in early life. Epidemiological and experimental studies showed an inseparable relationship between T cell developmental toxicity and immune diseases in adults. Considering that the inflammatory and immune disorders have become a growing health problem worldwide, increasing attention is now being paid to the T cell developmental toxicity. We propose that adverse factors may have programming effects on the crucial functions of immune system during early life which is critical for fetal T cell development and the establishment of the distinct T cell repertoires balance. The permanently disturbed intrathymic or peripheral T cell development may in turn lead to the immune disorders in later life. In this manuscript, we reviewed how adverse factors affected T cell development in early-life with the consequence of the immune dysfunction and immune diseases, and further elucidate the mechanisms. These mechanisms will be helpful in prevention and treatment of the increased prevalence of immune diseases by interfering those pathways. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Transcriptome study of differential expression in schizophrenia

PubMed Central

Sanders, Alan R.; Göring, Harald H. H.; Duan, Jubao; Drigalenko, Eugene I.; Moy, Winton; Freda, Jessica; He, Deli; Shi, Jianxin; Gejman, Pablo V.

2013-01-01

Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves’ disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia. PMID:23904455

Effect of porcine circovirus type 2 (PCV2) on the function of splenic CD11c+ dendritic cells in mice.

PubMed

Wang, Xiaobo; Chen, Ligong; Yuan, Wanzhe; Li, Yanqin; Li, Limin; Li, Tanqing; Li, Huanrong; Song, Qinye

2017-05-01

Porcine circovirus-associated disease (PCVAD) caused by porcine circovirus type 2 (PCV2) is an important disease in the global pig industry. Dendritic cells (DCs) are the primary immune cells capable of initiating adaptive immune responses as well as major target cells of PCV2. To determine whether PCV2 affects the immune functions of DCs, we evaluated the expression of endocytosis and co-stimulatory molecules on DCs (CD11c + ) from PCV2-infected mouse spleen by flow cytometry (FCM). We also analyzed the main cytokines secreted by DCs (CD11c + ) and activation of CD4 + and CD8 + T cells by DCs (CD11c + ) through measurement of cytokine secretion, using ELISA. Compared with control mice, PCV2 did not affect the endocytic activity of DCs but it significantly enhanced TNF-α secretion and markedly decreased IFN-α secretion. Subsets of CD40 + , MHCII + CD40 + and CD137L + CD86 + DCs did not increase obviously, but MHCII + CD40 - and CD137L - CD80 + /CD86 + DCs increased significantly in PCV2-infected mouse spleen. Under the stimulation of DCs from PCV2-infected mouse, secretion of IFN-γ by CD4 + and CD8 + T cells and of IL-12 by CD8 + T cells was significantly lower than in control mice, while secretion of IL-4 by CD4 + T cells was remarkably higher. These results indicate that PCV2 modulates cytokine secretion and co-stimulatory molecule expression of DCs, and alters activation of CD4 + and CD8 + T cells by DCs. The immunomodulatory effects of PCV2 on DCs might be related to the host's immune dysfunction and persistent infection with this virus.

Sublethal red tide toxin exposure in free-ranging manatees (Trichechus manatus) affects the immune system through reduced lymphocyte proliferation responses, inflammation, and oxidative stress.

PubMed

Walsh, Catherine J; Butawan, Matthew; Yordy, Jennifer; Ball, Ray; Flewelling, Leanne; de Wit, Martine; Bonde, Robert K

2015-04-01

The health of many Florida manatees (Trichechus manatus latirostris) is adversely affected by exposure to blooms of the toxic dinoflagellate, Karenia brevis. K. brevis blooms are common in manatee habitats of Florida's southwestern coast and produce a group of cyclic polyether toxins collectively referred to as red tide toxins, or brevetoxins. Although a large number of manatees exposed to significant levels of red tide toxins die, several manatees are rescued from sublethal exposure and are successfully treated and returned to the wild. Sublethal brevetoxin exposure may potentially impact the manatee immune system. Lymphocyte proliferative responses and a suite of immune function parameters in the plasma were used to evaluate effects of brevetoxin exposure on health of manatees rescued from natural exposure to red tide toxins in their habitat. Blood samples were collected from rescued manatees at Lowry Park Zoo in Tampa, FL and from healthy, unexposed manatees in Crystal River, FL. Peripheral blood leukocytes (PBL) isolated from whole blood were stimulated with T-cell mitogens, ConA and PHA. A suite of plasma parameters, including plasma protein electrophoresis profiles, lysozyme activity, superoxide dismutase (SOD) activity, and reactive oxygen/nitrogen (ROS/RNS) species, was also used to assess manatee health. Significant decreases (p<0.05) in lymphocyte proliferation were observed in ConA and PHA stimulated lymphocytes from rescued animals compared to non-exposed animals. Significant correlations were observed between oxidative stress markers (SOD, ROS/RNS) and plasma brevetoxin concentrations. Sublethal exposure to brevetoxins in the wild impacts some immune function components, and thus, overall health, in the Florida manatee. Copyright © 2015 Elsevier B.V. All rights reserved.

Rice Exo70 interacts with a fungal effector, AVR-Pii, and is required for AVR-Pii-triggered immunity.

PubMed

Fujisaki, Koki; Abe, Yoshiko; Ito, Akiko; Saitoh, Hiromasa; Yoshida, Kentaro; Kanzaki, Hiroyuki; Kanzaki, Eiko; Utsushi, Hiroe; Yamashita, Tetsuro; Kamoun, Sophien; Terauchi, Ryohei

2015-09-01

Vesicle trafficking including the exocytosis pathway is intimately associated with host immunity against pathogens. However, we still have insufficient knowledge about how it contributes to immunity, and how pathogen factors affect it. In this study, we explore host factors that interact with the Magnaporthe oryzae effector AVR-Pii. Gel filtration chromatography and co-immunoprecipitation assays identified a 150 kDa complex of proteins in the soluble fraction comprising AVR-Pii and OsExo70-F2 and OsExo70-F3, two rice Exo70 proteins presumably involved in exocytosis. Simultaneous knockdown of OsExo70-F2 and F3 totally abrogated Pii immune receptor-dependent resistance, but had no effect on Pia- and Pik-dependent resistance. Knockdown levels of OsExo70-F3 but not OsExo70-F2 correlated with reduction of Pii function, suggesting that OsExo70-F3 is specifically involved in Pii-dependent resistance. Under our current experimental conditions, over-expression of AVR-Pii or knockdown of OsExo70-F2 and -F3 genes in rice did not affect the virulence of compatible isolates of M. oryzae. AVR-Pii interaction with OsExo70-F3 appears to play a crucial role in immunity triggered by Pii, suggesting a role for OsExo70 as a decoy or helper in Pii/AVR-Pii interactions. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

An evolving new paradigm: endothelial cells – conditional innate immune cells

PubMed Central

2013-01-01

Endothelial cells (ECs) are a heterogeneous population that fulfills many physiological processes. ECs also actively participate in both innate and adaptive immune responses. ECs are one of the first cell types to detect foreign pathogens and endogenous metabolite-related danger signals in the bloodstream, in which ECs function as danger signal sensors. Treatment with lipopolysaccharide activates ECs, causing the production of pro-inflammatory cytokines and chemokines, which amplify the immune response by recruiting immune cells. Thus, ECs function as immune/inflammation effectors and immune cell mobilizers. ECs also induce cytokine production by immune cells, in which ECs function as immune regulators either by activating or suppressing immune cell function. In addition, under certain conditions, ECs can serve as antigen presenting cells (antigen presenters) by expressing both MHC I and II molecules and presenting endothelial antigens to T cells. These facts along with the new concept of endothelial plasticity suggest that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. Based on these novel EC functions, we propose a new paradigm that ECs are conditional innate immune cells. This paradigm provides a novel insight into the functions of ECs in inflammatory/immune pathologies. PMID:23965413

An evolving new paradigm: endothelial cells--conditional innate immune cells.

PubMed

Mai, Jietang; Virtue, Anthony; Shen, Jerry; Wang, Hong; Yang, Xiao-Feng

2013-08-22

Endothelial cells (ECs) are a heterogeneous population that fulfills many physiological processes. ECs also actively participate in both innate and adaptive immune responses. ECs are one of the first cell types to detect foreign pathogens and endogenous metabolite-related danger signals in the bloodstream, in which ECs function as danger signal sensors. Treatment with lipopolysaccharide activates ECs, causing the production of pro-inflammatory cytokines and chemokines, which amplify the immune response by recruiting immune cells. Thus, ECs function as immune/inflammation effectors and immune cell mobilizers. ECs also induce cytokine production by immune cells, in which ECs function as immune regulators either by activating or suppressing immune cell function. In addition, under certain conditions, ECs can serve as antigen presenting cells (antigen presenters) by expressing both MHC I and II molecules and presenting endothelial antigens to T cells. These facts along with the new concept of endothelial plasticity suggest that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. Based on these novel EC functions, we propose a new paradigm that ECs are conditional innate immune cells. This paradigm provides a novel insight into the functions of ECs in inflammatory/immune pathologies.

Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis.

PubMed

Tylee, Daniel S; Hess, Jonathan L; Quinn, Thomas P; Barve, Rahul; Huang, Hailiang; Zhang-James, Yanli; Chang, Jeffrey; Stamova, Boryana S; Sharp, Frank R; Hertz-Picciotto, Irva; Faraone, Stephen V; Kong, Sek Won; Glatt, Stephen J

2017-04-01

Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Blood Transcriptomic Comparison of Individuals with and without Autism Spectrum Disorder: A Combined-Samples Mega-Analysis

PubMed Central

Tylee, Daniel S.; Hess, Jonathan L.; Quinn, Thomas P.; Barve, Rahul; Huang, Hailiang; Zhang-James, Yanli; Chang, Jeffrey; Stamova, Boryana S.; Sharp, Frank R.; Hertz-Picciotto, Irva; Faraone, Stephen V.; Kong, Sek Won; Glatt, Stephen J.

2017-01-01

Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex-vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. PMID:27862943

Natural and Sun-Induced Aging of Human Skin

PubMed Central

Rittié, Laure; Fisher, Gary J.

2015-01-01

With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases. PMID:25561721

Probiotics Improve Inflammation-Associated Sickness Behavior by Altering Communication between the Peripheral Immune System and the Brain.

PubMed

D'Mello, Charlotte; Ronaghan, Natalie; Zaheer, Raza; Dicay, Michael; Le, Tai; MacNaughton, Wallace K; Surrette, Michael G; Swain, Mark G

2015-07-29

Patients with systemic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, chronic liver disease) commonly develop debilitating symptoms (i.e., sickness behaviors) that arise from changes in brain function. The microbiota-gut-brain axis alters brain function and probiotic ingestion can influence behavior. However, how probiotics do this remains unclear. We have previously described a novel periphery-to-brain communication pathway in the setting of peripheral organ inflammation whereby monocytes are recruited to the brain in response to systemic TNF-α signaling, leading to microglial activation and subsequently driving sickness behavior development. Therefore, we investigated whether probiotic ingestion (i.e., probiotic mixture VSL#3) alters this periphery-to-brain communication pathway, thereby reducing subsequent sickness behavior development. Using a well characterized mouse model of liver inflammation, we now show that probiotic (VSL#3) treatment attenuates sickness behavior development in mice with liver inflammation without affecting disease severity, gut microbiota composition, or gut permeability. Attenuation of sickness behavior development was associated with reductions in microglial activation and cerebral monocyte infiltration. These events were paralleled by changes in markers of systemic immune activation, including decreased circulating TNF-α levels. Our observations highlight a novel pathway through which probiotics mediate cerebral changes and alter behavior. These findings allow for the potential development of novel therapeutic interventions targeted at the gut microbiome to treat inflammation-associated sickness behaviors in patients with systemic inflammatory diseases. This research shows that probiotics, when eaten, can improve the abnormal behaviors (including social withdrawal and immobility) that are commonly associated with inflammation. Probiotics are able to cause this effect within the body by changing how the immune system signals the brain to alter brain function. These findings broaden our understanding of how probiotics may beneficially affect brain function in the context of inflammation occurring within the body and may open potential new therapeutic alternatives for the treatment of these alterations in behavior that can greatly affect patient quality of life. Copyright © 2015 the authors 0270-6474/15/3510822-10$15.00/0.

QTL for white spot syndrome virus resistance and the sex-determining locus in the Indian black tiger shrimp (Penaeus monodon).

PubMed

Robinson, Nicholas A; Gopikrishna, Gopalapillay; Baranski, Matthew; Katneni, Vinaya Kumar; Shekhar, Mudagandur S; Shanmugakarthik, Jayakani; Jothivel, Sarangapani; Gopal, Chavali; Ravichandran, Pitchaiyappan; Gitterle, Thomas; Ponniah, Alphis G

2014-08-28

Shrimp culture is a fast growing aquaculture sector, but in recent years there has been a shift away from tiger shrimp Penaeus monodon to other species. This is largely due to the susceptibility of P. monodon to white spot syndrome virus disease (Whispovirus sp.) which has impacted production around the world. As female penaeid shrimp grow more rapidly than males, mono-sex production would be advantageous, however little is known about genes controlling or markers associated with sex determination in shrimp. In this study, a mapped set of 3959 transcribed single nucleotide polymorphisms were used to scan the P. monodon genome for loci associated with resistance to white-spot syndrome virus and sex in seven full-sibling tiger shrimp families challenged with white spot syndrome virus. Linkage groups 2, 3, 5, 6, 17, 18, 19, 22, 27 and 43 were found to contain quantitative trait loci significantly associated with hours of survival after white spot syndrome virus infection (P < 0.05 after Bonferroni correction). Nine QTL were significantly associated with hours of survival. Of the SNPs mapping to these and other regions with suggestive associations, many were found to occur in transcripts showing homology to genes with putative immune functions of interest, including genes affecting the action of the ubiquitin-proteasome pathway, lymphocyte-cell function, heat shock proteins, the TOLL pathway, protein kinase signal transduction pathways, mRNA binding proteins, lectins and genes affecting the development and differentiation of the immune system (eg. RUNT protein 1A). Several SNPs significantly associated with sex were mapped to linkage group 30, the strongest associations (P < 0.001 after Bonferroni correction) for 3 SNPs located in a 0.8 cM stretch between positions 43.5 and 44.3 cM where the feminisation gene (FEM-1, affecting sexual differentiation in Caenorhabditis elegans) mapped. The markers for disease resistance and sexual differentiation identified by this study could be useful for marker assisted selection to improve resistance to WSSV and for identifying homogametic female individuals for mono-sex (all female) production. The genes with putative functions affecting immunity and sexual differentiation that were found to closely map to these loci provide leads about the mechanisms affecting these important economic traits in shrimp.

Impaired immune function in seals and laboratory rats exposed to dioxin-like compounds from Baltic herring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ross, P.S.; Swart, R.L. de; Timmerman, H.H.

Complex mixtures of lipophilic contaminants have been shown to affect certain top predators in the aquatic food chain, including seals. A recent demonstration that harbor seals (Phoca vitulina) fed Baltic Sea herring displayed impaired natural killer cell activity and T-lymphocyte function represented the first demonstration of immunotoxicity induced by ambient levels of contaminants in the environment. While these animals had a lower ability to respond to immunizations with inactivated vaccines, specific antibody responses, and in vitro antigen-specific lymphoproliferative responses, obvious constraints limited the ability to extend these results with host resistance tests or an evaluation of thymus and other lymphoidmore » organs. The authors therefore set up a parallel study by exposing pregnant laboratory rats to the same Baltic herring contaminant mixture as received the seals. They then examined immune function parameters and host resistance to virus infection. As in the seals, rat pups of the Baltic group had impaired T-lymphocyte function. In addition, thymus cells and/or their precursors appeared to be targeted, as their numbers and function were reduced in the rats. Following challenge with rat cytomegalovirus in a host resistance study, rat pups in the Baltic group had impaired natural killer cell responses to the virus infection, and lower specific CD8 + (cytotoxic T-lymphocyte) responses following in vitro stimulation. By extrapolation, these results suggest that the impaired immune responses observed in the Baltic group of seals may lead to a less effective defense against virus infections in marine mammals inhabiting polluted coastal waters. Toxicological profiles and results of both the captive seal and laboratory rat experiments tend to implicate the 2,3,7,8-TCDD-like PCB, dioxin and furan congeners in the immunosuppression, and point to a major role for the PCBs.« less

The effects of sex hormones on immune function: a meta-analysis.

PubMed

Foo, Yong Zhi; Nakagawa, Shinichi; Rhodes, Gillian; Simmons, Leigh W

2017-02-01

The effects of sex hormones on immune function have received much attention, especially following the proposal of the immunocompetence handicap hypothesis. Many studies, both experimental and correlational, have been conducted to test the relationship between immune function and the sex hormones testosterone in males and oestrogen in females. However, the results are mixed. We conducted four cross-species meta-analyses to investigate the relationship between sex hormones and immune function: (i) the effect of testosterone manipulation on immune function in males, (ii) the correlation between circulating testosterone level and immune function in males, (iii) the effect of oestrogen manipulation on immune function in females, and (iv) the correlation between circulating oestrogen level and immune function in females. The results from the experimental studies showed that testosterone had a medium-sized immunosuppressive effect on immune function. The effect of oestrogen, on the other hand, depended on the immune measure used. Oestrogen suppressed cell-mediated immune function while reducing parasite loads. The overall correlation (meta-analytic relationship) between circulating sex hormone level and immune function was not statistically significant for either testosterone or oestrogen despite the power of meta-analysis. These results suggest that correlational studies have limited value for testing the effects of sex hormones on immune function. We found little evidence of publication bias in the four data sets using indirect tests. There was a weak and positive relationship between year of publication and effect size for experimental studies of testosterone that became non-significant after we controlled for castration and immune measure, suggesting that the temporal trend was due to changes in these moderators over time. Graphical analyses suggest that the temporal trend was due to an increased use of cytokine measures across time. We found substantial heterogeneity in effect sizes, except in correlational studies of testosterone, even after we accounted for the relevant random and fixed factors. In conclusion, our results provide good evidence that testosterone suppresses immune function and that the effect of oestrogen varies depending on the immune measure used. © 2016 Cambridge Philosophical Society.

Signaling in Human and Murine Lymphocytes in Microgravity: Parallels and Contrasts

NASA Technical Reports Server (NTRS)

Neal, Pellis; Alamelu, Sundaresan; Kulkarni, A. D.; Yamauchi, K.

2006-01-01

Immune function in space undergoes dramatic changes, some of which are detrimental to lymphocyte function. These changes may lead to significant immune suppression. Studies with human lymphocytes both in space flight and with ground-based models (NASA in vitro ground-based microgravity analog) indicate that T cell activation is inhibited in microgravity. Other lymphocyte functions, such as locomotion, are also inhibited. There is about an 80 percent homology in the immune response of mice to that of humans. A murine model was investigated because of its ability to parallel some microgravity using hind limb suspension. In in vivo antiorthostatically (AOS)-suspended mice, T cell activation is greatly suppressed, with the majority of activation related cytokines being inhibited. PHA activation in lymphocytes derived from AOS mice (in vivo ground-based microgravity analog) is also suppressed. Calcium ionophore studies in human lymphocytes exposed to modeled microgravity indicate that the calcium pathways are probably unaffected in microgravity. IP3 (inositol triphosphate) receptor expression in both human and mouse lymphocytes cultured in modeled microgravity indicate no suppression of calcium signaling. In the human system, microgravity seems to inhibit signaling cascades either at the level of, or up-stream of, Protein Kinase C (PKC). In particular, a membrane event, such as phospholipase C gamma 1 activity in human lymphocytes is affected, with its direct upstream effector, LAT, being deficiently expressed. In the mouse pathway, LAT is undiminished while another critical intermediate, SLP-76, is diminished significantly. This study identifies critical stages in the human and mouse immune systems and in lymphocytes as a function of microgravity.

Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

PubMed

Wang, Rui; Wan, Qi; Kozhaya, Lina; Fujii, Hodaka; Unutmaz, Derya

2008-07-16

Regulatory T (T(reg)) cells control immune activation and maintain tolerance. How T(regs) mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32), which within T cells is specifically expressed in T(regs) activated through the T cell receptor (TCR). Ectopic expression of GARP in human naïve T (T(N)) cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N) cells induced expression of T(reg) master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg) cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

The Diagnosis of Depression in People with Severe Limitations in Intellectual Functioning

ERIC Educational Resources Information Center

Scott, Haleigh; Havercamp, Susan M.

2015-01-01

People with intellectual disability (ID) were once considered immune to developing psychopathology, including affective disorders such as depression. Now research has shown that people with ID do suffer from depression, and the focus is on understanding how to best diagnose and provide treatment. Research has come a long way in adapting the…

Clinical implications of basic science discoveries: nociceptive neurons as targets to control immunity--potential relevance for transplantation.

PubMed

Larregina, A T; Divito, S J; Morelli, A E

2015-06-01

Increasing evidence indicates the existence of a complex cross-regulation between the most important biosensors of the human body: The immune and nervous systems. Cytokines control body temperature and trigger autoimmune disorders in the central nervous system, whereas neuropeptides released in peripheral tissues and lymphoid organs modulate inflammatory (innate) and adaptive immune responses. Surprisingly, the effects of nerve fibers and the antidromic release of its pro-inflammatory neuropeptides on the leukocytes of the immune system that mediate graft rejection are practically unknown. In the transplantation field, such area of research remains practically unexplored. A recent study by Riol-Blanco et al has revealed new details on how nociceptive nerves regulate the pro-inflammatory function of leukocytes in peripheral tissues. Although the mechanism(s) by which neuroinflammation affects the immune response against the allograft remains unknown, recent data suggest that this new area of research is worth exploring for potential development of novel complementary therapies for prevention/treatment of graft rejection. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Waning and aging of cellular immunity to Bordetella pertussis.

PubMed

van Twillert, Inonge; Han, Wanda G H; van Els, Cécile A C M

2015-11-01

While it is clear that the maintenance of Bordetella pertussis-specific immunity evoked both after vaccination and infection is insufficient, it is unknown at which pace waning occurs and which threshold levels of sustained functional memory B and T cells are required to provide long-term protection. Longevity of human cellular immunity to B. pertussis has been studied less extensively than serology, but is suggested to be key for the observed differences between the duration of protection induced by acellular vaccination and whole cell vaccination or infection. The induction and maintenance of levels of protective memory B and T cells may alter with age, associated with changes of the immune system throughout life and with accumulating exposures to circulating B. pertussis or vaccine doses. This is relevant since pertussis affects all age groups. This review summarizes current knowledge on the waning patterns of human cellular immune responses to B. pertussis as addressed in diverse vaccination and infection settings and in various age groups. Knowledge on the effectiveness and flaws in human B. pertussis-specific cellular immunity ultimately will advance the improvement of pertussis vaccination strategies. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

How sex and age affect immune responses, susceptibility to infections, and response to vaccination

PubMed Central

Giefing-Kröll, Carmen; Berger, Peter; Lepperdinger, Günter; Grubeck-Loebenstein, Beatrix

2015-01-01

Do men die young and sick, or do women live long and healthy? By trying to explain the sexual dimorphism in life expectancy, both biological and environmental aspects are presently being addressed. Besides age-related changes, both the immune and the endocrine system exhibit significant sex-specific differences. This review deals with the aging immune system and its interplay with sex steroid hormones. Together, they impact on the etiopathology of many infectious diseases, which are still the major causes of morbidity and mortality in people at old age. Among men, susceptibilities toward many infectious diseases and the corresponding mortality rates are higher. Responses to various types of vaccination are often higher among women thereby also mounting stronger humoral responses. Women appear immune-privileged. The major sex steroid hormones exhibit opposing effects on cells of both the adaptive and the innate immune system: estradiol being mainly enhancing, testosterone by and large suppressive. However, levels of sex hormones change with age. At menopause transition, dropping estradiol potentially enhances immunosenescence effects posing postmenopausal women at additional, yet specific risks. Conclusively during aging, interventions, which distinctively consider the changing level of individual hormones, shall provide potent options in maintaining optimal immune functions. PMID:25720438

Multivariate immune defences and fitness in the wild: complex but ecologically important associations among plasma antibodies, health and survival

PubMed Central

Nussey, Daniel H.; Watt, Kathryn A.; Clark, Abigail; Pilkington, Jill G.; Pemberton, Josephine M.; Graham, Andrea L.; McNeilly, Tom N.

2014-01-01

Despite our rapidly advancing mechanistic understanding of vertebrate immunity under controlled laboratory conditions, the links between immunity, infection and fitness under natural conditions remain poorly understood. Antibodies are central to acquired immune responses, and antibody levels circulating in vivo reflect a composite of constitutive and induced functional variants of diverse specificities (e.g. binding antigens from prevalent parasites, self tissues or novel non-self sources). Here, we measured plasma concentrations of 11 different antibody types in adult females from an unmanaged population of Soay sheep on St Kilda. Correlations among antibody measures were generally positive but weak, and eight of the measures independently predicted body mass, strongyle parasite egg count or survival over the subsequent winter. These independent and, in some cases, antagonistic relationships point to important multivariate immunological heterogeneities affecting organismal health and fitness in natural systems. Notably, we identified a strong positive association between anti-nematode immunoglobulin (Ig) G antibodies in summer and subsequent over-winter survival, providing rare evidence for a fitness benefit of helminth-specific immunity under natural conditions. Our results highlight both the evolutionary and ecological importance and the complex nature of the immune phenotype in the wild. PMID:24500168

The Spleen: A Hub Connecting Nervous and Immune Systems in Cardiovascular and Metabolic Diseases

PubMed Central

Lori, Andrea; Perrotta, Marialuisa; Lembo, Giuseppe; Carnevale, Daniela

2017-01-01

Metabolic disorders have been identified as major health problems affecting a large portion of the world population. In addition, obesity and insulin resistance are principal risk factors for the development of cardiovascular diseases. Altered immune responses are common features of both hypertension and obesity and, moreover, the involvement of the nervous system in the modulation of immune system is gaining even more attention in both pathophysiological contexts. For these reasons, during the last decades, researches focused their efforts on the comprehension of the molecular mechanisms connecting immune system to cardiovascular and metabolic diseases. On the other hand, it has been reported that in these pathological conditions, central neural pathways modulate the activity of the peripheral nervous system, which is strongly involved in onset and progression of the disease. It is interesting to notice that neural reflex can also participate in the modulation of immune functions. In this scenario, the spleen becomes the crucial hub allowing the interaction of different systems differently involved in metabolic and cardiovascular diseases. Here, we summarize the major findings that dissect the role of the immune system in disorders related to metabolic and cardiovascular dysfunctions, and how this could also be influenced by neural reflexes. PMID:28590409

A stochastic chemical dynamic approach to correlate autoimmunity and optimal vitamin-D range.

PubMed

Roy, Susmita; Shrinivas, Krishna; Bagchi, Biman

2014-01-01

Motivated by several recent experimental observations that vitamin-D could interact with antigen presenting cells (APCs) and T-lymphocyte cells (T-cells) to promote and to regulate different stages of immune response, we developed a coarse grained but general kinetic model in an attempt to capture the role of vitamin-D in immunomodulatory responses. Our kinetic model, developed using the ideas of chemical network theory, leads to a system of nine coupled equations that we solve both by direct and by stochastic (Gillespie) methods. Both the analyses consistently provide detail information on the dependence of immune response to the variation of critical rate parameters. We find that although vitamin-D plays a negligible role in the initial immune response, it exerts a profound influence in the long term, especially in helping the system to achieve a new, stable steady state. The study explores the role of vitamin-D in preserving an observed bistability in the phase diagram (spanned by system parameters) of immune regulation, thus allowing the response to tolerate a wide range of pathogenic stimulation which could help in resisting autoimmune diseases. We also study how vitamin-D affects the time dependent population of dendritic cells that connect between innate and adaptive immune responses. Variations in dose dependent response of anti-inflammatory and pro-inflammatory T-cell populations to vitamin-D correlate well with recent experimental results. Our kinetic model allows for an estimation of the range of optimum level of vitamin-D required for smooth functioning of the immune system and for control of both hyper-regulation and inflammation. Most importantly, the present study reveals that an overdose or toxic level of vitamin-D or any steroid analogue could give rise to too large a tolerant response, leading to an inefficacy in adaptive immune function.

Host Immune Response to Histophilus somni.

PubMed

Corbeil, Lynette B

2016-01-01

Histophilus somni is known to cause several overlapping syndromes or to be found in genital or upper respiratory carrier states in ruminants. Vaccines have been used for decades, yet efficacy is controversial and mechanisms of protective immunity are not well understood. Since H. somni survives phagocytosis, it has sometimes been considered to be a facultative intercellular parasite, implying that cell-mediated immunity would be critical in protection. However, H. somni not only inhibits phagocyte function, but also is cytotoxic for macrophages. Therefore, it does not live for long periods in healthy phagocytes. Protection of calves against H. somni pneumonia by passive immunization is also evidence that H. somni is more like an extracellular pathogen than an intracellular pathogen. Several studies showed that bovine IgG2 antibodies are more protective than IgG1 antibodies. Even the IgG2 allotypes tend to vary in protection. Of course, antigenic specificity also determines protection. So far, there is most evidence for protection by a 40 K outer membrane protein and by Immunoglobulin binding protein A fibrils. Serology and immunohistochemistry have both been used for immunodiagnosis. Many evasive mechanisms by H. somni have been defined, including decreased phagocyte function, antibodies bound by shed antigens, decreased immune stimulation, and antigenic variation. Interaction of H. somni with other bovine respiratory disease organisms is another layer of pathogenesis. Studies of bovine respiratory syncytial virus (BRSV) and H. somni in calfhood pneumonia revealed an increase in IgE antibodies to H. somni, which were associated with more severe disease of longer duration than with either agent alone. Innate immune mechanisms at the epithelial cell level are also affected by dual infection by BRSV and H. somni as compared to either pathogen alone. Although much more work needs to be done, the complex mechanisms of H. somni immunity are becoming clearer.

Interleukin-10 reorganizes the cytoskeleton of mature dendritic cells leading to their impaired biophysical properties and motilities.

PubMed

Xu, Xiaoli; Liu, Xianmei; Long, Jinhua; Hu, Zuquan; Zheng, Qinni; Zhang, Chunlin; Li, Long; Wang, Yun; Jia, Yi; Qiu, Wei; Zhou, Jing; Yao, Weijuan; Zeng, Zhu

2017-01-01

Interlukin-10 (IL-10) is an immunomodulatory cytokine which predominantly induces immune-tolerance. It has been also identified as a major cytokine in the tumor microenvironment that markedly mediates tumor immune escape. Previous studies on the roles of IL-10 in tumor immunosuppression mainly focus on its biochemical effects. But the effects of IL-10 on the biophysical characteristics of immune cells are ill-defined. Dendritic cells (DCs) are the most potent antigen-presenting cells and play a key role in the anti-tumor immune response. IL-10 can affect the immune regulatory functions of DCs in various ways. In this study, we aim to explore the effects of IL-10 on the biophysical functions of mature DCs (mDCs). mDCs were treated with different concentrations of IL-10 and their biophysical characteristics were identified. The results showed that the biophysical properties of mDCs, including electrophoresis mobility, osmotic fragility and deformability, as well as their motilities, were impaired by IL-10. Meanwhile, the cytoskeleton (F-actin) of mDCs was reorganized by IL-10. IL-10 caused the alternations in the expressions of fasin1 and profilin1 as well as the phosphorylation of cofilin1 in a concentration-dependent fashion. Moreover, Fourier transformed infrared resonance data showed that IL-10 made the status of gene transcription and metabolic turnover of mDCs more active. These results demonstrate a new aspect of IL-10's actions on the immune system and represent one of the mechanisms for immune escape of tumors. It may provide a valuable clue to optimize and improve the efficiency of DC-based immunotherapy against cancer.

The clandestine organs of the endocrine system.

PubMed

Garcia-Reyero, Natàlia

2018-02-01

This review analyzes what could be regarded as the "clandestine organs" of the endocrine system: the gut microbiome, the immune system, and the stress system. The immune system is very closely related to the endocrine system, with many intertwined processes and signals. Many researchers now consider the microbiome as an 'organ' that affects the organism at many different levels. While stress is certainly not an organ, it affects so many processes, including endocrine-related processes, that the stress response system deserved a special section in this review. Understanding the connections, effects, and feedback mechanisms between the different "clandestine organs" and the endocrine system will provide us with a better understanding of how an organism functions, as well as reinforce the idea that there are no independent organs or systems, but a complex, interacting network of molecules, cells, tissues, signaling pathways, and mechanisms that constitute an individual. Published by Elsevier Inc.

Effects of rearing temperature on immune functions in sockeye salmon (Oncorhynchus nerka)

USGS Publications Warehouse

Alcorn, S.W.; Murray, A.L.; Pascho, R.J.

2002-01-01

To determine if the defences of sockeye salmon (Oncorhynchus nerka) raised in captivity are affected by the rearing temperature or their life-cycle stage, various indices of the humoral and cellular immune functions were measured in fish reared at either 8 or 12??C for their entire life-cycle. Measures of humoral immunity included the commonly used haematological parameters, as well as measurements of complement, and lysozyme activity. Cellular assays quantified the ability of macrophages from the anterior kidney to phagocytise Staphylococcus aureus cells, or the activities of certain bactericidal systems of those cells. The T-dependent antibody response to a recombinant 57 kDa protein of Renibacterium salmoninarum was used to quantify the specific immune response. Fish were sampled during the spring and fall of their second, third and fourth years, corresponding to a period that began just before smolting and ended at sexual maturation. Fish reared at 8??C tended to have a greater percentage of phagocytic kidney macrophages during the first 2 years of sampling than the fish reared at 12??C. During the last half of the study the complement activity of the fish reared at 8??C was greater than that of the 12??C fish. Conversely, a greater proportion of the blood leucocytes were lymphocytes in fish reared at 12??C compared to the fish reared at 8??C. Fish reared at 12??C also produced a greater antibody response than those reared at 8??C. Results suggested that the immune apparatus of sockeye salmon reared at 8??C relied more heavily on the non-specific immune response, while the specific immune response was used to a greater extent when the fish were reared at 12??C. Although a seasonal effect was not detected in any of the indices measured, varying effects were observed in some measurements during sexual maturation of fish in both temperature groups. At that time there were dramatic decreases in complement activity and lymphocyte numbers. This study was unique in its scope because it was the first quantitative assessment of salmon immune functions for an entire life-cycle. ?? 2002 Elsevier Science Ltd.

Barley disease susceptibility factor RACB acts in epidermal cell polarity and positioning of the nucleus

PubMed Central

Scheler, Björn; Schnepf, Vera; Galgenmüller, Carolina; Ranf, Stefanie; Hückelhoven, Ralph

2016-01-01

RHO GTPases are regulators of cell polarity and immunity in eukaryotes. In plants, RHO-like RAC/ROP GTPases are regulators of cell shaping, hormone responses, and responses to microbial pathogens. The barley (Hordeum vulgare L.) RAC/ROP protein RACB is required for full susceptibility to penetration by Blumeria graminis f.sp. hordei (Bgh), the barley powdery mildew fungus. Disease susceptibility factors often control host immune responses. Here we show that RACB does not interfere with early microbe-associated molecular pattern-triggered immune responses such as the oxidative burst or activation of mitogen-activated protein kinases. RACB also supports rather than restricts expression of defence-related genes in barley. Instead, silencing of RACB expression by RNAi leads to defects in cell polarity. In particular, initiation and maintenance of root hair growth and development of stomatal subsidiary cells by asymmetric cell division is affected by silencing expression of RACB. Nucleus migration is a common factor of developmental cell polarity and cell-autonomous interaction with Bgh. RACB is required for positioning of the nucleus near the site of attack from Bgh. We therefore suggest that Bgh profits from RACB’s function in cell polarity rather than from immunity-regulating functions of RACB. PMID:27056842

Dietary ribonucleic acid suppresses inflammation of adipose tissue and improves glucose intolerance that is mediated by immune cells in C57BL/6 mice fed a high-fat diet.

PubMed

Sakai, Tohru; Taki, Tomoyo; Nakamoto, Akiko; Tazaki, Shiho; Arakawa, Mai; Nakamoto, Mariko; Tsutsumi, Rie; Shuto, Emi

2015-01-01

Recent evidence suggests that immune cells play an important role in differentiation of inflammatory macrophages in adipose tissue, which contributes to systemic chronic inflammation. Dietary ribonucleic acid (RNA) has been shown to modulate immune function. We hypothesized that RNA affects immune cell function in adipose tissue and then improves inflammatory response in adipose tissue. C57/BL6 mice and recombination activating gene-1 (RAG-1) knockout mice on a C57BL/6 mice background were fed a high-fat diet containing 1% RNA for 12 wk. An oral glucose tolerance test was performed. Supplementation of dietary RNA in C57BL/6 mice fed a high-fat diet resulted in a smaller area under the curve (AUC) after oral glucose administration than that for control mice. The mRNA expression levels of inflammation-related cytokines in adipose tissue and serum interleukin-6 levels were reduced by dietary RNA supplementation. Interestingly, reduction of the AUC value by RNA supplementation was abolished in T and B cell-deficient RAG-1 knockout mice. These results indicate that RNA improves inflammation in adipose tissue and reduces the AUC value following oral glucose administration in a T and B cell-dependent manner.

Barley disease susceptibility factor RACB acts in epidermal cell polarity and positioning of the nucleus.

PubMed

Scheler, Björn; Schnepf, Vera; Galgenmüller, Carolina; Ranf, Stefanie; Hückelhoven, Ralph

2016-05-01

RHO GTPases are regulators of cell polarity and immunity in eukaryotes. In plants, RHO-like RAC/ROP GTPases are regulators of cell shaping, hormone responses, and responses to microbial pathogens. The barley (Hordeum vulgare L.) RAC/ROP protein RACB is required for full susceptibility to penetration by Blumeria graminis f.sp. hordei (Bgh), the barley powdery mildew fungus. Disease susceptibility factors often control host immune responses. Here we show that RACB does not interfere with early microbe-associated molecular pattern-triggered immune responses such as the oxidative burst or activation of mitogen-activated protein kinases. RACB also supports rather than restricts expression of defence-related genes in barley. Instead, silencing of RACB expression by RNAi leads to defects in cell polarity. In particular, initiation and maintenance of root hair growth and development of stomatal subsidiary cells by asymmetric cell division is affected by silencing expression of RACB. Nucleus migration is a common factor of developmental cell polarity and cell-autonomous interaction with Bgh RACB is required for positioning of the nucleus near the site of attack from Bgh We therefore suggest that Bgh profits from RACB's function in cell polarity rather than from immunity-regulating functions of RACB. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Supernatural T cells: genetic modification of T cells for cancer therapy.

PubMed

Kershaw, Michael H; Teng, Michele W L; Smyth, Mark J; Darcy, Phillip K

2005-12-01

Immunotherapy is receiving much attention as a means of treating cancer, but complete, durable responses remain rare for most malignancies. The natural immune system seems to have limitations and deficiencies that might affect its ability to control malignant disease. An alternative to relying on endogenous components in the immune repertoire is to generate lymphocytes with abilities that are greater than those of natural T cells, through genetic modification to produce 'supernatural' T cells. This Review describes how such T cells can circumvent many of the barriers that are inherent in the tumour microenvironment while optimizing T-cell specificity, activation, homing and antitumour function.

Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems.

PubMed

Okamoto, Kazuo; Nakashima, Tomoki; Shinohara, Masahiro; Negishi-Koga, Takako; Komatsu, Noriko; Terashima, Asuka; Sawa, Shinichiro; Nitta, Takeshi; Takayanagi, Hiroshi

2017-10-01

The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system. Copyright © 2017 the American Physiological Society.

Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets

PubMed Central

Jensen, Michael L.; Thymann, Thomas; Cilieborg, Malene S.; Lykke, Mikkel; Mølbak, Lars; Jensen, Bent B.; Schmidt, Mette; Kelly, Denise; Mulder, Imke; Burrin, Douglas G.

2013-01-01

Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum antibiotic treatment improves NEC resistance and intestinal structure, function, and immunity in neonates. Caesarean-delivered preterm pigs were fed 3 days of parenteral nutrition followed by 2 days of enteral formula. Immediately after birth, they were assigned to receive either antibiotics (oral and parenteral doses of gentamycin, ampicillin, and metronidazole, ANTI, n = 11) or saline in the control group (CON, n = 13), given twice daily. NEC lesions and intestinal structure, function, microbiology, and immunity markers were recorded. None of the ANTI but 85% of the CON pigs developed NEC lesions by day 5 (0/11 vs. 11/13, P < 0.05). ANTI pigs had higher intestinal villi (+60%), digestive enzyme activities (+53–73%), and goblet cell densities (+110%) and lower myeloperoxidase (−51%) and colonic microbial density (105 vs. 1010 colony-forming units, all P < 0.05). Microarray transcriptomics showed strong downregulation of genes related to inflammation and innate immune response to microbiota and marked upregulation of genes related to amino acid metabolism, in particular threonine, glucose transport systems, and cell cycle in 5-day-old ANTI pigs. In a follow-up experiment, 5 days of antibiotics prevented NEC at least until day 10. Neonatal prophylactic antibiotics effectively reduced gut bacterial load, prevented NEC, intestinal atrophy, dysfunction, and inflammation and enhanced expression of genes related to gut metabolism and immunity in preterm pigs. PMID:24157972

HIV-I Nef inhibitors: a novel class of HIV-specific immune adjuvants in support of a cure.

PubMed

Dekaban, Gregory A; Dikeakos, Jimmy D

2017-09-12

The success of many current vaccines relies on a formulation that incorporates an immune activating adjuvant. This will hold true for the design of a successful therapeutic HIV vaccine targeted at controlling reactivated virus following cessation of combined antiretroviral therapy (cART). The HIV accessory protein Nef functions by interfering with HIV antigen presentation through the major histocompatibility complex I (MHC-I) pathway thereby suppressing CD8 + cytotoxic T cell (CTL)-mediated killing of HIV infected cells. Thus, this important impediment to HIV vaccine success must be circumvented. This review covers our current knowledge of Nef inhibitors that may serve as immune adjuvants that will specifically restore and enhance CTL-mediated killing of reactivated HIV infected cells as part of an overall vaccine strategy to affect a cure for HIV infection.

The Emerging Importance of IgG Fab Glycosylation in Immunity.

PubMed

van de Bovenkamp, Fleur S; Hafkenscheid, Lise; Rispens, Theo; Rombouts, Yoann

2016-02-15

Human IgG is the most abundant glycoprotein in serum and is crucial for protective immunity. In addition to conserved IgG Fc glycans, ∼15-25% of serum IgG contains glycans within the variable domains. These so-called "Fab glycans" are primarily highly processed complex-type biantennary N-glycans linked to N-glycosylation sites that emerge during somatic hypermutation. Specific patterns of Fab glycosylation are concurrent with physiological and pathological conditions, such as pregnancy and rheumatoid arthritis. With respect to function, Fab glycosylation can significantly affect stability, half-life, and binding characteristics of Abs and BCRs. Moreover, Fab glycans are associated with the anti-inflammatory activity of IVIgs. Consequently, IgG Fab glycosylation appears to be an important, yet poorly understood, process that modulates immunity. Copyright © 2016 by The American Association of Immunologists, Inc.

Immune response in the adipose tissue of lean mice infected with the protozoan parasite Neospora caninum

PubMed Central

Teixeira, Luzia; Moreira, João; Melo, Joana; Bezerra, Filipa; Marques, Raquel M; Ferreirinha, Pedro; Correia, Alexandra; Monteiro, Mariana P; Ferreira, Paula G; Vilanova, Manuel

2015-01-01

The adipose tissue can make important contributions to immune function. Nevertheless, only a limited number of reports have investigated in lean hosts the immune response elicited in this tissue upon infection. Previous studies suggested that the intracellular protozoan Neospora caninum might affect adipose tissue physiology. Therefore, we investigated in mice challenged with this protozoan if immune cell populations within adipose tissue of different anatomical locations could be differently affected. Early in infection, parasites were detected in the adipose tissue and by 7 days of infection increased numbers of macrophages, regulatory T (Treg) cells and T-bet+ cells were observed in gonadal, mesenteric, omental and subcutaneous adipose tissue. Increased expression of interferon-γ was also detected in gonadal adipose tissue of infected mice. Two months after infection, parasite DNA was no longer detected in these tissues, but T helper type 1 (Th1) cell numbers remained above control levels in the infected mice. Moreover, the Th1/Treg cell ratio was higher than that of controls in the mesenteric and subcutaneous adipose tissue. Interestingly, chronically infected mice presented a marked increase of serum leptin, a molecule that plays a role in energy balance regulation as well as in promoting Th1-type immune responses. Altogether, we show that an apicomplexa parasitic infection influences immune cellular composition of adipose tissue throughout the body as well as adipokine production, still noticed at a chronic phase of infection when parasites were already cleared from that particular tissue. This strengthens the emerging view that infections can have long-term consequences for the physiology of adipose tissue. PMID:25581844

Testing the carotenoid trade-off hypothesis in the polychromatic Midas cichlid, Amphilophus citrinellus.

PubMed

Lin, Susan M; Nieves-Puigdoller, Katherine; Brown, Alexandria C; McGraw, Kevin J; Clotfelter, Ethan D

2010-01-01

Many animals use carotenoid pigments derived from their diet for coloration and immunity. The carotenoid trade-off hypothesis predicts that, under conditions of carotenoid scarcity, individuals may be forced to allocate limited carotenoids to either coloration or immunity. In polychromatic species, the pattern of allocation may differ among individuals. We tested the carotenoid trade-off hypothesis in the Midas cichlid, Amphilophus citrinellus, a species with two ontogenetic color morphs, barred and gold, the latter of which is the result of carotenoid expression. We performed a diet-supplementation experiment in which cichlids of both color morphs were assigned to one of two diet treatments that differed only in carotenoid content (beta-carotene, lutein, and zeaxanthin). We measured integument color using spectrometry, quantified carotenoid concentrations in tissue and plasma, and assessed innate immunity using lysozyme activity and alternative complement pathway assays. In both color morphs, dietary carotenoid supplementation elevated plasma carotenoid circulation but failed to affect skin coloration. Consistent with observable differences in integument coloration, we found that gold fish sequestered more carotenoids in skin tissue than barred fish, but barred fish had higher concentrations of carotenoids in plasma than gold fish. Neither measure of innate immunity differed between gold and barred fish, or as a function of dietary carotenoid supplementation. Lysozyme activity, but not complement activity, was strongly affected by body condition. Our data show that a diet low in carotenoids is sufficient to maintain both coloration and innate immunity in Midas cichlids. Our data also suggest that the developmental transition from the barred to gold morph is not accompanied by a decrease in innate immunity in this species.

An experimental heat wave changes immune defense and life history traits in a freshwater snail.

PubMed

Leicht, Katja; Jokela, Jukka; Seppälä, Otto

2013-12-01

The predicted increase in frequency and severity of heat waves due to climate change is expected to alter disease dynamics by reducing hosts' ability to resist infections. This could take place via two different mechanisms: (1) through general reduction in hosts' performance under harsh environmental conditions and/or (2) through altered resource allocation that reduces expression of defense traits in order to maintain other traits. We tested these alternative hypotheses by measuring the effect of an experimental heat wave (25 vs. 15°C) on the constitutive level of immune defense (hemocyte concentration, phenoloxidase [PO]-like activity, antibacterial activity of hemolymph), and life history traits (growth and number of oviposited eggs) of the great pond snail Lymnaea stagnalis. We also manipulated the exposure time to high temperature (1, 3, 5, 7, 9, or 11 days). We found that if the exposure to high temperature lasted <1 week, immune function was not affected. However, when the exposure lasted longer than that, the level of snails' immune function (hemocyte concentration and PO-like activity) was reduced. Snails' growth and reproduction increased within the first week of exposure to high temperature. However, longer exposures did not lead to a further increase in cumulative reproductive output. Our results show that short experimental heat waves do not alter immune function but lead to plastic responses that increase snails' growth and reproduction. Thus, although the relative expression of traits changes, short experimental heat waves do not impair snails' defenses. Negative effects on performance get pronounced when the heat waves are prolonged suggesting that high performance cannot be maintained over long time periods. This ultimately reduces the levels of defense traits.

Dendritic Cells: A Spot on Sialic Acid

PubMed Central

Crespo, Hélio J.; Lau, Joseph T. Y.; Videira, Paula A.

2013-01-01

Glycans decorating cell surface and secreted proteins and lipids occupy the juncture where critical host–host and host-pathogen interactions occur. The role of glycan epitopes in cell–cell and cell-pathogen adhesive events is already well-established, and cell surface glycan structures change rapidly in response to stimulus and inflammatory cues. Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how glycans and their changes contribute to the overall immune response remains poorly defined. Sialic acids are unique sugars that usually occupy the terminal position of the glycan chains and may be modified by external factors, such as pathogens, or upon specific physiological cellular events. At cell surface, sialic acid-modified structures form the key fundamental determinants for a number of receptors with known involvement in cellular adhesiveness and cell trafficking, such as the Selectins and the Siglec families of carbohydrate recognizing receptors. Dendritic cells (DCs) preside over the transition from innate to the adaptive immune repertoires, and no other cell has such relevant role in antigen screening, uptake, and its presentation to lymphocytes, ultimately triggering the adaptive immune response. Interestingly, sialic acid-modified structures are involved in all DC functions, such as antigen uptake, DC migration, and capacity to prime T cell responses. Sialic acid content changes along DC differentiation and activation and, while, not yet fully understood, these changes have important implications in DC functions. This review focuses on the developmental regulation of DC surface sialic acids and how manipulation of DC surface sialic acids can affect immune-critical DC functions by altering antigen endocytosis, pathogen and tumor cell recognition, cell recruitment, and capacity for T cell priming. The existing evidence points to a potential of DC surface sialylation as a therapeutic target to improve and diversify DC-based therapies. PMID:24409183

Does RBC Storage Age Effect Inflammation, Immune Function and Susceptibility to Transfusion Associated Microchimerism in Critically Ill Patients? Adverse Effects of RBC Storage in Critically Ill Patients

DTIC Science & Technology

2014-12-01

repository; Microparticles ; Coagulation; Microchimerism 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 11 19a. NAME...inflammation, coagulation, microparticle concentrations and microchimerism. Since the last annual report, preliminary data from the ABLE trial have...function correlate with clinical outcomes. 1b.) To determine if RBC unit storage time affects microparticle concentrations in the critically ill and if

Impact of Depleting Therapeutic Monoclonal Antibodies on the Host Adaptive Immunity: A Bonus or a Malus?

PubMed Central

Deligne, Claire; Milcent, Benoît; Josseaume, Nathalie; Teillaud, Jean-Luc; Sibéril, Sophie

2017-01-01

Clinical responses to anti-tumor monoclonal antibody (mAb) treatment have been regarded for many years only as a consequence of the ability of mAbs to destroy tumor cells by innate immune effector mechanisms. More recently, it has also been shown that anti-tumor antibodies can induce a long-lasting anti-tumor adaptive immunity, likely responsible for durable clinical responses, a phenomenon that has been termed the vaccinal effect of antibodies. However, some of these anti-tumor antibodies are directed against molecules expressed both by tumor cells and normal immune cells, in particular lymphocytes, and, hence, can also strongly affect the host adaptive immunity. In addition to a delayed recovery of target cells, lymphocyte depleting-mAb treatments can have dramatic consequences on the adaptive immune cell network, its rebound, and its functional capacities. Thus, in this review, we will not only discuss the mAb-induced vaccinal effect that has emerged from experimental preclinical studies and clinical trials but also the multifaceted impact of lymphocytes-depleting therapeutic antibodies on the host adaptive immunity. We will also discuss some of the molecular and cellular mechanisms of action whereby therapeutic mAbs induce a long-term protective anti-tumor effect and the relationship between the mAb-induced vaccinal effect and the immune response against self-antigens. PMID:28855903

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

PubMed Central

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

2016-01-01

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

Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.

PubMed

Mulder, Sasja F; Jacobs, Joannes F M; Olde Nordkamp, Michel A M; Galama, Joep M D; Desar, Ingrid M E; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F A; Vissers, Kris C P; Punt, Cornelis J A; de Vries, I Jolanda M; van Herpen, Carla M L

2011-07-01

The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

Social instability and immunity in rhesus monkeys: the role of the sympathetic nervous system.

PubMed

Capitanio, John P; Cole, Steven W

2015-05-26

Social instability can adversely affect endocrine, immune and health outcomes, and recent evidence suggests that the sympathetic nervous system (SNS) might mediate these effects. We conducted two studies with adult male rhesus monkeys (Macaca mulatta) to understand how social conditions affect measures of SNS activity and immune function. In Experiment 1, animals were socialized in stable social conditions, then were switched to unstable (stressful) social conditions, then were returned to stable conditions. Analysis revealed quadratic effects for measures of behaviour, urinary metabolites of epinephrine and norepinephrine, and expression of immune response genes: as expected, social instability adversely impacted most measures, and the effects remediated upon re-imposition of stable conditions. Cortisol levels were unaffected. In Experiment 2, we used the sympathomimetic drug methamphetamine to challenge the SNS; animals also underwent socialization in stable or unstable groups. Surprisingly, while methamphetamine elevated plasma catecholamines, responses in lymph nodes tracked the social, and not the drug, condition: social instability upregulated the density of SNS fibres in lymph nodes and downregulated Type I interferon gene expression. Together, these results indicate that the SNS is extremely sensitive to social conditions; full understanding of the adverse effects of social instability on health should therefore incorporate measures of this health-relevant system. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Effect of subacute exposure to lead and estrogen on immature pre-weaning rat leukocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villagra, R.; Tchernitchin, N.N.; Tchernitchin, A.N.

1997-02-01

Lead is an environmental pollutant known to cause damage to human health, affecting specially the central nervous system, reproductive organs, the immune system and kidney. From the perspective or reproduction, lead affects both men and women. Reported effects in women include infertility, miscarriage, pre-eclampsia, pregnancy hypertension and premature delivery. In experimental animals, lead affects female reproductive organs through different mechanisms. The heavy metal may interact at the enzyme level. It may interfere with the action of reproductive hormones at the target organ, modifying the activity of estrogen receptors in the pregnant uterus and inhibiting responses where estrogens play a role.more » Lead may induce imprinting mechanism, causing persistent changes in uterine estrogen receptors and ovary LH receptors following perinatal exposure. Finally, it may interfere at the level of hypothalamus-pituitary, decreasing pituitary response to growth hormone releasing factor, affecting levels of FSH and LH and increasing blood levels of glucocorticoids, which modify the action of estrogens in the uterus. This study examines the mechanisms of lead-induced interference with female reproductive and immune functions. 33 refs., 2 figs., 2 tabs.« less

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

PubMed Central

Semenkovich, Nicholas P.; Planer, Joseph D.; Ahern, Philip P.; Griffin, Nicholas W.; Lin, Charles Y.; Gordon, Jeffrey I.

2016-01-01

The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ+ and γδ+ intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling–weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages. PMID:27911843

Cryotherapy with concurrent CpG oligonucleotide treatment controls local tumor recurrence and modulates HER2/neu immunity.

PubMed

Veenstra, Jesse J; Gibson, Heather M; Littrup, Peter J; Reyes, Joyce D; Cher, Michael L; Takashima, Akira; Wei, Wei-Zen

2014-10-01

Percutaneous cryoablation is a minimally invasive procedure for tumor destruction, which can potentially initiate or amplify antitumor immunity through the release of tumor-associated antigens. However, clinically efficacious immunity is lacking and regional recurrences are a limiting factor relative to surgical excision. To understand the mechanism of immune activation by cryoablation, comprehensive analyses of innate immunity and HER2/neu humoral and cellular immunity following cryoablation with or without peritumoral CpG injection were conducted using two HER2/neu(+) tumor systems in wild-type (WT), neu-tolerant, and SCID mice. Cryoablation of neu(+) TUBO tumor in BALB/c mice resulted in systemic immune priming, but not in neu-tolerant BALB NeuT mice. Cryoablation of human HER2(+) D2F2/E2 tumor enabled the functionality of tumor-induced immunity, but secondary tumors were refractory to antitumor immunity if rechallenge occurred during the resolution phase of the cryoablated tumor. A step-wise increase in local recurrence was observed in WT, neu-tolerant, and SCID mice, indicating a role of adaptive immunity in controlling residual tumor foci. Importantly, local recurrences were eliminated or greatly reduced in WT, neu tolerant, and SCID mice when CpG was incorporated in the cryoablation regimen, showing significant local control by innate immunity. For long-term protection, however, adaptive immunity was required because most SCID mice eventually succumbed to local tumor recurrence even with combined cryoablation and CpG treatment. This improved understanding of the mechanisms by which cryoablation affects innate and adaptive immunity will help guide appropriate combination of therapeutic interventions to improve treatment outcomes. ©2014 American Association for Cancer Research.

Changes in Nutritional Status Impact Immune Cell Metabolism and Function.

PubMed

Alwarawrah, Yazan; Kiernan, Kaitlin; MacIver, Nancie J

2018-01-01

Immune cell function and metabolism are closely linked. Many studies have now clearly demonstrated that alterations in cellular metabolism influence immune cell function and that, conversely, immune cell function determines the cellular metabolic state. Less well understood, however, are the effects of systemic metabolism or whole organism nutritional status on immune cell function and metabolism. Several studies have demonstrated that undernutrition is associated with immunosuppression, which leads to both increased susceptibility to infection and protection against several types of autoimmune disease, whereas overnutrition is associated with low-grade, chronic inflammation that increases the risk of metabolic and cardiovascular disease, promotes autoreactivity, and disrupts protective immunity. Here, we review the effects of nutritional status on immunity and highlight the effects of nutrition on circulating cytokines and immune cell populations in both human studies and mouse models. As T cells are critical members of the immune system, which direct overall immune response, we will focus this review on the influence of systemic nutritional status on T cell metabolism and function. Several cytokines and hormones have been identified which mediate the effects of nutrition on T cell metabolism and function through the expression and action of key regulatory signaling proteins. Understanding how T cells are sensitive to both inadequate and overabundant nutrients may enhance our ability to target immune cell metabolism and alter immunity in both malnutrition and obesity.

Differential roles of fibrinogen and von Willebrand factor on clot formation and platelet adhesion in reconstituted and immune thrombocytopenia.

PubMed

Misgav, Mudi; Shenkman, Boris; Budnik, Ivan; Einav, Yulia; Martinowitz, Uri

2011-05-01

Bleeding tendencies in immune thrombocytopenia (ITP) do not always correlate with the number of platelets, suggesting platelet function variation. We used a model of normal whole blood thrombocytopenia to compare platelet function and other hemostatic variables with ITP patients. We further investigated the effect of in vitro spiking with von Willebrand factor (vWF) and fibrinogen on platelet function and hemostatic variables. The Cone and Plate(let) Analyzer was used to measure platelet adhesion (surface coverage [SC], %) and aggregation (average size, μm(2)) under defined shear rate (1200 s(-1)). Rotational thromboelastometry was used to determine variables of clot formation triggered by CaCl(2) and tissue factor. In both the model of thrombocytopenia as well as in ITP, the SC and to some extent the average size were correlated to the platelet number over a range of 5 to 80 × 10(6)/mL. The results obtained for most ITP samples were within the boundaries of the lower and upper limits set by the whole blood model of thrombocytopenia. The addition of 2 U/mL vWF (Haemate-P) to whole blood (calculated to plasma volume) results in an increase in the SC and average size without affecting clot formation. Spiking with fibrinogen (100 and 300 mg/dL) did not affect platelet deposition but improved clot formation. Using a model of whole blood thrombocytopenia enables us to establish reference variables for the Cone and Plate(let) Analyzer and rotational thromboelastometry and to assess platelet function and clot formation in the presence of severe thrombocytopenia. We demonstrated that in most cases of ITP, platelet function is comparable to normal platelets. This work also suggests that vWF and fibrinogen differentially affect primary and secondary hemostasis and therefore both may perform a function in the bleeding phenotype and possibly may be considered for treatment in patients with ITP. © 2011 International Anesthesia Research Society

[Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.

Intestinal barrier: A gentlemen’s agreement between microbiota and immunity

PubMed Central

Caricilli, Andrea Moro; Castoldi, Angela; Câmara, Niels Olsen Saraiva

2014-01-01

Our body is colonized by more than a hundred trillion commensals, represented by viruses, bacteria and fungi. This complex interaction has shown that the microbiome system contributes to the host’s adaptation to its environment, providing genes and functionality that give flexibility of diet and modulate the immune system in order not to reject these symbionts. In the intestine, specifically, the microbiota helps developing organ structures, participates of the metabolism of nutrients and induces immunity. Certain components of the microbiota have been shown to trigger inflammatory responses, whereas others, anti-inflammatory responses. The diversity and the composition of the microbiota, thus, play a key role in the maintenance of intestinal homeostasis and explain partially the link between intestinal microbiota changes and gut-related disorders in humans. Tight junction proteins are key molecules for determination of the paracellular permeability. In the context of intestinal inflammatory diseases, the intestinal barrier is compromised, and decreased expression and differential distribution of tight junction proteins is observed. It is still unclear what is the nature of the luminal or mucosal factors that affect the tight junction proteins function, but the modulation of the immune cells found in the intestinal lamina propria is hypothesized as having a role in this modulation. In this review, we provide an overview of the current understanding of the interaction of the gut microbiota with the immune system in the development and maintenance of the intestinal barrier. PMID:24891972

Toll-Like Receptor Function in Acute Wounds

PubMed Central

Chen, Lin; DiPietro, Luisa A.

2017-01-01

Significance: Inflammation is an integral part of immune response and supports optimal wound healing in adults. Inflammatory cells such as neutrophils, macrophages, dendritic cells, lymphocytes, and mast cells produce important cytokines, chemokines, and growth factors. These immune cells interact with keratinocytes, fibroblasts, and endothelial cells (ECs), as well as the extracellular matrix within a complicated network that promotes and regulates wound healing. Aberrant and persistent inflammation may result in delayed wound healing, scar formation, or chronic wounds. Targeting the molecules involved in the inflammatory response may have great potential therapeutic value. Recent Advances and Critical Issues: Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen-associated molecular patterns from microbes or danger-associated molecular patterns from damaged cells. The discovery of TLRs sheds new light on the mechanism by which the inflammatory or innate immune response is initiated in wound healing. Convincing evidence now shows that multiple types of cells, including infiltrating or resident inflammatory cells, keratinocytes, fibroblasts, and ECs, express specific types of TLRs. Experimental reduction of certain TLRs or treatment of wounds with TLR ligands has been shown to affect wound healing. A better understanding of the involvement of TLRs in the innate immune response during skin wound healing may suggest novel strategies to improve the quality of tissue repair. Future Directions: Despite the indisputable role of TLRs in regulating the immune response in acute wound healing, the functions of TLRs that are relevant to human wound healing and chronic wounds are poorly understood. PMID:29062591

Effects of selenium on mallard duck reproduction and immune function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whiteley, P.L.; Yuill, T.M.; Fairbrother, A.

Selenium from irrigation drain water and coal-fired power stations is a significant environmental contaminant in some regions of the USA. The objectives were to examine whether selenium-exposed waterfowl had altered immune function, disease resistance, or reproduction. Pairs of adult mallards were exposed for 95-99 days on streams with sodium selenite-treated water at 10 and 30 ppb, or on untreated streams. Selenium biomagnified through the food chain to the ducks. Disease resistance was decreased in ducklings hatched on the streams and challenged with duck hepatitis virus 1 (DHV1) when 15-days old. Liver selenium concentrations for these ducklings on the 10 andmore » 30 ppb streams was 3.6 and 7.6 ppm dry weight, respectively. Mortality of ducklings purchased when 7-days old, exposed to selenium for 14 days, and challenged when 22-days old was not affected. However, their selenium exposure was lower (liver selenium 4.1 ppm dry weight for the 30 ppb stream). Five parameters of immune function were measured in adult ducks. Phagocytosis of killed Pasteurella multocida by blood heterophils and monocytes, and blood monocyte concentrations were higher in adult males following 84 days exposure to 30 ppb selenium. Their liver selenium concentrations were 11.1 ppm dry weight after 95-99 days exposure.« less

Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors

PubMed Central

Breece, Elizabeth; Paciotti, Brian; Nordahl, Christine Wu; Ozonoff, Sally; Van de Water, Judy A.; Rogers, Sally J.; Amaral, David; Ashwood, Paul

2012-01-01

The pathophysiology of Autism Spectrum Disorder (ASD) is not yet known; however, studies suggest that dysfunction of the immune system affects many children with ASD. Increasing evidence points to dysfunction of the innate immune system including activation of microglia and perivascular macrophages, increases in inflammatory cytokines/chemokines in brain tissue and CSF, and abnormal peripheral monocyte cell function. Dendritic cells are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, antigen presentation, activation of naïve T cells, induction of tolerance and cytokine/chemokine production. In this study, we assessed circulating frequencies of myeloid dendritic cells (defined as Lin-1−BDCA1+CD11c+ and Lin-1−BDCA3+CD123−) and plasmacytoid dendritic cells (Lin-1− BDCA2+CD123+ or Lin-1−BDCA4+ CD11c−) in 57 children with ASD, and 29 typically developing controls of the same age, all of who were enrolled as part of the Autism Phenome Project (APP). The frequencies of dendritic cells and associations with behavioral assessment and MRI measurements of amygdala volume were compared in the same participants. The frequencies of myeloid dendritic cells were significantly increased in children with ASD compared to typically developing controls (p < 0.03). Elevated frequencies of myeloid dendritic cells were positively associated with abnormal right and left amygdala enlargement, severity of gastrointestinal symptoms and increased repetitive behaviors. The frequencies of plasmacytoid dendritic cells were also associated with amygdala volumes as well as developmental regression in children with ASD. Dendritic cells play key roles in modulating immune responses and differences in frequencies or functions of these cells may result in immune dysfunction in children with ASD. These data further implicate innate immune cells in the complex pathophysiology of ASD. PMID:23063420

Antioxidant, Immunomodulating, and Microbial-Modulating Activities of the Sustainable and Ecofriendly Spirulina

PubMed Central

Finamore, Alberto; Bensehaila, Sarra

2017-01-01

The highly nutritional and ecofriendly Spirulina (Arthrospira platensis) has hypolipidemic, hypoglycemic, and antihypertensive properties. Spirulina contains functional compounds, such as phenolics, phycocyanins, and polysaccharides, with antioxidant, anti-inflammatory, and immunostimulating effects. Studies conducted on Spirulina suggest that it is safe in healthy subjects, but attitude to eating probably affects the acceptability of Spirulina containing foods. Although the antioxidant effect of Spirulina is confirmed by the intervention studies, the concerted modulation of antioxidant and inflammatory responses, suggested by in vitro and animal studies, requires more confirmation in humans. Spirulina supplements seem to affect more effectively the innate immunity, promoting the activity of natural killer cells. The effects on cytokines and on lymphocytes' proliferation depend on age, gender, and body weight differences. In this context, ageing and obesity are both associated with chronic low grade inflammation, immune impairment, and intestinal dysbiosis. Microbial-modulating activities have been reported in vitro, suggesting that the association of Spirulina and probiotics could represent a new strategy to improve the growth of beneficial intestinal microbiota. Although Spirulina might represent a functional food with potential beneficial effects on human health, the human interventions used only supplements. Therefore, the effect of food containing Spirulina should be evaluated in the future. PMID:28182098

Immune function and hematology of male cotton rats (Sigmodon hispidus) in response to food supplementation and methionine

USGS Publications Warehouse

Webb, R.E.; Leslie, David M.; Lochmiller, R.L.; Masters, R.E.

2003-01-01

We examined effects of supplementation of food quantity and quality (=enhanced methionine) on hematologic and immunologic parameters of wild, but enclosed, adult male cotton rats (Sigmodon hispidus) in north-central Oklahoma. Sheet metal enclosures were stocked with a high density of wild-caught cotton rats (160 animals/ha) and randomly assigned a treatment of no supplementation, mixed-ration supplementation or methionine-enhanced supplementation. Aside from small increases in counts of red blood cells and hematocrit levels, most indices of erythrocytic characteristics were not affected by supplementation with the mixed-ration or enhanced methionine. In contrast, platelet counts were highest in mixed-ration and methionine treatments and counts of total white blood cells were highest with methionine supplementation, albeit relative proportions of different leukocytes did not differ among treatments. Immunologically, neither delayed-type hypersensitivity response nor hemolytic-complement activity differed among treatments. Supplementation of food quantity and quality did not broadly affect hematologic parameters and immune function of male cotton rats, but enhanced platelet and leukocyte counts may confer advantages to overall health. Clarification of the role of such effects on population limitation or regulation requires additional research.

Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype.

PubMed

van Til, Niek P; Stok, Merel; Aerts Kaya, Fatima S F; de Waard, Monique C; Farahbakhshian, Elnaz; Visser, Trudi P; Kroos, Marian A; Jacobs, Edwin H; Willart, Monique A; van der Wegen, Pascal; Scholte, Bob J; Lambrecht, Bart N; Duncker, Dirk J; van der Ploeg, Ans T; Reuser, Arnold J J; Verstegen, Monique M; Wagemaker, Gerard

2010-07-01

Pompe disease (acid alpha-glucosidase deficiency) is a lysosomal glycogen storage disorder characterized in its most severe early-onset form by rapidly progressive muscle weakness and mortality within the first year of life due to cardiac and respiratory failure. Enzyme replacement therapy prolongs the life of affected infants and supports the condition of older children and adults but entails lifelong treatment and can be counteracted by immune responses to the recombinant enzyme. We have explored the potential of lentiviral vector-mediated expression of human acid alpha-glucosidase in hematopoietic stem cells (HSCs) in a Pompe mouse model. After mild conditioning, transplantation of genetically engineered HSCs resulted in stable chimerism of approximately 35% hematopoietic cells that overexpress acid alpha-glucosidase and in major clearance of glycogen in heart, diaphragm, spleen, and liver. Cardiac remodeling was reversed, and respiratory function, skeletal muscle strength, and motor performance improved. Overexpression of acid alpha-glucosidase did not affect overall hematopoietic cell function and led to immune tolerance as shown by challenge with the human recombinant protein. On the basis of the prominent and sustained therapeutic efficacy without adverse events in mice we conclude that ex vivo HSC gene therapy is a treatment option worthwhile to pursue.

Modulation of human alveolar macrophage properties by ozone exposure in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Becker, S.; Madden, M.C.; Newman, S.L.

The study investigated changes in human alveolar macrophage (HAM) function after exposure in vitro to ozone (O3)(0.1-1.0 ppm for 2-4 hr). The functions studied reflect concern that O3 is detrimental to host defense mechanisms in the bronchoalveolar spaces. Exposure of HAM to O3 caused a concentration-dependent increase in release of prostaglandin E2(PGE2), an important modulator of inflammation, phagocytosis, and oxidative burst. Although phagocytosis of particulate immune complexes was decreased by O3, the authors found no change in the quantity of Fc receptors and complement receptors on the HAM surface. Superoxide (O2) production in response to phorbol ester was reduced aftermore » exposure of HAM to O3 while the basal O2 release in response to plastic adherence was not affected. Growth inhibition of the opportunistic yeast Cryptococcus neoformans by HAM was not affected by O3 exposure. The production of inflammatory mediators and immune modulators such as tumor necrosis factor-alpha, interleukin 1, and interleukin 6 were not induced by exposure to O3. However, compared to controls, O3-exposed HAM produced significantly lower levels of these cytokines when simulated with bacterial lipopolysaccharide (LPS).« less

Behavioral stress alters corticolimbic microglia in a sex- and brain region-specific manner.

PubMed

Bollinger, Justin L; Collins, Kaitlyn E; Patel, Rushi; Wellman, Cara L

2017-01-01

Women are more susceptible to numerous stress-linked psychological disorders (e.g., depression) characterized by dysfunction of corticolimbic brain regions critical for emotion regulation and cognitive function. Although sparsely investigated, a number of studies indicate sex differences in stress effects on neuronal structure, function, and behaviors associated with these regions. We recently demonstrated a basal sex difference in- and differential effects of stress on- microglial activation in medial prefrontal cortex (mPFC). The resident immune cells of the brain, microglia are implicated in synaptic and dendritic plasticity, and cognitive-behavioral function. Here, we examined the effects of acute (3h/day, 1 day) and chronic (3h/day, 10 days) restraint stress on microglial density and morphology, as well as immune factor expression in orbitofrontal cortex (OFC), basolateral amygdala (BLA), and dorsal hippocampus (DHC) in male and female rats. Microglia were visualized, classified based on their morphology, and stereologically counted. Microglia-associated transcripts (CD40, iNOS, Arg1, CX3CL1, CX3CR1, CD200, and CD200R) were assessed in brain punches from each region. Expression of genes linked with cellular stress, neuroimmune state, and neuron-microglia communication varied between unstressed male and female rats in a region-specific manner. In OFC, chronic stress upregulated a wider variety of immune factors in females than in males. Acute stress increased microglia-associated transcripts in BLA in males, whereas chronic stress altered immune factor expression in BLA more broadly in females. In DHC, chronic stress increased immune factor expression in males but not females. Moreover, acute and chronic stress differentially affected microglial morphological activation state in male and female rats across all brain regions investigated. In males, chronic stress altered microglial activation in a pattern consistent with microglial involvement in stress-induced dendritic remodeling across OFC, BLA, and DHC. Together, these data suggest the potential for microglia-mediated sex differences in stress effects on neural structure, function, and behavior.

Behavioral stress alters corticolimbic microglia in a sex- and brain region-specific manner

PubMed Central

Bollinger, Justin L.; Collins, Kaitlyn E.; Patel, Rushi

2017-01-01

Women are more susceptible to numerous stress-linked psychological disorders (e.g., depression) characterized by dysfunction of corticolimbic brain regions critical for emotion regulation and cognitive function. Although sparsely investigated, a number of studies indicate sex differences in stress effects on neuronal structure, function, and behaviors associated with these regions. We recently demonstrated a basal sex difference in- and differential effects of stress on- microglial activation in medial prefrontal cortex (mPFC). The resident immune cells of the brain, microglia are implicated in synaptic and dendritic plasticity, and cognitive-behavioral function. Here, we examined the effects of acute (3h/day, 1 day) and chronic (3h/day, 10 days) restraint stress on microglial density and morphology, as well as immune factor expression in orbitofrontal cortex (OFC), basolateral amygdala (BLA), and dorsal hippocampus (DHC) in male and female rats. Microglia were visualized, classified based on their morphology, and stereologically counted. Microglia-associated transcripts (CD40, iNOS, Arg1, CX3CL1, CX3CR1, CD200, and CD200R) were assessed in brain punches from each region. Expression of genes linked with cellular stress, neuroimmune state, and neuron-microglia communication varied between unstressed male and female rats in a region-specific manner. In OFC, chronic stress upregulated a wider variety of immune factors in females than in males. Acute stress increased microglia-associated transcripts in BLA in males, whereas chronic stress altered immune factor expression in BLA more broadly in females. In DHC, chronic stress increased immune factor expression in males but not females. Moreover, acute and chronic stress differentially affected microglial morphological activation state in male and female rats across all brain regions investigated. In males, chronic stress altered microglial activation in a pattern consistent with microglial involvement in stress-induced dendritic remodeling across OFC, BLA, and DHC. Together, these data suggest the potential for microglia-mediated sex differences in stress effects on neural structure, function, and behavior. PMID:29194444

Nutritionally mediated programming of the developing immune system.

PubMed

Palmer, Amanda C

2011-09-01

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

Immune drug discovery from venoms.

PubMed

Jimenez, Rocio; Ikonomopoulou, Maria P; Lopez, J Alejandro; Miles, John J

2018-01-01

This review catalogues recent advances in knowledge on venoms as standalone therapeutic agents or as blueprints for drug design, with an emphasis on venom-derived compounds that affects the immune system. We discuss venoms and venom-derived compounds that affect total immune cell numbers, immune cell proliferation, immune cell migration, immune cell phenotype and cytokine secretion. Identifying novel compounds that 'tune' the system, up-regulating the immune response during infectious disease and cancer and down-regulating the immune response during autoimmunity, will greatly expand the tool kit of human immunotherapeutics. Targeting these pathways may also open therapeutic options that alleviate symptoms of envenomation. Finally, combining recent advances in venomics with progress in low cost, high-throughput screening platforms will no doubt yield hundreds of prototype immune modulating compounds in the coming years. Copyright © 2017 Elsevier Ltd. All rights reserved.

O-GlcNAc: a novel regulator of immunometabolism.

PubMed

Machacek, Miranda; Slawson, Chad; Fields, Patrick E

2018-06-01

The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4 + T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4 + T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4 + T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc's role in the plasticity and pathogenicity of CD4 + T cells and uncover new potential therapeutic targets.

Cystic fibrosis: a mucosal immunodeficiency syndrome

PubMed Central

Cohen, Taylor Sitarik; Prince, Alice

2013-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes—airway inflammation and spontaneous infection—may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance. PMID:22481418

Nodavirus Colonizes and Replicates in the Testis of Gilthead Seabream and European Sea Bass Modulating Its Immune and Reproductive Functions

PubMed Central

Valero, Yulema; Arizcun, Marta; Esteban, M. Ángeles; Bandín, Isabel; Olveira, José G.; Patel, Sonal; Cuesta, Alberto; Chaves-Pozo, Elena

2015-01-01

Viruses are threatening pathogens for fish aquaculture. Some of them are transmitted through gonad fluids or gametes as occurs with nervous necrosis virus (NNV). In order to be transmitted through the gonad, the virus should colonize and replicate inside some cell types of this tissue and avoid the subsequent immune response locally. However, whether NNV colonizes the gonad, the cell types that are infected, and how the immune response in the gonad is regulated has never been studied. We have demonstrated for the first time the presence and localization of NNV into the testis after an experimental infection in the European sea bass (Dicentrarchus labrax), and in the gilthead seabream (Sparus aurata), a very susceptible and an asymptomatic host fish species, respectively. Thus, we localized in the testis viral RNA in both species using in situ PCR and viral proteins in gilthead seabream by immunohistochemistry, suggesting that males might also transmit the virus. In addition, we were able to isolate infective particles from the testis of both species demonstrating that NNV colonizes and replicates into the testis of both species. Blood contamination of the tissues sampled was discarded by completely fish bleeding, furthermore the in situ PCR and immunocytochemistry techniques never showed staining in blood vessels or cells. Moreover, we also determined how the immune and reproductive functions are affected comparing the effects in the testis with those found in the brain, the main target tissue of the virus. Interestingly, NNV triggered the immune response in the European sea bass but not in the gilthead seabream testis. Regarding reproductive functions, NNV infection alters 17β-estradiol and 11-ketotestosterone production and the potential sensitivity of brain and testis to these hormones, whereas there is no disruption of testicular functions according to several reproductive parameters. Moreover, we have also studied the NNV infection of the testis in vitro to assess local responses. Our in vitro results show that the changes observed on the expression of immune and reproductive genes in the testis of both species are different to those observed upon in vivo infections in most of the cases. PMID:26691348

Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator.

PubMed

Lin, Chia-Wen; Chen, Chiung-Ya; Cheng, Sin-Jhong; Hu, Hsiao-Tang; Hsueh, Yi-Ping

2014-01-01

Innate immune responses have been shown to influence brain development and function. Dysregulation of innate immunity is significantly associated with psychiatric disorders such as autism spectrum disorders and schizophrenia, which are well-known neurodevelopmental disorders. Recent studies have revealed that critical players of the innate immune response are expressed in neuronal tissues and regulate neuronal function and activity. For example, Sarm1, a negative regulator that acts downstream of Toll-like receptor (TLR) 3 and 4, is predominantly expressed in neurons. We have previously shown that Sarm1 regulates neuronal morphogenesis and the expression of inflammatory cytokines in the brain, which then affects learning ability, cognitive flexibility, and social interaction. Because impaired neuronal morphogenesis and dysregulation of cytokine expression may disrupt neuronal activity, we investigated whether Sarm1 knockdown affects the synaptic responses of neurons. We here show that reduced Sarm1 expression impairs metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) formation but enhances N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation production in hippocampal CA1 neurons. The expression levels of post-synaptic proteins, including NR2a, NR1, Shank1 and Shank3, are also altered in Sarm1 knockdown mice, suggesting a role for Sarm1 in the maintenance of synaptic homeostasis. The addition of a positive allosteric modulator of mGluR5, CDPPB, ameliorates the LTD defects in slice recording and the behavioral deficits in social interaction and associative memory. These results suggest an important role for mGluR5 signaling in the function of Sarm1. In conclusion, our study demonstrates a role for Sarm1 in the regulation of synaptic plasticity. Through these mechanisms, Sarm1 knockdown results in the impairment of associative memory and social interactions in mice.

Argemone oil, an edible oil adulterant, induces systemic immunosuppression in Balb/c mice in an oral 28 days repeated dose toxicity study.

PubMed

Mandal, Payal; Tewari, Prachi; Kumar, Sachin; Yadav, Sarika; Ayanur, Anjaneya; Chaturvedi, Rajnish K; Das, Mukul; Tripathi, Anurag

2018-05-01

Consumption of edible oils contaminated with Argemone oil (AO) leads to a clinical condition called "Epidemic dropsy". Earlier studies have reported that metabolism and oxidative stress primarily contributes to AO toxicity, however, the involvement of immune system has not been assessed so far. Therefore, the present study was undertaken to systematically assess the effect of AO exposure on the function of immune system in Balb/c mice. The repeated exposure of AO for 28 days caused prominent regression of spleen and thymus; severe inflammatory changes in spleen depicted by the loss of distinct follicles, increased megakaryocyte infiltration, and enhanced expression levels of inflammatory markers (iNOS & COX-2). At the functional level, AO exposure significantly abrogated the mixed lymphocyte reaction and mitogen-stimulated lymphoproliferative activity of T and B cells, which is reflective of profound lymphocyte dysfunction upon antigen exposure. In concordance with the loss in functional activity of lymphocytes in AO exposed animals, it was found the AO altered the relative percentage of CD3 + , CD4 + , and CD28  +  T cells. Further, there was a marked decrease in the relative distribution of cells with prominent MHC I and CD1d expression in AO exposed splenocytes. Moreover, reduced levels of immune stimulatory cytokines (TNF-α, IFN-γ, IL-2, IL-4, and IL-6), and increased levels of immunosuppressive cytokine IL-10 were detected in the serum of AO treated mice. Along with T and B cells, AO exposure also affected the phenotype and activation status of macrophages suggesting the inclination towards "alternative activation of macrophages". Altogether, these functional changes in the immune cells are contributing factors in AO induced immunosuppression. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of zinc-fortified drinking skim milk (as functional food) on cytokine release and thymic hormone activity in very old persons: a pilot study.

PubMed

Costarelli, Laura; Giacconi, Robertina; Malavolta, Marco; Basso, Andrea; Piacenza, Francesco; DeMartiis, MariLuisa; Giannandrea, Elvio; Renieri, Carlo; Busco, Franco; Galeazzi, Roberta; Mocchegiani, Eugenio

2014-06-01

Zinc is a relevant nutritional factor for the whole life of an organism because it affects the inflammatory/immune response and antioxidant activity, leading to a healthy state. Despite its important function, the dietary intake of zinc is inadequate in elderly. Possible interventions include food fortification because it does not require changes in dietary patterns, the cost is low and it can reach a large portion of the elderly population, including very old subjects. Studies evaluating the impact of Zn-fortified foods on functional parameters in elderly, in particular, in very old individuals, are missing. The objective of this study was to evaluate the efficacy of consumption of a zinc-fortified drinking skim milk (Zn-FMilk) for a period of 2 months in comparison to standard non-fortified milk (No-FMilk) on some biochemical parameters, zinc status, inflammatory/immune response and on a key parameter of the T cell-mediated immunity (thymulin hormone) in healthy very old subjects. The treatment with zinc-fortified milk (Zn-FMilk) is a good omen to increase the cell-mediated immunity in very old age represented by thymulin activity and some cytokine (IL-12p70, IFN-γ) release. At clinical level, a good healthy state occurs in 70 % of the subjects with no hospitalization after 1 year of the follow-up in comparison to very old control subjects that did not participate to crossover design. In conclusion, the Zn-FMilk can be considered a good functional food for elderly, including older people. It might be a good replacement to the zinc tablets or lozenges taking into account the attitude of old people to uptake milk as a preferential food.

Effects of thyroid cystectomy for primary hyperparathyroidism on immune function.

PubMed

Yin, Xiangdang; Hu, Liang; Wang, Xiaochun

2016-01-01

To evaluate the effects of thyroid cystectomy for primary hyperparathyroidism on immune function. Ninety-two patients with parathyroid cysts complicated with primary hyperparathyroidism were randomly divided into a treatment group and a control group (n=46). The treatment group received endoscopic thyroidectomy through the anterior chest wall via the areolar approach, and the control group was treated with conventional open thyroidectomy. The two groups had similar immune function indices as well as thyroid hormone, serum calcium and phosphorus levels before surgery (P>0.05). After surgery, FT3 and FT4 levels significantly increased in both groups, whereas that of TSH significantly decreased (P<0.05). The levels of the two groups differed significantly on the postoperative 5th day (P<0.05). NK%, CD3+%, CD4+% and CD8+%, which significantly fluctuated on the postoperative 1st day in both groups (P<0.05), were basically recovered on the postoperative 5th day in the treatment group that had significantly different outcomes from those of the control group (P<0.05). On the postoperative 1st and 5th days, the treatment group had significantly lower serum calcium level and significantly higher serum phosphorus level than those of the control group (P<0.05). The surgeries were successfully performed for all patients. During three months of follow-up, the treatment group was significantly less prone to complications such as surgical site infection, recurrent laryngeal nerve injury, parathyroid crisis and hoarseness than the control group (P<0.05). For treatment of primary hyperparathyroidism, endoscopic thyroidectomy through the anterior chest wall via the areolar approach decreased the incidence rate of complications, as well as promoted the recovery of serum calcium and phosphorous levels, probably by only mildly affecting immune function and thyroid hormone levels.

A Modified Surface Killing Assay (MSKA) as a Functional in vitro Assay for Identifying Protective Antibodies Against Pneumococcal Surface Protein A (PspA)

PubMed Central

Genschmer, Kristopher R.; Accavitti-Loper, Mary Ann; Briles, David E.

2013-01-01

Streptococcus pneumoniae causes otitis media, meningitis and pneumonia in patients worldwide; predominantly affecting young children, the elderly, and the immune compromised. Current vaccines against invasive pneumococcal disease are based on the polysaccharide capsules of the most clinically relevant serotypes. Due to serotype replacement, non-vaccine serotypes of S. pneumoniae have become more clinically relevant and as a result pneumococcal vaccines are becoming increasingly complex. These events emphasize the need to evaluate the potential for pneumococcal cross-reactive proteins to contribute to future vaccines. Antibody elicited by the immunization of humans with pneumococcal surface protein A (PspA) can passively protect mice from infection. However, robust in vitro functional assays for antibody to PspA are not available to predict the protective capacity of immune serum. For polysaccharide based vaccines, a standardized opsonophagocytosis killing assay (OPKA) is used. Antibody to PspA, however, does not work well in the standard OPKA. The present studies take advantage of past observations that phagocytosis is more efficient on tissue surfaces than in solution. In a modified surface killing assay (MSKA), monoclonal antibody to PspA, in the presence of complement, opsonized pneumococci for killing by phagocytes on an agar surface. Five monoclonal antibodies to PspA were tested; three demonstrated increased amounts of killing compared to the diluent control and protected mice by passive protection against type 3 pneumococci. The two antibodies that were not functional in the MSKA also failed to protect mice. Thus, an MSKA might be useful as a functional assay for immunity to PspA. PMID:24211169

Risk factors for incomplete immunization in children with HIV infection.

PubMed

Bhattacharya, Sangeeta Das; Bhattacharyya, Subhasish; Chatterjee, Devlina; Niyogi, Swapan Kumar; Chauhan, Nageshwar; Sudar, A

2014-09-01

To document the immunization rates, factors associated with incomplete immunization, and missed opportunities for immunizations in children affected by HIV presenting for routine outpatient follow-up. A cross-sectional study of immunization status of children affected by HIV presenting for routine outpatient care was conducted. Two hundred and six HIV affected children were enrolled. The median age of children in this cohort was 6 y. One hundred ninety seven of 206 children were HIV infected, nine were HIV exposed, but indeterminate. Fifty (25 %) children had incomplete immunizations per the Universal Immunization Program (UIP) of India. Hundred percent of children had received OPV. Ninety three percent of children got their UIP vaccines from a government clinic. Children with incomplete immunization were older, median age of 8 compared to 5 (p = 0.003). Each year of maternal education increased the odds of having a child with complete UIP immunizations by 1.18 (p = 0.008)-children of mothers with 6 y of education compared to those with no education were seven times more likely to have complete UIP vaccine status. The average number of visits to the clinic by an individual child in a year was 4. This represents 200 missed opportunities for immunizations. HIV infected children are at risk for incomplete immunization coverage though they regularly access medical care. Including routine immunizations, particularly catch-up immunizations in programs for HIV infected children maybe an effective way of protecting these children from vaccine preventable disease.

Ovarian function and reproductive outcomes of female patients with systemic lupus erythematosus and the strategies to preserve their fertility.

PubMed

Oktem, Ozgur; Guzel, Yılmaz; Aksoy, Senai; Aydin, Elvin; Urman, Bulent

2015-03-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune systemic disease that mainly affects women of reproductive age. Emerging data from recent molecular studies show us that estrogen hormone plays a central role in the development of this disease. By acting via its cognate receptors ERα and ERβ expressed on immune cells, estrogen can modulate immune function in both the innate and adaptive immune responses. Interestingly, estrogen may also evoke autoimmune responses after binding to B lymphocytes leading to the generation of high-affinity autoantibodies and proinflammatory cytokines (so-called estrogen-induced autoimmunity). Unfortunately, reproductive function of young female patients with this disease is commonly compromised by different pathophysiologic processes. First, ovarian reserve is diminished even in the presence of mild disease suggesting a direct impact of the disease itself on ovarian function possibly due to ovarian involvement in the form of autoimmune oophoritis. Second, SLE patients with severe manifestations of the disease are treated with alkylating chemotherapy agent cyclophosphamide. Cyclophosphamide and other drugs of alkylating category have the highest gonadotoxicity. Therefore, SLE patients exposed to cyclophosphamide have a much higher risk of developing infertility and premature ovarian failure than do the counterparts who are treated with other less toxic treatments. Third, the functions of the hypothalamic pituitary ovarian axis are perturbed by chronic inflammatory state. And finally adverse pregnancy outcomes are more commonly observed in SLE patients such as fetal loss, preterm birth, intrauterine fetal growth restriction, preeclampsia-eclampsia, and fetal congenital heart block. We aimed in this review article to provide the readers an update on how estrogen hormone closely interacts with and induces lupus-prone changes in the immune system. We also discuss ovarian function and other reproductive outcomes in SLE patients and the current strategies to preserve their fertility in the light of the most recent evidence-based findings of the clinical trials and molecular studies.

Microanatomy of the intestinal lymphatic system

PubMed Central

Miller, Mark J.; Newberry, Rodney D.

2011-01-01

The intestinal lymphatic system is comprised of two non-communicating lymphatic networks; one containing the lacteals draining the villi and the connecting submucosal lymphatic network, and one containing the lymphatics that drain the intestine muscular layer. These systems deliver lymph into a common network of collecting lymphatics originating near the mesenteric border. The intestinal lymphatic system serves vital functions in the regulation of tissue fluid homeostasis, immune surveillance, and the transport of nutrients, and conversely this system is affected by, and directly contributes to, disease processes within the intestine. Recent discoveries of specific lymphatic markers, factors promoting lymphangiogenesis, and factors selectively affecting the development of intestinal lymphatics hold promise for unlocking the role of lymphatics in the pathogenesis of diseases affecting the intestine and for intestinal lymphatic selective therapies. Vital to progress in understanding how the intestinal lymphatic system functions is integrating of recent advances identifying molecular pathways for lymphatic growth and remodeling with advanced imaging modalities to observe lymphatic function and dysfunction in vivo. PMID:20961303

Current and Novel Therapeutic Options for Irritable Bowel Syndrome Management

PubMed Central

Camilleri, Michael; Andresen, Viola

2009-01-01

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting up to 3-15% of the general population in western countries. It is characterized by unexplained abdominal pain, discomfort, and bloating in association with altered bowel habits. The pathophysiology of IBS is multifactorial involving disturbances of the brain-gut-axis. The pathophysiology provides the rationale for pharmacotherapy: abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction, and mucosal immune activation. Understanding the mechanisms, and their mediators or modulators including neurotransmitters and receptors have led to several therapeutic approaches including agents acting on the serotonin receptor or serotonin transporter system, antidepressants, novel selective anticholinergics, α-adrenergic agonists, opioid agents, cholecystokinin-antagonists, neurokinin-antagonists, somatostatin receptor agonists, corticotropin releasing factor antagonists, chloride-channel activators, guanylate-cyclase-c agonists, melatonin, atypical benzodiazepines, antibiotics, immune modulators and probiotics. The mechanisms and current evidence regarding efficacy of these agents are reviewed. PMID:19665953

Costs of immune responses are related to host body size and lifespan

DOE PAGES

Brace, Amber J.; Lajeunesse, Marc J.; Ardia, Daniel R.; ...

2017-06-01

A central assumption in ecological immunology is that immune responses are costly, with costs manifesting directly (e.g., increases in metabolic rate and increased amino acid usage) or as tradeoffs with other life processes (e.g., reduced growth and reproductive success). Across taxa, host longevity, timing of maturity, and reproductive effort affect the organization of immune systems. It is reasonable, therefore, to expect that these and related factors should also affect immune activation costs. Specifically, species that spread their breeding efforts over a long lifetime should experience lower immune costs than those that mature and breed quickly and die comparatively early. Likewise,more » body mass should affect immune costs, as body size affects the extent to which hosts are exposed to parasites as well as how hosts can combat infections (via its effects on metabolic rates and other factors). Here in this paper, we used phylogenetic meta-regression to reveal that, in general, animals incur costs of immune activation, but small species that are relatively long-lived incur the largest costs. These patterns probably arise because of the relative need for defense when infection risk is comparatively high and fitness can only be realized over a comparatively long period. However, given the diversity of species considered here and the overall modest effects of body mass and life history on immune costs, much more research is necessary before generalizations are appropriate.« less

Costs of immune responses are related to host body size and lifespan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brace, Amber J.; Lajeunesse, Marc J.; Ardia, Daniel R.

A central assumption in ecological immunology is that immune responses are costly, with costs manifesting directly (e.g., increases in metabolic rate and increased amino acid usage) or as tradeoffs with other life processes (e.g., reduced growth and reproductive success). Across taxa, host longevity, timing of maturity, and reproductive effort affect the organization of immune systems. It is reasonable, therefore, to expect that these and related factors should also affect immune activation costs. Specifically, species that spread their breeding efforts over a long lifetime should experience lower immune costs than those that mature and breed quickly and die comparatively early. Likewise,more » body mass should affect immune costs, as body size affects the extent to which hosts are exposed to parasites as well as how hosts can combat infections (via its effects on metabolic rates and other factors). Here in this paper, we used phylogenetic meta-regression to reveal that, in general, animals incur costs of immune activation, but small species that are relatively long-lived incur the largest costs. These patterns probably arise because of the relative need for defense when infection risk is comparatively high and fitness can only be realized over a comparatively long period. However, given the diversity of species considered here and the overall modest effects of body mass and life history on immune costs, much more research is necessary before generalizations are appropriate.« less

Molecular and clinical characterization of IDH associated immune signature in lower-grade gliomas.

PubMed

Qian, Zenghui; Li, Yiming; Fan, Xing; Zhang, Chuanbao; Wang, Yinyan; Jiang, Tao; Liu, Xing

2018-01-01

Background : Mutations in isocitrate dehydrogenase (IDH) affect the development and prognosis of gliomas. We investigated the role of IDH mutations in the regulation of immune phenotype in lower-grade gliomas (LGGs). Method and patients : A total of 1,008 cases with clinical and IDH mutation data from five cohorts were enrolled. Samples with RNA sequencing data from the Chinese Glioma Genome Atlas (CGGA) were used as training set, whereas RNA data from the Cancer Genome Atlas, Repository for Molecular Brain Neoplasia, GSE16011, and CGGA microarray databases were used for validation. R language tools and bioinformatics analysis were used for gene signature construction and biological function annotation. Results : We found that IDH mutations caused down-regulation of local immune response as among 332 immune system-related genes, 196(59.0%) were differentially expressed according to IDH mutation status. Nearly 70% of those differentially expressed genes exhibited prognostic value in LGGs. An immune response-based gene signature was constructed that distinguished cases with high- or low-risk of unfavorable prognosis and remained an independent prognostic factor in multivariate analyses in both training and validation cohorts. Samples from high-risk cases exhibited elevated expression of genes involved in immune response and NF-κB pathway activation. Furthermore, we found a strong correlation between the risk score and T cells, macrophage-related immune response, and expression of several prominent immune checkpoints. Conclusion : Our results indicated that mutant IDH is highly associated with the regulation of the immune microenvironment in LGGs. The observed immune system gene signature, which was sensitive to IDH mutation status, efficiently predicted patient survival.

Gut Microbiota as a Target for Preventive and Therapeutic Intervention against Food Allergy.

PubMed

Aitoro, Rosita; Paparo, Lorella; Amoroso, Antonio; Di Costanzo, Margherita; Cosenza, Linda; Granata, Viviana; Di Scala, Carmen; Nocerino, Rita; Trinchese, Giovanna; Montella, Mariangela; Ercolini, Danilo; Berni Canani, Roberto

2017-06-28

The gut microbiota plays a pivotal role in immune system development and function. Modification in the gut microbiota composition (dysbiosis) early in life is a critical factor affecting the development of food allergy. Many environmental factors including caesarean delivery, lack of breast milk, drugs, antiseptic agents, and a low-fiber/high-fat diet can induce gut microbiota dysbiosis, and have been associated with the occurrence of food allergy. New technologies and experimental tools have provided information regarding the importance of select bacteria on immune tolerance mechanisms. Short-chain fatty acids are crucial metabolic products of gut microbiota responsible for many protective effects against food allergy. These compounds are involved in epigenetic regulation of the immune system. These evidences provide a foundation for developing innovative strategies to prevent and treat food allergy. Here, we present an overview on the potential role of gut microbiota as the target of intervention against food allergy.

Apoptosis-induced lymphopenia in sepsis and other severe injuries.

PubMed

Girardot, Thibaut; Rimmelé, Thomas; Venet, Fabienne; Monneret, Guillaume

2017-02-01

Sepsis and other acute injuries such as severe trauma, extensive burns, or major surgeries, are usually followed by a period of marked immunosuppression. In particular, while lymphocytes play a pivotal role in immune response, their functions and numbers are profoundly altered after severe injuries. Apoptosis plays a central role in this process by affecting immune response at various levels. Indeed, apoptosis-induced lymphopenia duration and depth have been associated with higher risk of infection and mortality in various clinical settings. Therapies modulating apoptosis represent an interesting approach to restore immune competence after acute injury, although their use in clinical practice still presents several limitations. After briefly describing the apoptosis process in physiology and during severe injuries, we will explore the immunological consequences of injury-induced lymphocyte apoptosis, and describe associations with clinically relevant outcomes in patients. Therapeutic perspectives targeting apoptosis will also be discussed.

Affect of Early Life Oxygen Exposure on Proper Lung Development and Response to Respiratory Viral Infections

PubMed Central

Domm, William; Misra, Ravi S.; O’Reilly, Michael A.

2015-01-01

Children born preterm often exhibit reduced lung function and increased severity of response to respiratory viruses, suggesting that premature birth has compromised proper development of the respiratory epithelium and innate immune defenses. Increasing evidence suggests that premature birth promotes aberrant lung development likely due to the neonatal oxygen transition occurring before pulmonary development has matured. Given that preterm infants are born at a point of time where their immune system is also still developing, early life oxygen exposure may also be disrupting proper development of innate immunity. Here, we review current literature in hopes of stimulating research that enhances understanding of how the oxygen environment at birth influences lung development and host defense. This knowledge may help identify those children at risk for disease and ideally culminate in the development of novel therapies that improve their health. PMID:26322310

The ecology of immune state in a wild mammal, Mus musculus domesticus.

PubMed

Abolins, Stephen; Lazarou, Luke; Weldon, Laura; Hughes, Louise; King, Elizabeth C; Drescher, Paul; Pocock, Michael J O; Hafalla, Julius C R; Riley, Eleanor M; Viney, Mark

2018-04-01

The immune state of wild animals is largely unknown. Knowing this and what affects it is important in understanding how infection and disease affects wild animals. The immune state of wild animals is also important in understanding the biology of their pathogens, which is directly relevant to explaining pathogen spillover among species, including to humans. The paucity of knowledge about wild animals' immune state is in stark contrast to our exquisitely detailed understanding of the immunobiology of laboratory animals. Making an immune response is costly, and many factors (such as age, sex, infection status, and body condition) have individually been shown to constrain or promote immune responses. But, whether or not these factors affect immune responses and immune state in wild animals, their relative importance, and how they interact (or do not) are unknown. Here, we have investigated the immune ecology of wild house mice-the same species as the laboratory mouse-as an example of a wild mammal, characterising their adaptive humoral, adaptive cellular, and innate immune state. Firstly, we show how immune variation is structured among mouse populations, finding that there can be extensive immune discordance among neighbouring populations. Secondly, we identify the principal factors that underlie the immunological differences among mice, showing that body condition promotes and age constrains individuals' immune state, while factors such as microparasite infection and season are comparatively unimportant. By applying a multifactorial analysis to an immune system-wide analysis, our results bring a new and unified understanding of the immunobiology of a wild mammal.

A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme

PubMed Central

Galore-Haskel, Gilli; Nemlich, Yael; Greenberg, Eyal; Ashkenazi, Shira; Hakim, Motti; Itzhaki, Orit; Shoshani, Noa; Shapira-Fromer, Ronnie; Ben-Ami, Eytan; Ofek, Efrat; Anafi, Liat; Besser, Michal J.

2015-01-01

The blossom of immunotherapy in melanoma highlights the need to delineate mechanisms of immune resistance. Recently, we have demonstrated that the RNA editing protein, adenosine deaminase acting on RNA-1 (ADAR1) is down-regulated during metastatic transition of melanoma, which enhances melanoma cell proliferation and tumorigenicity. Here we investigate the role of ADAR1 in melanoma immune resistance. Importantly, knockdown of ADAR1 in human melanoma cells induces resistance to tumor infiltrating lymphocytes in a cell contact-dependent mechanism. We show that ADAR1, in an editing-independent manner, regulates the biogenesis of miR-222 at the transcription level and thereby Intercellular Adhesion Molecule 1 (ICAM1) expression, which consequently affects melanoma immune resistance. ADAR1 thus has a novel, pivotal, role in cancer immune resistance. Corroborating with these results, the expression of miR-222 in melanoma tissue specimens was significantly higher in patients who had no clinical benefit from treatment with ipilimumab as compared to patients that responded clinically, suggesting that miR-222 could function as a biomarker for the prediction of response to ipilimumab. These results provide not only novel insights on melanoma immune resistance, but also pave the way to the development of innovative personalized tools to enable optimal drug selection and treatment. PMID:26338962

Insect parents improve the anti-parasitic and anti-bacterial defence of their offspring by priming the expression of immune-relevant genes.

PubMed

Trauer-Kizilelma, Ute; Hilker, Monika

2015-09-01

Insect parents that experienced an immune challenge are known to prepare (prime) the immune activity of their offspring for improved defence. This phenomenon has intensively been studied by analysing especially immunity-related proteins. However, it is unknown how transgenerational immune priming affects transcript levels of immune-relevant genes of the offspring upon an actual threat. Here, we investigated how an immune challenge of Manduca sexta parents affects the expression of immune-related genes in their eggs that are attacked by parasitoids. Furthermore, we addressed the question whether the transgenerational immune priming of expression of genes in the eggs is still traceable in adult offspring. Our study revealed that a parental immune challenge did not affect the expression of immune-related genes in unparasitised eggs. However, immune-related genes in parasitised eggs of immune-challenged parents were upregulated to a higher level than those in parasitised eggs of unchallenged parents. Hence, this transgenerational immune priming of the eggs was detected only "on demand", i.e. upon parasitoid attack. The priming effects were also traceable in adult female progeny of immune-challenged parents which showed higher transcript levels of several immune-related genes in their ovaries than non-primed progeny. Some of the primed genes showed enhanced expression even when the progeny was left unchallenged, whereas other genes were upregulated to a greater extent in primed female progeny than non-primed ones only when the progeny itself was immune-challenged. Thus, the detection of transgenerational immune priming strongly depends on the analysed genes and the presence or absence of an actual threat for the offspring. We suggest that M. sexta eggs laid by immune-challenged parents "afford" to upregulate the transcription of immunity-related genes only upon attack, because they have the chance to be endowed by parentally directly transferred protective proteins. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model.

PubMed

Zhang, Baihao; Chikuma, Shunsuke; Hori, Shohei; Fagarasan, Sidonia; Honjo, Tasuku

2016-07-26

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3(+) Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis.

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans.

PubMed

Cuesta, Marc; Boudreau, Philippe; Dubeau-Laramée, Geneviève; Cermakian, Nicolas; Boivin, Diane B

2016-03-15

Recent research unveiled a circadian regulation of the immune system in rodents, yet little is known about rhythms of immune functions in humans and how they are affected by circadian disruption. In this study, we assessed rhythms of cytokine secretion by immune cells and tested their response to simulated night shifts. PBMCs were collected from nine participants kept in constant posture over 24 h under a day-oriented schedule (baseline) and after 3 d under a night-oriented schedule. Monocytes and T lymphocytes were stimulated with LPS and PHA, respectively. At baseline, a bimodal rhythmic secretion was detected for IL-1β, IL-6, and TNF-α: a night peak was primarily due to a higher responsiveness of monocytes, and a day peak was partly due to a higher proportion of monocytes. A rhythmic release was also observed for IL-2 and IFN-γ, with a nighttime peak due to a higher cell count and responsiveness of T lymphocytes. Following night shifts, with the exception of IL-2, cytokine secretion was still rhythmic but with peak levels phase advanced by 4.5-6 h, whereas the rhythm in monocyte and T lymphocyte numbers was not shifted. This suggests distinct mechanisms of regulation between responsiveness to stimuli and cell numbers of the human immune system. Under a night-oriented schedule, only cytokine release was partly shifted in response to the change in the sleep-wake cycle. This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers. Copyright © 2016 by The American Association of Immunologists, Inc.

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

PubMed Central

Zhang, Baihao; Chikuma, Shunsuke; Hori, Shohei; Fagarasan, Sidonia; Honjo, Tasuku

2016-01-01

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3+ Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1–deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis. PMID:27410049

Development and evaluation of the mallard duck as a model to investigate the immunotoxicity of environmental chemicals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowles, J.R.

Studies were conducted to characterize the mallard duck (Anas platyrhyncos) as a model for evaluating the immunotoxic effects of environmental chemicals. A battery of immunotoxicity tests was validated for the mallard, including natural killer cell (NKC) activity, lymphocyte mitogenesis, antibody titers to sheep erythrocytes, peripheral differential leukocyte counts, macrophage phagocytosis and prostaglandin-E[sub 2] (PGE2) production. To investigate potential hormonal-immune axes, dexamethasone (DEX), methimazole, and thyroxine (T4) were used to study the influence of glucocorticoid excess, hypo-, and hyperthyroidism on immunity, respectively. Subsequently, the effects of polychlorinated biphenyls (PCBs, Aroclor 1254) on immune, endocrine, and hepatic cytochrome-P450 function were evaluated andmore » interpreted using results from the endocrine/immune studies. Results of these studies showed that antibody production was susceptible to suppression by DEX at doses which also caused significant changes in clinical plasma biochemistry values. NKC activity was enhanced by exposure to DEX in vivo, a phenomenon due to the inhibition of PGE2 production by adherent peripheral blood cells by DEX and mimicked in vitro with addition of indomethacin or DEX. Macrophage phagocytosis was significantly suppressed by DEX in vitro. Macrophage production of PGE2 ex vivo was suppressed in birds treated with DEX. In contrast to DEX, T4 or methimazole treatment elicited only slight physiologic changes in plasma albumin and cholesterol levels. No immune/thyroid axis was observed in mallards. Exposure to Aroclor 1254 induced significant hepatic microsomal ethoxy- and pentoxy-resorufin-O-deethylase activities in addition to increasing total cytochrome P450 content, but did not affect immune function, plasma corticosterone, or clinical biochemistry values. Total triiodothyronine, but not T4, was dose-dependently suppressed by PCB treatment.« less

Cell-Mediated Immune Function and Cytokine Regulation During Space Flight

NASA Technical Reports Server (NTRS)

Sams, Clarence F.; Pierson, Duane L.; Paloski, W. H. (Technical Monitor)

2000-01-01

The changes in immune function which occur during space flight potentially expose the crews to an increased risk for development of illness. Decreased cellular immune function has been repeatedly documented after space flight and confirmed during flight by in vivo delayed-type hypersensitivity testing. However, correlation of immune changes with a clinically significant risk factor has not yet been performed. Our hypothesis is that space flight induces a decrease in cell-mediated immune function accompanied by a shift from a type 1 cytokine pattern (favoring cell-mediated immunity) to a type 2 cytokine pattern (favoring humoral immunity). We further hypothesize that reactivation of latent viruses will occur during space flight in association with the decreased cellular immunity. To test these hypotheses, we will determine the effects of space flight on cell-mediated immunity and viral reactivation. We will utilize delayed-type hypersensitivity testing as an in vivo measure of integrated cell-mediated immune function. The production of cytokines and immunoregulatory factors by lymphocytes and monocytes will be measured to determine whether changes in cytokine patterns are associated with the space flight-induced immune dysregulation. Correlation of antigen-specific immune changes with reactivation of latent herpes viruses will be determined by measuring peripheral levels of viral (CMV, VZV, EBV) antigen-specific T cells and comparing to the levels of EBV-infected B-cells by fluorescence in situ hybridization and flow cytometry. A comparison of cell-mediated immune function, cytokine regulation and viral reactivation will provide new insights into crew member health risks during flight.

COMPARATIVE STUDY OF TUMORIGENESIS AND TUMOR IMMUNITY IN INVERTEBRATES AND NONMAMMALIAN VERTEBRATES

PubMed Central

Robert, Jacques

2010-01-01

Despite intense study in mammals, the different roles played by the immune system in detecting (immunosurveillance), controlling and remodeling (immunoediting) neoplasia, and perhaps in metastasis are not fully understood. In this review, I will present evidence of neoplasia and invasive malignancy, as well as tumor immunity in invertebrates and nonmammalian vertebrates. I will also present a comparative and evolutionary view of the complex interactions between neoplasia and the host immune system. Overall, I wish to go beyond the too simplistic dichotomy between invertebrates with innate immunity that are only affected with benign neoplasia and vertebrates with adaptive immunity that are affected by metastatic malignancies or cancer. PMID:20553753

Impact of a novel synbiotic supplementation during gestation and lactation on immune responses in the Swiss albino mice offspring.

PubMed

Nallagatla, Himaja; Hemalatha, Rajkumar; Kondapalli, Narendra Babu; Mohammed, Shujauddin

2017-06-01

Prebiotics from various regularly consumed cereals and novel substrates are currently being utilised as functional foods. The aim of this study was to determine the effect of synbiotic, formulated with prebiotic extracted from natural resources like green gram (Vigna radiata) along with probiotic Lactobacillus rhamnosus GG (LGG) in modulating immune responses in the offspring when supplemented during gestation and lactation. Synbiotic supplementation was effective in improving cell mediated immunity and humoral immunity among F0 dams. Among F1 pups (F1 Syn + and F1 Syn-), synbiotic supplementation showed significantly heightened (P < 0.05) splenocyte proliferation, increased interleukin-10, interferon gamma and interleukin-17 responses, leucocyte phagocytic ability and increased secretory-immunoglobulin A. However, four-fold increase in IgG titres to Hepatitis-B vaccine was observed only in those mice that were supplemented with synbiotic postweaning (F1 Syn+). Synbiotic supplementation to pregnant dams affected the offspring's cellular and mucosal immunity favorably. However, IgG response to Hepatitis-B vaccine was influenced positively only when the supplementation was extended to the offsprings in the post weaning period. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Humoral Immune Response against Neural Antigens and Its Effects on Cognition in Lung Cancer Patients.

PubMed

Rybacka-Mossakowska, J; Ramlau, R; Gazdulska, J; Gołda-Gocka, I; Kozubski, W; Michalak, S

2016-01-01

Cognitive impairment develops as a clinical manifestation of immune-mediated indirect effects of malignancy in lung cancer patients. This study aimed to evaluate the effects of humoral immune response on cognition in lung cancer patients. Fifty-one lung cancer patients were subjected to neurological examination: Mini Mental State Examination (MMSE), Trail Making Test (TMT), and Hamilton scale. The Psychology Experiment Building Language software was used for the evaluation of digit span, simple reaction time (SRT), and choice reaction time (CRT) tests. Serum samples were tested for the presence of onconeuronal antibodies and antineural antibodies. The results demonstrate that autoantibodies were found in 31 % patients. MMSE scores were lower (26.7 ± 2.7) in seropositive patients than in seronegative subjects (28.7 ± 1.2; p = 0.013). Executive functions were also influenced by the presence of autoantibodies. The humoral immune response in lung cancer patients affected both SRT and CRT. We conclude that the humoral immune response in lung cancer patients is associated with cognitive impairment. Cognitive impairment is associated with both specific reactions against onconeuronal or antineural antigens and non-organ specific reactions against nucleosome antigens.

Will Global Climate Change Alter Fundamental Human Immune Reactivity: Implications for Child Health?

PubMed

Swaminathan, Ashwin; Lucas, Robyn M; Harley, David; McMichael, Anthony J

2014-11-11

The human immune system is an interface across which many climate change sensitive exposures can affect health outcomes. Gaining an understanding of the range of potential effects that climate change could have on immune function will be of considerable importance, particularly for child health, but has, as yet, received minimal research attention. We postulate several mechanisms whereby climate change sensitive exposures and conditions will subtly impair aspects of the human immune response, thereby altering the distribution of vulnerability within populations-particularly for children-to infection and disease. Key climate change-sensitive pathways include under-nutrition, psychological stress and exposure to ambient ultraviolet radiation, with effects on susceptibility to infection, allergy and autoimmune diseases. Other climate change sensitive exposures may also be important and interact, either additively or synergistically, to alter health risks. Conducting directed research in this area is imperative as the potential public health implications of climate change-induced weakening of the immune system at both individual and population levels are profound. This is particularly relevant for the already vulnerable children of the developing world, who will bear a disproportionate burden of future adverse environmental and geopolitical consequences of climate change.

Kidney transplantation: a systematic review of interventional and observational studies of physical activity on intermediate outcomes.

PubMed

Macdonald, Jamie Hugo; Kirkman, Danielle; Jibani, Mahdi

2009-11-01

Kidney transplant patients have decreased quality and longevity of life. Whether exercise can positively affect associated outcomes such as physical functioning, metabolic syndrome, kidney function, and immune function, has only been addressed in relatively small studies. Thus the aim of this systematic review was to determine effects of physical activity level on these intermediate outcomes in kidney transplant patients. We electronically and hand searched to identify 21 studies (6 retrospective assessments of habitual physical activity and 15 intervention studies including 6 controlled trials). After study quality assessment, intermediate outcomes associated with quality and longevity of life were expressed as correlations or percentage changes in addition to effect sizes. Habitual physical activity level was positively associated with quality of life and aerobic fitness and negatively associated with body fat (medium to large effect sizes). Exercise interventions also showed medium to large positive effects on aerobic capacity (10%-114% increase) and muscle strength (10%-22% increase). However, exercise programs had minimal or contradictory effects on metabolic syndrome and immune and kidney function. In kidney transplant patients, physical activity intervention is warranted to enhance physical functioning. Whether exercise impacts on outcomes associated with longevity of life requires further study.

Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions

PubMed Central

Boor, P P C; Metselaar, H J; Mancham, S; van der Laan, L J W; Kwekkeboom, J

2013-01-01

Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (Treg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (−64%) but TLR-9-induced IFN-α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4+forkhead box protein 3 (FoxP3)+ regulatory T cells, but did not affect the generation of suppressive CD8+CD38+lymphocyte activation gene (LAG)-3+ Treg. In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4+ T cell proliferation and induce CD4+FoxP3+ regulatory T cell generation. PMID:23968562

A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome

PubMed Central

Broderick, Gordon; Fuite, Jim; Kreitz, Andrea; Vernon, Suzanne D; Klimas, Nancy; Fletcher, Mary Ann

2010-01-01

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard preprogrammed responses. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group. These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components. These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LTα stimulus. These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key subnetworks such as IL-2:IFNγ:TNFα that might be targeted in restoring normal immune function. PMID:20447453

Coping strategies and immune neglect in affective forecasting: Direct evidence and key moderators

PubMed Central

Hoerger, Michael

2012-01-01

Affective forecasting skills have important implications for decision making. However, recent research suggests that immune neglect – the tendency to overlook coping strategies that reduce future distress – may lead to affective forecasting problems. Prior evidence for immune neglect has been indirect. More direct evidence and a deeper understanding of immune neglect are vital to informing the design of future decision-support interventions. In the current study, young adults (N = 325) supplied predicted, actual, and recollected reactions to an emotionally-evocative interpersonal event, Valentine’s Day. Based on participants’ qualitative descriptions of the holiday, a team of raters reliably coded the effectiveness of their coping strategies. Supporting the immune neglect hypothesis, participants overlooked the powerful role of coping strategies when predicting their emotional reactions. Immune neglect was present not only for those experiencing the holiday negatively (non-daters) but also for those experiencing it positively (daters), suggesting that the bias may be more robust than originally theorized. Immune neglect was greater for immediate emotional reactions than more enduring reactions. Further, immune neglect was conspicuously absent from recollected emotional reactions. Implications for decision-support interventions are discussed. PMID:22375161

Dietary selenium in adjuvant therapy of viral and bacterial infections.

PubMed

Steinbrenner, Holger; Al-Quraishy, Saleh; Dkhil, Mohamed A; Wunderlich, Frank; Sies, Helmut

2015-01-01

Viral and bacterial infections are often associated with deficiencies in macronutrients and micronutrients, including the essential trace element selenium. In selenium deficiency, benign strains of Coxsackie and influenza viruses can mutate to highly pathogenic strains. Dietary supplementation to provide adequate or supranutritional selenium supply has been proposed to confer health benefits for patients suffering from some viral diseases, most notably with respect to HIV and influenza A virus (IAV) infections. In addition, selenium-containing multimicronutrient supplements improved several clinical and lifestyle variables in patients coinfected with HIV and Mycobacterium tuberculosis. Selenium status may affect the function of cells of both adaptive and innate immunity. Supranutritional selenium promotes proliferation and favors differentiation of naive CD4-positive T lymphocytes toward T helper 1 cells, thus supporting the acute cellular immune response, whereas excessive activation of the immune system and ensuing host tissue damage are counteracted through directing macrophages toward the M2 phenotype. This review provides an up-to-date overview on selenium in infectious diseases caused by viruses (e.g., HIV, IAV, hepatitis C virus, poliovirus, West Nile virus) and bacteria (e.g., M. tuberculosis, Helicobacter pylori). Data from epidemiologic studies and intervention trials, with selenium alone or in combination with other micronutrients, and animal experiments are discussed against the background of dietary selenium requirements to alter immune functions. © 2015 American Society for Nutrition.

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

PubMed Central

Torres, Juan Manuel; Martinez-Barricarte, Rubén; García-Gómez, Sonia; Mazariegos, Marina S.; Itan, Yuval; Boisson, Bertrand; ρlvarez, Rita; Jiménez-Reinoso, Anaïs; del Pino, Lucia; Rodríguez-Pena, Rebeca; Ferreira, Antonio; Hernández-Jiménez, Enrique; Toledano, Victor; Cubillos-Zapata, Carolina; Díaz-Almirón, Mariana; López-Collazo, Eduardo; Unzueta-Roch, José L.; Sánchez-Ramón, Silvia; Regueiro, Jose R.; López-Granados, Eduardo; Casanova, Jean-Laurent; Pérez de Diego, Rebeca

2014-01-01

Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain–containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient’s myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB–mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects. PMID:25365219

Dietary Selenium in Adjuvant Therapy of Viral and Bacterial Infections12

PubMed Central

Steinbrenner, Holger; Al-Quraishy, Saleh; Dkhil, Mohamed A; Wunderlich, Frank; Sies, Helmut

2015-01-01

Viral and bacterial infections are often associated with deficiencies in macronutrients and micronutrients, including the essential trace element selenium. In selenium deficiency, benign strains of Coxsackie and influenza viruses can mutate to highly pathogenic strains. Dietary supplementation to provide adequate or supranutritional selenium supply has been proposed to confer health benefits for patients suffering from some viral diseases, most notably with respect to HIV and influenza A virus (IAV) infections. In addition, selenium-containing multimicronutrient supplements improved several clinical and lifestyle variables in patients coinfected with HIV and Mycobacterium tuberculosis. Selenium status may affect the function of cells of both adaptive and innate immunity. Supranutritional selenium promotes proliferation and favors differentiation of naive CD4-positive T lymphocytes toward T helper 1 cells, thus supporting the acute cellular immune response, whereas excessive activation of the immune system and ensuing host tissue damage are counteracted through directing macrophages toward the M2 phenotype. This review provides an up-to-date overview on selenium in infectious diseases caused by viruses (e.g., HIV, IAV, hepatitis C virus, poliovirus, West Nile virus) and bacteria (e.g., M. tuberculosis, Helicobacter pylori). Data from epidemiologic studies and intervention trials, with selenium alone or in combination with other micronutrients, and animal experiments are discussed against the background of dietary selenium requirements to alter immune functions. PMID:25593145

CD4+CD25+ Treg derived from hepatocellular carcinoma mice inhibits tumor immunity.

PubMed

Chen, Xin; Du, Yong; Huang, Zhiming

2012-01-01

CD4+CD25+ regulatory T cells (Tregs) play an essential role in the establishment and persistence of tumor immune suppression. Tregs can prevent anti-tumor-specific T cells from clearing the tumor, making Tregs a significant barrier for effective immunotherapy. An increase in the number of Tregs has been detected in the peripheral blood and tumor infiltrating lymphocytes of patients with hepatocellular carcinoma. Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in the initiation of immune responses. The evidence for their ability to act as natural adjuvant in the stimulation of specific anti-tumor cytotoxic T lymphocytes and in the induction of protective and therapeutic anti-tumor immunity is now overwhelming. The aim of our study was to investigate the variation of Tregs in hepatocellular carcinoma mice and how Tregs derived from the tumor mice affect DCs' function. We found that Tregs derived from the tumor mice down-regulated the expression of costimulatory molecules CD80/CD86 on DCs and inhibited the production of TNF-α and IL-12 from DCs. The suppressive function of Tregs was mediated by cell-to-cell contact, CTLA-4 expression and IL-10 secretion. In conclusion, these mechanisms acting in hepatocellular carcinoma may be necessary to better understand the immunosuppression of Tregs and helpful to the tumor immunotherapy. Copyright © 2012 Elsevier B.V. All rights reserved.

Immune Function and Reactivation of Latent Viruses

NASA Technical Reports Server (NTRS)

Butel, Janet S.

1999-01-01

A major concern associated with long-duration space flight is the possibility of infectious diseases posing an unacceptable medical risk to crew members. One major hypothesis addressed in this project is that space flight will cause alterations in the immune system that will allow latent viruses that are endogenous in the human population to reactivate and shed to higher levels than normal, which may affect the health of crew members. The second major hypothesis being examined is that the effects of space flight will alter the mucosal immune system, the first line of defense against many microbial infections, including herpesviruses, polyomaviruses, and gastroenteritis viruses, rendering crew members more susceptible to virus infections across the mucosa. We are focusing the virus studies on the human herpesviruses and polyomaviruses, important pathogens known to establish latent infections in most of the human population. Both primary infection and reactivation from latent infection with these groups of viruses (especially certain herpesviruses) can cause a variety of illnesses that result in morbidity and, occasionally, mortality. Both herpesviruses and polyomaviruses have been associated with human cancer, as well. Effective vaccines exist for only one of the eight known human herpesviruses and available antivirals are of limited use. Whereas normal individuals display minimal consequences from latent viral infections, events which alter immune function (such as immunosuppressive therapy following solid organ transplantation) are known to increase the risk of complications as a result of viral reactivations.

Human Invariant Natural Killer T cells possess immune-modulating functions during Aspergillus infection.

PubMed

Beitzen-Heineke, Antonia; Bouzani, Maria; Schmitt, Anna-Lena; Kurzai, Oliver; Hünniger, Kerstin; Einsele, Hermann; Loeffler, Juergen

2016-02-01

Aspergillus fumigatus is the most common cause for invasive fungal infections, a disease associated with high mortality in immune-compromised patients. CD1d-restricted invariant natural killer T (iNKT) cells compose a small subset of T cells known to impact the immune response toward various infectious pathogens. To investigate the role of human iNKT cells during A. fumigatus infection, we studied their activation as determined by CD69 expression and cytokine production in response to distinct fungal morphotypes in the presence of different CD1d(+) antigen presenting cells using flow cytometry and multiplex enzyme-linked immunosorbent assay (ELISA). Among CD1d(+) subpopulations, CD1d(+)CD1c(+) mDCs showed the highest potential to activate iNKT cells on a per cell basis. The presence of A. fumigatus decreased this effect of CD1d(+)CD1c(+) mDCs on iNKT cells and led to reduced secretion of TNF-α, G-CSF and RANTES. Production of other Th1 and Th2 cytokines was not affected by the fungus, suggesting an immune-modulating function for human iNKT cells during A. fumigatus infection. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The epigenomic landscape of African rainforest hunter-gatherers and farmers.

PubMed

Fagny, Maud; Patin, Etienne; MacIsaac, Julia L; Rotival, Maxime; Flutre, Timothée; Jones, Meaghan J; Siddle, Katherine J; Quach, Hélène; Harmant, Christine; McEwen, Lisa M; Froment, Alain; Heyer, Evelyne; Gessain, Antoine; Betsem, Edouard; Mouguiama-Daouda, Patrick; Hombert, Jean-Marie; Perry, George H; Barreiro, Luis B; Kobor, Michael S; Quintana-Murci, Lluis

2015-11-30

The genetic history of African populations is increasingly well documented, yet their patterns of epigenomic variation remain uncharacterized. Moreover, the relative impacts of DNA sequence variation and temporal changes in lifestyle and habitat on the human epigenome remain unknown. Here we generate genome-wide genotype and DNA methylation profiles for 362 rainforest hunter-gatherers and sedentary farmers. We find that the current habitat and historical lifestyle of a population have similarly critical impacts on the methylome, but the biological functions affected strongly differ. Specifically, methylation variation associated with recent changes in habitat mostly concerns immune and cellular functions, whereas that associated with historical lifestyle affects developmental processes. Furthermore, methylation variation--particularly that correlated with historical lifestyle--shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Our work provides new insight into the genetic and environmental factors affecting the epigenomic landscape of human populations over time.

Effect of excess dietary L-valine on laying hen performance, egg quality, serum free amino acids, immune function and antioxidant enzyme activity.

PubMed

Azzam, M M M; Dong, X Y; Dai, L; Zou, X T

2015-01-01

1. The aim of this study was to evaluate the tolerance of laying hens for an excessive L-valine (L-val) supply on laying performance, egg quality, serum free amino acids, immune function and antioxidant enzyme activities of laying hens. 2. A total of 720 HyLine Brown hens were allocated to 5 dietary treatment groups, each of which included 6 replicates of 24 hens, from 40 to 47 weeks of age. Graded amounts of L-val were added to the basal diet to achieve concentrations of 0 (control), 1, 2, 3 and 4 g/kg, respectively, in the experimental diets. 3. Supplementing the diet with L-val did not affect egg production, egg mass, egg weight, feed conversion ratio (FCR) or egg quality. The average daily feed intake response to supplemental L-val was quadratic and was maximised at 2.0 g L-val/kg diet. No differences were observed for total protein, total amino acids, blood urea nitrogen (BUN), uric acid, lactate dehydrogenase (LDH), alkaline phosphatase (AKP), Ca and P concentrations among the treatments. 4. Serum albumin concentration increased significantly in response to supplemental L-val and was also maximised at 2.0 g/kg. In addition, serum glucose increased quadratically to peak at 2.0 g L-val/kg diet. Serum free valine increased as L-val concentration increased to 2.0 g/kg diet and then decreased linearly. 5. Supplementation of L-val did not affect the serum concentrations of total antioxidative capability (T-AOC), superoxide dismutase (SOD) and malondialdehyde (MDA). L-val supplementation did not affect the concentrations of immunoglobulins IgG, IgA, IgM and complements (C3 and C4). Serum concentration of triiodothyronine (T3) increased significantly at 2.0 g L-val/kg diet. 6. It is concluded that high concentrations of L-val are tolerated and can be successfully supplemented into diets without detrimental effects on laying performance or immune function of laying hens.

The eye: A window to the soul of the immune system.

PubMed

Perez, V L; Saeed, A M; Tan, Y; Urbieta, M; Cruz-Guilloty, F

2013-09-01

The eye is considered as an immune privileged site, and with good reason. It has evolved a variety of molecular and cellular mechanisms that limit immune responses to preserve vision. For example, the cornea is mainly protected from autoimmunity by the lack of blood and lymphatic vessels, whereas the retina-blood barrier is maintained in an immunosuppressive state by the retinal pigment epithelium. However, there are several scenarios in which immune privilege is altered and the eye becomes susceptible to immune attack. In this review, we highlight the role of the immune system in two clinical conditions that affect the anterior and posterior segments of the eye: corneal transplantation and age-related macular degeneration. Interestingly, crosstalk between the innate and adaptive immune systems is critical in both acute and chronic inflammatory responses in the eye, with T cells playing a central role in combination with neutrophils and macrophages. In addition, we emphasize the advantage of using the eye as a model for in vivo longitudinal imaging of the immune system in action. Through this technique, it has been possible to identify functionally distinct intra-graft motility patterns of responding T cells, as well as the importance of chemokine signaling in situ for T cell activation. The detailed study of ocular autoimmunity could provide novel therapeutic strategies for blinding diseases while also providing more general information on acute versus chronic inflammation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities.

PubMed

Diegeler, Sebastian; Hellweg, Christine E

2017-01-01

Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

When is affect variability bad for health? The association between affect variability and immune response to the influenza vaccination.

PubMed

Jenkins, Brooke N; Hunter, John F; Cross, Marie P; Acevedo, Amanda M; Pressman, Sarah D

2018-01-01

This study addresses methodological and theoretical questions about the association between affect and physical health. Specifically, we examine the role of affect variability and its interaction with mean levels of affect to predict antibody (Ab) levels in response to an influenza vaccination. Participants (N=83) received the vaccination and completed daily diary measures of affect four times a day for 13days. At one and four months post-vaccination, blood was collected from the participants to assess Ab levels. Findings indicate that affect variability and its interaction with mean levels of affect predict an individual's immune response. Those high in mean positive affect (PA) who had more PA variability were more likely to have a lower Ab response in comparison to those who had high mean PA and less PA variability. Although it did not interact with mean negative affect (NA), NA variability on its own was associated with Ab response, whereby those with less NA variability mounted a more robust immune response. Affect variability is related to immune response to an influenza vaccination and, in some cases, interacts with mean levels of affect. These oscillations in affective experiences are critical to consider in order to unpack the intricacies of how affect influences health. These findings suggest that future researchers should consider the important role of affect variability on physical health-relevant outcomes as well as examine the moderating effect of mean affect levels. Copyright © 2017 Elsevier Inc. All rights reserved.

Microbiota-induced changes in drosophila melanogaster host gene expression and gut morphology.

PubMed

Broderick, Nichole A; Buchon, Nicolas; Lemaitre, Bruno

2014-05-27

To elucidate mechanisms underlying the complex relationships between a host and its microbiota, we used the genetically tractable model Drosophila melanogaster. Consistent with previous studies, the microbiota was simple in composition and diversity. However, analysis of single flies revealed high interfly variability that correlated with differences in feeding. To understand the effects of this simple and variable consortium, we compared the transcriptome of guts from conventionally reared flies to that for their axenically reared counterparts. Our analysis of two wild-type fly lines identified 121 up- and 31 downregulated genes. The majority of these genes were associated with immune responses, tissue homeostasis, gut physiology, and metabolism. By comparing the transcriptomes of young and old flies, we identified temporally responsive genes and showed that the overall impact of microbiota was greater in older flies. In addition, comparison of wild-type gene expression with that of an immune-deficient line revealed that 53% of upregulated genes exerted their effects through the immune deficiency (Imd) pathway. The genes included not only classic immune response genes but also those involved in signaling, gene expression, and metabolism, unveiling new and unexpected connections between immunity and other systems. Given these findings, we further characterized the effects of gut-associated microbes on gut morphology and epithelial architecture. The results showed that the microbiota affected gut morphology through their impacts on epithelial renewal rate, cellular spacing, and the composition of different cell types in the epithelium. Thus, while bacteria in the gut are highly variable, the influence of the microbiota at large has far-reaching effects on host physiology. The guts of animals are in constant association with microbes, and these interactions are understood to have important roles in animal development and physiology. Yet we know little about the mechanisms underlying the establishment and function of these associations. Here, we used the fruit fly to understand how the microbiota affects host function. Importantly, we found that the microbiota has far-reaching effects on host physiology, ranging from immunity to gut structure. Our results validate the notion that important insights on complex host-microbe relationships can be obtained from the use of a well-established and genetically tractable invertebrate model. Copyright © 2014 Broderick et al.

Myocardial aging as a T-cell–mediated phenomenon

PubMed Central

Ramos, Gustavo Campos; van den Berg, Anne; Nunes-Silva, Vânia; Weirather, Johannes; Peters, Laura; Burkard, Matthias; Friedrich, Mike; Pinnecker, Jürgen; Abeßer, Marco; Heinze, Katrin G.; Schuh, Kai; Beyersdorf, Niklas; Kerkau, Thomas; Demengeot, Jocelyne; Frantz, Stefan; Hofmann, Ulrich

2017-01-01

In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissue-resident leukocytes and with an accumulation of activated CD4+ Foxp3− (forkhead box P3) IFN-γ+ T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population. PMID:28255084

The immunomodulatory role of the hypothalamus-pituitary-gonad axis: Proximate mechanism for reproduction-immune trade offs?

PubMed

Segner, Helmut; Verburg-van Kemenade, B M Lidy; Chadzinska, Magdalena

2017-01-01

The present review discusses the communication between the hypothalamic-pituitary-gonad (HPG) axis and the immune system of vertebrates, attempting to situate the HPG-immune interaction into the context of life history trade-offs between reproductive and immune functions. More specifically, (i) we review molecular and cellular interactions between hormones of the HPG axis, and, as far as known, the involved mechanisms on immune functions, (ii) we evaluate whether the HPG-immune crosstalk serves as proximate mechanism mediating reproductive-immune trade-offs, and (iii) we ask whether the nature of the HPG-immune interaction is conserved throughout vertebrate evolution, despite the changes in immune functions, reproductive modes, and life histories. In all vertebrate classes studied so far, HPG hormones have immunomodulatory functions, and indications exist that they contribute to reproduction-immunity resource trade-offs, although the very limited information available for most non-mammalian vertebrates makes it difficult to judge how comparable or different the interactions are. There is good evidence that the HPG-immune crosstalk is part of the proximate mechanisms underlying the reproductive-immune trade-offs of vertebrates, but it is only one factor in a complex network of factors and processes. The fact that the HPG-immune interaction is flexible and can adapt to the functional and physiological requirements of specific life histories. Moreover, the assumption of a relatively fixed pattern of HPG influence on immune functions, with, for example, androgens always leading to immunosuppression and estrogens always being immunoprotective, is probably oversimplified, but the HPG-immune interaction can vary depending on the physiological and envoironmental context. Finally, the HPG-immune interaction is not only driven by resource trade-offs, but additional factors such as, for instance, the evolution of viviparity shape this neuroendocrine-immune relationship. Copyright © 2016 Elsevier Ltd. All rights reserved.

Photoperiod but not food restriction modulates innate immunity in an opportunistic breeder, Loxia curvirostra.

PubMed

Schultz, Elizabeth M; Hahn, Thomas P; Klasing, Kirk C

2017-02-15

An organism's investment in immune function often varies seasonally but understanding of how fluctuations in environmental conditions directly modulate investment remains limited. This experiment investigated how changes in photoperiod and food availability affect investment in constitutive innate immunity and the acute phase response induced by lipopolysaccharide (LPS) injections in captive red crossbills ( Loxia curvirostra ). Crossbills are reproductively flexible songbirds that specialize on an unpredictably available food resource and display temporal variation in immunity in the wild. Birds were separated into four treatments and exposed to long or short day lengths for 6 weeks before continuing on an ad libitum diet or experiencing a 20% food reduction for 10 days. Birds were un-injected or injected with LPS both before and after diet change. Innate immunity was quantified throughout the experiment to assess effects of photoperiod, food availability and their interactions on hemolysis-hemagglutination, haptoglobin, bacterial killing ability and leukocyte counts. Overall, increasing day length significantly increased both bacterial killing ability and leukocyte counts. Surprisingly, food restriction had little effect on the immune parameters, potentially owing to the 'low-cost' environment of captivity and suggesting that investment in innate immunity is prioritized and maintained whenever possible. LPS injections induced stereotypical sickness behaviors and increased bacterial killing ability in short day birds and complement activity (hemolysis) both before and after food restriction. These results demonstrate robust seasonal modulation of immune investment and an ability to maintain innate immunity in the face of limited resources in these temporally flexible songbirds. © 2017. Published by The Company of Biologists Ltd.

Nutritionally Mediated Programming of the Developing Immune System12

PubMed Central

Palmer, Amanda C.

2011-01-01

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

Integration of Immunity with Physical and Cognitive Function in Definitions of Successful Aging

PubMed Central

Griffin, Patricia; Michel, Joshua J.; Huysman, Kristy; Logar, Alison J.; Vallejo, Abbe N.

2012-01-01

Studies comparing chronologically “young” versus “old” humans document age-related decline of classical immunological functions. However, older adults aged ≥65 years have very heterogeneous health phenotypes. A significant number of them are functionally independent and are surviving well into their 8th–11th decade life, observations indicating that aging or old age is not synonymous with immune incompetence. While there are dramatic age-related changes in the immune system, not all of these changes may be considered detrimental. Here, we review evidences for novel immunologic processes that become elaborated with advancing age that complement preserved classical immune functions and promote immune homeostasis later in life. We propose that elaboration such of late life immunologic properties is indicative of beneficial immune remodeling that is an integral component of successful aging, an emerging physiologic construct associated with similar age-related physiologic adaptations underlying maintenance of physical and cognitive function. We suggest that a systems approach integrating immune, physical, and cognitive functions, rather than a strict immunodeficiency-minded approach, will be key towards innovations in clinical interventions to better promote protective immunity and functional independence among the elderly. PMID:22500270

Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury.

PubMed

Luo, Dandan; Ge, Weihong; Hu, Xiao; Li, Chen; Lee, Chia-Ming; Zhou, Liqiang; Wu, Zhourui; Yu, Juehua; Lin, Sheng; Yu, Jing; Xu, Wei; Chen, Lei; Zhang, Chong; Jiang, Kun; Zhu, Xingfei; Li, Haotian; Gao, Xinpei; Geng, Yanan; Jing, Bo; Wang, Zhen; Zheng, Changhong; Zhu, Rongrong; Yan, Qiao; Lin, Quan; Ye, Keqiang; Sun, Yi E; Cheng, Liming

2018-06-28

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

Oral iron supplementation: Potential implications for the gut microbiome and metabolome in patients with CKD.

PubMed

Kortman, Guus A M; Reijnders, Dorien; Swinkels, Dorine W

2017-06-01

Patients with chronic kidney disease (CKD) and loss of kidney function are at increased risk for morbidity and mortality. The risks of CKD are attributed to "uremia," an increased concentration of uremic retention solutes (toxins) in the plasma. Recently, a colo-renal axis became clearly apparent and uremia has been associated with an altered gut microbiome composition and metabolism. There is a high prevalence of anemia in patients with CKD, for which patients are often treated with oral or intravenous iron. Recent in vivo and in vitro studies have reported adverse effects of oral iron supplementation on the gut microbiota composition, gut metabolome, and intestinal health, which in turn may result in an increased production of uremic toxins. It may also affect circulating levels of other microbe-derived molecules, that can act as mediators of immune regulation. Changes in body iron levels have also been reported to exert subtle effects on host immune function by modulating immune cell proliferation and differentiation, and by directly regulating cytokine formation and antimicrobial immune effector mechanisms. Based on the foregoing it is conceivable that oral iron supplementation in iron deficient predialysis CKD patients adversely changes gut microbiota composition, the gut and systemic metabolome, and host immunity and infection. Future studies are needed to confirm these hypotheses and to assess whether, compared to IV iron supplementation, oral iron supplementation negatively impacts on morbidity of CKD, and whether these adverse effects depend on the iron bioavailability of the iron formulation to the microbiota. © 2017 International Society for Hemodialysis.

Immunologic effects of hydroxyurea in sickle cell anemia.

PubMed

Lederman, Howard M; Connolly, Margaret A; Kalpatthi, Ram; Ware, Russell E; Wang, Winfred C; Luchtman-Jones, Lori; Waclawiw, Myron; Goldsmith, Jonathan C; Swift, Andrea; Casella, James F

2014-10-01

Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced. Copyright © 2014 by the American Academy of Pediatrics.

Immunologic Effects of Hydroxyurea in Sickle Cell Anemia

PubMed Central

Lederman, Howard M.; Connolly, Margaret A.; Kalpatthi, Ram; Ware, Russell E.; Wang, Winfred C.; Luchtman-Jones, Lori; Waclawiw, Myron; Goldsmith, Jonathan C.; Swift, Andrea

2014-01-01

BACKGROUND AND OBJECTIVE: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea’s effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1–S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. METHODS: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). RESULTS: Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. CONCLUSIONS: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced. PMID:25180279

Immune Responses of Female BALB/c and C57BL/6 Neonatal Mice to Vaccination or Intestinal Infection Are Unaltered by Exposure to Breast Milk Lycopene123

PubMed Central

Adkins, Becky; Contractor, Nikhat

2011-01-01

Lycopene, a carotenoid produced by some commonly consumed plants such as tomatoes, is not synthesized by animals. Thus, the levels of lycopene found in the breast milk of lactating females reflect the dietary lycopene supply. Lycopene has potent antioxidant activity but has also been implicated in modulating immune function. Therefore, lycopene in breast milk has the potential to affect the development and/or function of the immune system in the suckling pups. Here, we have investigated the impact of breast milk lycopene on systemic and mucosal immunity in mouse neonates. Diets containing 0.3 g/kg lycopene (Lyc) or control (Con) diets were fed to mouse dams beginning at late gestation and continuing throughout lactation. Seven-day-old female BALB/c pups were parenterally immunized with a model vaccine antigen dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH) and then reimmunized as adults. The levels of DNP-KLH–specific IgG in the sera as well as keyhole limpet hemocyanin-specific IFNγ and IL-4 production by splenic CD4+ cells were similar in the Lyc and Con pups. In addition, female neonatal (d7) C57BL/6 Lyc and Con pups were infected orally with the enteropathogen Yersinia enterocolitica. Breast milk lycopene had no effect on the recruitment of neutrophils to intestinal lymphoid tissues or on bacterial tissue colonization of the intestines, spleens, and livers. Thus, suckling pups exposed to lycopene in breast milk appear to develop normal innate and adaptive responses both systemically and at intestinal mucosal surfaces. PMID:21593356

Immune-Mediated Mechanisms of Action of Probiotics and Synbiotics in Treating Pediatric Intestinal Diseases

PubMed Central

Gil-Campos, Mercedes

2018-01-01

The pediatric population is continually at risk of developing infectious and inflammatory diseases. The treatment for infections, particularly gastrointestinal conditions, focuses on oral or intravenous rehydration, nutritional support and, in certain case, antibiotics. Over the past decade, the probiotics and synbiotics administration for the prevention and treatment of different acute and chronic infectious diseases has dramatically increased. Probiotic microorganisms are primarily used as treatments because they can stimulate changes in the intestinal microbial ecosystem and improve the immunological status of the host. The beneficial impact of probiotics is mediated by different mechanisms. These mechanisms include the probiotics’ capacity to increase the intestinal barrier function, to prevent bacterial transferation and to modulate inflammation through immune receptor cascade signaling, as well as their ability to regulate the expression of selected host intestinal genes. Nevertheless, with respect to pediatric intestinal diseases, information pertaining to these key mechanisms of action is scarce, particularly for immune-mediated mechanisms of action. In the present work, we review the biochemical and molecular mechanisms of action of probiotics and synbiotics that affect the immune system. PMID:29303974

Transient immune deficiency in patients with acute Epstein-Barr virus infection.

PubMed

Junker, A K; Ochs, H D; Clark, E A; Puterman, M L; Wedgwood, R J

1986-09-01

To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage phi X174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying Ia and T8 (CD8) phenotypes was increased and the T helper/suppressor (T4/T8) ratio was decreased (less than 1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage phi X174 both in vivo and in vitro. In vitro coculture experiments indicated that the Ia+ suppressor T cells could inhibit antibody production and isotype switch. Removal of T8+ lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infectious mononucleosis.

Novel Functions of Hendra Virus G N-Glycans and Comparisons to Nipah Virus.

PubMed

Bradel-Tretheway, Birgit G; Liu, Qian; Stone, Jacquelyn A; McInally, Samantha; Aguilar, Hector C

2015-07-01

Hendra virus (HeV) and Nipah virus (NiV) are reportedly the most deadly pathogens within the Paramyxoviridae family. These two viruses bind the cellular entry receptors ephrin B2 and/or ephrin B3 via the viral attachment glycoprotein G, and the concerted efforts of G and the viral fusion glycoprotein F result in membrane fusion. Membrane fusion is essential for viral entry into host cells and for cell-cell fusion, a hallmark of the disease pathobiology. HeV G is heavily N-glycosylated, but the functions of the N-glycans remain unknown. We disrupted eight predicted N-glycosylation sites in HeV G by conservative mutations (Asn to Gln) and found that six out of eight sites were actually glycosylated (G2 to G7); one in the stalk (G2) and five in the globular head domain (G3 to G7). We then tested the roles of individual and combined HeV G N-glycan mutants and found functions in the modulation of shielding against neutralizing antibodies, intracellular transport, G-F interactions, cell-cell fusion, and viral entry. Between the highly conserved HeV and NiV G glycoproteins, similar trends in the effects of N-glycans on protein functions were observed, with differences in the levels at which some N-glycan mutants affected such functions. While the N-glycan in the stalk domain (G2) had roles that were highly conserved between HeV and NiV G, individual N-glycans in the head affected the levels of several protein functions differently. Our findings are discussed in the context of their contributions to our understanding of HeV and NiV pathogenesis and immune responses. Viral envelope glycoproteins are important for viral pathogenicity and immune evasion. N-glycan shielding is one mechanism by which immune evasion can be achieved. In paramyxoviruses, viral attachment and membrane fusion are governed by the close interaction of the attachment proteins H/HN/G and the fusion protein F. In this study, we show that the attachment glycoprotein G of Hendra virus (HeV), a deadly paramyxovirus, is N-glycosylated at six sites (G2 to G7) and that most of these sites have important roles in viral entry, cell-cell fusion, G-F interactions, G oligomerization, and immune evasion. Overall, we found that the N-glycan in the stalk domain (G2) had roles that were very conserved between HeV G and the closely related Nipah virus G, whereas individual N-glycans in the head quantitatively modulated several protein functions differently between the two viruses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Drugs of abuse and virus susceptibility.

PubMed

Friedman, H; Klein, T; Specter, S; Pross, S; Newton, C; Blanchard, D K; Widen, R

1988-01-01

It is widely recognized that various microorganisms including viruses have immunomodulatory effects and, under appropriate circumstances, may markedly suppress the immune response mechanisms. Cannabinoids present in marijuana also have immunomodulatory effects. In the present studies THC as well as its metabolic product 11-OH THC were studied in regard to their effects in vivo and in vitro on selected parameters of the immune response system known to be important in antiviral resistance, including immunity to retroviruses. Cannabinoids markedly suppressed the ability of murine macrophages to spread on glass (an important functional marker of macrophages) as well as to phagocytize yeast particles. Splenic macrophage cultures treated with the cannabinoids also were deficient in their ability to produce interleukin 1 on appropriate stimulation with bacterial LPS. Spleen cells capable of producing antibody to sheep erythrocytes when stimulated with this antigen in vitro were markedly affected when treated with graded doses of THC or 11-OH THC. Furthermore, the blastogenic responsiveness of normal mouse splenocytes to the T-cell mitogens Con A and PHA as well as the B-cell mitogen E. coli LPS was markedly suppressed by graded concentrations of the cannabinoids in doses that did not affect the viability of the cells. Natural killer cell activity of normal mouse spleen cells was also markedly inhibited by THC and 11-OH THC. Similarly, these cannabinoids suppressed the blastogenic responsiveness and NK activity of human peripheral blood leukocytes from normal individuals. The ability of mouse spleen cells to produce interferon on in vitro stimulation was also suppressed by THC. In addition, injection of THC into mice suppressed blastogenic responsiveness of spleen cells, NK activity, and the production of interferon by lymphoid cells. Thus, it was apparent that these cannabinoids had immunomodulatory effects, both in vivo and in vitro, at noncytotoxic small doses and impaired the ability of the lymphoid cells to express immune function necessary for antiviral resistance.

Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility.

PubMed

Vaithilingam, Vijayaganapathy; Kollarikova, Gabriella; Qi, Meirigeng; Lacik, Igor; Oberholzer, Jose; Guillemin, Gilles J; Tuch, Bernard E

2011-01-01

Pericapsular fibrotic overgrowth (PFO) may be attributed to an immune response against microcapsules themselves or to antigen shedding through microcapsule pores from encapsulated islet tissue. Modification of microcapsules aimed at reducing pore size should prevent PFO and improve graft survival. This study investigated the effect of increased gelling time (20 vs. 2 min) in barium chloride on intrinsic properties of alginate microcapsules and tested their biocompatibility in vivo. Prolonged gelling time affected neither permeability nor size of the microcapsules. However, prolonged gelling time for 20 min produced brittle microcapsules compared to 2 min during compression test. Encapsulation of human islets in both types of microcapsules affected neither islet viability nor function. The presence of PFO when transplanted into a large animal model such as baboon and its absence in small animal models such as rodents suggest that the host immune response towards alginate microcapsules is species rather than alginate specific.

The Cell Surface Markers Expression in Postmenopausal Women and Relation to Obesity and Bone Status.

PubMed

Horváthová, Mira; Ilavská, Silvia; Štefíková, Kornélia; Szabová, Michaela; Krivošíková, Zora; Jahnová, Eva; Tulinská, Jana; Spustová, Viera; Gajdoš, Martin

2017-07-11

The age-related changes and hormonal deprivation in postmenopausal women are associated with the immune response alteration. The excessive fat accumulation, local and systemic inflammation may lead to dysregulation in immune function and relevant health problems, including obesity and osteoporosis. We analyzed the expression of cell surface markers in the venous blood specimens, stained with fluorophores-conjugated monoclonal antibodies and analysed by multicolour flow cytometry. The significant changes of cytotoxic, naive, and memory T-lymphocytes, plasmacytoid dendritic cells (DCs) were in postmenopausal women versus fertile women. Body mass index (BMI) affected markedly the cell surface expression of CD265/RANK. Osteoporosis is linked to reduced percentage of plasmacytoid DCs, and elevated natural Treg cells ( p < 0.05). The confounding factors such as women age, BMI, bone mineral density (BMD), waist size and tissue fat affect the expression of RANK on myeloid DCs and CD40L on T-lymphocytes that might be the immunophenotypic modulators after menopause.

The Cell Surface Markers Expression in Postmenopausal Women and Relation to Obesity and Bone Status

PubMed Central

Horváthová, Mira; Ilavská, Silvia; Štefíková, Kornélia; Szabová, Michaela; Krivošíková, Zora; Jahnová, Eva; Tulinská, Jana; Spustová, Viera; Gajdoš, Martin

2017-01-01

The age-related changes and hormonal deprivation in postmenopausal women are associated with the immune response alteration. The excessive fat accumulation, local and systemic inflammation may lead to dysregulation in immune function and relevant health problems, including obesity and osteoporosis. We analyzed the expression of cell surface markers in the venous blood specimens, stained with fluorophores-conjugated monoclonal antibodies and analysed by multicolour flow cytometry. The significant changes of cytotoxic, naive, and memory T-lymphocytes, plasmacytoid dendritic cells (DCs) were in postmenopausal women versus fertile women. Body mass index (BMI) affected markedly the cell surface expression of CD265/RANK. Osteoporosis is linked to reduced percentage of plasmacytoid DCs, and elevated natural Treg cells (p < 0.05). The confounding factors such as women age, BMI, bone mineral density (BMD), waist size and tissue fat affect the expression of RANK on myeloid DCs and CD40L on T-lymphocytes that might be the immunophenotypic modulators after menopause. PMID:28696349

Sea Buckthorn Pomace Supplementation in the Diet of Growing Pigs-Effects on Fatty Acid Metabolism, HPA Activity and Immune Status.

PubMed

Dannenberger, Dirk; Tuchscherer, Margret; Nürnberg, Gerd; Schmicke, Marion; Kanitz, Ellen

2018-02-21

There is evidence that sea buckthorn, as a source of n -3 polyunsaturated fatty acids ( n -3 PUFA), possesses health-enhancing properties and may modulate neuroendocrine and immune functions. In the present study, we investigated the effect of sea buckthorn pomace (SBP) supplementation in the diet of growing German Landrace pigs on fatty acids in the blood and hypothalamus, peripheral immune parameters and mRNA expression of corticotropin-releasing hormone (CRH), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hypothalamus and spleen. Pigs were fed diets supplemented with 12% of dried SBP or 0% SBP (control group) over an intervention period of eight weeks. The fatty acid profiles in blood plasma were significantly affected by SBP supplementation only for C18:2 n -6 and n -6/ n -3 PUFA ratio compared with the control group. SBP supplementation did not significantly affect the fatty acid concentrations in the hypothalamus. Furthermore, there were no significant differences in mRNA expression of CRH, MR and GR in the hypothalamus or of GR mRNA expression in the spleen. Concerning the immune status, the plasma IgG levels tended to be higher in SBP pigs, whereas the leukocyte distribution, mitogen-stimulated lymphocyte proliferation, and serum IgM levels remained unchanged. In conclusion, the SBP supplementation of the diet only caused moderate effects on fatty acid metabolism, but no significant effects on hypothalamic-pituitary-adrenal (HPA) activity and immunity in growing pigs. It seems that a beneficial effect of dietary n -3 PUFA on health and welfare is more likely to be expected during stressful situations.

Sea Buckthorn Pomace Supplementation in the Diet of Growing Pigs—Effects on Fatty Acid Metabolism, HPA Activity and Immune Status

PubMed Central

Dannenberger, Dirk; Tuchscherer, Margret; Nürnberg, Gerd; Kanitz, Ellen

2018-01-01

There is evidence that sea buckthorn, as a source of n-3 polyunsaturated fatty acids (n-3 PUFA), possesses health-enhancing properties and may modulate neuroendocrine and immune functions. In the present study, we investigated the effect of sea buckthorn pomace (SBP) supplementation in the diet of growing German Landrace pigs on fatty acids in the blood and hypothalamus, peripheral immune parameters and mRNA expression of corticotropin-releasing hormone (CRH), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hypothalamus and spleen. Pigs were fed diets supplemented with 12% of dried SBP or 0% SBP (control group) over an intervention period of eight weeks. The fatty acid profiles in blood plasma were significantly affected by SBP supplementation only for C18:2n-6 and n-6/n-3 PUFA ratio compared with the control group. SBP supplementation did not significantly affect the fatty acid concentrations in the hypothalamus. Furthermore, there were no significant differences in mRNA expression of CRH, MR and GR in the hypothalamus or of GR mRNA expression in the spleen. Concerning the immune status, the plasma IgG levels tended to be higher in SBP pigs, whereas the leukocyte distribution, mitogen-stimulated lymphocyte proliferation, and serum IgM levels remained unchanged. In conclusion, the SBP supplementation of the diet only caused moderate effects on fatty acid metabolism, but no significant effects on hypothalamic–pituitary–adrenal (HPA) activity and immunity in growing pigs. It seems that a beneficial effect of dietary n-3 PUFA on health and welfare is more likely to be expected during stressful situations. PMID:29466282

Induced lung inflammation and dietary protein supply affect nitrogen retention and amino acid metabolism in growing pigs.

PubMed

Kampman-van de Hoek, Esther; Sakkas, Panagiotis; Gerrits, Walter J J; van den Borne, Joost J G C; van der Peet-Schwering, Carola M C; Jansman, Alfons J M

2015-02-14

It is hypothesised that during immune system activation, there is a competition for amino acids (AA) between body protein deposition and immune system functioning. The aim of the present study was to quantify the effect of immune system activation on N retention and AA metabolism in growing pigs, depending on dietary protein supply. A total of sixteen barrows received an adequate (Ad) or restricted (Res) amount of dietary protein, and were challenged at day 0 with intravenous complete Freund's adjuvant (CFA). At days - 5, 3 and 8, an irreversible loss rate (ILR) of eight AA was determined. CFA successfully activated the immune system, as indicated by a 2- to 4-fold increase in serum concentrations of acute-phase proteins (APP). Pre-challenge C-reactive protein concentrations were lower (P< 0·05) and pre- and post-challenge albumin tended to be lower in Res-pigs. These findings indicate that a restricted protein supply can limit the acute-phase response. CFA increased urinary N losses (P= 0·04) and tended to reduce N retention in Ad-pigs, but not in Res-pigs (P= 0·07). The ILR for Val was lower (P= 0·05) at day 8 than at day 3 in the post-challenge period. The ILR of most AA, except for Trp, were strongly affected by dietary protein supply and positively correlated with N retention. The correlations between the ILR and APP indices were absent or negative, indicating that changes in AA utilisation for APP synthesis were either not substantial or more likely outweighed by a decrease in muscle protein synthesis during immune system activation in growing pigs.

Chronic bystander infections and immunity to unrelated antigens

PubMed Central

Stelekati, Erietta; Wherry, E. John

2012-01-01

Chronic infections with persistent pathogens such as helminths, mycobacteria, Plasmodium and hepatitis viruses affect more than a third of the human population and are associated with increased susceptibility to other pathogens as well as reduced vaccine efficacy. Although these observations suggest an impact of chronic infections in modulating immunity to unrelated antigens, little is known regarding the underlying mechanisms. Here, we summarize evidence of the most prevalent infections affecting immunity to unrelated pathogens and vaccines, and discuss potential mechanisms of how different bystander chronic infections might impact immune responses. We suggest that bystander chronic infections affect different stages of host responses and may impact transmission of other pathogens, recognition and innate immune responses, priming and differentiation of adaptive effector responses, as well as the development and maintenance of immunological memory. Further understanding of the immunological effects of co-infection should provide opportunities to enhance vaccine efficacy and control infectious diseases. PMID:23084915

Sex differences in immune variables and respiratory infection incidence in an athletic population.

PubMed

Gleeson, Michael; Bishop, Nicolette; Oliveira, Marta; McCauley, Tracey; Tauler, Pedro

2011-01-01

The purpose of this study was to examine sex differences in immune variables and upper respiratory tract infection (URTI) incidence in 18-35 year-old athletes engaged in endurance-based physical activity during the winter months. Eighty physically active individuals (46 males, 34 females) provided resting venous blood samples for determination of differential leukocyte counts, lymphocyte subsets and whole blood culture multi-antigen stimulated cytokine production. Timed collections of unstimulated saliva were also made for determination of saliva flow rate, immunoglobulin A (IgA) concentration and IgA secretion rate. Weekly training and illness logs were kept for the following 4 months. Training loads averaged 10 h/week of moderate-vigorous physical activity and were not different for males and females. Saliva flow rates, IgA concentration and IgA secretion rates were significantly higher in males than females (all P < 0.01). Plasma IgA, IgG and IgM concentrations and total blood leukocyte, neutrophil, monocyte and lymphocyte counts were not different between the sexes but males had higher numbers of B cells (P < 0.05) and NK cells (P < 0.001). The production of interleukins 1 beta, 2, 4, 6, 8 and 10, interferon-gamma and tumour necrosis factor-alpha in response to multi-antigen challenge were not significantly different in males and females (all P > 0.05). The average number of weeks with URTI symptoms was 1.7 +/- 2.1 (mean +/- SD) in males and 2.3 +/- 2.5 in females (P = 0.311). It is concluded that most aspects of immunity are similar in men and women in an athletic population and that the observed differences in a few immune variables are not sufficient to substantially affect URTI incidence. Sex differences in immune function among athletes probably do not need to be considered in future mixed gender studies on exercise, infection and immune function unless the focus is on mucosal immunity or NK cells.

Alteration of Lymphocyte Phenotype and Function in Sickle Cell Anemia: Implications for Vaccine Responses

PubMed Central

Balandya, Emmanuel; Reynolds, Teri; Obaro, Stephen; Makani, Julie

2016-01-01

Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper : CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (Treg), skewing of CD4+ T cells towards Th2 response and loss of IgM-secreting CD27+IgMhighIgDlow memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C-reactive protein and pro-inflammatory cytokines IL-6 and TNF-α, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub-Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. PMID:27237467

Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells

PubMed Central

Valdor, Rut; García-Bernal, David; Bueno, Carlos; Ródenas, Mónica; Moraleda, José M.; Macian, Fernando; Martínez, Salvador

2017-01-01

The establishment of immune tolerance during Glioblastoma Multiforme (GBM) progression, is characterized by high levels expression of anti-inflammatory cytokines, which suppress the function of tumor assocciated myeloid cells, and the activation and expansion of tumor antigen specific T cells. However, the mechanisms underlying the failed anti-tumor immune response around the blood vessels during GBM, are poorly understood. The consequences of possible interactions between cancer cells and the perivascular compartment might affect the tumor growth. In this work we show for the first time that GBM cells induce immunomodulatory changes in pericytes in a cell interaction-dependent manner, acquiring an immunosuppresive function that possibly assists the evasion of the anti-tumor immune response and consequently participates in tumor growth promotion. Expression of high levels of anti-inflammatory cytokines was detected in vitro and in vivo in brain pericytes that interacted with GBM cells (GBC-PC). Furthermore, reduction of surface expression of co-stimulatory molecules and major histocompatibility complex molecules in GBC-PC correlated with a failure of antigen presentation to T cells and the acquisition of the ability to supress T cell responses. In vivo, orthotopic xenotransplant of human glioblastoma in an immunocompetent mouse model showed significant GBM cell proliferation and tumor growth after the establishment of interspecific immunotolerance that followed GMB interaction with pericytes. PMID:28978142

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats.

PubMed

Luck, Christian; DeMarco, Vincent G; Mahmood, Abuzar; Gavini, Madhavi P; Pulakat, Lakshmi

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750  μ g/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters ( E / E ', E '/ A ', E / Vp ) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFN γ , and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes.

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

PubMed Central

Luck, Christian; DeMarco, Vincent G.; Mahmood, Abuzar; Gavini, Madhavi P.

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E′, E′/A′, E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes. PMID:28408970

Neuro-immune modulation of the thymus microenvironment (review).

PubMed

Mignini, Fiorenzo; Sabbatini, Maurizio; Mattioli, Laura; Cosenza, Monica; Artico, Marco; Cavallotti, Carlo

2014-06-01

The thymus is the primary site for T-cell lympho-poiesis. Its function includes the maturation and selection of antigen specific T cells and selective release of these cells to the periphery. These highly complex processes require precise parenchymal organization and compartmentation where a plethora of signalling pathways occur, performing strict control on the maturation and selection processes of T lymphocytes. In this review, the main morphological characteristics of the thymus microenvironment, with particular emphasis on nerve fibers and neuropeptides were assessed, as both are responsible for neuro-immune‑modulation functions. Among several neurotransmitters that affect thymus function, we highlight the dopaminergic system as only recently has its importance on thymus function and lymphocyte physiology come to light.

The multi-faceted role of allergen exposure to the local airway mucosa.

PubMed

Golebski, K; Röschmann, K I L; Toppila-Salmi, S; Hammad, H; Lambrecht, B N; Renkonen, R; Fokkens, W J; van Drunen, C M

2013-02-01

Airway epithelial cells are the first to encounter aeroallergens and therefore have recently become an interesting target of many studies investigating their involvement in the modulation of allergic inflammatory responses. Disruption of a passive structural barrier composed of epithelial cells by intrinsic proteolytic activity of allergens may facilitate allergen penetration into local tissues and additionally affect chronic and ongoing inflammatory processes in respiratory tissues. Furthermore, the ability of rhinoviruses to disrupt and interfere with epithelial tight junctions may alter the barrier integrity and enable a passive passage of inhaled allergens through the airway epithelium. On the other hand, epithelial cells are no longer considered to act only as a physical barrier toward inhaled allergens, but also to actively contribute to airway inflammation by detecting and responding to environmental factors. Epithelial cells can produce mediators, which may affect the recruitment and activation of more specialized immune cells to the local tissue and also create a microenvironment in which these activated immune cells may function and propagate the inflammatory processes. This review presents the dual role of epithelium acting as a passive and active barrier when encountering an inhaled allergen and how this double role contributes to the start of local immune responses. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Phylogeny and immune evasion: a putative correlation for cerebral Pseudallescheria/Scedosporium infections.

PubMed

Rainer, Johannes; Rambach, Günter; Kaltseis, Josef; Hagleitner, Magdalena; Heiss, Silvia; Speth, Cornelia

2011-10-01

Representatives of the genus Pseudallescheria (anamorph: Scedosporium) are saprobes and the aetiologic agent of invasive mycosis in humans. After dissemination, the central nervous system (CNS) is one of the most affected organs. Prerequisites for the survival of Pseudallescheria/Scedosporium in the host are the ability to acquire nutrients and to evade the immune attack. The cleavage of complement compounds via the secretion of fungal proteases might meet both challenges since proteolytic degradation of proteins can provide nutrients and destroy the complement factors, a fast and effective immune weapon in the CNS. Therefore, we studied the capacity of different Pseudallescheria/Scedosporium species to degrade key elements of the complement cascade in the cerebrospinal fluid and investigated a correlation with the phylogenetic background. The majority of the Pseudallescheria apiosperma isolates tested were demonstrated to efficiently eliminate proteins like complement factors C3 and C1q, thus affecting two main components of a functional complement cascade, presumably by proteolytic degradation, and using them as nutrient source. In contrast, the tested strains of Pseudallescheria boydii have no or only weak capacity to eliminate these complement proteins. We hypothesise that the ability of Pseudallescheria/Scedosporium strains to acquire nutrients and to undermine the complement attack is at least partly phylogenetically determined. © 2011 Blackwell Verlag GmbH.

Effects of environmental change on wildlife health

PubMed Central

Acevedo-Whitehouse, Karina; Duffus, Amanda L. J.

2009-01-01

Environmental change has negatively affected most biological systems on our planet and is becoming of increasing concern for the well-being and survival of many species. At an organism level, effects encompass not only endocrine disruptions, sex-ratio changes and decreased reproductive parameters, but also include teratogenic and genotoxic effects, immunosuppression and other immune-system impairments that can lead directly to disease or increase the risk of acquiring disease. Living organisms will strive to maintain health by recognizing and resolving abnormal situations, such as the presence of invading microorganisms or harmful peptides, abnormal cell replication and deleterious mutations. However, fast-paced environmental changes may pose additional pressure on immunocompetence and health maintenance, which may seriously impact population viability and persistence. Here, we outline the importance of a functional immune system for survival and examine the effects that exposure to a rapidly changing environment might exert on immunocompetence. We then address the various levels at which anthropogenic environmental change might affect wildlife health and identify potential deficits in reproductive parameters that might arise owing to new immune challenges in the context of a rapidly changing environment. Throughout the paper, a series of examples and case studies are used to illustrate the impact of environmental change on wildlife health. PMID:19833653

Hepatitis B Virus Lacks Immune Activating Capacity, but Actively Inhibits Plasmacytoid Dendritic Cell Function

PubMed Central

Woltman, Andrea M.; Shi, Cui C.; Janssen, Harry L. A.

2011-01-01

Chronic 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 patients and chronic HBV patients display impaired IFNα production by pDC. Therefore, HBV and HBV-derived proteins were examined for their effect on human pDC in vitro. In addition, the in vitro findings were compared to the function of pDC derived from chronic HBV patients ex vivo. In contrast to other viruses, HBV did not activate pDC. Moreover, HBV and HBsAg abrogated CpG-A/TLR9-induced, but not Loxoribine/TLR7-induced, mTOR-mediated S6 phosphorylation, subsequent IRF7 phosphorylation and IFNα gene transcription. HBV/HBsAg also diminished upregulation of co-stimulatory molecules, production of TNFα, IP-10 and IL-6 and pDC-induced NK cell function, whereas TLR7-induced pDC function was hardly affected. In line, HBsAg preferentially bound to TLR9-triggered pDC demonstrating that once pDC are able to bind HBV/HBsAg, the virus exerts its immune regulatory effect. HBV not only directly interfered with pDC function, but also indirectly by interfering with monocyte-pDC interaction. Also HBeAg diminished pDC function to a certain extent, but via another unknown mechanism. Interestingly, patients with HBeAg-positive chronic hepatitis B displayed impaired CpG-induced IFNα production by pDC without significant alterations in Loxoribine-induced pDC function compared to HBeAg-negative patients and healthy controls. The lack of activation and the active inhibition of pDC by HBV may both contribute to HBV persistence. The finding that the interaction between pDC and HBV may change upon activation may aid in the identification of a scavenging receptor supporting immunosuppressive effects of HBV and also in the design of novel treatment strategies for chronic HBV. PMID:21246041

Interaction between the macrophage system and IgA immune complexes in IgA nephropathy.

PubMed

Roccatello, D; Coppo, R; Basolo, B; Martina, G; Rollino, C; Cordonnier, D; Busquet, G; Picciotto, G; Sena, L M; Piccoli, G

1983-01-01

In nine patients with IgA nephropathy, the function of the mononuclear phagocyte system was assessed by measuring in vivo clearance of anti-D coated red blood cells (RBC) and in vitro phagocytosis of sensitised RBC by monocytes. A strict correlation was found between in vivo macrophage function and in vitro monocyte phagocytosis. Statistical correlations were also found between in vivo clearance values and IgAIC and C3d values. A defective macrophage and monocyte function affects patients with major signs of clinical activity, highest IgAIC values, signs of complement activation and the most unfavourable clinical course.

Proposed method to construct Boolean functions with maximum possible annihilator immunity

NASA Astrophysics Data System (ADS)

Goyal, Rajni; Panigrahi, Anupama; Bansal, Rohit

2017-07-01

Nonlinearity and Algebraic(annihilator) immunity are two core properties of a Boolean function because optimum values of Annihilator Immunity and nonlinearity are required to resist fast algebraic attack and differential cryptanalysis respectively. For a secure cypher system, Boolean function(S-Boxes) should resist maximum number of attacks. It is possible if a Boolean function has optimal trade-off among its properties. Before constructing Boolean functions, we fixed the criteria of our constructions based on its properties. In present work, our construction is based on annihilator immunity and nonlinearity. While keeping above facts in mind,, we have developed a multi-objective evolutionary approach based on NSGA-II and got the optimum value of annihilator immunity with good bound of nonlinearity. We have constructed balanced Boolean functions having the best trade-off among balancedness, Annihilator immunity and nonlinearity for 5, 6 and 7 variables by the proposed method.

Immune System Toxicity and Immunotoxicity Hazard Identification

EPA Science Inventory

Exposure to chemicals may alter immune system health, increasing the risk of infections, allergy and autoimmune diseases. The chapter provides a concise overview of the immune system, host factors that affect immune system heal, and the effects that xenobiotic exposure may have ...

Viruses are a dominant driver of protein adaptation in mammals.

PubMed

Enard, David; Cai, Le; Gwennap, Carina; Petrov, Dmitri A

2016-05-17

Viruses interact with hundreds to thousands of proteins in mammals, yet adaptation against viruses has only been studied in a few proteins specialized in antiviral defense. Whether adaptation to viruses typically involves only specialized antiviral proteins or affects a broad array of virus-interacting proteins is unknown. Here, we analyze adaptation in ~1300 virus-interacting proteins manually curated from a set of 9900 proteins conserved in all sequenced mammalian genomes. We show that viruses (i) use the more evolutionarily constrained proteins within the cellular functions they interact with and that (ii) despite this high constraint, virus-interacting proteins account for a high proportion of all protein adaptation in humans and other mammals. Adaptation is elevated in virus-interacting proteins across all functional categories, including both immune and non-immune functions. We conservatively estimate that viruses have driven close to 30% of all adaptive amino acid changes in the part of the human proteome conserved within mammals. Our results suggest that viruses are one of the most dominant drivers of evolutionary change across mammalian and human proteomes.

Viruses are a dominant driver of protein adaptation in mammals

PubMed Central

Enard, David; Cai, Le; Gwennap, Carina; Petrov, Dmitri A

2016-01-01

Viruses interact with hundreds to thousands of proteins in mammals, yet adaptation against viruses has only been studied in a few proteins specialized in antiviral defense. Whether adaptation to viruses typically involves only specialized antiviral proteins or affects a broad array of virus-interacting proteins is unknown. Here, we analyze adaptation in ~1300 virus-interacting proteins manually curated from a set of 9900 proteins conserved in all sequenced mammalian genomes. We show that viruses (i) use the more evolutionarily constrained proteins within the cellular functions they interact with and that (ii) despite this high constraint, virus-interacting proteins account for a high proportion of all protein adaptation in humans and other mammals. Adaptation is elevated in virus-interacting proteins across all functional categories, including both immune and non-immune functions. We conservatively estimate that viruses have driven close to 30% of all adaptive amino acid changes in the part of the human proteome conserved within mammals. Our results suggest that viruses are one of the most dominant drivers of evolutionary change across mammalian and human proteomes. DOI: http://dx.doi.org/10.7554/eLife.12469.001 PMID:27187613

Impaired Subset Progression and Polyfunctionality of T Cells in Mice Exposed to Methamphetamine during Chronic LCMV Infection

PubMed Central

Sriram, Uma; Hill, Beth L.; Cenna, Jonathan M.; Gofman, Larisa; Fernandes, Nicole C.; Haldar, Bijayesh; Potula, Raghava

2016-01-01

Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host’s innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStone™ to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection. Furthermore, we have studied in detail the effects of METH on splenic T cell functions, such as cytokine production and degranulation, and how they regulate each other. We used the Probability State Modeling (PSM) program to visualize the differentiation of effector/memory T cell subsets during LCMV infection and analyze the effects of METH on T cell subset progression. We recently demonstrated that METH increased PD-1 expression on T cells during viral infection. In this study, we further analyzed the impact of PD-1 expression on T cell functional markers as well as its expression in the effector/memory subsets. Overall, our study indicates that analyzing polyfunctionality of T cells can provide additional insight into T cell effector functions. Analysis of T cell heterogeneity is important to highlight changes in the evolution of memory/effector functions during chronic viral infections. Our study also highlights the impact of METH on PD-1 expression and its consequences on T cell responses. PMID:27760221

Impaired Subset Progression and Polyfunctionality of T Cells in Mice Exposed to Methamphetamine during Chronic LCMV Infection.

PubMed

Sriram, Uma; Hill, Beth L; Cenna, Jonathan M; Gofman, Larisa; Fernandes, Nicole C; Haldar, Bijayesh; Potula, Raghava

2016-01-01

Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host's innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStone™ to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection. Furthermore, we have studied in detail the effects of METH on splenic T cell functions, such as cytokine production and degranulation, and how they regulate each other. We used the Probability State Modeling (PSM) program to visualize the differentiation of effector/memory T cell subsets during LCMV infection and analyze the effects of METH on T cell subset progression. We recently demonstrated that METH increased PD-1 expression on T cells during viral infection. In this study, we further analyzed the impact of PD-1 expression on T cell functional markers as well as its expression in the effector/memory subsets. Overall, our study indicates that analyzing polyfunctionality of T cells can provide additional insight into T cell effector functions. Analysis of T cell heterogeneity is important to highlight changes in the evolution of memory/effector functions during chronic viral infections. Our study also highlights the impact of METH on PD-1 expression and its consequences on T cell responses.

Distinctive gene expression profiles characterize donor biopsies from HCV-positive kidney donors.

PubMed

Mas, Valeria R; Archer, Kellie J; Suh, Lacey; Scian, Mariano; Posner, Marc P; Maluf, Daniel G

2010-12-15

Because of the shortage of organs for transplantation, procurement of kidneys from extended criteria donors is inevitable. Frequently, donors infected with hepatitis C virus (HCV) are used. To elucidate an initial compromise of molecular pathways in HCV graft, gene expression profiles were evaluated. Twenty-four donor allograft biopsies (n=12 HCV positive (+) and n=12 HCV negative (-)) were collected at preimplantation time and profiled using microarrays. Donors were age, race, gender, and cold and warm ischemia time matched between groups. Probe level data were read into the R programming environment using the affy Bioconductor package, and the robust multiarray average method was used to obtain probe set expression summaries. To identify probe sets exhibiting differential expression, a two sample t test was performed. Molecular and biologic functions were analyzed using Interaction Networks and Functional Analysis. Fifty-eight probe sets were differentially expressed between HCV (+) versus HCV (-) donors (P<0.001). The molecular functions associated with the two top scored networks from the analysis of the differentially expressed genes were connective tissue development and function and tissue morphology (score 34), cell death, cell signaling, cellular assembly, and organization (score 32). Among the differentially affected top canonical pathways, we found the role of RIG1-like receptors in antiviral innate immunity (P<0.001), natural killer cell signaling (P=0.007), interleukin-8 signaling (P=0.048), interferon signaling (P=0.0 11; INFA21, INFGR1, and MED14), ILK signaling (P=0.001), and apoptosis signaling. A unique gene expression pattern was identified in HCV (+) kidney grafts. Innate immune system and inflammatory pathways were the most affected.

[Effect of polysaccharides in processed Sibiraea on immunologic function of immunosuppression mice].

PubMed

Duan, Bowen; Li, Yun; Liu, Xin; Yang, Yongjian

2010-06-01

To study the effect of polysaccharides in processed Sibiraea on the immunologic function of immunosuppression mice. The immunosuppressed mice were induced by cyclophosphamide. After the treatment, the organ weight index and the delayed type hypersensitivity of the mice were investigated. The humoral immune function was determined by serum hemolysin assay. Non-specific immune function was determined by carbon clearance method. Cellular immune function was determined by spleen lymphocyte proliferation test. Two hundred kunming mice were randomly divided into five groups: normal controls, model group, low-dose group (110 mg x kg(-1)), middle-dose group (220 mg x kg(-1)), high-dose group (440 mg x kg(-1)). Drugs were given to the mice by oral gavage every day. The immunosuppressed mice treated with Sibiraea polysibcharide at intragastrica dose of 110-440 mg x kg(-1) have increased weight of the immune organs, increased content of DTH and content in serum hemolysin lgG and lgM. Mean while the rate of carbon clearance was enhanced and the proliferation of spleen lymphocyte was increased. Polysaccharides in processed Sibiraea can increase the weight of the immune organs. At the same time, non-specific immune, DTH, humoral immune and cellular immune function were enhanced significantly.

In immune defense: redefining the role of the immune system in chronic disease.

PubMed

Rubinow, Katya B; Rubinow, David R

2017-03-01

The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors. Further, the inordinate complexity of immune function renders a simplistic, binary model incapable of capturing critical mechanistic insights. In this perspective article, we propose alternative paradigms for understanding the role of the immune system in chronic disease. By invoking allostasis or systems biology rather than inflammation, we can ascribe greater functional significance to immune mediators, gain newfound appreciation of the adaptive facets of altered immune activity, and better avoid the potentially disastrous effects of translating erroneous assumptions into novel therapeutic strategies.

Can sleep deprivation studies explain why human adults sleep?

PubMed

Brown, Lee K

2012-11-01

This review will concentrate on the consequences of sleep deprivation in adult humans. These findings form a paradigm that serves to demonstrate many of the critical functions of the sleep states. The drive to obtain food, water, and sleep constitutes important vegetative appetites throughout the animal kingdom. Unlike nutrition and hydration, the reasons for sleep have largely remained speculative. When adult humans are nonspecifically sleep-deprived, systemic effects may include defects in cognition, vigilance, emotional stability, risk-taking, and, possibly, moral reasoning. Appetite (for foodstuffs) increases and glucose intolerance may ensue. Procedural, declarative, and emotional memory are affected. Widespread alterations of immune function and inflammatory regulators can be observed, and functional MRI reveals profound changes in regional cerebral activity related to attention and memory. Selective deprivation of rapid eye movement (REM) sleep, on the contrary, appears to be more activating and to have lesser effects on immunity and inflammation. The findings support a critical need for sleep due to the widespread effects on the adult human that result from nonselective sleep deprivation. The effects of selective REM deprivation appear to be different and possibly less profound, and the functions of this sleep state remain enigmatic.

Geographical variation in parasitism shapes larval immune function in a phytophagous insect

NASA Astrophysics Data System (ADS)

Vogelweith, Fanny; Dourneau, Morgane; Thiéry, Denis; Moret, Yannick; Moreau, Jérôme

2013-12-01

Two of the central goals of immunoecology are to understand natural variation in the immune system among populations and to identify those selection pressures that shape immune traits. Maintenance of the immune system can be costly, and both food quality and parasitism selection pressure are factors potentially driving immunocompetence. In tritrophic interactions involving phytophagous insects, host plants, and natural enemies, the immunocompetence of phytophagous insects is constrained by selective forces from both the host plants and the natural enemies. Here, we assessed the roles of host plants and natural enemies as selective pressures on immune variation among natural populations of Lobesia botrana. Our results showed marked geographical variation in immune defenses and parasitism among different natural populations. Larval immune functions were dependent of the host plant quality and were positively correlated to parasitism, suggesting that parasitoids select for greater investment into immunity in moth. Furthermore, investment in immune defense was negatively correlated with body size, suggesting that it is metabolically expensive. The findings emphasize the roles of host plants and parasitoids as selective forces shaping host immune functions in natural conditions. We argue that kinds of study are central to understanding natural variations in immune functions, and the selective forces beyond.

Continuous Dual Resetting of the Immune Repertoire as a Basic Principle of the Immune System Function.

PubMed

Balzar, Silvana

2017-01-01

Idiopathic chronic inflammatory conditions (ICIC) such as allergy, asthma, chronic obstructive pulmonary disease, and various autoimmune conditions are a worldwide health problem. Understanding the pathogenesis of ICIC is essential for their successful therapy and prevention. However, efforts are hindered by the lack of comprehensive understanding of the human immune system function. In line with those efforts, described here is a concept of stochastic continuous dual resetting (CDR) of the immune repertoire as a basic principle that governs the function of immunity. The CDR functions as a consequence of system's thermodynamically determined intrinsic tendency to acquire new states of inner equilibrium and equilibrium against the environment. Consequently, immune repertoire undergoes continuous dual (two-way) resetting: against the physiologic continuous changes of self and against the continuously changing environment. The CDR-based dynamic concept of immunity describes mechanisms of self-regulation, tolerance, and immunosenescence, and emphasizes the significance of immune system's compartmentalization in the pathogenesis of ICIC. The CDR concept's relative simplicity and concomitantly documented congruency with empirical, clinical, and experimental data suggest it may represent a plausible theoretical framework to better understand the human immune system function.

Trade-offs between sexual advertisement and immune function in the pied flycatcher (Ficedula hypoleuca).

PubMed

Kilpimaa, Janne; Alatalo, Rauno V; Siitari, Heli

2004-02-07

Good genes models of sexual selection assume that sexual advertisement is costly and thus the level of advertisement honestly reveals heritable viability. Recently it has been suggested that an important cost of sexual advertisement might be impairment of the functioning of the immune system. In this field experiment we investigated the possible trade-offs between immune function and sexual advertisement by manipulating both mating effort and activity of immune defence in male pied flycatchers. Mating effort was increased in a non-arbitrary manner by removing females from mated males during nest building. Widowed males sustained higher haematocrit levels than control males and showed higher expression of forehead patch height, suggesting that manipulation succeeded in increasing mating effort. Males that were experimentally forced to increase mating effort had reduced humoral immune responsiveness compared with control males. In addition, experimental activation of immune defence by vaccination with novel antigens reduced the expression of male ornament dimensions. To conclude, our results indicate that causality behind the trade-off between immune function and sexual advertisement may work in both directions: sexual activity suppresses immune function but immune challenge also reduces sexual advertisement.

Trade-offs between sexual advertisement and immune function in the pied flycatcher (Ficedula hypoleuca).

PubMed Central

Kilpimaa, Janne; Alatalo, Rauno V.; Siitari, Heli

2004-01-01

Good genes models of sexual selection assume that sexual advertisement is costly and thus the level of advertisement honestly reveals heritable viability. Recently it has been suggested that an important cost of sexual advertisement might be impairment of the functioning of the immune system. In this field experiment we investigated the possible trade-offs between immune function and sexual advertisement by manipulating both mating effort and activity of immune defence in male pied flycatchers. Mating effort was increased in a non-arbitrary manner by removing females from mated males during nest building. Widowed males sustained higher haematocrit levels than control males and showed higher expression of forehead patch height, suggesting that manipulation succeeded in increasing mating effort. Males that were experimentally forced to increase mating effort had reduced humoral immune responsiveness compared with control males. In addition, experimental activation of immune defence by vaccination with novel antigens reduced the expression of male ornament dimensions. To conclude, our results indicate that causality behind the trade-off between immune function and sexual advertisement may work in both directions: sexual activity suppresses immune function but immune challenge also reduces sexual advertisement. PMID:15058434

Reproduction Alters Hydration State but Does Not Impact the Positive Effects of Dehydration on Innate Immune Function in Children's Pythons (Antaresia childreni).

PubMed

Brusch, George A; Billy, Gopal; Blattman, Joseph N; DeNardo, Dale F

Resource availability can impact immune function, with the majority of studies of such influences focusing on the allocation of energy investment into immune versus other physiological functions. When energy is a limited resource, performance trade-offs can result, compromising immunity. Dehydration is also considered a physiological challenge resulting from the limitation of a vital resource, yet previous research has found a positive relationship between dehydration and innate immune performance. However, these studies did not examine the effects of dehydration on immunity when there was another concurrent, substantial physiological challenge. Thus, we examined the impact of reproduction and water deprivation, individually and in combination, on immune performance in Children's pythons (Antaresia childreni). We collected blood samples from free-ranging A. childreni to evaluate osmolality and innate immune function (lysis, agglutination, bacterial growth inhibition) during the austral dry season, when water availability is limited and this species is typically reproducing. To examine how reproduction and water imbalance, both separately and combined, impact immune function, we used a laboratory-based 2 × 2 experiment. Our results demonstrate that A. childreni experience significant dehydration during the dry season and that, overall, osmolality, regardless of the underlying cause (seasonal rainfall, water deprivation, or reproduction), is positively correlated with increased innate immune performance.

Space flight and the immune system

NASA Technical Reports Server (NTRS)

Cogoli, A.

1993-01-01

Depression of lymphocyte response to mitogens in cosmonauts after space flight was reported for the first time in the early 1970s by Soviet immunologists. Today we know that depression of lymphocyte function affects at least 50% of space crew members. Investigations on the ground on subjects undergoing physical and psychological stress indicate that stress is a major factor in immune depression of astronauts. This is despite the fact that weightlessness per se has a strong inhibitory effect on lymphocyte activation in vitro. Although the changes observed never harmed the health of astronauts, immunological changes must be seriously investigated and understood in view of long-duration flight on space stations in an Earth orbit, to other planets such as Mars and to the Moon.

Autophagy plays an important role in protecting Pacific oysters from OsHV-1 and Vibrio aestuarianus infections

PubMed Central

Moreau, Pierrick; Moreau, Kevin; Segarra, Amélie; Tourbiez, Delphine; Travers, Marie-Agnès; Rubinsztein, David C; Renault, Tristan

2015-01-01

Recent mass mortality outbreaks around the world in Pacific oysters, Crassostrea gigas, have seriously affected the aquaculture economy. Although the causes for these mortality outbreaks appear complex, infectious agents are involved. Two pathogens are associated with mass mortality outbreaks, the virus ostreid herpesvirus 1 (OsHV-1) and the bacterium Vibrio aestuarianus. Here we describe the interactions between these 2 pathogens and autophagy, a conserved intracellular pathway playing a key role in innate immunity. We show for the first time that autophagy pathway is present and functional in Pacific oysters and plays an important role to protect animals from infections. This study contributes to better understand the innate immune system of Pacific oysters. PMID:25714877

Autophagy plays an important role in protecting Pacific oysters from OsHV-1 and Vibrio aestuarianus infections.

PubMed

Moreau, Pierrick; Moreau, Kevin; Segarra, Amélie; Tourbiez, Delphine; Travers, Marie-Agnès; Rubinsztein, David C; Renault, Tristan

2015-01-01

Recent mass mortality outbreaks around the world in Pacific oysters, Crassostrea gigas, have seriously affected the aquaculture economy. Although the causes for these mortality outbreaks appear complex, infectious agents are involved. Two pathogens are associated with mass mortality outbreaks, the virus ostreid herpesvirus 1 (OsHV-1) and the bacterium Vibrio aestuarianus. Here we describe the interactions between these 2 pathogens and autophagy, a conserved intracellular pathway playing a key role in innate immunity. We show for the first time that autophagy pathway is present and functional in Pacific oysters and plays an important role to protect animals from infections. This study contributes to better understand the innate immune system of Pacific oysters.

Animal Viruses, Bacteria, and Cancer: A Brief Commentary

PubMed Central

Efird, Jimmy T.; Davies, Stephen W.; O’Neal, Wesley T.; Anderson, Ethan J.

2014-01-01

Animal viruses and bacteria are ubiquitous in the environment. However, little is known about their mode of transmission and etiologic role in human cancers, especially among high-risk groups (e.g., farmers, veterinarians, poultry plant workers, pet owners, and infants). Many factors may affect the survival, transmissibility, and carcinogenicity of these agents, depending on the animal-host environment, hygiene practices, climate, travel, herd immunity, and cultural differences in food consumption and preparation. Seasonal variations in immune function also may increase host susceptibility at certain times of the year. The lack of objective measures, inconsistent study designs, and sources of epidemiologic bias (e.g., residual confounding, recall bias, and non-randomized patient selection) are some of the factors that complicate a clear understanding of this subject. PMID:24592380

Inflammatory response, growth, and thyroid hormone concentrations are affected by long-term boron supplementation in gilts.

PubMed

Armstrong, T A; Spears, J W; Lloyd, K E

2001-06-01

An experiment was conducted to determine the long-term effects of dietary boron (B) on growth performance, immune function, and plasma and serum characteristics in gilts. Fifty weanling gilts were allotted to 10 pens based on weaning weight and litter origin. Pens were randomly assigned to receive one of two dietary treatments. Treatments consisted of a basal diet low in B (control) and the basal diet supplemented with 5 mg B/kg diet as sodium borate. Gilts remained on their respective experimental diets and with their penmates throughout the nursery, growing, and finishing phases. The B concentration of the basal diet was 0.98, 2.1, and 2.2 mg/kg diet during the nursery, growing, and finishing phases, respectively. At the end of each production phase, animals were weighed and feed consumption was determined to assess growth performance variables. In addition, blood samples were obtained from three randomly selected gilts per pen at the completion of each phase. Boron had no affect (P > 0.58) on growth performance during the nursery phase, but gilts receiving supplemental B had increased (P < 0.05) ADG at the end of the finishing phase and over the entire growing-finishing period. Serum concentrations of triiodothyronine (T3) tended (P < 0.07) to be reduced by dietary B at the end of the nursery phase, but serum thyroxine (T4) was not affected (P = 0.46) by B. At the completion of the growing phase, supplemental B decreased (P < 0.05) the concentrations of T3 and T4 in the serum. In addition, serum concentrations of total cholesterol and the activity of alkaline phosphatase were increased (P < 0.05) by dietary B at the end of the growing phase. Serum concentrations of urea N tended (P < 0.09) to be increased by B at the end of the growing phase. Beginning at d 95 of the experimental period, measures of immune function were assessed in randomly selected gilts. Boron decreased (P < 0.05) the inflammatory response to an intradermal injection of phytohemagglutinin. Boron did not affect (P > 0.30) the blastogenic response of isolated lymphocytes to mitogen stimulation or the humoral immune response against a sheep red blood cell suspension. Results indicate that B may affect serum thyroid hormone concentrations, the inflammatory response, and growth in pigs.

Consequences of Longterm-Confinement and Hypobaric Hypoxia on Immunity in the Antarctic Concordia Environment

NASA Technical Reports Server (NTRS)

Crucian, Brian; Chouker, Alexander; Pierson, Duane; Mehta, Satish; Stowe, Raymond; Salam, Alex; Sams, Clarence

2010-01-01

This slide presentation reviews the affects of longterm-confinement and hypobaric hypoxia on immunity in the Antarctic Concordia environment. It includes information on spaceflight-associated immune dysregulation, immune-related knowledge gaps, and ground-based space flight analogs.

[Environmental pollutants as adjuvant factors of immune system derived diseases].

PubMed

Lehmann, Irina

2017-06-01

The main task of the immune system is to protect the body against invading pathogens. To be able to do so, immune cells must be able to recognize and combat exogenous challenges and at the same time tolerate body-borne structures. A complex regulatory network controls the sensitive balance between defense and tolerance. Perturbation of this network ultimately leads to the development of chronic inflammation, such as allergies, autoimmune reactions, and infections, because the immune system is no longer able to efficiently eliminate invading pathogens. Environmental pollutants can cause such perturbations by affecting the function of immune cells in such a way that they would react hypersensitively against allergens and the body's own structures, respectively, or that they would be no longer able to adequately combat pathogens. This indirect effect is also known as adjuvant effect. For pesticides, heavy metals, wood preservatives, or volatile organic compounds such adjuvant effects are well known. Examples of the mechanism by which environmental toxins contribute to chronic inflammatory diseases are manifold and will be discussed along asthma and allergies.While the immune system of healthy adults is typically well able to distinguish between foreign and endogenous substances even under adverse environmental conditions, that of children would react much more sensible upon comparable environmental challenges. To prevent priming for diseases by environmental cues during that highly sensitive period of early childhood children are to be particularly protected.

Immune defense in leaf-cutting ants: a cross-fostering approach.

PubMed

Armitage, Sophie A O; Broch, Jens F; Marín, Hermogenes Fernández; Nash, David R; Boomsma, Jacobus J

2011-06-01

To ameliorate the impact of disease, social insects combine individual innate immune defenses with collective social defenses. This implies that there are different levels of selection acting on investment in immunity, each with their own trade-offs. We present the results of a cross-fostering experiment designed to address the influences of genotype and social rearing environment upon individual and social immune defenses. We used a multiply mating leaf-cutting ant, enabling us to test for patriline effects within a colony, as well as cross-colony matriline effects. The worker's father influenced both individual innate immunity (constitutive antibacterial activity) and the size of the metapleural gland, which secretes antimicrobial compounds and functions in individual and social defense, indicating multiple mating could have important consequences for both defense types. However, the primarily social defense, a Pseudonocardia bacteria that helps to control pathogens in the ants' fungus garden, showed a significant colony of origin by rearing environment interaction, whereby ants that acquired the bacteria of a foster colony obtained a less abundant cover of bacteria: one explanation for this pattern would be co-adaptation between host colonies and their vertically transmitted mutualist. These results illustrate the complexity of the selection pressures that affect the expression of multilevel immune defenses. © 2011 The Author(s). Evolution© 2011 The Society for the Study of Evolution.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

PubMed Central

Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

2016-01-01

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

Epigenetic Regulation of Non-Lymphoid Cells by Bisphenol A, a Model Endocrine Disrupter: Potential Implications for Immunoregulation

PubMed Central

Khan, Deena; Ahmed, S. Ansar

2015-01-01

Endocrine disrupting chemicals (EDC) abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical, and consumer product industries. Many of the EDCs such as Bisphenol A (BPA) have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth, and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation, and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight the BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non-lymphoid cells is emphasized. We recognize that most of these studies are on non-lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system. PMID:26097467

Quantitative genetics of immunity and life history under different photoperiods.

PubMed

Hammerschmidt, K; Deines, P; Wilson, A J; Rolff, J

2012-05-01

Insects with complex life-cycles should optimize age and size at maturity during larval development. When inhabiting seasonal environments, organisms have limited reproductive periods and face fundamental decisions: individuals that reach maturity late in season have to either reproduce at a small size or increase their growth rates. Increasing growth rates is costly in insects because of higher juvenile mortality, decreased adult survival or increased susceptibility to parasitism by bacteria and viruses via compromised immune function. Environmental changes such as seasonality can also alter the quantitative genetic architecture. Here, we explore the quantitative genetics of life history and immunity traits under two experimentally induced seasonal environments in the cricket Gryllus bimaculatus. Seasonality affected the life history but not the immune phenotypes. Individuals under decreasing day length developed slower and grew to a bigger size. We found ample additive genetic variance and heritability for components of immunity (haemocyte densities, proPhenoloxidase activity, resistance against Serratia marcescens), and for the life history traits, age and size at maturity. Despite genetic covariance among traits, the structure of G was inconsistent with genetically based trade-off between life history and immune traits (for example, a strong positive genetic correlation between growth rate and haemocyte density was estimated). However, conditional evolvabilities support the idea that genetic covariance structure limits the capacity of individual traits to evolve independently. We found no evidence for G × E interactions arising from the experimentally induced seasonality.

Relationship between energy dense diets and white adipose tissue inflammation in metabolic syndrome.

PubMed

Alemany, Marià

2013-01-01

Metabolic syndrome (MS) is a widespread pathologic state that manifests as multiple intertwined diseases affecting the entire body. This review analyzes the contribution of adipose tissue inflammation to its development. The main factor in the appearance of MS is an excess of dietary energy (largely fats), eliciting insulin resistance and creating the problem of excess energy disposal. Under these conditions, amino acid catabolism is diminished, which indirectly alters the production of nitric oxide and affects blood flow regulation. The oxidation of nitric oxide to nitrite and nitrate affects microbiota composition and functions. Adipose tissue cannot incorporate excessive nutrients after cell enlargement and loss of function. Tissue damage is a form of aggression, and the response is proinflammatory cytokine release. Cytokines favor the massive penetration of immune system cells, such as macrophages, which unsuccessfully try to fight an elusive danger for which they are not prepared. The consequence is low-level maintenance of the inflammatory state, which affects endoplasmic reticulum function and the endothelial response to excess regulatory mechanisms affecting blood flow and substrate/oxygen supply. When inflammation becomes chronic, the pathologic consequences are disseminated throughout the body because unused substrates and signals from adipose tissue affect energy partitioning and organ function. This maintenance of an unbalanced state ultimately results in the establishment of MS and associated pathologies. New research should focus on identifying ways to disarm the inflammatory response of adipose tissue when the dangers of dietary excess have already been controlled. Copyright © 2013. Published by Elsevier Inc.

Histomorphology and innate immunity during the progression of osteoarthritis: Does synovitis affect cartilage degradation?

PubMed

Wang, Huan; Wang, Qingguo; Yang, Meijuan; Yang, Lili; Wang, Weili; Ding, Haobin; Zhang, Dong; Xu, Jing; Tang, Xuezhang; Ding, Haitao; Wang, Qingfu

2018-02-01

Osteoarthritis (OA) is a common chronic degenerative disease that affects all joints. At present, the pathological processes and mechanisms of OA are still unclear. Innate immunity, a key player in damage to the structure of the joint and the mechanism by which the host attempts to repair OA, affects all pathological stages of the disease. In the present study, our aim was to assess changes in innate immunity during the pathological processes of OA in articular cartilage (AC) and the synovial membrane (SM), which are the major structures in joints, and to systematically examine the histological changes in AC and SM in mild, moderate and severe cases of OA, in order to further speculate about the manner in which the interactions of AC and SM are facilitated by innate immunity. Histological methods (including HE and Safranin O-fast green staining), immunofluorescent double staining, TUNEL stain, and Western blots were used to assess the morphological changes within AC and SM tissues in healthy and mild, moderate, or severe OA rats. Our results showed that the damage to AC and SM within the joints progressively worsened in different degrees during the course of the disease, and that the innate immune system was closely involved in the AC and SM during each stage of OA. These findings also confirmed that SM may affect the pathological changes in AC through the innate immune system, and therefore affect the progress of OA. © 2017 Wiley Periodicals, Inc.

Validation of Procedures for Monitoring Crewmember Immune Function - Short Duration Biological Investigation

NASA Technical Reports Server (NTRS)

Sams, Clarence; Crucian, Brian; Stowe, Raymond; Pierson, Duane; Mehta, Satish; Morukov, Boris; Uchakin, Peter; Nehlsen-Cannarella, Sandra

2008-01-01

Validation of Procedures for Monitoring Crew Member Immune Function - Short Duration Biological Investigation (Integrated Immune-SDBI) will assess the clinical risks resulting from the adverse effects of space flight on the human immune system and will validate a flightcompatible immune monitoring strategy. Immune system changes will be monitored by collecting and analyzing blood, urine and saliva samples from crewmembers before, during and after space flight.

Computational immune profiling in lung adenocarcinoma reveals reproducible prognostic associations with implications for immunotherapy

PubMed Central

Varn, Frederick S.; Tafe, Laura J.; Amos, Christopher I.; Cheng, Chao

2018-01-01

ABSTRACT Non-small cell lung cancer is one of the leading causes of cancer-related death in the world. Lung adenocarcinoma, the most common type of non-small cell lung cancer, has been well characterized as having a dense lymphocytic infiltrate, suggesting that the immune system plays an active role in shaping this cancer's growth and development. Despite these findings, our understanding of how this infiltrate affects patient prognosis and its association with lung adenocarcinoma-specific clinical factors remains limited. To address these questions, we inferred the infiltration level of six distinct immune cell types from a series of four lung adenocarcinoma gene expression datasets. We found that naive B cell, CD8+ T cell, and myeloid cell-derived expression signals of immune infiltration were significantly predictive of patient survival in multiple independent datasets, with B cell and CD8+ T cell infiltration associated with prolonged prognosis and myeloid cell infiltration associated with shorter survival. These associations remained significant even after accounting for additional clinical variables. Patients stratified by smoking status exhibited decreased CD8+ T cell infiltration and altered prognostic associations, suggesting potential immunosuppressive mechanisms in smokers. Survival analyses accounting for immune checkpoint gene expression and cellular immune infiltrate indicated checkpoint protein-specific modulatory effects on CD8+ T cell and B cell function that may be associated with patient sensitivity to immunotherapy. Together, these analyses identified reproducible associations that can be used to better characterize the role of immune infiltration in lung adenocarcinoma and demonstrate the utility in using computational approaches to systematically characterize tissue-specific tumor-immune interactions. PMID:29872556

Homeostasis of the gut barrier and potential biomarkers.

PubMed

Wells, Jerry M; Brummer, Robert J; Derrien, Muriel; MacDonald, Thomas T; Troost, Freddy; Cani, Patrice D; Theodorou, Vassilia; Dekker, Jan; Méheust, Agnes; de Vos, Willem M; Mercenier, Annick; Nauta, Arjen; Garcia-Rodenas, Clara L

2017-03-01

The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of secretory IgA (sIgA) and antimicrobial peptides and proteins. With the exception of sIgA, expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions through the production of short-chain fatty acids (SCFAs) and interactions with innate pattern recognition receptors in the mucosa, driving the steady-state expression of mucus and antimicrobial factors. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability, and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of a variety of gastrointestinal disorders. Additionally, gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the hypothalamus-pituitary-adrenal axis and both mast cell-dependent and mast cell-independent mechanisms. The modulation of gut barrier function through nutritional interventions, including strategies to manipulate the microbiota, is considered a relevant target for novel therapeutic and preventive treatments against a range of diseases. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in intestinal diseases, but there remains a need to explore their use in assessing the effect of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of available biomarkers and their predictive value for gut health in human cohorts. Copyright © 2017 the American Physiological Society.

Immunotoxicity assessment for the novel Spleen tyrosine kinase inhibitor R406

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu Yanhong; Herlaar, Ellen; Masuda, Esteban S.

2007-06-15

Spleen tyrosine kinase (Syk) is a novel pharmaceutical target for treatment of allergic, autoimmune, and neoplastic disorders. Previous studies have indicated that Syk signaling plays critical roles in regulating the lymphohematopoietic system. These observations prompted us to investigate whether inhibition of Syk would promote immunotoxicity. In a series of studies, rats were treated orally with R406, at dose levels up to and including 100 mg/kg/day (or its prodrug R788 at dose levels up to and including 100 mg/kg/day, reduced to 50 mg/kg/day for females as MTD was exceeded), a potent Syk inhibitor, twice daily for 28 days. In addition tomore » standard toxicological assessments, immunophenotyping by flow cytometric analysis, and a study of humoral immune response measuring anti-KLH IgM and IgG levels, were undertaken. Other immunotoxicity studies included three host resistance models in female Balb/c mice to further ascertain effects of R406 on innate and acquired immunity. Following R406 treatment, expected immunomodulating effects (e.g., decreased thymic and spleen weight, hypocellularity of bone marrow, and reduced lymphocyte counts, including T and B cells) were observed in the rat studies. These changes essentially resolved during a 14-day treatment-free recovery period. A KLH challenge in rats demonstrated no adverse effects on IgG or IgM response. R788/406, administered orally at dose levels up to and including 80 mg/kg/day for 28 days, did not affect bacterial or viral clearance in the Listeria, Streptococcal, or Influenza host resistance mouse models, respectively. This correlated with previous in vitro macrophage and neutrophil function assays (assessing migration, phagocytosis, oxidative burst and microbicidal activity), which revealed that R406 did not adversely affect macrophage or neutrophil function in innate immune responses. Collectively, these results demonstrate that R406 has minimal functional immunotoxicity notwithstanding its lymphocytopenic effect, suggesting that inhibition of Syk might not lead to unacceptable mechanism-based adverse effects.« less

Effect of Dietary Vitamin A on Reproductive Performance and Immune Response of Broiler Breeders

PubMed Central

Guo, Yuming; Wang, Yongwei; Guo, Shuangshuang

2014-01-01

The effects of dietary vitamin A supplementation on reproductive performance, liver function, fat-soluble vitamin retention, and immune response were studied in laying broiler breeders. In the first phase of the experiment, 1,120 Ross-308 broiler breeder hens were fed a diet of corn and soybean meal supplemented with 5,000 to 35,000 IU/kg vitamin A (retinyl acetate) for 20 weeks. In the second phase, 384 Ross-308 broiler breeder hens were fed the same diet supplemented with 5,000 to 135,000 IU/kg vitamin A (retinyl acetate) for 24 weeks. The hens' reproductive performance, the concentrations of vitamins A and E in liver and egg yolk, liver function, mRNA expression of vitamin D receptor in duodenal mucosa, antibody titers against Newcastle disease virus vaccine, and T-cell proliferation responses were evaluated. Supplementation of vitamin A at levels up to and including 35,000 IU/kg did not affect reproductive performance and quadratically affected antibody titer to Newcastle disease virus vaccine (p<0.05). Dietary addition of vitamin A linearly increased vitamin A concentration in liver and yolk and linearly decreased α-, γ-, and total tocopherol concentration in yolk (p<0.01) and α-tocopherol in liver (p<0.05). Supplementation of vitamin A at doses of 45,000 IU/kg and above significantly decreased egg weight, yolk color, eggshell thickness and strength, and reproductive performance. Dietary vitamin A significantly increased mRNA expression of vitamin D receptor in duodenal mucosa (p<0.05), increased aspartate amino transferase activity, and decreased total bilirubin concentration in serum. Supplementation of vitamin A at 135,000 IU/kg decreased the proliferation of peripheral blood lymphocytes (p<0.05). Therefore, the maximum tolerable dose of vitamin A for broiler breeders appears to be 35,000 IU/kg, as excessive supplementation has been shown to impair liver function, reproductive performance, and immune response. PMID:25148198