Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X Syndrome

PubMed Central

Yuskaitis, Christopher J.; Beurel, Eleonore; Jope, Richard S.

2010-01-01

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is one of the few known genetic causes of autism. FXS results from the loss of Fmr1 gene function, thus Fmr1 knockout mice provide a model to study impairments associated with FXS and autism and to test potential therapeutic interventions. The inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3) is lower in brain regions of Fmr1 knockout mice than wild-type mice and the GSK3 inhibitor lithium rescues several behavioral impairments in Fmr1 knockout mice. Therefore, we examined if the serine-phosphorylation of GSK3 in Fmr1 knockout mice also was altered outside the brain and if administration of lithium ameliorated the macroorchidism phenotype. Additionally, since GSK3 regulates numerous functions of the immune system and immune alterations have been associated with autism, we tested if immune function is altered in Fmr1 knockout mice. The inhibitory serine-phosphorylation of GSK3 was significantly lower in the testis and liver of Fmr1 knockout mice than wild-type mice, and chronic lithium treatment reduced macroorchidism in Fmr1 knockout mice. No alterations in peripheral immune function were identified in Fmr1 knockout mice. However, examination of glia, the immune cells of the brain, revealed reactive astrocytes in several brain regions of Fmr1 knockout mice and treatment with lithium reduced this in the striatum and cerebellum. These results provide further evidence of the involvement of dysregulated GSK3 in FXS, and demonstrate that lithium administration reduces macroorchidism and reactive astrocytes in Fmr1 knockout mice. PMID:20600866

Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1

PubMed Central

Patera, Andriani C.; Drewry, Anne M.; Chang, Katherine; Beiter, Evan R.; Osborne, Dale; Hotchkiss, Richard S.

2016-01-01

Sepsis is a heterogeneous syndrome comprising a highly diverse and dynamic mixture of hyperinflammatory and compensatory anti-inflammatory immune responses. This immune phenotypic diversity highlights the importance of proper patient selection for treatment with the immunomodulatory drugs that are entering clinical trials. To better understand the serial changes in immunity of critically ill patients and to evaluate the potential efficacy of blocking key inhibitory pathways in sepsis, we undertook a broad phenotypic and functional analysis of innate and acquired immunity in the same aliquot of blood from septic, critically ill nonseptic, and healthy donors. We also tested the ability of blocking the checkpoint inhibitors programmed death receptor-1 (PD-1) and its ligand (PD-L1) to restore the function of innate and acquired immune cells. Neutrophil and monocyte function (phagocytosis, CD163, cytokine expression) were progressively diminished as sepsis persisted. An increasing frequency in PD-L1+-suppressor phenotype neutrophils [low-density neutrophils (LDNs)] was also noted. PD-L1+ LDNs and defective neutrophil function correlated with disease severity, consistent with the potential importance of suppressive neutrophil populations in sepsis. Reduced neutrophil and monocyte function correlated both with their own PD-L1 expression and with PD-1 expression on CD8+ T cells and NK cells. Conversely, reduced CD8+ T cell and NK cell functions (IFN-γ production, granzyme B, and CD107a expression) correlated with elevated PD-L1+ LDNs. Importantly, addition of antibodies against PD-1 or PD-L1 restored function in neutrophil, monocyte, T cells, and NK cells, underlining the impact of the PD-1:PD-L1 axis in sepsis-immune suppression and the ability to treat multiple deficits with a single immunomodulatory agent. PMID:27671246

Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees

PubMed Central

Steinmann, Nadja; Corona, Miguel; Neumann, Peter; Dainat, Benjamin

2015-01-01

The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee’s susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions. PMID:26121358

Chronic exposure to dim light at night suppresses immune responses in Siberian hamsters.

PubMed

Bedrosian, Tracy A; Fonken, Laura K; Walton, James C; Nelson, Randy J

2011-06-23

Species have been adapted to specific niches optimizing survival and reproduction; however, urbanization by humans has dramatically altered natural habitats. Artificial light at night (LAN), termed 'light pollution', is an often overlooked, yet increasing disruptor of habitats, which perturbs physiological processes that rely on precise light information. For example, LAN alters the timing of reproduction and activity in some species, which decreases the odds of successful breeding and increases the threat of predation for these individuals, leading to reduced fitness. LAN also suppresses immune function, an important proxy for survival. To investigate the impact of LAN in a species naive to light pollution in its native habitat, immune function was examined in Siberian hamsters derived from wild-caught stock. After four weeks exposure to dim LAN, immune responses to three different challenges were assessed: (i) delayed-type hypersensitivity (DTH), (ii) lipopolysaccharide-induced fever, and (iii) bactericide activity of blood. LAN suppressed DTH response and reduced bactericide activity of blood after lipopolysaccharide treatment, in addition to altering daily patterns of locomotor activity, suggesting that human encroachment on habitats via night-time lighting may inadvertently compromise immune function and ultimately fitness.

Impaired interferon signaling is a common immune defect in human cancer

PubMed Central

Critchley-Thorne, Rebecca J.; Simons, Diana L.; Yan, Ning; Miyahira, Andrea K.; Dirbas, Frederick M.; Johnson, Denise L.; Swetter, Susan M.; Carlson, Robert W.; Fisher, George A.; Koong, Albert; Holmes, Susan; Lee, Peter P.

2009-01-01

Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-α)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-γ)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction. PMID:19451644

Pneumococcal Capsular Polysaccharide Immunity in the Elderly

PubMed Central

Ferreira, Daniela M.; Gordon, Stephen B.; Rylance, Jamie

2017-01-01

ABSTRACT Immunity to pneumococcal infections is impaired in older people, and current vaccines are poorly protective against pneumococcal disease in this population. Naturally acquired immunity to pneumococcal capsular polysaccharides develops during childhood and is robust in young adults but deteriorates with advanced age. In particular, antibody levels and function are reduced in older people. Pneumococcal vaccines are recommended for people >65 years old. However, the benefits of polysaccharide and protein-conjugated vaccines in this population are small, because of both serotype replacement and incomplete protection against vaccine serotype pneumococcal disease. In this review, we overview the immune mechanisms by which naturally acquired and vaccine-induced pneumococcal capsular polysaccharide immunity declines with age, including altered colonization dynamics, reduced opsonic activity of antibodies (particularly IgM), and impaired mucosal immunity. PMID:28424198

Caloric Restriction reduces inflammation and improves T cell-mediated immune response in obese mice but concomitant consumption of curcumin/piperine adds no further benefit

USDA-ARS?s Scientific Manuscript database

Obesity is associated with low-grade inflammation and impaired immune response. Caloric restriction (CR) has been shown to inhibit inflammatory response and enhance cell-mediated immune function. Curcumin, the bioactive phenolic component of turmeric spice, is proposed to have anti-obesity and anti-...

Lactobacillus johnsonii Supplementation Attenuates Respiratory Viral Infection via Metabolic Reprogramming and Immune Cell Modulation

PubMed Central

Fonseca, Wendy; Lucey, Kaitlyn; Jang, Sihyug; Fujimura, Kei E.; Rasky, Andrew; Ting, Hung-An; Petersen, Julia; Johnson, Christine C.; Boushey, Homer A.; Zoratti, Edward; Ownby, Dennis R.; Levine, Albert M.; Bobbit, Kevin R.

2017-01-01

Summary Regulation of respiratory mucosal immunity by microbial-derived metabolites has been a proposed mechanism that may provide airway protection. Here we examine the effect of oral Lactobacillus johnsonii-supplementation on metabolic and immune response dynamics during respiratory syncytial virus (RSV) infection. L. johnsonii-supplementation reduced airway Th2 cytokines, dendritic cell function, increased T-regulatory cells, and was associated with a reprogrammed circulating metabolic environment, including docosahexanoic acid (DHA) enrichment. RSV-infected bone-marrow derived dendritic cells (BMDC) from L. johnsonii-supplemented mice had altered cytokine secretion, reduced expression of co-stimulatory molecules, and modified CD4+ T cell cytokines. This was replicated upon co-incubation of wild-type BMDCs with either plasma from L. johnsonii-supplemented mice, or DHA. Finally, airway transfer of BMDCs from L. johnsonii-supplemented mice, or with wild-type derived BMDCs pre-treated with plasma from L. johnsonii-supplemented mice, reduced airway pathologic responses to infection in recipient animals. Thus, L. johnsonii-supplementation mediates airway mucosal protection via immunomodulatory metabolites and altered immune function. PMID:28295020

Lactobacillus johnsonii supplementation attenuates respiratory viral infection via metabolic reprogramming and immune cell modulation.

PubMed

Fonseca, W; Lucey, K; Jang, S; Fujimura, K E; Rasky, A; Ting, H-A; Petersen, J; Johnson, C C; Boushey, H A; Zoratti, E; Ownby, D R; Levine, A M; Bobbit, K R; Lynch, S V; Lukacs, N W

2017-11-01

Regulation of respiratory mucosal immunity by microbial-derived metabolites has been a proposed mechanism that may provide airway protection. Here we examine the effect of oral Lactobacillus johnsonii supplementation on metabolic and immune response dynamics during respiratory syncytial virus (RSV) infection. L. johnsonii supplementation reduced airway T helper type 2 cytokines and dendritic cell (DC) function, increased regulatory T cells, and was associated with a reprogrammed circulating metabolic environment, including docosahexanoic acid (DHA) enrichment. RSV-infected bone marrow-derived DCs (BMDCs) from L. johnsonii-supplemented mice had altered cytokine secretion, reduced expression of co-stimulatory molecules, and modified CD4+ T-cell cytokines. This was replicated upon co-incubation of wild-type BMDCs with either plasma from L. johnsonii-supplemented mice or DHA. Finally, airway transfer of BMDCs from L. johnsonii-supplemented mice or with wild-type derived BMDCs pretreated with plasma from L. johnsonii-supplemented mice reduced airway pathological responses to infection in recipient animals. Thus L. johnsonii supplementation mediates airway mucosal protection via immunomodulatory metabolites and altered immune function.

Immunological hazards from nutritional imbalance in athletes.

PubMed

Shephard, R J; Shek, P N

1998-01-01

This review examines the influences of nutritional imbalance on immune function of competitive athletes, who may adopt an unusual diet in an attempt to enhance performance. A major increase in body fat can have adverse effects on immune response. In contrast, a negative energy balance and reduction of body mass are likely to impair immune function in an already thin athlete. A moderate increase in polyunsaturated fat enhances immune function, but excessive consumption can be detrimental. Since endurance exercise leads to protein catabolism, an athlete may need 2.0 g/kg protein rather than the 0.7-1.0 g/kg recommended for a sedentary individual. Both sustained exercise and overtraining reduce plasma glutamine levels, which may contribute to suppressed immune function postexercise. A large intake of carbohydrate counters glutamine depletion but may also modify immune responses by altering the secretion of glucose-regulating hormones. Vitamins are important to immune function because of their antioxidant role. However, the clinical benefits of vitamin C supplementation are not enhanced by the use of more complex vitamin mixtures, and excessive vitamin E can have negative effects. Iron, selenium, zinc, calcium, and magnesium ion all influence immune function. Supplements may be required after heavy sweating, but an excessive intake of iron facilitates bacterial growth. In making dietary recommendations to athletes, it is important to recognize that immune response can be jeopardized not only by deficiencies but also by excessive intake of certain nutrients. The goal should be a well-balanced diet.

Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM.

PubMed

Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae

2008-01-01

The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans. Copyright (c) 2007 John Wiley & Sons, Ltd.

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function.

PubMed

Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J; He, Wei; Voss, Oliver H; Gonzalez-Mejia, M Elba; Guttridge, Denis C; Grotewold, Erich; Doseff, Andrea I

2016-03-01

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo.

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.

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.

Social isolation disrupts innate immune responses in both male and female prairie voles and enhances agonistic behavior in female prairie voles (Microtus ochrogaster).

PubMed

Scotti, Melissa-Ann L; Carlton, Elizabeth D; Demas, Gregory E; Grippo, Angela J

2015-04-01

Psychosocial stress, specifically social isolation, is an important risk factor for the development of a variety of psychological and physiological disorders. Changes in immune function have been hypothesized to mediate this relationship. The current study used the prairie vole (Microtus ochrogaster) model of isolation-induced depressive-like behavior to test whether social isolation led to changes in innate immune function. Specifically, we used hemolytic complement (CH50) and bacteria killing assays to assess innate immunity, in paired or singly housed male and female prairie voles. Further, in a second experiment we tested whether females exposed to an additional short-term social stressor, a resident-intruder trial, would show changes in immune function as well as enhanced hypothalamic pituitary axis (HPA) activity as indicated by elevated plasma corticosterone levels. Socially isolated animals, regardless of sex, had significantly reduced CH50s and bacteria killing ability. Socially isolated females exposed to a resident-intruder stressor also showed reduced CH50s and bacteria killing ability as well as significant increases in aggressive behavior, however, they did not show elevated circulating corticosterone levels. Collectively, these data will help inform our understanding of the relationship between social isolation and physiological and psychological health. Copyright © 2015 Elsevier Inc. All rights reserved.

The immune system in children with malnutrition--a systematic review.

PubMed

Rytter, Maren Johanne Heilskov; Kolte, Lilian; Briend, André; Friis, Henrik; Christensen, Vibeke Brix

2014-01-01

Malnourished children have increased risk of dying, with most deaths caused by infectious diseases. One mechanism behind this may be impaired immune function. However, this immune deficiency of malnutrition has not previously been systematically reviewed. To review the scientific literature about immune function in children with malnutrition. A systematic literature search was done in PubMed, and additional articles identified in reference lists and by correspondence with experts in the field. The inclusion criteria were studies investigating immune parameters in children aged 1-60 months, in relation to malnutrition, defined as wasting, underweight, stunting, or oedematous malnutrition. The literature search yielded 3402 articles, of which 245 met the inclusion criteria. Most were published between 1970 and 1990, and only 33 after 2003. Malnutrition is associated with impaired gut-barrier function, reduced exocrine secretion of protective substances, and low levels of plasma complement. Lymphatic tissue, particularly the thymus, undergoes atrophy, and delayed-type hypersensitivity responses are reduced. Levels of antibodies produced after vaccination are reduced in severely malnourished children, but intact in moderate malnutrition. Cytokine patterns are skewed towards a Th2-response. Other immune parameters seem intact or elevated: leukocyte and lymphocyte counts are unaffected, and levels of immunoglobulins, particularly immunoglobulin A, are high. The acute phase response appears intact, and sometimes present in the absence of clinical infection. Limitations to the studies include their observational and often cross-sectional design and frequent confounding by infections in the children studied. The immunological alterations associated with malnutrition in children may contribute to increased mortality. However, the underlying mechanisms are still inadequately understood, as well as why different types of malnutrition are associated with different immunological alterations. Better designed prospective studies are needed, based on current understanding of immunology and with state-of-the-art methods.

The effect of PDIA3 gene knockout on the mucosal immune function in IBS rats.

PubMed

Zhuang, Zhao-Meng; Wang, Xiao-Teng; Zhang, Lu; Tao, Li-Yuan; Lv, Bin

2015-01-01

To observe the changes of intestinal inflammation on PDIA3 gene knockout IBS rats and its effect on immune function. 36 SD rats were randomly divided into four groups: the control group (n = 8); IBS- empty virus group (IBS-GFP, which); IBS-PDIA3 knockout group (n = 12); IBS- the control group (n = 12). After modeling, colon and ileocecal tissue pathology in each group were observed separately. Changes of immune and inflammatory markers were measured. At the same time, ultrastructural changes in each group were observed by electron microscopy. Compared with the IBS control group, inflammation was reduced significantly in IBS-PDIA3 knockout group. IgE, IL-4 and IL-9 and the level of intestinal trypsin type were decreased significantly. Furthermore, mast cell degranulation and PAR 2 receptor reduced significantly. PDIA3 may play an important role in the development of IBS by mediating through immune responses of mucosal abnormalities. However, the mechanism needs to be confirmed in further study.

Immune biomarkers in older adults: Role of physical activity.

PubMed

Valdiglesias, Vanessa; Sánchez-Flores, María; Maseda, Ana; Lorenzo-López, Laura; Marcos-Pérez, Diego; López-Cortón, Ana; Strasser, Barbara; Fuchs, Dietmar; Laffon, Blanca; Millán-Calenti, José C; Pásaro, Eduardo

2017-01-01

Aging is associated with a decline in the normal functioning of the immune system. Several studies described the relationship between immunological alterations, including immunosenescence and inflammation, and aging or age-related outcomes, such as sarcopenia, depression, and neurodegenerative disorders. Physical activity is known to improve muscle function and to exert a number of benefits on older adult health, including reduced risk for heart and metabolic system chronic diseases. However, the positive influence of physical activity on the immune system has not been elucidated. In order to shed light on the role of physical activity in immune responses of older individuals, a number of immunological parameters comprising % lymphocyte subsets (CD3 + , CD4 + , CD8 + , CD19 + , and CD16 + 56 + ) and serum levels of neopterin and tryptophan metabolism products were evaluated in peripheral blood samples of older adults performing normal (N = 170) or reduced (N = 89) physical activity. In addition, the potential influence of other clinical and epidemiological factors was also considered. Results showed that subjects with reduced physical activity displayed significantly higher levels of CD4 + /CD8 + ratio, kynurenine/tryptophan ratio, and serum neopterin, along with lower %CD19 + cells and tryptophan concentrations. Further, some immunological biomarkers were associated with cognitive impairment and functional status. These data contribute to reinforce the postulation that physical activity supports healthy aging, particularly by helping to protect the immunological system from aging-related changes.

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.

Endothelial cells of extremely premature infants display impaired immune response after proinflammatory stimulation.

PubMed

Wisgrill, Lukas; Muck, Martina; Wessely, Isabelle; Berger, Angelika; Spittler, Andreas; Förster-Waldl, Elisabeth; Sadeghi, Kambis

2018-01-01

BackgroundEndothelial cells (ECs) exert immunological functions such as production of proinflammatory cytokines/chemokines as well as facilitation of extravasation of immune cells into infected tissue. Limited data are available on the functionality of ECs from extremely preterm neonates during infection. Accordingly, the aim of our study was to investigate the immune response of premature ECs after proinflammatory stimulation.MethodsCell adhesion receptors' expression and function, nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB) signaling, and chemokine production were analyzed in umbilical cord ECs from extremely preterm and term neonates after proinflammatory stimulation.ResultsP-selectin and E-selectin surface expression as well as NFκB signaling were lower after lipopolysaccharide (LPS) stimulation in premature ECs. Preterm ECs exhibited lower, but significant, cell-adhesive functions after LPS stimulation compared with term ECs. CCL2/CXCL8 chemokine secretion was significantly upregulated after proinflammatory stimulation in both groups. CXCL10 production was significantly increased in term but not in preterm ECs upon stimulation with tumor necrosis factor compared with unstimulated ECs.ConclusionExtremely premature ECs showed partly reduced expression levels and function of cell adhesion molecules. Both NFκB signaling and chemokine/cytokine production were reduced in premature ECs. The diminished endothelial proinflammatory immune response might result in impaired infection control of preterm newborns rendering them prone to severe infection.

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.

Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs

PubMed Central

Du Four, Stephanie; Maenhout, Sarah K; Niclou, Simone P; Thielemans, Kris; Neyns, Bart; Aerts, Joeri L

2016-01-01

Melanoma brain metastases (MBM) occur in 10% to 50% of melanoma patients. They are often associated with a high morbidity and despite the improvements in the treatment of advanced melanoma, including immunotherapy, patients with MBM still have a poor prognosis. Antiangiogenic treatment was shown to reduce the immunosuppressive tumor microenvironment. Therefore we investigated the effect of the combination of VEGFR- and CTLA-4 blockade on the immune cells within the tumor microenvironment. In this study we investigated the effect of the combination of axitinib, a TKI against VEGFR-1, -2 and -3, with therapeutic inhibition of CTLA-4 in subcutaneous and intracranial mouse melanoma models. The combination of axitinib with αCTLA-4 reduced tumor growth and increased survival in both intracranial and subcutaneous models. Investigation of the splenic immune cells showed an increased number of CD4+ and CD8+ T cells after combination treatment. Moreover, combination treatment increased the number of intratumoral dendritic cells (DCs) and monocytic myeloid-derived suppressor cells (moMDSCs). When these immune cell populations were sorted from the subcutaneous and intracranial tumors of mice treated with axitinib+αCTLA-4, we observed an increased antigen-presenting function of DCs and a reduced suppressive capacity of moMDSCs on a per cell basis. Our results suggest that the combination of antiangiogenesis and checkpoint inhibition can lead to an enhanced antitumor effect leading to increased survival. We found that this effect is in part due to an enhanced antitumor immune response generated by an increased antigen-presenting function of intratumoral DCs in combination with a reduced suppressive capacity of intratumoral moMDSCs. PMID:27904768

Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults.

PubMed

Lustgarten, Michael S; Fielding, Roger A

2017-12-15

Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p≤0.05 and q<0.30) associated with NDM/LDM. Decreased renal function and the immune response have been previously linked with reduced muscle density, but the mechanisms underlying these connections are less clear. Metabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (β±SE: -0.3±0.1, p=0.01, q=0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle may be a compensatory antimicrobial response to protect against an elevated microbial burden. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Embracing the gut microbiota: the new frontier for inflammatory and infectious diseases

PubMed Central

van den Elsen, Lieke WJ; Poyntz, Hazel C; Weyrich, Laura S; Young, Wayne; Forbes-Blom, Elizabeth E

2017-01-01

The gut microbiota provides essential signals for the development and appropriate function of the immune system. Through this critical contribution to immune fitness, the gut microbiota has a key role in health and disease. Recent advances in the technological applications to study microbial communities and their functions have contributed to a rapid increase in host–microbiota research. Although it still remains difficult to define a so-called ‘normal' or ‘healthy' microbial composition, alterations in the gut microbiota have been shown to influence the susceptibility of the host to different diseases. Current translational research combined with recent technological and computational advances have enabled in-depth study of the link between microbial composition and immune function, addressing the interplay between the gut microbiota and immune responses. As such, beneficial modulation of the gut microbiota is a promising clinical target for many prevalent diseases including inflammatory bowel disease, metabolic abnormalities such as obesity, reduced insulin sensitivity and low-grade inflammation, allergy and protective immunity against infections. PMID:28197336

Phenytoin promotes Th2 type immune response in mice

PubMed Central

Okada, K; Sugiura, T; Kuroda, E; Tsuji, S; Yamashita, U

2001-01-01

The effects of chronic administration of phenytoin, a common anticonvulsive drug, on immune responses were studied in mice. Anti-keyhole limpet haemocyanin (KLH) IgE antibody response after KLH-immunization was enhanced in phenytoin-treated mice. Proliferative responses of spleen cells induced with KLH, concanavalin A (ConA), lipopolysaccharide and anti-CD3 antibody were reduced in phenytoin-treated mice. Accessory function of spleen adherent cells on ConA-induced T cell proliferative response was reduced in phenytoin-treated mice. KLH-induced IL-4 production of spleen cells was enhanced, while IFN-γ production was reduced in phenytoin-treated mice. In addition, production of IL-1α, but not IL-6 and IL-12 by spleen adherent cells from phenytoin-treated mice was reduced. Natural killer cell activity was reduced in phenytoin-treated mice. These results suggest that phenytoin treatment preferentially induces a Th2 type response. We also observed that plasma ACTH and corticosterone levels were increased in phenytoin-treated mice, and speculated that phenytoin might act directly and indirectly, through HPA axis activation, on the immune system to modulate Th1/Th2 balance. PMID:11472401

Dietary Apigenin Exerts Immune-Regulatory Activity in Vivo by Reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function

PubMed Central

Cardenas, Horacio; Arango, Daniel; Nicholas, Courtney; Duarte, Silvia; Nuovo, Gerard J.; He, Wei; Voss, Oliver H.; Gonzalez-Mejia, M. Elba; Guttridge, Denis C.; Grotewold, Erich; Doseff, Andrea I.

2016-01-01

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors’ accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo. PMID:26938530

In-Vitro Induced Immunosuppression in a Rotary Cell Culture System

NASA Technical Reports Server (NTRS)

Grimm, Elizabeth A.

1998-01-01

The function of the innate immune system is to provide a first-line of defense against infectious organisms, via control of bacterial and viral growth using antigen nonspecific means. These nonspecific immune effectors include macrophages and Natural Killing (NK) cells, and certain cytokines elicited in response to "super antigens" on the infectious agents. This innate system usually keeps most infectious agents from rapidly growing while the adaptive immune system is generating a specific response complete with immunologic memory. Compelling evidence suggests that space flight results in various immunosuppressive effects, including reduced innate and adaptive immune responses. We were particularly concerned with reduced NK activity at landing, and have asked whether the microgravity component of space flight could be responsible for the previously observed NK defect. We have conclusively demonstrated that simulated microgravity as provided by the Synthecon bioreactors does not inhibit the NK function nor the IL-2 activation of lymphokine-activated killing (LAK). Interleukin-2 is the key cytokine responsible for activation of NK cells to express LAK, as well as to support differentiation of lymphocytes during adaptive immune responses. Therefore, we have disproved our original hypothesis based on poor NK in many of the astronauts upon landing.

Diversification of MIF immune regulators in aphids: link with agonistic and antagonistic interactions.

PubMed

Dubreuil, Géraldine; Deleury, Emeline; Crochard, Didier; Simon, Jean-Christophe; Coustau, Christine

2014-09-05

The widespread use of genome sequencing provided evidences for the high degree of conservation in innate immunity signalling pathways across animal phyla. However, the functioning and evolutionary history of immune-related genes remains unknown for most invertebrate species. A striking observation coming from the analysis of the pea aphid Acyrthosiphon pisum genome is the absence of important conserved genes known to be involved in the antimicrobial responses of other insects. This reduction in antibacterial immune defences is thought to be related to their long-term association with beneficial symbiotic bacteria and to facilitate symbiont maintenance. An additional possibility to avoid elimination of mutualistic symbionts is a fine-tuning of the host immune response. To explore this hypothesis we investigated the existence and potential involvement of immune regulators in aphid agonistic and antagonistic interactions. In contrast to the limited antibacterial arsenal, we showed that the pea aphid Acyrthosiphon pisum expresses 5 members of Macrophage Migration Inhibitory Factors (ApMIF), known to be key regulators of the innate immune response. In silico searches for MIF members in insect genomes followed by phylogenetic reconstruction suggest that evolution of MIF genes in hemipteran species has been shaped both by differential losses and serial duplications, raising the question of the functional importance of these genes in aphid immune responses. Expression analyses of ApMIFs revealed reduced expression levels in the presence, or during the establishment of secondary symbionts. By contrast, ApMIFs expression levels significantly increased upon challenge with a parasitoid or a Gram-negative bacteria. This increased expression in the presence of a pathogen/parasitoid was reduced or missing, in the presence of facultative symbiotic bacteria. This work provides evidence that while aphid's antibacterial arsenal is reduced, other immune genes widely absent from insect genomes are present, diversified and differentially regulated during antagonistic or agonistic interactions.

West African Sorghum bicolor Leaf Sheaths Have Anti-Inflammatory and Immune-Modulating Properties In Vitro

PubMed Central

Benson, Kathleen F.; Beaman, Joni L.; Ou, Boxin; Okubena, Ademola; Okubena, Olajuwon

2013-01-01

Abstract The impact of chronic inflammatory conditions on immune function is substantial, and the simultaneous application of anti-inflammatory and immune modulating modalities has potential for reducing inflammation-induced immune suppression. Sorghum-based foods, teas, beers, and extracts are used in traditional medicine, placing an importance on obtaining an increased understanding of the biological effects of sorghum. This study examined selected anti-inflammatory and immune-modulating properties in vitro of Jobelyn™, containing the polyphenol-rich leaf sheaths from a West African variant of Sorghum bicolor (SBLS). Freshly isolated primary human polymorphonuclear (PMN) and mononuclear cell subsets were used to test selected cellular functions in the absence versus presence of aqueous and ethanol extracts of SBLS. Both aqueous and nonaqueous compounds contributed to reduced reactive oxygen species formation by inflammatory PMN cells, and reduced the migration of these cells in response to the inflammatory chemoattractant leukotriene B4. Distinct effects were seen on lymphocyte and monocyte subsets in cultures of peripheral blood mononuclear cells. The aqueous extract of SBLS triggered robust upregulation of the CD69 activation marker on CD3− CD56+ natural killer (NK) cells, whereas the ethanol extract of SBLS triggered similar upregulation of CD69 on CD3+ CD56+ NKT cells, CD3+ T lymphocytes, and monocytes. This was accompanied by many-fold increases in the chemokines RANTES/CCL5, Mip-1α/CCL3, and MIP-1β/CCL4. Both aqueous and nonaqueous compounds contribute to anti-inflammatory effects, combined with multiple effects on immune cell activation status. These observations may help suggest mechanisms of action that contribute to the traditional use of sorghum-based products, beverages, and extracts for immune support. PMID:23289787

ACE Over Expression in Myelomonocytic Cells: Effect on a Mouse Model of Alzheimer's Disease

PubMed Central

Koronyo-Hamaoui, Maya; Shah, Kandarp; Koronyo, Yosef; Bernstein, Ellen; Giani, Jorge F.; Janjulia, Tea; Black, Keith L.; Shi, Peng D.; Gonzalez-Villalobos, Romer A.; Fuchs, Sebastien; Shen, Xiao Z.; Bernstein, Kenneth E.

2014-01-01

While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice over express ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-β protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD. PMID:24792094

Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span.

PubMed

Dixit, Vishwa Deep

2008-10-01

Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan.

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

PubMed Central

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

2017-01-01

Burn patients suffer from immunological dysfunction for which there are currently no successful interventions. Similar to previous observations, we find that burn shock patients (≥15% Total Burn Surface Area (TBSA) injury) have elevated levels of the innate immune cytokines Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1)/CC-motif Chemokine Ligand 2(CCL2) early after hospital admission (0–48 Hours Post-hospital Admission (HPA). Functional immune assays with patient Peripheral Blood Mononuclear Cells (PBMCs) revealed that burn shock patients (≥15% TBSA) produced elevated levels of MCP-1/CCL2 after innate immune stimulation ex vivo relative to mild burn patients. Interestingly, treatment of patient PBMCs with the Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) agonist, CDDO-Me(bardoxolone methyl), reduced MCP-1 production but not IL-6 or Interleukin-10 (IL-10) secretion. In enriched monocytes from healthy donors, CDDO-Me(bardoxolone methyl) also reduced LPS-induced MCP1/CCL2 production but did not alter IL-6 or IL-10 secretion. Similar immunomodulatory effects were observed with Compound 7, which activates the NRF2 pathway through a different and non-covalent Mechanism Of Action (MOA). Hence, our findings with CDDO-Me(bardoxolone methyl) and Compound 7 are likely to reflect a generalizable aspect of NRF2 activation. These observed effects were not specific to LPS-induced immune responses, as NRF2 activation also reduced MCP-1/CCL2 production after stimulation with IL-6. Pharmacological NRF2 activation reduced Mcp-1/Ccl2 transcript accumulation without inhibiting either Il-6 or Il-10 transcript levels. Hence, we describe a novel aspect of NRF2 activation that may contribute to the beneficial effects of NRF2 agonists during disease. Our work also demonstrates that the NRF2 pathway is retained and can be modulated to regulate important immunomodulatory functions in burn patient immune cells. PMID:28886135

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

PubMed

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

2017-01-01

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

Impairment of innate immune responses in cirrhotic patients and treatment by branched-chain amino acids

PubMed Central

Nakamura, Ikuo

2014-01-01

It has been reported that host defense responses, such as phagocytic function of neutrophils and natural killer (NK) cell activity of lymphocytes, are impaired in cirrhotic patients. This review will concentrate on the impairment of innate immune responses in decompensated cirrhotic patients and the effect of the treatment by branched-chain amino acids (BCAA) on innate immune responses. We already reported that phagocytic function of neutrophils was significantly improved by 3-mo BCAA supplementation. In addition, the changes of NK activity were also significant at 3 mo of supplementation compared with before supplementation. Also, Fisher’s ratios were reported to be significantly increased at 3 mo of BCAA supplementation compared with those before oral supplementation. Therefore, administration of BCAA could reduce the risk of bacterial and viral infection in patients with decompensated cirrhosis by restoring impaired innate immune responses of the host. In addition, it was also revealed that BCAA oral supplementation could reduce the risk of development of hepatocellular carcinoma in cirrhotic patients. The mechanisms of the effects will also be discussed in this review article. PMID:24966600

Age-dependent trade-offs between immunity and male, but not female, reproduction.

PubMed

McNamara, Kathryn B; van Lieshout, Emile; Jones, Therésa M; Simmons, Leigh W

2013-01-01

Immune function is costly and must be traded off against other life-history traits, such as gamete production. Studies of immune trade-offs typically focus on adult individuals, yet the juvenile stage can be a highly protracted period when reproductive resources are acquired and immune challenges are ubiquitous. Trade-offs during development are likely to be important, yet no studies have considered changes in adult responses to immune challenges imposed at different stages of juvenile development. By manipulating the timing of a bacterial immune challenge to the larvae of the cotton bollworm moth, we examined potential trade-offs between investment into immunity at different stages of juvenile development (early or late) and subsequent adult reproductive investment into sperm or egg production. Our data reveal an age-dependent trade-off between juvenile immune function and adult male reproductive investment. Activation of the immune response during late development resulted in a reduced allocation of resources to eupyrene (fertilizing) sperm production. Immune activation from the injection procedure itself (irrespective of whether individuals were injected with an immune elicitor or a control solution) also caused reproductive trade-offs; males injected early in development produced fewer apyrene (nonfertilizing) sperm. Contrary to many other studies, our study demonstrates these immune trade-offs under ad libitum nutritional conditions. No trade-offs were observed between female immune activation and adult reproductive investment. We suggest the differences in trade-offs observed between male sperm types and the absence of reproductive trade-offs in females may be the result of ontogenetic differences in gamete production in this species. Our data reveal developmental windows when trade-offs between immune function and gametic investment are made, and highlight the importance of considering multiple developmental periods when making inferences regarding the fundamental trade-offs expected between immune function and reproduction. © 2012 The Authors. Journal of Animal Ecology © 2012 British Ecological Society.

Age‐related alterations in immune responses to West Nile virus infection

PubMed Central

2016-01-01

Summary West Nile virus (WNV) is the most important causative agent of viral encephalitis worldwide and an important public health concern in the United States due to its high prevalence, severe disease, and the absence of effective treatments. Infection with WNV is mainly asymptomatic, but some individuals develop severe, possibly fatal, neurological disease. Individual host factors play a role in susceptibility to WNV infection, including genetic polymorphisms in key anti‐viral immune genes, but age is the most well‐defined risk factor for susceptibility to severe disease. Ageing is associated with distinct changes in immune cells and a decline in immune function leading to increased susceptibility to infection and reduced responses to vaccination. WNV is detected by pathogen recognition receptors including Toll‐like receptors (TLRs), which show reduced expression and function in ageing. Neutrophils, monocyte/macrophages and dendritic cells, which first recognize and respond to infection, show age‐related impairment of many functions relevant to anti‐viral responses. Natural killer cells control many viral infections and show age‐related changes in phenotype and functional responses. A role for the regulatory receptors Mertk and Axl in blood–brain barrier permeability and in facilitating viral uptake through phospholipid binding may be relevant for susceptibility to WNV, and age‐related up‐regulation of Axl has been noted previously in human dendritic cells. Understanding the specific immune parameters and mechanisms that influence susceptibility to symptomatic WNV may lead to a better understanding of increased susceptibility in elderly individuals and identify potential avenues for therapeutic approaches: an especially relevant goal, as the world's populating is ageing. PMID:27612657

Functional changes in neutrophils and psychoneuroendocrine responses during 105 days of confinement.

PubMed

Strewe, C; Muckenthaler, F; Feuerecker, M; Yi, B; Rykova, M; Kaufmann, I; Nichiporuk, I; Vassilieva, G; Hörl, M; Matzel, S; Schelling, G; Thiel, M; Morukov, B; Choukèr, A

2015-05-01

The innate immune system as one key element of immunity and a prerequisite for an adequate host defense is of emerging interest in space research to ensure crew health and thus mission success. In ground-based studies, spaceflight-associated specifics such as confinement caused altered immune functions paralleled by changes in stress hormone levels. In this study, six men were confined for 105 days to a space module of ~500 m(3) mimicking conditions of a long-term space mission. Psychic stress was surveyed by different questionnaires. Blood, saliva, and urine samples were taken before, during, and after confinement to determine quantitative and qualitative immune responses by analyzing enumerative assays and quantifying microbicide and phagocytic functions. Additionally, expression and shedding of L-selectin (CD62L) on granulocytes and different plasma cytokine levels were measured. Cortisol and catecholamine levels were analyzed in saliva and urine. Psychic stress or an activation of the psychoneuroendocrine system could not be testified. White blood cell counts were not significantly altered, but innate immune functions showed increased cytotoxic and reduced microbicide capabilities. Furthermore, a significantly enhanced shedding of CD62L might be a hint at increased migratory capabilities. However, this was observed in the absence of any acute inflammatory state, and no rise in plasma cytokine levels was detected. In summary, confinement for 105 days caused changes in innate immune functions. Whether these changes result from an alert immune state in preparation for further immune challenges or from a normal adaptive process during confinement remains to be clarified in future research. Copyright © 2015 the American Physiological Society.

Recovery of the immune system after exercise.

PubMed

Peake, Jonathan M; Neubauer, Oliver; Walsh, Neil P; Simpson, Richard J

2017-05-01

The notion that prolonged, intense exercise causes an "open window" of immunodepression during recovery after exercise is well accepted. Repeated exercise bouts or intensified training without sufficient recovery may increase the risk of illness. However, except for salivary IgA, clear and consistent markers of this immunodepression remain elusive. Exercise increases circulating neutrophil and monocyte counts and reduces circulating lymphocyte count during recovery. This lymphopenia results from preferential egress of lymphocyte subtypes with potent effector functions [e.g., natural killer (NK) cells, γδ T cells, and CD8 + T cells]. These lymphocytes most likely translocate to peripheral sites of potential antigen encounter (e.g., lungs and gut). This redeployment of effector lymphocytes is an integral part of the physiological stress response to exercise. Current knowledge about changes in immune function during recovery from exercise is derived from assessment at the cell population level of isolated cells ex vivo or in blood. This assessment can be biased by large changes in the distribution of immune cells between blood and peripheral tissues during and after exercise. Some evidence suggests that reduced immune cell function in vitro may coincide with changes in vivo and rates of illness after exercise, but more work is required to substantiate this notion. Among the various nutritional strategies and physical therapies that athletes use to recover from exercise, carbohydrate supplementation is the most effective for minimizing immune disturbances during exercise recovery. Sleep is an important aspect of recovery, but more research is needed to determine how sleep disruption influences the immune system of athletes. Copyright © 2017 the American Physiological Society.

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.

IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation.

PubMed

Metz, Richard; Smith, Courtney; DuHadaway, James B; Chandler, Phillip; Baban, Babak; Merlo, Lauren M F; Pigott, Elizabeth; Keough, Martin P; Rust, Sonja; Mellor, Andrew L; Mandik-Nayak, Laura; Muller, Alexander J; Prendergast, George C

2014-07-01

IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice. No apparent defects were observed in Ido2 (-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2 (-/-) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation

PubMed Central

Metz, Richard; Smith, Courtney; DuHadaway, James B.; Chandler, Phillip; Baban, Babak; Merlo, Lauren M. F.; Pigott, Elizabeth; Keough, Martin P.; Rust, Sonja; Mellor, Andrew L.; Mandik-Nayak, Laura; Muller, Alexander J.

2014-01-01

IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 −/− mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 –/– mice. No apparent defects were observed in Ido2 –/– mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 −/− mice, supporting Ido1–Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 −/− and Ido2 −/− mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 −/− mice did not phenocopy Ido1 −/− mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation. PMID:24402311

The Immune System in Children with Malnutrition—A Systematic Review

PubMed Central

Rytter, Maren Johanne Heilskov; Kolte, Lilian; Briend, André; Friis, Henrik; Christensen, Vibeke Brix

2014-01-01

Background Malnourished children have increased risk of dying, with most deaths caused by infectious diseases. One mechanism behind this may be impaired immune function. However, this immune deficiency of malnutrition has not previously been systematically reviewed. Objectives To review the scientific literature about immune function in children with malnutrition. Methods A systematic literature search was done in PubMed, and additional articles identified in reference lists and by correspondence with experts in the field. The inclusion criteria were studies investigating immune parameters in children aged 1–60 months, in relation to malnutrition, defined as wasting, underweight, stunting, or oedematous malnutrition. Results The literature search yielded 3402 articles, of which 245 met the inclusion criteria. Most were published between 1970 and 1990, and only 33 after 2003. Malnutrition is associated with impaired gut-barrier function, reduced exocrine secretion of protective substances, and low levels of plasma complement. Lymphatic tissue, particularly the thymus, undergoes atrophy, and delayed-type hypersensitivity responses are reduced. Levels of antibodies produced after vaccination are reduced in severely malnourished children, but intact in moderate malnutrition. Cytokine patterns are skewed towards a Th2-response. Other immune parameters seem intact or elevated: leukocyte and lymphocyte counts are unaffected, and levels of immunoglobulins, particularly immunoglobulin A, are high. The acute phase response appears intact, and sometimes present in the absence of clinical infection. Limitations to the studies include their observational and often cross-sectional design and frequent confounding by infections in the children studied. Conclusion The immunological alterations associated with malnutrition in children may contribute to increased mortality. However, the underlying mechanisms are still inadequately understood, as well as why different types of malnutrition are associated with different immunological alterations. Better designed prospective studies are needed, based on current understanding of immunology and with state-of-the-art methods. PMID:25153531

Mutations in a Highly Conserved Motif of nsp1β Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus

PubMed Central

Li, Yanhua; Shyu, Duan-Liang; Shang, Pengcheng; Bai, Jianfa; Ouyang, Kang; Dhakal, Santosh; Hiremath, Jagadish; Binjawadagi, Basavaraj

2016-01-01

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (nsp1β) is a multifunctional viral protein, which is involved in suppressing the host innate immune response and activating a unique −2/−1 programmed ribosomal frameshifting (PRF) signal for the expression of frameshifting products. In this study, site-directed mutagenesis analysis showed that the R128A or R129A mutation introduced into a highly conserved motif (123GKYLQRRLQ131) reduced the ability of nsp1β to suppress interferon beta (IFN-β) activation and also impaired nsp1β's function as a PRF transactivator. Three recombinant viruses, vR128A, vR129A, and vRR129AA, carrying single or double mutations in the GKYLQRRLQ motif were characterized. In comparison to the wild-type (WT) virus, vR128A and vR129A showed slightly reduced growth abilities, while the vRR129AA mutant had a significantly reduced growth ability in infected cells. Consistent with the attenuated growth phenotype in vitro, pigs infected with nsp1β mutants had lower levels of viremia than did WT virus-infected pigs. Compared to the WT virus in infected cells, all three mutated viruses stimulated high levels of IFN-α expression and exhibited a reduced ability to suppress the mRNA expression of selected interferon-stimulated genes (ISGs). In pigs infected with nsp1β mutants, IFN-α production was increased in the lungs at early time points postinfection, which was correlated with increased innate NK cell function. Furthermore, the augmented innate response was consistent with the increased production of IFN-γ in pigs infected with mutated viruses. These data demonstrate that residues R128 and R129 are critical for nsp1β function and that modifying these key residues in the GKYLQRRLQ motif attenuates virus growth ability and improves the innate and adaptive immune responses in infected animals. IMPORTANCE PRRSV infection induces poor antiviral innate IFN and cytokine responses, which results in weak adaptive immunity. One of the strategies in next-generation vaccine construction is to manipulate viral proteins/genetic elements involved in antagonizing the host immune response. PRRSV nsp1β was identified to be a strong innate immune antagonist. In this study, two basic amino acids, R128 and R129, in a highly conserved GKYLQRRLQ motif were determined to be critical for nsp1β function. Mutations introduced into these two residues attenuated virus growth and improved the innate and adaptive immune responses of infected animals. Technologies developed in this study could be broadly applied to current commercial PRRSV modified live-virus (MLV) vaccines and other candidate vaccines. PMID:26792733

Unique aspects of the perinatal immune system.

PubMed

Zhang, Xiaoming; Zhivaki, Dania; Lo-Man, Richard

2017-08-01

The early stages of life are associated with increased susceptibility to infection, which is in part due to an ineffective immune system. In the context of infection, the immune system must be stimulated to provide efficient protection while avoiding insufficient or excessive activation. Yet, in early life, age-dependent immune regulation at molecular and cellular levels contributes to a reduced immunological fitness in terms of pathogen clearance and response to vaccines. To enable microbial colonization to be tolerated at birth, epigenetic immune cell programming and early life-specific immune regulatory and effector mechanisms ensure that vital functions and organ development are supported and that tissue damage is avoided. Advancement in our understanding of age-related remodelling of immune networks and the consequent tuning of immune responsiveness will open up new possibilities for immune intervention and vaccine strategies that are designed specifically for early life.

Age-Associated Decline in Dendritic Cell Function and the Impact of Mediterranean Diet Intervention in Elderly Subjects.

PubMed

Clements, Sarah J; Maijo, Monica; Ivory, Kamal; Nicoletti, Claudio; Carding, Simon R

2017-01-01

Aging is accompanied by increased susceptibility to infection and age-associated chronic diseases. It is also associated with reduced vaccine responses, which is often attributed to immunosenescence and the functional decline of the immune system. Immunosenescence is characterized by a chronic, low-grade, inflammatory state termed inflammaging. Habitants of Mediterranean (MED) regions maintain good health into old age; often attributed to MED diets. Adoption of a MED-diet by elderly subjects, in Norfolk (UK), may improve immune responses of these individuals and in particular, dendritic cell (DC) function. A total of 120 elderly subjects (65-79 years old) recruited onto the Nu-AGE study, a multicenter European dietary study specifically addressing the needs of the elderly, across five countries, and were randomized to the control or MED-diet groups, for one year. Blood samples were taken pre- and post-intervention for DC analysis and were compared with each other, and to samples obtained from 45 young (18-40 years old) subjects. MED-diet compliance was assessed using high performance liquid chromatography-with tandem mass spectrometry analysis of urine samples. Immune cell and DC subset numbers and concentrations of secreted proteins were determined by flow cytometric analysis. As expected, reduced myeloid DC numbers were observed in blood samples from elderly subjects compared with young. The elevated secretion of the adipokine, resistin, after ex vivo stimulation of peripheral blood mononuclear cells from elderly subjects, was significantly reduced after MED-diet intervention. This study provides further evidence of numerical and functional effects of aging on DCs. The MED-diet showed potential to impact on the aging immune cells investigated and could provide an economical approach to address problems associated with our aging population.

Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

PubMed Central

Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

2017-01-01

The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study.

PubMed

Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

2017-01-01

The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3 + , CD4 + , CD8 + , and CD19 + ) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

Epigallocatechin-3-gallate protects Kuruma shrimp Marsupeneaus japonicus from white spot syndrome virus and Vibrio alginolyticus.

PubMed

Wang, Zhi; Sun, Baozhen; Zhu, Fei

2018-07-01

Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea and exhibits potential antibacterial and anticancer activities. In this study, EGCG was used in pathogen-challenge experiments in shrimp to discover its effect on the innate immune system of an invertebrate. Kuruma shrimp Marsupeneaus japonicus was used as an experimental model and challenged with white spot syndrome virus (WSSV) and the Gram-negative bacterium Vibrio alginolyticus. Pathogen-challenge experiments showed that EGCG pretreatment significantly delayed and reduced mortality upon WSSV and V. alginolyticus infection, with VP-28 copies of WSSV also reduced. Quantitative reverse transcription polymerase chain reaction revealed the positive influence of EGCG on several innate immune-related genes, including IMD, proPO, QM, myosin, Rho, Rab7, p53, TNF-alpha, MAPK, and NOS, and we observed positive influences on three immune parameters, including total hemocyte count and phenoloxidase and superoxide dismutase activities, by EGCG treatment. Additionally, results showed that EGCG treatment significantly reduced apoptosis upon V. alginolyticus challenge. These results indicated the positive role of EGCG in the shrimp innate immune system as an enhancer of immune parameters and an inhibitor of apoptosis, thereby delaying and reducing mortality upon pathogen challenge. Our findings provide insight into potential therapeutic or preventive functions associated with EGCG to enhance shrimp immunity and protect shrimp from pathogen infection. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Parental Exposure to Dim Light at Night Prior to Mating Alters Offspring Adaptive Immunity.

PubMed

Cissé, Yasmine M; Russart, Kathryn L G; Nelson, Randy J

2017-03-31

Exposure to dim light at night (dLAN) disrupts natural light/dark cycles and impairs endogenous circadian rhythms necessary to maintain optimal biological function, including the endocrine and immune systems. We have previously demonstrated that white dLAN compromises innate and cell mediated immune responses in adult Siberian hamsters (Phodopus sungorus). We hypothesized that dLAN has transgenerational influences on immune function. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 9 weeks, then paired in full factorial design, mated, and thereafter housed under dark nights. Offspring were gestated and reared in dark nights, then tested as adults for cell-mediated and humoral immunity. Maternal exposure to dLAN dampened delayed type hypersensitivity (DTH) responses in male offspring. Maternal and paternal exposure to dLAN reduced DTH responses in female offspring. IgG antibodies to a novel antigen were elevated in offspring of dams exposed to dLAN. Paternal exposure to dLAN decreased splenic endocrine receptor expression and global methylation in a parental sex-specific manner. Together, these data suggest that exposure to dLAN has transgenerational effects on endocrine-immune function that may be mediated by global alterations in the epigenetic landscape of immune tissues.

Parental Exposure to Dim Light at Night Prior to Mating Alters Offspring Adaptive Immunity

PubMed Central

Cissé, Yasmine M.; Russart, Kathryn L.G.; Nelson, Randy J.

2017-01-01

Exposure to dim light at night (dLAN) disrupts natural light/dark cycles and impairs endogenous circadian rhythms necessary to maintain optimal biological function, including the endocrine and immune systems. We have previously demonstrated that white dLAN compromises innate and cell mediated immune responses in adult Siberian hamsters (Phodopus sungorus). We hypothesized that dLAN has transgenerational influences on immune function. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 9 weeks, then paired in full factorial design, mated, and thereafter housed under dark nights. Offspring were gestated and reared in dark nights, then tested as adults for cell-mediated and humoral immunity. Maternal exposure to dLAN dampened delayed type hypersensitivity (DTH) responses in male offspring. Maternal and paternal exposure to dLAN reduced DTH responses in female offspring. IgG antibodies to a novel antigen were elevated in offspring of dams exposed to dLAN. Paternal exposure to dLAN decreased splenic endocrine receptor expression and global methylation in a parental sex-specific manner. Together, these data suggest that exposure to dLAN has transgenerational effects on endocrine-immune function that may be mediated by global alterations in the epigenetic landscape of immune tissues. PMID:28361901

Nutritional modulation of immune function in broilers.

PubMed

Kidd, M T

2004-04-01

Collaborative research efforts across disciplines typically result in more insight toward the hypothesis being tested due to the omnibus nature of the projects. For example, nutritional experiments evaluating a nutrient response will benefit greatly by incorporating biochemical, physiological, and immunological endpoints for measurement. Clearly, commercial poultry producers do not have the luxury of focusing on specific disciplines when field problems occur. Hence, in practice interplay exists among nutrition, genetics, management, and diseases. Dietary composition impacts immune function of the chicken. As research in the area of nutritional immunology has increased, it is becoming apparent that nutrient needs for immunity do not coincide with those for growth or skeletal tissue accretion. This review is not a comprehensive assessment of nutrient needs for immunity in the chicken. Rather, this review is concerned with nutritional modulation of immunity in broilers that offers insight for nutritionists and researchers to implement nutritional regimens to reduce the severity of disease and to test or validate nutritional regimens that heighten immunity. Nutritional modulation of the hen diet and in ovo nutrient modulation to improve chick immunity and disease resistance are discussed.

Effects of sodium fluoride on blood cellular and humoral immunity in mice.

PubMed

Guo, Hongrui; Kuang, Ping; Luo, Qin; Cui, Hengmin; Deng, Huidan; Liu, Huan; Lu, Yujiao; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Li, Yinglun; Wang, Xun; Zhao, Ling

2017-10-17

Exposure to high fluorine can cause toxicity in human and animals. Currently, there are no systematic studies on effects of high fluorine on blood cellular immunity and humoral immunity in mice. We evaluated the alterations of blood cellular immunity and humoral immunity in mice by using flow cytometry and ELISA. In the cellular immunity, we found that sodium fluoride (NaF) in excess of 12 mg/Kg resulted in a significant decrease in the percentages of CD3 + , CD3 + CD4 + , CD3 + CD8 + T lymphocytes in the peripheral blood. Meanwhile, serum T helper type 1 (Th1) cytokines including interleukin (IL)-2, interferon (IFN)-γ, tumor necrosis factor (TNF), and Th2 cytokines including IL-4, IL-6, IL-10, and Th17 cytokine (IL-17A) contents were decreased. In the humoral immunity, NaF reduced the peripheral blood percentages of CD19 + B lymphocytes and serum immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM). The above results show that NaF can reduce blood cellular and humoral immune function in mice, providing an excellent animal model for clinical studies on immunotoxicity-related fluorosis.

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.

Understanding How Commensal Obligate Anaerobic Bacteria Regulate Immune Functions in the Large Intestine

PubMed Central

Maier, Eva; Anderson, Rachel C.; Roy, Nicole C.

2014-01-01

The human gastrointestinal tract is colonised by trillions of commensal bacteria, most of which are obligate anaerobes residing in the large intestine. Appropriate bacterial colonisation is generally known to be critical for human health. In particular, the development and function of the immune system depends on microbial colonisation, and a regulated cross-talk between commensal bacteria, intestinal epithelial cells and immune cells is required to maintain mucosal immune homeostasis. This homeostasis is disturbed in various inflammatory disorders, such as inflammatory bowel diseases. Several in vitro and in vivo studies indicate a role for Faecalibacterium prausnitzii, Bacteroides thetaiotaomicron, Bacteroides fragilis, Akkermansia muciniphila and segmented filamentous bacteria in maintaining intestinal immune homeostasis. These obligate anaerobes are abundant in the healthy intestine but reduced in several inflammatory diseases, suggesting an association with protective effects on human health. However, knowledge of the mechanisms underlying the effects of obligate anaerobic intestinal bacteria remains limited, in part due to the difficulty of co-culturing obligate anaerobes together with oxygen-requiring human epithelial cells. By using novel dual-environment co-culture models, it will be possible to investigate the effects of the unstudied majority of intestinal microorganisms on the human epithelia. This knowledge will provide opportunities for improving human health and reducing the risk of inflammatory diseases. PMID:25545102

Infection, inflammation and exercise in cystic fibrosis

PubMed Central

2013-01-01

Regular exercise is positively associated with health. It has also been suggested to exert anti-inflammatory effects. In healthy subjects, a single exercise session results in immune cell activation, which is characterized by production of immune modulatory peptides (e.g. IL-6, IL-8), a leukocytosis and enhanced immune cell functions. Upon cessation of exercise, immune activation is followed by a tolerizing phase, characterized by a reduced responsiveness of immune cells. Regular exercise of moderate intensity and duration has been shown to exert anti-inflammatory effects and is associated with a reduced disease incidence and viral infection susceptibility. Specific exercise programs may therefore be used to modify the course of chronic inflammatory and infectious diseases such as cystic fibrosis (CF). Patients with CF suffer from severe and chronic pulmonary infections and inflammation, leading to obstructive and restrictive pulmonary disease, exercise intolerance and muscle cachexia. Inflammation is characterized by a hyper-inflammatory phenotype. Patients are encouraged to engage in exercise programs to maintain physical fitness, quality of life, pulmonary function and health. In this review, we present an overview of available literature describing the association between regular exercise, inflammation and infection susceptibility and discuss the implications of these observations for prevention and treatment of inflammation and infection susceptibility in patients with CF. PMID:23497303

Understanding how commensal obligate anaerobic bacteria regulate immune functions in the large intestine.

PubMed

Maier, Eva; Anderson, Rachel C; Roy, Nicole C

2014-12-24

The human gastrointestinal tract is colonised by trillions of commensal bacteria, most of which are obligate anaerobes residing in the large intestine. Appropriate bacterial colonisation is generally known to be critical for human health. In particular, the development and function of the immune system depends on microbial colonisation, and a regulated cross-talk between commensal bacteria, intestinal epithelial cells and immune cells is required to maintain mucosal immune homeostasis. This homeostasis is disturbed in various inflammatory disorders, such as inflammatory bowel diseases. Several in vitro and in vivo studies indicate a role for Faecalibacterium prausnitzii, Bacteroides thetaiotaomicron, Bacteroides fragilis, Akkermansia muciniphila and segmented filamentous bacteria in maintaining intestinal immune homeostasis. These obligate anaerobes are abundant in the healthy intestine but reduced in several inflammatory diseases, suggesting an association with protective effects on human health. However, knowledge of the mechanisms underlying the effects of obligate anaerobic intestinal bacteria remains limited, in part due to the difficulty of co-culturing obligate anaerobes together with oxygen-requiring human epithelial cells. By using novel dual-environment co-culture models, it will be possible to investigate the effects of the unstudied majority of intestinal microorganisms on the human epithelia. This knowledge will provide opportunities for improving human health and reducing the risk of inflammatory diseases.

Sexual dimorphism in immune function changes during the annual cycle in house sparrows

NASA Astrophysics Data System (ADS)

Pap, Péter László; Czirják, Gábor Árpád; Vágási, Csongor István; Barta, Zoltán; Hasselquist, Dennis

2010-10-01

Difference between sexes in parasitism is a common phenomenon among birds, which may be related to differences between males and females in their investment into immune functions or as a consequence of differential exposure to parasites. Because life-history strategies change sex specifically during the annual cycle, immunological responses of the host aiming to reduce the impact of parasites may be sexually dimorphic. Despite the great complexity of the immune system, studies on immunoecology generally characterise the immune status through a few variables, often overlooking potentially important seasonal and gender effects. However, because of the differences in physiological and defence mechanisms among different arms of the immune system, we expect divergent responses of immune components to environmental seasonality. In male and female house sparrows ( Passer domesticus), we measured the major components of the immune system (innate, acquired, cellular and humoral) during four important life-history stages across the year: (1) mating, (2) breeding, (3) moulting and (4) during the winter capture and also following introduction to captivity in aviary. Different individuals were sampled from the same population during the four life cycle stages. We found that three out of eight immune variables showed a significant life cycle stage × sex interaction. The difference in immune response between the sexes was significant in five immune variables during the mating stage, when females had consistently stronger immune function than males, while variables varied generally non-significantly with sex during the remaining three life cycle stages. Our results show that the immune system is highly variable between life cycle stages and sexes, highlighting the potential fine tuning of the immune system to specific physiological states and environmental conditions.

Glutamine granule-supplemented enteral nutrition maintains immunological function in severely burned patients.

PubMed

Peng, Xi; Yan, Hong; You, Zhongyi; Wang, Pei; Wang, Shiliang

2006-08-01

Glutamine is an important energy source for immune cells. It is a necessary nutrient for cell proliferation, and serves as specific fuel for lymphocytes, macrophages, and enterocytes when it is present in appropriate concentrations. The purpose of this clinical study was to observe the effects of enteral nutrition supplemented with glutamine granules on immunologic function in severely burned patients. Forty-eight severely burned patients (total burn surface area 30-75%, full thickness burn area 20-58%) who met the requirements of the protocol joined this double-blind randomized controlled clinical trail. Patients were randomly divided into two groups: burn control group (B group, 23 patients) and glutamine treated group (Gln group, 25 patients). There was isonitrogenous and isocaloric intake in both groups, Gln and B group patents were given glutamine granules or placebo (glycine) at 0.5 g/kgd for 14 days with oral feeding or tube feeding, respectively. The plasma level of glutamine and several indices of immunologic function including lymphocyte transformation ratio, neutrophil phagocytosis index (NPI), CD4/CD8 ratio, the content of immunoglobulin, complement C3, C4 and IL-2 levels were determined. Moreover, wound healing rate of burn area was observed and then hospital stay was recorded. The results showed significantly reduced plasma glutamine and damaged immunological function after severe burn Indices of cellular immunity function were remarkably decreased from normal controls. After taking glutamine granules for 14 days, plasma glutamine concentration was significantly higher in Gln group than that in B group (607.86+/-147.25 micromol/L versus 447.63+/-132.38 micromol/L, P<0.01). On the other hand, cellular immunity functions were improved in Gln group, such as lymphocyte transformation ratio, NPI, CD4/CD8 ratio and IL-2 compared those in the B group (P<0.05-0.01). However, for humoral immunity function such as the concentration of IgG, IgM, C3, C4, no marked changes were seen compared with the B group (P>0.05). In addition, wound healing was better and hospital stay days were reduced in Gln group (46.59+/-12.98 days versus 55.68+/-17.36 days, P<0.05). These indicated that immunological function damage is present after severe burn; supplemented glutamine granules with oral feeding or tube feeding abate the degree of immunosuppression, improve immunological function especially cellular immunity function, ameliorate wound healing and reduce hospital stay.

The effects of stress hormones on immune function may be vital for the adaptive reconfiguration of the immune system during fight-or-flight behavior.

PubMed

Adamo, Shelley A

2014-09-01

Intense, short-term stress (i.e., robust activation of the fight-or-flight response) typically produces a transient decline in resistance to disease in animals across phyla. Chemical mediators of the stress response (e.g., stress hormones) help induce this decline, suggesting that this transient immunosuppression is an evolved response. However, determining the function of stress hormones on immune function is difficult because of their complexity. Nevertheless, evidence suggests that stress hormones help maintain maximal resistance to disease during the physiological changes needed to optimize the body for intense physical activity. Work on insects demonstrates that stress hormones both shunt resources away from the immune system during fight-or-flight responses as well as reconfigure the immune system. Reconfiguring the immune system minimizes the impact of the loss of these resources and reduces the increased costs of some immune functions due to the physiological changes demanded by the fight-or-flight response. For example, during the stress response of the cricket Gryllus texensis, some molecular resources are shunted away from the immune system and toward lipid transport, resulting in a reduction in resistance to disease. However, insects' immune cells (hemocytes) have receptors for octopamine (the insect stress neurohormone). Octopamine increases many hemocyte functions, such as phagocytosis, and these changes would tend to mitigate the decline in immunity due to the loss of molecular resources. Moreover, because the stress response generates oxidative stress, some immune responses are probably more costly when activated during a stress response (e.g., those that produce reactive molecules). Some of these immune responses are depressed during stress in crickets, while others, whose costs are probably not increased during a stress response, are enhanced. Some effects of stress hormones on immune systems may be better understood as examples of reconfiguration rather than as mediating a trade-off. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

More than Fever: Thermoregulatory Responses to Immunological Stimulation and Consequences of Thermoregulatory Strategy on Innate Immunity in Gopher Tortoises (Gopherus polyphemus).

PubMed

Goessling, Jeffrey M; Guyer, Craig; Mendonça, Mary T

Organisms possess a range of thermoregulatory strategies that may vary in response to sickness, thereby driving important life-history consequences. Because the immune system is vital to maintaining organism function, understanding the suite of immune responses to infection indicates basic costs and benefits of physiological strategies. Here, we assessed consequences of thermoregulation and seasonality on immune function in both immunologically stimulated and nonstimulated gopher tortoises (Gopherus polyphemus). An ectothermic vertebrate was used as an experimental model because the effects of thermoregulation on immunity remain understudied and are of increasing importance in light of anthropogenic alterations to thermal environments. We found that G. polyphemus increased body temperature (T b ) at 1 h after injection with lipopolysaccharide (LPS) when compared with saline controls (P = 0.04), consistent with behavioral fever. LPS increased plasma bactericidal ability (BA; P = 0.006), reduced plasma iron concentration (P = 0.041), and increased heterophil∶lymphocyte ratios (P < 0.001). In nonstimulated animals, thermoregulatory strategy had a strong effect on innate immunity, which demonstrated that individuals have the ability to facultatively adjust immune function when infection burden is low; this relationship was not present in LPS-injected animals, which suggested that animals stimulated with LPS maximize bactericidal ability independently of temperature. Seasonal acclimation state did not influence responses to LPS, although baseline plasma iron was significantly lower in animals acclimated to winter. These results support that a trade-off exists between immunity and other conflicting physiological interests. Moreover, these results clearly demonstrate the ability of individuals to modulate immune function as a direct result of thermoregulatory decisions.

Cell mechanics and immune system link up to fight infections

NASA Astrophysics Data System (ADS)

Ekpenyong, Andrew; Man, Si Ming; Tourlomousis, Panagiotis; Achouri, Sarra; Cammarota, Eugenia; Hughes, Katherine; Rizzo, Alessandro; Ng, Gilbert; Guck, Jochen; Bryant, Clare

2015-03-01

Infectious diseases, in which pathogens invade and colonize host cells, are responsible for one third of all mortality worldwide. Host cells use special proteins (immunoproteins) and other molecules to fight viral and bacterial invaders. The mechanisms by which immunoproteins enable cells to reduce bacterial loads and survive infections remain unclear. Moreover, during infections, some immunoproteins are known to alter the cytoskeleton, the structure that largely determines cellular mechanical properties. We therefore used an optical stretcher to measure the mechanical properties of primary immune cells (bone marrow derived macrophages) during bacterial infection. We found that macrophages become stiffer upon infection. Remarkably, macrophages lacking the immunoprotein, NLR-C4, lost the stiffening response to infection. This in vitro result correlates with our in vivo data whereby mice lacking NLR-C4 have more lesions and hence increased bacterial distribution and spread. Thus, the immune-protein-dependent increase in cell stiffness in response to bacterial infection (in vitro result) seems to have a functional role in the system level fight against pathogens (in vivo result). We will discuss how this functional link between cell mechanical properties and innate immunity, effected by actin polymerization, reduces the spread of infection.

Drosophila 14-3-3ε has a crucial role in anti-microbial peptide secretion and innate immunity.

PubMed

Shandala, Tetyana; Woodcock, Joanna M; Ng, Yeap; Biggs, Lisa; Skoulakis, Efthimios M C; Brooks, Doug A; Lopez, Angel F

2011-07-01

The secretion of anti-microbial peptides is recognised as an essential step in innate immunity, but there is limited knowledge of the molecular mechanism controlling the release of these effectors from immune response cells. Here, we report that Drosophila 14-3-3ε mutants exhibit reduced survival when infected with either Gram-positive or Gram-negative bacteria, indicating a functional role for 14-3-3ε in innate immunity. In 14-3-3ε mutants, there was a reduced release of the anti-microbial peptide Drosomycin into the haemolymph, which correlated with an accumulation of Drosomycin-containing vesicles near the plasma membrane of cells isolated from immune response tissues. Drosomycin appeared to be delivered towards the plasma membrane in Rab4- and Rab11-positive vesicles and smaller Rab11-positive vesicles. RNAi silencing of Rab11 and Rab4 significantly blocked the anterograde delivery of Drosomycin from the perinuclear region to the plasma membrane. However, in 14-3-3ε mutants there was an accumulation of small Rab11-positive vesicles near the plasma membrane. This vesicular phenotype was similar to that observed in response to the depletion of the vesicular Syntaxin protein Syx1a. In wild-type Drosophila immune tissue, 14-3-3ε was detected adjacent to Rab11, and partially overlapping with Syx1a, on vesicles near the plasma membrane. We conclude that 14-3-3ε is required for Rab11-positive vesicle function, which in turn enables antimicrobial peptide secretion during an innate immune response.

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.

Ectodysplasin signalling deficiency in mouse models of hypohidrotic ectodermal dysplasia leads to middle ear and nasal pathology

PubMed Central

Azar, Ali; Piccinelli, Chiara; Brown, Helen; Headon, Denis; Cheeseman, Michael

2016-01-01

Hypohidrotic ectodermal dysplasia (HED) results from mutation of the EDA, EDAR or EDARADD genes and is characterized by reduced or absent eccrine sweat glands, hair follicles and teeth, and defective formation of salivary, mammary and craniofacial glands. Mouse models with HED also carry Eda, Edar or Edaradd mutations and have defects that map to the same structures. Patients with HED have ear, nose and throat disease, but this has not been investigated in mice bearing comparable genetic mutations. We report that otitis media, rhinitis and nasopharyngitis occur at high frequency in Eda and Edar mutant mice and explore the pathogenic mechanisms related to glandular function, microbial and immune parameters in these lines. Nasopharynx auditory tube glands fail to develop in HED mutant mice and the functional implications include loss of lysozyme secretion, reduced mucociliary clearance and overgrowth of nasal commensal bacteria accompanied by neutrophil exudation. Heavy nasopharynx foreign body load and loss of gland protection alters the auditory tube gating function and the auditory tubes can become pathologically dilated. Accumulation of large foreign body particles in the bulla stimulates granuloma formation. Analysis of immune cell populations and myeloid cell function shows no evidence of overt immune deficiency in HED mutant mice. Our findings using HED mutant mice as a model for the human condition support the idea that ear and nose pathology in HED patients arises as a result of nasal and nasopharyngeal gland deficits, reduced mucociliary clearance and impaired auditory tube gating function underlies the pathological sequelae in the bulla. PMID:27378689

Ionizing Radiation Selectively Reduces Skin Regulatory T Cells and Alters Immune Function

PubMed Central

Zhou, Yu; Ni, Houping; Balint, Klara; Sanzari, Jenine K.; Dentchev, Tzvete; Diffenderfer, Eric S.; Wilson, Jolaine M.; Cengel, Keith A.; Weissman, Drew

2014-01-01

The skin serves multiple functions that are critical for life. The protection from pathogens is achieved by a complicated interaction between aggressive effectors and controlling functions that limit damage. Inhomogeneous radiation with limited penetration is used in certain types of therapeutics and is experienced with exposure to solar particle events outside the protection of the Earth’s magnetic field. This study explores the effect of ionizing radiation on skin immune function. We demonstrate that radiation, both homogeneous and inhomogeneous, induces inflammation with resultant specific loss of regulatory T cells from the skin. This results in a hyper-responsive state with increased delayed type hypersensitivity in vivo and CD4+ T cell proliferation in vitro. The effects of inhomogeneous radiation to the skin of astronauts or as part of a therapeutic approach could result in an unexpected enhancement in skin immune function. The effects of this need to be considered in the design of radiation therapy protocols and in the development of countermeasures for extended space travel. PMID:24959865

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.

An XA21-Associated Kinase (OsSERK2) Regulates Immunity Mediated by the XA21 and XA3 Immune Receptors

PubMed Central

Chen, Xuewei; Zuo, Shimin; Schwessinger, Benjamin; Chern, Mawsheng; Canlas, Patrick E.; Ruan, Deling; Zhou, Xiaogang; Wang, Jing; Daudi, Arsalan; Petzold, Christopher J.; Heazlewood, Joshua L.; Ronald, Pamela C.

2014-01-01

The rice XA21 immune receptor kinase and the structurally related XA3 receptor confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast two-hybrid system in a kinase activity-dependent manner. OsSERK2 undergoes bidirectional transphosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3, and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR. PMID:24482436

Effects of early-life adversity on immune function are mediated by prenatal environment: Role of prenatal alcohol exposure.

PubMed

Raineki, Charlis; Bodnar, Tamara S; Holman, Parker J; Baglot, Samantha L; Lan, Ni; Weinberg, Joanne

2017-11-01

The contribution of the early postnatal environment to the pervasive effects of prenatal alcohol exposure (PAE) is poorly understood. Moreover, PAE often carries increased risk of exposure to adversity/stress during early life. Dysregulation of immune function may play a role in how pre- and/or postnatal adversity/stress alters brain development. Here, we combine two animal models to examine whether PAE differentially increases vulnerability to immune dysregulation in response to early-life adversity. PAE and control litters were exposed to either limited bedding (postnatal day [PN] 8-12) to model early-life adversity or normal bedding, and maternal behavior and pup vocalizations were recorded. Peripheral (serum) and central (amygdala) immune (cytokines and C-reactive protein - CRP) responses of PAE animals to early-life adversity were evaluated at PN12. Insufficient bedding increased negative maternal behavior in both groups. Early-life adversity increased vocalization in all animals; however, PAE pups vocalized less than controls. Early-life adversity reduced serum TNF-α, KC/GRO, and IL-10 levels in control but not PAE animals. PAE increased serum CRP, and levels were even higher in pups exposed to adversity. Finally, PAE reduced KC/GRO and increased IL-10 levels in the amygdala. Our results indicate that PAE alters immune system development and both behavioral and immune responses to early-life adversity, which could have subsequent consequences for brain development and later life health. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment.

PubMed

Criscitiello, Carmen; Viale, Giulia; Gelao, Lucia; Esposito, Angela; De Laurentiis, Michele; De Placido, Sabino; Santangelo, Michele; Goldhirsch, Aron; Curigliano, Giuseppe

2015-02-01

There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival. Copyright © 2014 Elsevier Ltd. All rights reserved.

Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan.

PubMed

Campbell, John P; Turner, James E

2018-01-01

Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory-referred to as the "open window" hypothesis-and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1-2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances-rather than suppresses-immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan.

Herpesvirus microRNAs for use in gene therapy immune-evasion strategies.

PubMed

Bots, S T F; Hoeben, R C

2017-07-01

Transplantation of allogeneic cells as well as of genetically corrected autologous cells are potent approaches to restore cellular functions in patients suffering from genetic diseases. The recipient's immune responses against non-self-antigens may compromise the survival of the grafted cells. Recipients of the graft may therefore require lifelong treatment with immunosuppressive drugs. An alternative approach to reduce graft rejection could involve the use of immune-evasion molecules. Expression of such molecules in cells of the graft may subvert recognition by the host's immune system. Viruses in particular are masters of exploitation and modulation of their hosts immune response. The Herpesviridae family provides a proof of concept for this as these viruses are capable to establish latency and a lifelong persistence in the infected hosts. While several viral proteins involved in immune evasion have been characterized, the Herpesviridae also encode a multitude of viral microRNA (miRNAs). Several of these miRNAs have been demonstrated to reduce the sensitivity of the infected cells to the destructive action of the host's immune cells. In this review, the miRNAs of some common herpesviruses that are associated with immune modulation will be discussed with a focus on their potential use in strategies aiming at generating non-immunogenic cells for transplantation.

Ischemia and reperfusion injury in renal transplantation: hemodynamic and immunological paradigms

PubMed Central

Requião-Moura, Lúcio Roberto; Durão, Marcelino de Souza; de Matos, Ana Cristina Carvalho; Pacheco-Silva, Alvaro

2015-01-01

Ischemia and reperfusion injury is an inevitable event in renal transplantation. The most important consequences are delayed graft function, longer length of stay, higher hospital costs, high risk of acute rejection, and negative impact of long-term follow-up. Currently, many factors are involved in their pathophysiology and could be classified into two different paradigms for education purposes: hemodynamic and immune. The hemodynamic paradigm is described as the reduction of oxygen delivery due to blood flow interruption, involving many hormone systems, and oxygen-free radicals produced after reperfusion. The immune paradigm has been recently described and involves immune system cells, especially T cells, with a central role in this injury. According to these concepts, new strategies to prevent ischemia and reperfusion injury have been studied, particularly the more physiological forms of storing the kidney, such as the pump machine and the use of antilymphocyte antibody therapy before reperfusion. Pump machine perfusion reduces delayed graft function prevalence and length of stay at hospital, and increases long-term graft survival. The use of antilymphocyte antibody therapy before reperfusion, such as Thymoglobulin™, can reduce the prevalence of delayed graft function and chronic graft dysfunction. PMID:25993079

Effect of citronellol and the Chinese medical herb complex on cellular immunity of cancer patients receiving chemotherapy/radiotherapy.

PubMed

Zhuang, Shu-Ru; Chen, Su-Lin; Tsai, Jih-Hsin; Huang, Chi-Chou; Wu, Tzu-Chin; Liu, Wen-Shan; Tseng, Hsien-Chun; Lee, Hong-Sen; Huang, Min-Chang; Shane, Guang-Tzuu; Yang, Cheng-Hua; Shen, You-Cheng; Yan, Yeong-Yu; Wang, Chin-Kun

2009-06-01

Leukopenia and immunity impairment usually occur during cancer therapy. Citronellol, an oil soluble compound derived from the geranium, has anticancer and antiinflammatory properties, as well as promoting wound healing. Ganoderma lucidum, Codonopsis pilosula and Angelicae sinensis are traditional Chinese herbs, all of which have proven immunomodulatory functions in laboratory-based research. This randomized, double-blind, placebo-controlled study examined whether the Chinese medicinal herb complex (CCMH; a mixture of citronellol and extracts of G. lucidum, C. pilosula and A. sinensis) improves the immune cell counts of cancer patients receiving chemotherapy and/or radiotherapy. A total of 105 cancer patients receiving chemotherapy or radiotherapy were enrolled. The quantities of immune cells in the blood of the subjects were determined before and after 6 weeks of cancer treatment, with either CCMH or a placebo. CCMH significantly reduced the depletion of leukocytes (14.2% compared with 28.2%) and neutrophils (11.0% compared with 29.1%). Analysis of the lymphocyte phenotype revealed that the patients receiving the placebo had reduced CD4 lymphocytes and natural killer (NK) cells than the CCMH-treated patients. Treatment with CCMH for patients receiving chemotherapy and/or radiotherapy may improve their immune function, improving their ability to fight off the cancer, as well as any secondary infections that could compromise their treatment and their health. (c) 2009 John Wiley & Sons, Ltd.

An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.

PubMed

Duggal, Niharika A; Upton, Jane; Phillips, Anna C; Sapey, Elizabeth; Lord, Janet M

2013-10-01

Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19(+) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19(+) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19(+) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19(+) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19(+) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19(+) CD24(hi) CD38(hi) cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19(+) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19(+) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging. © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Development of the Cellular Immune System of Drosophila Requires the Membrane Attack Complex/Perforin-Like Protein Torso-Like.

PubMed

Forbes-Beadle, Lauren; Crossman, Tova; Johnson, Travis K; Burke, Richard; Warr, Coral G; Whisstock, James C

2016-10-01

Pore-forming members of the membrane attack complex/perforin-like (MACPF) protein superfamily perform well-characterized roles as mammalian immune effectors. For example, complement component 9 and perforin function to directly form pores in the membrane of Gram-negative pathogens or virally infected/transformed cells, respectively. In contrast, the only known MACPF protein in Drosophila melanogaster, Torso-like, plays crucial roles during development in embryo patterning and larval growth. Here, we report that in addition to these functions, Torso-like plays an important role in Drosophila immunity. However, in contrast to a hypothesized effector function in, for example, elimination of Gram-negative pathogens, we find that torso-like null mutants instead show increased susceptibility to certain Gram-positive pathogens such as Staphylococcus aureus and Enterococcus faecalis We further show that this deficit is due to a severely reduced number of circulating immune cells and, as a consequence, an impaired ability to phagocytose bacterial particles. Together these data suggest that Torso-like plays an important role in controlling the development of the Drosophila cellular immune system. Copyright © 2016 by the Genetics Society of America.

Toll immune signal activates cellular immune response via eicosanoids.

PubMed

Shafeeq, Tahir; Ahmed, Shabbir; Kim, Yonggyun

2018-07-01

Upon immune challenge, insects recognize nonself. The recognition signal will propagate to nearby immune effectors. It is well-known that Toll signal pathway induces antimicrobial peptide (AMP) gene expression. Eicosanoids play crucial roles in mediating the recognition signal to immune effectors by enhancing humoral immune response through activation of AMP synthesis as well as cellular immune responses, suggesting a functional cross-talk between Toll and eicosanoid signals. This study tested a cross-talk between these two signals. Two signal transducing factors (MyD88 and Pelle) of Toll immune pathway were identified in Spodoptera exigua. RNA interference (RNAi) of either SeMyD88 or SePelle expression interfered with the expression of AMP genes under Toll signal pathway. Bacterial challenge induced PLA 2 enzyme activity. However, RNAi of these two immune factors significantly suppressed the induction of PLA 2 enzyme activity. Furthermore, RNAi treatment prevented gene expression of cellular PLA 2 . Inhibition of PLA 2 activity reduced phenoloxidase activity and subsequent suppression in cellular immune response measured by hemocyte nodule formation. However, immunosuppression induced by RNAi of Toll signal molecules was significantly reversed by addition of arachidonic acid (AA), a catalytic product of PLA 2 . The addition also significantly reduced the enhanced fungal susceptibility of S. exigua treated by RNAi against two Toll signal molecules. These results indicate that there is a cross-talk between Toll and eicosanoid signals in insect immunity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Study Protocol on Hormonal Mediation of Exercise on Cognition, Stress and Immunity (PRO-HMECSI): Effects of Different Exercise Programmes in Institutionalized Elders

PubMed Central

Teixeira, Ana Maria; Ferreira, José Pedro; Hogervorst, Eef; Braga, Margarida Ferreira; Bandelow, Stephan; Rama, Luís; Figueiredo, António; Campos, Maria João; Furtado, Guilherme Eustáquio; Chupel, Matheus Uba; Pedrosa, Filipa Martins

2016-01-01

Physical activity (PA) in elders has been shown to have positive effects on a plethora of chronic diseases and to improve immunity, mental health, and cognition. Chronic stress has also been shown to have immuno-suppressive effects and to accelerate immunosenescence. Exercise could be a significant factor in ameliorating the deleterious effects of chronic stress, but variables such as the type, intensity, and frequency of exercise that should be performed in order to effectively reduce the stress burden need to be defined clearly. PRO-HMECSI will allow us to investigate which hormonal and immunological parameters are able to mediate the effects of exercise on mucosal immunity, psychological/biological stress, and cognitive functioning in older people. Phase I consists of an observational cross-sectional study that compares elders groups (n = 223, >65 years) by functional fitness levels aiming to identify biomarkers involved in maintaining immune and mental health. Neuroendocrine and immune biomarkers of stress, psychological well-being related to mental health, neurocognitive function, functional fitness, and daily PA will be evaluated. Phase II consists of a 28-week intervention in elders with mild cognitive impairment (MCI) profile (n = 149, >65 years, divided in three groups of exercise and one control group), aiming to investigate whether the positive effect of three different types of chair-based exercise programs on physical and psychological health is mediated by an optimal endocrine environment. Primary outcomes are measures of cognitive function and global health. Secondary outcomes include the evaluation the other dimensions such as immune function, psychological health, and depression. Few studies addressed the effects of different types of exercise interventions in older population samples with MCI. We will also be able to determine which type of exercise is more effective in the immune and hormonal function of this population. PMID:27446898

Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation.

PubMed

Previte, Dana M; O'Connor, Erin C; Novak, Elizabeth A; Martins, Christina P; Mollen, Kevin P; Piganelli, Jon D

2017-01-01

The immune system is necessary for protecting against various pathogens. However, under certain circumstances, self-reactive immune cells can drive autoimmunity, like that exhibited in type 1 diabetes (T1D). CD4+ T cells are major contributors to the immunopathology in T1D, and in order to drive optimal T cell activation, third signal reactive oxygen species (ROS) must be present. However, the role ROS play in mediating this process remains to be further understood. Recently, cellular metabolic programs have been shown to dictate the function and fate of immune cells, including CD4+ T cells. During activation, CD4+ T cells must transition metabolically from oxidative phosphorylation to aerobic glycolysis to support proliferation and effector function. As ROS are capable of modulating cellular metabolism in other models, we sought to understand if blocking ROS also regulates CD4+ T cell activation and effector function by modulating T cell metabolism. To do so, we utilized an ROS scavenging and potent antioxidant manganese metalloporphyrin (MnP). Our results demonstrate that redox modulation during activation regulates the mTOR/AMPK axis by maintaining AMPK activation, resulting in diminished mTOR activation and reduced transition to aerobic glycolysis in diabetogenic splenocytes. These results correlated with decreased Myc and Glut1 upregulation, reduced glucose uptake, and diminished lactate production. In an adoptive transfer model of T1D, animals treated with MnP demonstrated delayed diabetes progression, concurrent with reduced CD4+ T cell activation. Our results demonstrate that ROS are required for driving and sustaining T cell activation-induced metabolic reprogramming, and further support ROS as a target to minimize aberrant immune responses in autoimmunity.

Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: results of a randomized, controlled, phase II trial.

PubMed

Torre-Amione, Guillermo; Sestier, François; Radovancevic, Branislav; Young, James

2004-09-15

We sought to determine whether a novel, non-pharmacological form of immune modulation therapy (IMT), shown experimentally to reduce inflammatory and increase anti-inflammatory cytokines, improved outcomes in patients with advanced heart failure (HF). Immune activation contributes to the progression of HF, but treatments directed against inflammation have been largely unsuccessful. Seventy-five HF patients (New York Heart Association [NYHA] functional class III to IV) were randomized to receive either IMT (n = 38) or placebo (n = 37) in a double-blind trial for six months, with continuation of standard HF therapy. Patients were evaluated using the 6-min walk test, changes in NYHA functional class, cardiac function, and quality of life assessments, as well as occurrence of death and hospitalization. There was no between-group difference in 6-min walk test, but 15 IMT patients (compared with 9 placebo) improved NYHA functional classification by at least one class (p = 0.140). The Kaplan-Meier survival analysis showed that IMT significantly reduced the risk of death (p = 0.022) and hospitalization (p = 0.008). Analysis of a clinical composite score demonstrated a significant between-group difference (p = 0.006). There was no difference in left ventricular ejection fraction, but there was a trend toward improved quality of life (p = 0.110). These preliminary findings are consistent with the hypothesis that immune activation is important in the pathogenesis of HF and establish the basis for a phase III trial to define the benefit of IMT in chronic HF.

Immune cell phenotype and function in sepsis

PubMed Central

Rimmelé, Thomas; Payen, Didier; Cantaluppi, Vincenzo; Marshall, John; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A.

2015-01-01

Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis. The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of non extracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed. A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8 and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes and the cell function. PMID:26529661

IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS.

PubMed

Rimmelé, Thomas; Payen, Didier; Cantaluppi, Vincenzo; Marshall, John; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A

2016-03-01

Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.

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.

Vegetated land cover near residence is associated with reduced allostatic load and improved biomarkers of neuroendocrine, metabolic and immune functions

EPA Science Inventory

Abstract Background: Greater exposure to urban green spaces has been linked to reduced risks of depression, cardiovascular disease, diabetes and premature death. Alleviation of chronic stress is a hypothesized pathway to improved health. Previous studies linked chronic stress wit...

Immunogenicity and malaria transmission reducing potency of Pfs48/45 and Pfs25 encoded by DNA vaccines administered by intramuscular electroporation.

PubMed

Datta, Dibyadyuti; Bansal, Geetha P; Gerloff, Dietlind L; Ellefsen, Barry; Hannaman, Drew; Kumar, Nirbhay

2017-01-05

Pfs48/45 and Pfs25 are leading candidates for the development of Plasmodium falciparum transmission blocking vaccines (TBV). Expression of Pfs48/45 in the erythrocytic sexual stages and presentation to the immune system during infection in the human host also makes it ideal for natural boosting. However, it has been challenging to produce a fully folded, functionally active Pfs48/45, using various protein expression platforms. In this study, we demonstrate that full-length Pfs48/45 encoded by DNA plasmids is able to induce significant transmission reducing immune responses. DNA plasmids encoding Pfs48/45 based on native (WT), codon optimized (SYN), or codon optimized and mutated (MUT1 and MUT2), to prevent any asparagine (N)-linked glycosylation were compared with or without intramuscular electroporation (EP). EP significantly enhanced antibody titers and transmission blocking activity elicited by immunization with SYN Pfs48/45 DNA vaccine. Mosquito membrane feeding assays also revealed improved functional immunogenicity of SYN Pfs48/45 (N-glycosylation sites intact) as compared to MUT1 or MUT2 Pfs48/45 DNA plasmids (all N-glycosylation sites mutated). Boosting with recombinant Pfs48/45 protein after immunization with each of the different DNA vaccines resulted in significant boosting of antibody response and improved transmission reducing capabilities of all four DNA vaccines. Finally, immunization with a combination of DNA plasmids (SYN Pfs48/45 and SYN Pfs25) also provides support for the possibility of combining antigens targeting different life cycle stages in the parasite during transmission through mosquitoes. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Phenotype and function of nasal dendritic cells

PubMed Central

Lee, Haekyung; Ruane, Darren; Law, Kenneth; Ho, Yan; Garg, Aakash; Rahman, Adeeb; Esterházy, Daria; Cheong, Cheolho; Goljo, Erden; Sikora, Andrew G.; Mucida, Daniel; Chen, Benjamin; Govindraj, Satish; Breton, Gaëlle; Mehandru, Saurabh

2015-01-01

Intranasal vaccination generates immunity across local, regional and distant sites. However, nasal dendritic cells (DC), pivotal for the induction of intranasal vaccine- induced immune responses, have not been studied in detail. Here, using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of “classical” DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were FLT3 ligand-responsive and displayed unique phenotypic and functional characteristics including the ability to present antigen, induce an allogeneic T cell response and migrate in response to LPS or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1+ DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1+ and BDCA-3hi DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic and functional properties of nasal DCs and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis. PMID:25669151

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 stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors.

PubMed

Thevenot, Paul T; Sierra, Rosa A; Raber, Patrick L; Al-Khami, Amir A; Trillo-Tinoco, Jimena; Zarreii, Parisa; Ochoa, Augusto C; Cui, Yan; Del Valle, Luis; Rodriguez, Paulo C

2014-09-18

Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant of their survival and growth. However, the interaction between tumor-linked stress and antitumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune-regulatory functions and showed the ability to prime T cell function and induce antitumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Validation of Procedures for Monitoring Crewmember Immune Function

NASA Technical Reports Server (NTRS)

Crucian, Brian; Stowe, Raymond; Mehta, Satish; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

2009-01-01

There is ample evidence to suggest that space flight leads to immune system dysregulation, however the nature of the phenomenon as it equilibrates over longer flights has not been determined. This dysregulation may be a result of microgravity, confinement, physiological stress, radiation, environment or other mission-associated factors. The clinical risk (if any) for exploration-class space flight is unknown, but may include increased incidence of infection, allergy, hypersensitivity, hematological malignancy or altered wound healing. The objective of this Supplemental Medical Objective (SMO) is to determine the status of the immune system, physiological stress and latent viral reactivation (a clinical outcome that can be measured) during both short and long-duration spaceflight. In addition, this study will develop and validate an immune monitoring strategy consistent with operational flight requirements and constraints. Pre-mission, in-flight and post-flight blood and saliva samples will be obtained from participating crewmembers. Assays included peripheral immunophenotype, T cell function, cytokine profiles (RNA, intracellular, secreted), viral-specific immunity, latent viral reactivation (EBV, CMV, VZV), and stress hormone measurements. This study is currently ongoing. To date, 10 short duration and 5 long-duration crewmembers have completed the study. Technically, the study is progressing well. In-flight blood samples are being collected, and returned for analysis, including functional assays that require live cells. For all in-flight samples to date, sample viability has been acceptable. Preliminary data (n = 4/7; long/short duration, respectively) indicate that distribution of most peripheral leukocyte subsets is largely unaltered during flight. Exceptions include elevated T cells, reduced B/NK cells, increased memory T cells and increased central memory CD8+ T cells. General T cell function, early blastogenesis response to mitogenic stimulation, is markedly reduced in-flight. In-vivo cytokine production profiles are altered, with in-flight dysregulation observed in the Th1/Th2/Treg equilibrium. EBV specific T cell levels are increased during flight, whereas their function is reduced. VZV reactivation was observed inflight and several days post flight with highest levels measured later during long-duration flight. The shedding of CMV in the urine was detected of 4/5 long duration and 4/7 short duration crewmembers. Plasma cortisol was not elevated during flight. Further data will be required to validate the initial observations.

Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease.

PubMed

Kammerl, Ilona E; Dann, Angela; Mossina, Alessandra; Brech, Dorothee; Lukas, Christina; Vosyka, Oliver; Nathan, Petra; Conlon, Thomas M; Wagner, Darcy E; Overkleeft, Hermen S; Prasse, Antje; Rosas, Ivan O; Straub, Tobias; Krauss-Etschmann, Susanne; Königshoff, Melanie; Preissler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Behr, Jürgen; Heinzelmann, Katharina; Yildirim, Ali Ö; Noessner, Elfriede; Eickelberg, Oliver; Meiners, Silke

2016-06-01

Patients with chronic obstructive pulmonary disease (COPD) and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections. To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors and patients with COPD or idiopathic pulmonary fibrosis (IPF), as well as in cigarette smoke-exposed mice. Smoke-mediated alterations of immunoproteasome activity and MHC I surface expression were analyzed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of patients with COPD and in isolated alveolar macrophages of patients with COPD or IPF. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities. We here show that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF.

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.

Universal immunity to influenza must outwit immune evasion

PubMed Central

Quiñones-Parra, Sergio; Loh, Liyen; Brown, Lorena E.; Kedzierska, Katherine; Valkenburg, Sophie A.

2014-01-01

Although an influenza vaccine has been available for 70 years, influenza virus still causes seasonal epidemics and worldwide pandemics. Currently available vaccines elicit strain-specific antibody (Ab) responses to the surface haemagglutinin (HA) and neuraminidase (NA) proteins, but these can be ineffective against serologically-distinct viral variants and novel subtypes. Thus, there is a great need for cross-protective or “universal” influenza vaccines to overcome the necessity for annual immunization against seasonal influenza and to provide immunity to reduce the severity of infection with pandemic or outbreak viruses. It is well established that natural influenza infection can provide cross-reactive immunity that can reduce the impact of infection with distinct influenza type A strains and subtypes, including H1N1, H3N2, H2N2, H5N1, and H7N9. The key to generating universal influenza immunity through vaccination is to target functionally-conserved regions of the virus, which include epitopes on the internal proteins for cross-reactive T cell immunity or on the HA stem for broadly reactive Ab responses. In the wake of the 2009 H1N1 pandemic, broadly neutralizing antibodies (bnAbs) have been characterized and isolated from convalescent and vaccinated individuals, inspiring development of new vaccination techniques to elicit such responses. Induction of influenza-specific T cell responses through vaccination has also been recently examined in clinical trials. Strong evidence is available from human and animal models of influenza to show that established influenza-specific T cell memory can reduce viral shedding and symptom severity. However, the published evidence also shows that CD8+ T cells can efficiently select immune escape mutants early after influenza virus infection. Here, we discuss universal immunity to influenza viruses mediated by both cross-reactive T cells and Abs, the mechanisms of immune evasion in influenza, and propose how to counteract commonly occurring immune-escape variants. PMID:24971078

Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.

PubMed

Baird, Angela C; Mallon, Dominic; Radford-Smith, Graham; Boyer, Julien; Piche, Thierry; Prescott, Susan L; Lawrance, Ian C; Tulic, Meri K

2016-11-07

To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders" ( n = 12) and "non-responders" ( n = 12) and compared to healthy controls ( n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders ( P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls ( P < 0.01) and diminished TNF ( P < 0.001) and IL-1β ( P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) ( P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) ( P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation ( P < 0.001). Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.

Genetics Home Reference: transcobalamin deficiency

MedlinePlus

... also have a shortage of white blood cells (neutropenia), which can lead to reduced immune system function. ... deficiency Seattle Children's Hospital: Anemia Seattle Children's Hospital: Neutropenia Washington University, St. Louis: Neuromuscular Disease Center: Vitamin ...

Tricking the balance: NK cells in anti-cancer immunity.

PubMed

Pahl, Jens; Cerwenka, Adelheid

2017-01-01

Natural Killer (NK) cells are classically considered innate immune effector cells involved in the first line of defense against infected and malignant cells. More recently, NK cells have emerged to acquire properties of adaptive immunity in response to certain viral infections such as expansion of specific NK cell subsets and long-lasting virus-specific responses to secondary challenges. NK cells distinguish healthy cells from abnormal cells by measuring the net input of activating and inhibitory signals perceived from target cells through NK cell surface receptors. Acquisition of activating ligands in combination with reduced expression of MHC class I molecules on virus-infected and cancer cells activates NK cell cytotoxicity and release of immunostimulatory cytokines like IFN-γ. In the cancer microenvironment however, NK cells become functionally impaired by inhibitory factors produced by immunosuppressive immune cells and cancer cells. Here we review recent progress on the role of NK cells in cancer immunity. We describe regulatory factors of the tumor microenvironment on NK cell function which determine cancer cell destruction or escape from immune recognition. Finally, recent strategies that focus on exploiting NK cell anti-cancer responses for immunotherapeutic approaches are outlined. Copyright © 2015 Elsevier GmbH. All rights reserved.

Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system.

PubMed

Jijon, H B; Suarez-Lopez, L; Diaz, O E; Das, S; De Calisto, J; Yaffe, M B; Pittet, M J; Mora, J R; Belkaid, Y; Xavier, R J; Villablanca, E J

2018-05-01

Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARα resulted in increased KLF4 + goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased Reg3g, reduced luminal bacterial detection, and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARα signaling is critical to the global development of the intestinal immune system.

IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury

PubMed Central

Huang, Qingsong; Niu, Zhiguo; Tan, Jing; Yang, Jun; Liu, Yun; Ma, Haijun; Lee, Vincent W.S.; Sun, Shuming; Song, Xiangfeng; Guo, Minghao; Wang, Yiping

2015-01-01

IL-25 is an important immune regulator that can promote Th2 immune response-dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL-25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL-25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPPtype2) cells in kidney. IL-25–responsive ILC2 and MPPtype2 cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPPtype2 cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPPtype2 cells regulate macrophage phenotype in kidney and prevent renal IRI. PMID:25556172

Comparative Transcriptomic Analysis of Rectal Tissue from Beef Steers Revealed Reduced Host Immunity in Escherichia coli O157:H7 Super-Shedders

PubMed Central

Wang, Ou; Liang, Guanxiang; McAllister, Tim A.; Plastow, Graham; Stanford, Kim; Selinger, Brent; Guan, Le Luo

2016-01-01

Super-shedder cattle are a major disseminator of E. coli O157:H7 into the environment, and the terminal rectum has been proposed as the primary E. coli O157:H7 colonization site. This study aimed to identify host factors that are associated with the super-shedding process by comparing transcriptomic profiles in rectal tissue collected from 5 super-shedder cattle and 4 non-shedder cattle using RNA-Seq. In total, 17,859 ± 354 genes and 399 ± 16 miRNAs were detected, and 11,773 genes were expressed in all animals. Fifty-eight differentially expressed (DE) genes (false discovery rate < 0.05) including 11 up-regulated and 47 down-regulated (log 2 (fold change) ranged from -5.5 to 4.2), and 2 up-regulated DE miRNAs (log 2 (fold change) = 2.1 and 2.5, respectively) were identified in super-shedders compared to non-shedders. Functional analysis of DE genes revealed that 31 down-regulated genes were potentially associated with reduced innate and adaptive immune functions in super-shedders, including 13 lymphocytes membrane receptors, 3 transcription factors and 5 cytokines, suggesting the decreased key host immune functions in the rectal tissue of super-shedders, including decreased quantity and migration of immune cells such as lymphocytes, neutrophils and dendritic cells. The up-regulation of bta-miR-29d-3p and the down regulation of its predicted target gene, regulator of G-protein signaling 13, suggested a potential regulatory role of this miRNA in decreased migration of lymphocytes in super-shedders. Based on these findings, the rectal tissue of super-shedders may inherently exhibit less effective innate and adaptive immune protection. Further study is required to confirm if such effect on host immunity is due to the nature of the host itself or due to actions mediated by E. coli O157:H7. PMID:26959367

Comparative Transcriptomic Analysis of Rectal Tissue from Beef Steers Revealed Reduced Host Immunity in Escherichia coli O157:H7 Super-Shedders.

PubMed

Wang, Ou; Liang, Guanxiang; McAllister, Tim A; Plastow, Graham; Stanford, Kim; Selinger, Brent; Guan, Le Luo

2016-01-01

Super-shedder cattle are a major disseminator of E. coli O157:H7 into the environment, and the terminal rectum has been proposed as the primary E. coli O157:H7 colonization site. This study aimed to identify host factors that are associated with the super-shedding process by comparing transcriptomic profiles in rectal tissue collected from 5 super-shedder cattle and 4 non-shedder cattle using RNA-Seq. In total, 17,859 ± 354 genes and 399 ± 16 miRNAs were detected, and 11,773 genes were expressed in all animals. Fifty-eight differentially expressed (DE) genes (false discovery rate < 0.05) including 11 up-regulated and 47 down-regulated (log 2 (fold change) ranged from -5.5 to 4.2), and 2 up-regulated DE miRNAs (log 2 (fold change) = 2.1 and 2.5, respectively) were identified in super-shedders compared to non-shedders. Functional analysis of DE genes revealed that 31 down-regulated genes were potentially associated with reduced innate and adaptive immune functions in super-shedders, including 13 lymphocytes membrane receptors, 3 transcription factors and 5 cytokines, suggesting the decreased key host immune functions in the rectal tissue of super-shedders, including decreased quantity and migration of immune cells such as lymphocytes, neutrophils and dendritic cells. The up-regulation of bta-miR-29d-3p and the down regulation of its predicted target gene, regulator of G-protein signaling 13, suggested a potential regulatory role of this miRNA in decreased migration of lymphocytes in super-shedders. Based on these findings, the rectal tissue of super-shedders may inherently exhibit less effective innate and adaptive immune protection. Further study is required to confirm if such effect on host immunity is due to the nature of the host itself or due to actions mediated by E. coli O157:H7.

Nutritional support to maintain proper immune status during intense training.

PubMed

Gleeson, Michael

2013-01-01

Prolonged exercise and heavy training are associated with depressed immune function which can increase the risk of picking up minor infections. To maintain robust immunity, athletes should eat a well-balanced diet sufficient to meet their energy, carbohydrate, protein, and micronutrient requirements. Dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction and an adequate intake of iron, zinc, and vitamins A, D, E, B6 and B12 is particularly important in the maintenance of immune function. Consuming carbohydrate during prolonged strenuous exercise attenuates rises in stress hormones and appears to limit the degree of exercise-induced immune depression. Similar effects can be seen with daily ingestion of high-dose antioxidant vitamin supplements, though concerns have been expressed that excessive antioxidant intake may impair exercise training adaptations. It is safe to say with reasonable confidence that individual amino acids, colostrum, Echinacea, and zinc are unlikely to boost immunity or reduce infection risk in athletes. The ingestion of carbohydrate during exercise and daily consumption of probiotic and plant polyphenol (e.g. quercetin)-containing supplements or foodstuffs (e.g. non-alcoholic beer) currently offer the best chance of success. This approach is likely to be most effective for individuals who are particularly prone to illness. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.

Immune competence assessment in marine medaka (Orzyias melastigma)-a holistic approach for immunotoxicology.

PubMed

Ye, Roy R; Peterson, Drew R; Seemann, Frauke; Kitamura, Shin-Ichi; Lee, J S; Lau, Terrance C K; Tsui, Stephen K W; Au, Doris W T

2017-12-01

Many anthropogenic pollutants in coastal marine environments can induce immune impairments in wild fish and reduce their survival fitness. There is a pressing need to establish sensitive and high throughput in vivo tools to systematically evaluate the immunosuppressive effects of contaminants in marine teleosts. This study reviewed a battery of in vivo immune function detection technologies established for different biological hierarchies at molecular (immune function pathways and genes by next generation sequencing (NGS)), cellular (leukocytes profiles by flow cytometry), tissues/organ system (whole adult histo-array), and organism (host resistance assays (HRAs)) levels, to assess the immune competence of marine medaka Oryzias melastigma. This approach enables a holistic assessment of fish immune competence under different chemical exposure or environmental scenarios. The data obtained will also be useful to unravel the underlying immunotoxic mechanisms. Intriguingly, NGS analysis of hepatic immune gene expression profiles (male > female) are in support of the bacterial HRA findings, in which infection-induced mortality was consistently higher in females than in males. As such, reproductive stages and gender-specific responses must be taken into consideration when assessing the risk of immunotoxicants in the aquatic environment. The distinct phenotypic sexual dimorphism and short generation time (3 months) of marine medaka offer additional advantages for sex-related immunotoxicological investigation.

Mannose-binding lectin and the balance between immune protection and complication

PubMed Central

Takahashi, Kazue

2012-01-01

The innate immune system is evolutionarily ancient and biologically primitive. Historically, it was first identified as an element of the immune system that provides the first-line response to pathogens, and increasingly it is recognized for its central housekeeping role and its essential functions in tissue homeostasis, including coagulation and inflammation, among others. A pivotal link between the innate immune system and other functions is mannose-binding lectin (MBL), a pattern recognition molecule. Multiple studies have demonstrated that MBL deficiency increases susceptibility to infection, and the mechanisms associated with this susceptibility to infection include reduced opsonophagocytic killing and reduced activation of the lectin complement pathway. Results from our laboratory have demonstrated that MBL and MBL-associated serine protease (MASP)-1/3 together mediate coagulation factor-like activities, including thrombin-like activity. MBL and/or MASP-1/3-deficient hosts demonstrate in vivo evidence that MBL and MASP-1/3 are involved with hemostasis following injury. Staphylococcus aureus-infected MBL null mice developed disseminated intravascular coagulation, which was associated with elevated blood IL-6 levels (but not TNF-α) and systemic inflammatory responses. Infected MBL null mice also develop liver injury. These findings suggest that MBL deficiency may manifest as disseminated intravascular coagulation and organ failure with infection. Beginning from these observations, this review focuses on the interaction of innate immunity and other homeostatic systems, the derangement of which may lead to complications in infection and other inflammatory states. PMID:22114968

Ten weeks of high-intensity interval walk training is associated with reduced disease activity and improved innate immune function in older adults with rheumatoid arthritis: a pilot study.

PubMed

Bartlett, David B; Willis, Leslie H; Slentz, Cris A; Hoselton, Andrew; Kelly, Leslie; Huebner, Janet L; Kraus, Virginia B; Moss, Jennifer; Muehlbauer, Michael J; Spielmann, Guillaume; Kraus, William E; Lord, Janet M; Huffman, Kim M

2018-06-14

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which adults have significant joint issues leading to poor health. Poor health is compounded by many factors, including exercise avoidance and increased risk of opportunistic infection. Exercise training can improve the health of patients with RA and potentially improve immune function; however, information on the effects of high-intensity interval training (HIIT) in RA is limited. We sought to determine whether 10 weeks of a walking-based HIIT program would be associated with health improvements as measured by disease activity and aerobic fitness. Further, we assessed whether HIIT was associated with improved immune function, specifically antimicrobial/bacterial functions of neutrophils and monocytes. Twelve physically inactive adults aged 64 ± 7 years with either seropositive or radiographically proven (bone erosions) RA completed 10 weeks of high-intensity interval walking. Training consisted of 3 × 30-minute sessions/week of ten ≥ 60-second intervals of high intensity (80-90% VO 2reserve ) separated by similar bouts of lower-intensity intervals (50-60% VO 2reserve ). Pre- and postintervention assessments included aerobic and physical function; disease activity as measured by Disease Activity score in 28 joints (DAS28), self-perceived health, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR); plasma interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand (CXCL)-8, IL-10, and tumor necrosis factor (TNF)-α concentrations; and neutrophil and monocyte phenotypes and functions. Despite minimal body composition change, cardiorespiratory fitness increased by 9% (change in both relative and absolute aerobic capacity; p < 0.001), and resting blood pressure and heart rate were both reduced (both p < 0.05). Postintervention disease activity was reduced by 38% (DAS28; p = 0.001) with significant reductions in ESR and swollen joints as well as improved self-perceived health. Neutrophil migration toward CXCL-8 (p = 0.003), phagocytosis of Escherichia coli (p = 0.03), and ROS production (p < 0.001) all increased following training. The frequency of cluster of differentiation 14-positive (CD14 + )/CD16 + monocytes was reduced (p = 0.002), with both nonclassical (CD14 dim /CD16 bright ) and intermediate (CD14 bright /CD16 positive ) monocytes being reduced (both p < 0.05). Following training, the cell surface expression of intermediate monocyte Toll-like receptor 2 (TLR2), TLR4, and HLA-DR was reduced (all p < 0.05), and monocyte phagocytosis of E. coli increased (p = 0.02). No changes were observed for inflammatory markers IL-1β, IL-6, CXCL-8, IL-10, CRP, or TNF-α. We report for the first time, to our knowledge, that a high-intensity interval walking protocol in older adults with stable RA is associated with reduced disease activity, improved cardiovascular fitness, and improved innate immune functions, indicative of reduced infection risk and inflammatory potential. Importantly, the exercise program was well tolerated by these patients. ClinicalTrials.gov, NCT02528344 . Registered on 19 August 2015.

CXCR3+CD4+ T cells mediate innate immune function in the pathophysiology of liver ischemia/reperfusion injury.

PubMed

Zhai, Yuan; Shen, Xiu-da; Hancock, Wayne W; Gao, Feng; Qiao, Bo; Lassman, Charles; Belperio, John A; Strieter, Robert M; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W

2006-05-15

Ischemia-reperfusion injury (IRI), an innate immune-dominated inflammatory response, develops in the absence of exogenous Ags. The recently highlighted role of T cells in IRI raises a question as to how T lymphocytes interact with the innate immune system and function with no Ag stimulation. This study dissected the mechanism of innate immune-induced T cell recruitment and activation in rat syngeneic orthotopic liver transplantation (OLT) model. Liver IRI was induced after cold storage (24-36 h) at 4 degrees C in University of Wisconsin solution. Gene products contributing to IRI were identified by cDNA microarray at 4-h posttransplant. IRI triggered increased intrahepatic expression of CXCL10, along with CXCL9 and 11. The significance of CXCR3 ligand induction was documented by the ability of neutralizing anti-CXCR3 Ab treatment to ameliorate hepatocellular damage and improve 14-day survival of 30-h cold-stored OLTs (95 vs 40% in controls; p < 0.01). Immunohistology analysis confirmed reduced CXCR3+ and CD4+ T cell infiltration in OLTs after treatment. Interestingly, anti-CXCR3 Ab did not suppress innate immune activation in the liver, as evidenced by increased levels of IL-1beta, IL-6, inducible NO synthase, and multiple neutrophil/monokine-targeted chemokine programs. In conclusion, this study demonstrates a novel mechanism of T cell recruitment and function in the absence of exogenous Ag stimulation. By documenting that the execution of innate immune function requires CXCR3+CD4+ T cells, it highlights the critical role of CXCR3 chemokine biology for the continuum of innate to adaptive immunity in the pathophysiology of liver IRI.

Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen.

PubMed

Javid, Ashkan; Zlotnikov, Nataliya; Pětrošová, Helena; Tang, Tian Tian; Zhang, Yang; Bansal, Anil K; Ebady, Rhodaba; Parikh, Maitry; Ahmed, Mijhgan; Sun, Chunxiang; Newbigging, Susan; Kim, Yae Ram; Santana Sosa, Marianna; Glogauer, Michael; Moriarty, Tara J

2016-01-01

Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.

Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health.

PubMed

Bansal, Amita; Henao-Mejia, Jorge; Simmons, Rebecca A

2018-01-01

The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity. Copyright © 2018 Endocrine Society.

Biosignatures of Exposure/Transmission and Immunity.

PubMed

King, Christopher L; Davies, D Huw; Felgner, Phil; Baum, Elizabeth; Jain, Aarti; Randall, Arlo; Tetteh, Kevin; Drakeley, Christopher J; Greenhouse, Bryan

2015-09-01

A blood test that captures cumulative exposure over time and assesses levels of naturally acquired immunity (NAI) would provide a critical tool to monitor the impact of interventions to reduce malaria transmission and broaden our understanding of how NAI develops around the world as a function of age and exposure. This article describes a collaborative effort in multiple International Centers of Excellence in Malaria Research (ICEMRs) to develop such tests using malaria-specific antibody responses as biosignatures of transmission and immunity. The focus is on the use of Plasmodium falciparum and Plasmodium vivax protein microarrays to identify a panel of the most informative antibody responses in diverse malaria-endemic settings representing an unparalleled spectrum of malaria transmission and malaria species mixes before and after interventions to reduce malaria transmission. © The American Society of Tropical Medicine and Hygiene.

The RpoB H481Y Rifampicin Resistance Mutation and an Active Stringent Response Reduce Virulence and Increase Resistance to Innate Immune Responses in Staphylococcus aureus

PubMed Central

Gao, Wei; Cameron, David R.; Davies, John K.; Kostoulias, Xenia; Stepnell, Justin; Tuck, Kellie L.; Yeaman, Michael R.; Peleg, Anton Y.; Stinear, Timothy P.; Howden, Benjamin P.

2013-01-01

The occurrence of mutations in methicillin-resistant Staphylococcus aureus (MRSA) during persistent infection leads to antimicrobial resistance but may also impact host-pathogen interactions. Here, we investigate the host-pathogen consequences of 2 mutations arising in clinical MRSA during persistent infection: RpoB H481Y, which is linked to rifampicin resistance, and RelA F128Y, which is associated with an active stringent response. Allelic exchange experiments showed that both mutations cause global transcriptional changes, leading to upregulation of capsule production, with attenuated virulence in a murine bacteremia model and reduced susceptibility to both antimicrobial peptides and whole-blood killing. Disruption of capsule biosynthesis reversed these impacts on innate immune function. These data clearly link MRSA persistence and reduced virulence to the same mechanisms that alter antimicrobial susceptibility. Our study highlights the wider consequences of suboptimal antimicrobial use, where drug resistance and immune escape mechanisms coevolve, thus increasing the likelihood of treatment failure. PMID:23255563

Immune responses of eastern fence lizards (Sceloporus undulatus) to repeated acute elevation of corticosterone.

PubMed

McCormick, Gail L; Langkilde, Tracy

2014-08-01

Prolonged elevations of glucocorticoids due to long-duration (chronic) stress can suppress immune function. It is unclear, however, how natural stressors that result in repeated short-duration (acute) stress, such as frequent agonistic social encounters or predator attacks, fit into our current understanding of the immune consequences of stress. Since these types of stressors may activate the immune system due to increased risk of injury, immune suppression may be reduced at sites where individuals are repeatedly exposed to potentially damaging stressors. We tested whether repeated acute elevation of corticosterone (CORT, a glucocorticoid) suppresses immune function in eastern fence lizards (Sceloporus undulatus), and whether this effect varies between lizards from high-stress (high baseline CORT, invaded by predatory fire ants) and low-stress (low baseline CORT, uninvaded) sites. Lizards treated daily with exogenous CORT showed higher hemagglutination of novel proteins by their plasma (a test of constitutive humoral immunity) than control lizards, a pattern that was consistent across sites. There was no significant effect of CORT treatment on bacterial killing ability of plasma. These results suggest that repeated elevations of CORT, which are common in nature, produce immune effects more typical of those expected at the acute end of the acute-chronic spectrum and provide no evidence of modulated consequences of elevated CORT in animals from high-stress sites. Copyright © 2014 Elsevier Inc. All rights reserved.

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.

Modulation of antigen processing by haem-oxygenase 1. Implications on inflammation and tolerance.

PubMed

Riquelme, Sebastián A; Carreño, Leandro J; Espinoza, Janyra A; Mackern-Oberti, Juan Pablo; Alvarez-Lobos, Manuel M; Riedel, Claudia A; Bueno, Susan M; Kalergis, Alexis M

2016-09-01

Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases. © 2016 John Wiley & Sons Ltd.

Vaccine-elicited SIV and HIV envelope-specific IgA and IgG memory B cells in rhesus macaque peripheral blood correlate with functional antibody responses and reduced viremia

PubMed Central

Brocca-Cofano, Egidio; McKinnon, Katherine; Demberg, Thorsten; Venzon, David; Hidajat, Rachmat; Xiao, Peng; Daltabuit-Test, Mara; Patterson, L. Jean; Robert-Guroff, Marjorie

2011-01-01

An effective HIV vaccine requires strong systemic and mucosal, cellular and humoral immunity. Numerous non-human primate studies have investigated memory T cells, but not memory B cells. Humoral immunologic memory is mediated by long-lived antibody-secreting plasma cells and differentiation of memory B cells into short-lived plasma blasts following re-exposure to immunizing antigen. Here we studied memory B cells in vaccinated rhesus macaques. PBMC were stimulated polyclonally using CD40 Ligand, IL-21 and CpG to induce B cell proliferation and differentiation into antibody secreting cells (ASC). Flow cytometry was used for phenotyping and evaluating proliferation by CFSE dilution. B cell responses were quantified by ELISPOT. Methodology was established using PBMC of vaccinated elite-controller macaques that exhibited strong, multi-functional antibody activities. Subsequently, memory B cells elicited by two replicating Ad-recombinant prime/envelope boost regimens were retrospectively evaluated pre- and post- SIV and SHIV challenges. The vaccine regimens induced SIV and HIV Env-specific IgG and IgA memory B cells. Prior to challenge, IgA memory B cells were more numerous than IgG memory B cells, reflecting the mucosal priming immunizations. Pre- and post-challenge memory B cells were correlated with functional antibody responses including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated viral inhibition (ADCVI) and transcytosis inhibition. Post-challenge, Env-specific IgG and IgA memory B cells were correlated with reduced chronic viremia. We conclude that functional antibody responses elicited by our prime/boost regimen were effectively incorporated into the memory B cell pool where they contributed to control of viremia following re-exposure to the immunizing antigen. PMID:21382487

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.

Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion.

PubMed

Albacker, Lee A; Wu, Jeremy; Smith, Peter; Warmuth, Markus; Stephens, Philip J; Zhu, Ping; Yu, Lihua; Chmielecki, Juliann

2017-01-01

Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells. Therefore, we analyzed alterations in this family for the hypothesized signature of an immune evasion mutation. Here, we searched a database of 61,704 unique solid tumors for alterations in the JAK family kinases (JAK1/2/3, TYK2). We used The Cancer Genome Atlas and Cancer Cell Line Encyclopedia data to confirm and extend our findings by analyzing gene expression patterns. Recurrent frameshift mutations in JAK1 were associated with high mutation burden and microsatellite instability. These mutations occurred in multiple tumor types including endometrial, colorectal, stomach, and prostate carcinomas. Analyzing gene expression signatures in endometrial and stomach adenocarcinomas revealed that tumors with a JAK1 frameshift exhibited reduced expression of interferon response signatures and multiple anti-tumor immune signatures. Importantly, endometrial cancer cell lines exhibited similar gene expression changes that were expected to be tumor cell intrinsic (e.g. interferon response) but not those expected to be tumor cell extrinsic (e.g. NK cells). From these data, we derive two primary conclusions: 1) JAK1 frameshifts are loss of function alterations that represent a potential pan-cancer adaptation to immune responses against tumors with microsatellite instability; 2) The mechanism by which JAK1 loss of function contributes to tumor immune evasion is likely associated with loss of the JAK1-mediated interferon response.

The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis.

PubMed

Bello, Ramatu Omenesa; Chin, Voon Kin; Abd Rachman Isnadi, Mohammad Faruq; Abd Majid, Roslaini; Atmadini Abdullah, Maizaton; Lee, Tze Yan; Amiruddin Zakaria, Zainul; Hussain, Mohd Khairi; Basir, Rusliza

2018-04-11

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis.

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

PubMed Central

Abud, Edsel M.; Lakatos, Anita; Karimzadeh, Alborz; Yeung, Stephen T.; Davtyan, Hayk; Fote, Gianna M.; Lau, Lydia; Weinger, Jason G.; Lane, Thomas E.; Inlay, Matthew A.; Poon, Wayne W.; Blurton-Jones, Mathew

2016-01-01

The innate immune system is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting “Rag-5xfAD” mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive–innate immunity cross talk and accelerated disease progression. PMID:26884167

Consequences of contamination of the spacecraft environment: immunologic consequences

NASA Technical Reports Server (NTRS)

Shearer, W. T.

2001-01-01

Long-term space voyages pose numerous known and unknown health hazards, to the human immune system. Well-studied clinical examples of secondary immunodeficiencies created on Earth, lead one to predict that the conditions of prolonged space flight would weaken the human immune responses that normally hold infection and cancer in check. From evidence gathered from humans flown for prolonged periods in space and from human models of space flight studied on Earth it is reasonable to suspect that space travelers to the planet Mars would experience a weakening of immunity. Subtle defects of immune cell structure and function have been observed in astronauts, such as weakening of specific T-lymphocyte recall of specific antigens. Ground-based models also have demonstrated alterations of immune function, such as the elevation of neuroendocrine immune system messengers, interleukin-6, and soluble tumor necrosis factor-alpha receptor in sleep deprivation. Since severe immune compromise the clinical consequences of reactivation of latent virus infections and the development of cancer, has yet to be seen in space flight or in the Earth models, it is extremely important to begin to quantify early changes in immunity to predict the development of immune system collapse with poor clinical outcomes. This approach is designed to validate a number of surrogate markers that will predict trouble ahead. Inherent in this research is the development of countermeasures to reduce the risks of infection and cancer in the first humans going to Mars.

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.

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.

Silencing the Honey Bee (Apis mellifera) Naked Cuticle Gene (nkd) Improves Host Immune Function and Reduces Nosema ceranae Infections

PubMed Central

Li, Wenfeng; Evans, Jay D.; Huang, Qiang; Rodríguez-García, Cristina; Liu, Jie; Hamilton, Michele; Grozinger, Christina M.; Webster, Thomas C.; Su, Songkun

2016-01-01

ABSTRACT Nosema ceranae is a new and emerging microsporidian parasite of European honey bees, Apis mellifera, that has been implicated in colony losses worldwide. RNA interference (RNAi), a posttranscriptional gene silencing mechanism, has emerged as a potent and specific strategy for controlling infections of parasites and pathogens in honey bees. While previous studies have focused on the silencing of parasite/pathogen virulence factors, we explore here the possibility of silencing a host factor as a mechanism for reducing parasite load. Specifically, we used an RNAi strategy to reduce the expression of a honey bee gene, naked cuticle (nkd), which is a negative regulator of host immune function. Our studies found that nkd mRNA levels in adult bees were upregulated by N. ceranae infection (and thus, the parasite may use this mechanism to suppress host immune function) and that ingestion of double-stranded RNA (dsRNA) specific to nkd efficiently silenced its expression. Furthermore, we found that RNAi-mediated knockdown of nkd transcripts in Nosema-infected bees resulted in upregulation of the expression of several immune genes (Abaecin, Apidaecin, Defensin-1, and PGRP-S2), reduction of Nosema spore loads, and extension of honey bee life span. The results of our studies clearly indicate that silencing the host nkd gene can activate honey bee immune responses, suppress the reproduction of N. ceranae, and improve the overall health of honey bees. This study represents a novel host-derived therapeutic for honey bee disease treatment that merits further exploration. IMPORTANCE Given the critical role of honey bees in the pollination of agricultural crops, it is urgent to develop strategies to prevent the colony decline induced by the infection of parasites/pathogens. Targeting parasites and pathogens directly by RNAi has been proven to be useful for controlling infections in honey bees, but little is known about the disease impacts of RNAi silencing of host factors. Here, we demonstrate that knocking down the honey bee immune repressor-encoding nkd gene can suppress the reproduction of N. ceranae and improve the overall health of honey bees, which highlights the potential role of host-derived and RNAi-based therapeutics in controlling the infections in honey bees. The information obtained from this study will have positive implications for honey bee disease management practices. PMID:27613683

Silencing the Honey Bee (Apis mellifera) Naked Cuticle Gene (nkd) Improves Host Immune Function and Reduces Nosema ceranae Infections.

PubMed

Li, Wenfeng; Evans, Jay D; Huang, Qiang; Rodríguez-García, Cristina; Liu, Jie; Hamilton, Michele; Grozinger, Christina M; Webster, Thomas C; Su, Songkun; Chen, Yan Ping

2016-11-15

Nosema ceranae is a new and emerging microsporidian parasite of European honey bees, Apis mellifera, that has been implicated in colony losses worldwide. RNA interference (RNAi), a posttranscriptional gene silencing mechanism, has emerged as a potent and specific strategy for controlling infections of parasites and pathogens in honey bees. While previous studies have focused on the silencing of parasite/pathogen virulence factors, we explore here the possibility of silencing a host factor as a mechanism for reducing parasite load. Specifically, we used an RNAi strategy to reduce the expression of a honey bee gene, naked cuticle (nkd), which is a negative regulator of host immune function. Our studies found that nkd mRNA levels in adult bees were upregulated by N. ceranae infection (and thus, the parasite may use this mechanism to suppress host immune function) and that ingestion of double-stranded RNA (dsRNA) specific to nkd efficiently silenced its expression. Furthermore, we found that RNAi-mediated knockdown of nkd transcripts in Nosema-infected bees resulted in upregulation of the expression of several immune genes (Abaecin, Apidaecin, Defensin-1, and PGRP-S2), reduction of Nosema spore loads, and extension of honey bee life span. The results of our studies clearly indicate that silencing the host nkd gene can activate honey bee immune responses, suppress the reproduction of N. ceranae, and improve the overall health of honey bees. This study represents a novel host-derived therapeutic for honey bee disease treatment that merits further exploration. Given the critical role of honey bees in the pollination of agricultural crops, it is urgent to develop strategies to prevent the colony decline induced by the infection of parasites/pathogens. Targeting parasites and pathogens directly by RNAi has been proven to be useful for controlling infections in honey bees, but little is known about the disease impacts of RNAi silencing of host factors. Here, we demonstrate that knocking down the honey bee immune repressor-encoding nkd gene can suppress the reproduction of N. ceranae and improve the overall health of honey bees, which highlights the potential role of host-derived and RNAi-based therapeutics in controlling the infections in honey bees. The information obtained from this study will have positive implications for honey bee disease management practices. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Tribbles role in reproduction.

PubMed

Basatvat, Shaghayegh; Carter, Deborah Angela Louise; Kiss-Toth, Endre; Fazeli, Alireza

2015-10-01

Tribbles (TRIB) proteins, a family of evolutionary conserved psuedokinase proteins, modulate various signalling pathways within the cell. The regulatory roles of TRIB make them an important part of a number of biological processes ranging from cell proliferation to metabolism, immunity, inflammation and carcinogenesis. Innate immune system plays a pivotal role during the regulation of reproductive processes that allows successful creation of an offspring. Its involvement initiates from fertilization of the oocyte by spermatozoon and lasts throughout early embryonic development, pregnancy and labour. Therefore, there is a close cooperation between the reproductive system and the innate immune system. Evidence from our lab has demonstrated that improper activation of the innate immune system can reduce embryo implantation, thus leading to infertility. Therefore, control mechanisms regulating the innate immune system function can be critical for successful reproductive events. © 2015 Authors; published by Portland Press Limited.

Constant light suppresses production of Met-enkephalin-containing peptides in cultured splenic macrophages and impairs primary immune response in rats.

PubMed

Valdés-Tovar, Marcela; Escobar, Carolina; Solís-Chagoyán, Héctor; Asai, Miguel; Benítez-King, Gloria

2015-03-01

The light-dark cycle is an environmental factor that influences immune physiology, and so, variations of the photoperiod length result in altered immune responsivity. Macrophage physiology comprises a spectrum of functions that goes from host defense to immune down-regulation, in addition to their homeostatic activities. Macrophages also play a key role in the transition from innate to adaptive immune responses. Met-enkephalin (MEnk) has been recognized as a modulator of macrophage physiology acting in an autocrine or paracrine fashion to influence macrophage activation, phenotype polarization and production of cytokines that would enhance lymphocyte activation at early stages of an immune response. Previously it was shown that splenic MEnk tissue content is reduced in rats exposed to constant light. In this work, we explored whether production of Met-enkephalin-containing peptides (MECPs) in cultured splenic macrophages is affected by exposure of rats to a constant light regime. In addition, we explored whether primary immune response was impaired under this condition. We found that in rats, 15 days in constant light was sufficient to disrupt their general activity rhythm. Splenic MEnk content oscillations and levels were also blunted throughout a 24-h period in animals subjected to constant light. In agreement, de novo synthesis of MECPs evaluated through incorporation of (35)S-methionine was reduced in splenic macrophages from rats exposed to constant light. Moreover, MECPs immunocytochemistry showed a decrease in the intracellular content and lack of granule-like deposits in this condition. Furthermore, we found that primary T-dependent antibody response was compromised in rats exposed to constant light. In those animals, pharmacologic treatment with MEnk increased IFN-γ-secreting cells. Also, IL-2 secretion from antigen-stimulated splenocytes was reduced after incubation with naloxone, suggesting that immune-derived opioid peptides and stimulation of opioid receptors are involved in this process. Thus, the immune impairment observed from early stages of the response in constant light-subjected rats, could be associated with reduced production of macrophage-derived enkephalins, leading to a sub-optimal interaction between macrophages and lymphocytes in the spleen and the subsequent deficiency in antibody production.

Effect of micronutrient supplementation on the immune function of crossbred dairy cows under semi-arid tropical environment.

PubMed

De, Kalyan; Pal, Shashi; Prasad, Shiv; Dang, Ajay Kumar

2014-01-01

This study assessed the effect of micronutrient supplementation around peripartum period on immune function, reproductive performance, milk yield and milk quality of crossbred cows. Thirty pregnant crossbred cows in their late gestation were selected and randomly divided into five groups for study. Six cows in each group were supplemented with vitamin E (VE) (2000 IU/cow/day), vitamin A (VA) (100,000 IU/cow/day), copper (Cu) (20 ppm/cow/day), zinc (Zn) (80 ppm/cow/day) individually from 45 days pre-calving to 45 days post-calving and one group without any supplementation served as control. Immune function was studied by in vitro phagocytic activity (PA) of blood neutrophils, lymphocyte proliferation response (LPR) and plasma interleukin-8 (IL-8) concentration. Supplementation of VA significantly (P < 0.05) increased the in vitro PA of blood neutrophils and decreased milk somatic cell counts (SCC). Zn supplementation significantly (P < 0.05) increased the T lymphocyte proliferation response, whereas B lymphocyte LPR was significantly (P < 0.05) increased with both VA and Zn supplementation as compared to the control cows. Plasma IL-8 concentration was significantly (P < 0.05) higher in all supplemented cows. Supplementation of VE, VA and Zn significantly (P < 0.05) reduces days open, whereas VA significantly (P < 0.05) reduced the service per conception. In this study, it is concluded that VE, VA and Zn supplementation around peripartum period can boost the immunity and improve the reproductive performance of crossbred cows in a semi-arid tropical environment.

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.

PD-1 and its ligands are important immune checkpoints in cancer

PubMed Central

Dong, Yinan; Sun, Qian; Zhang, Xinwei

2017-01-01

Checkpoint programmed death-1 (PD-1)/programmed cell death ligands (PD-Ls) have been identified as negative immunoregulatory molecules that promote immune evasion of tumor cells. The interaction of PD-1 and PD-Ls inhibits the function of T cells and tumor-infiltrating lymphocytes (TIL) while increasing the function of immunosuppressive regulatory T cells (Tregs). This condition causes the tumor cells to evade immune response. Thus, the blockade of PD-1/PD-L1 enhances anti-tumor immunity by reducing the number and/or the suppressive activity of Tregs and by restoring the activity of effector T cells. Furthermore, some monoclonal antibodies blockading PD-1/PD-Ls axis have achieved good effect and received Food and Drug Administration approval. The role of PD-1/PD-Ls in tumors has been well studied, but little is known on the mechanism by which PD-1 blocks T-cell activation. In this study, we provide a brief overview on the discovery and regulatory mechanism of PD-1 and PD-L1 dysregulation in tumors, as well as the function and signaling pathway of PD-1 and its ligands; their roles in tumor evasion and clinical treatment were also studied. PMID:27974689

Massage Therapy for Reducing Stress Hormones and Enhancing Immune Function in Breast Cancer Survivors

DTIC Science & Technology

2001-08-01

massage therapy (n=20), a relaxation therapy (n=20) or a control group (n=20). Women in the massage and relaxation therapies will receive 3 sessions a...women reveal for the massage therapy group 1) reduced anxiety, 2) improved mood, 3) increased serotonin and dopamine levels and 4) increased Natural

Passive immunization with Pneumovax® 23 and pneumolysin in combination with vancomycin for pneumococcal endophthalmitis.

PubMed

Sanders, Melissa E; Taylor, Sidney; Tullos, Nathan; Norcross, Erin W; Moore, Quincy C; Thompson, Hilary; King, Lauren B; Marquart, Mary E

2013-03-11

Capsule and pneumolysin (PLY) are two major virulence factors of Streptococcus pneumoniae. S. pneumoniae is one of the leading causes of bacterial endophthalmitis. The aim of this study is to determine whether passive immunization with the 23-valent pneumococcal polysaccharide vaccine (Pneumovax® 23; PPSV23) or PLY protects against pneumococcal endophthalmitis. New Zealand white rabbits were passively immunized with antiserum to PLY, PPSV23, a mixture of PPSV23/PLY, or PBS (mock). Vitreous was infected with a clinical strain of S. pneumoniae. In a separate group of experiments, vancomycin was injected 4 hours post-infection (PI) for each passively immunized group. Severity of infection, bacterial recovery, myeloperoxidase (MPO) activity and percent loss of retinal function were determined. Passive immunization with each antiserum significantly lowered clinical severity compared to mock immunization (PPSV23 = 9.19, PPSV23/PLY = 10.45, PLY = 8.71, Mock = 16.83; P = 0.0467). A significantly higher bacterial load was recovered from the vitreous of PLY passively immunized rabbits 24 hours PI (7.87 log10 CFU) compared to controls (7.10 log10 CFU; P = 0.0134). Retinas from immunized rabbits were more intact. Vitreous of PLY (2.88 MPO untis/mL) and PPSV23/PLY (2.17) passively immunized rabbits had less MPO activity compared to controls (5.64; P = 0.0480), and both passive immunizations (PLY = 31.34% loss of retinal function, PPSV23/PLY = 27.44%) helped to significantly preserve retinal function compared to controls (64.58%; P = 0.0323). When vancomycin was administered 4 hours PI, all eyes were sterile at 24 hours PI. A significantly lower clinical severity was observed for rabbits administered the combination immunization (5.29) or PPSV23 (5.29) with vancomycin treatment compared to controls (17.68; P = 0.0469). Passive immunization with antisera to these antigens is effective in reducing clinical severity of pneumococcal endophthalmitis in rabbits. Addition of vancomycin to immunization is effective at eliminating the bacteria.

Alterations in adaptive immunity persist during long-duration spaceflight.

PubMed

Crucian, Brian; Stowe, Raymond P; Mehta, Satish; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

2015-01-01

It is currently unknown whether immune system alterations persist during long-duration spaceflight. In this study various adaptive immune parameters were assessed in astronauts at three intervals during 6-month spaceflight on board the International Space Station (ISS). To assess phenotypic and functional immune system alterations in astronauts participating in 6-month orbital spaceflight. Blood was collected before, during, and after flight from 23 astronauts participating in 6-month ISS expeditions. In-flight samples were returned to Earth within 48 h of collection for immediate analysis. Assays included peripheral leukocyte distribution, T-cell function, virus-specific immunity, and mitogen-stimulated cytokine production profiles. Redistribution of leukocyte subsets occurred during flight, including an elevated white blood cell (WBC) count and alterations in CD8 + T-cell maturation. A reduction in general T-cell function (both CD4 + and CD8 + ) persisted for the duration of the 6-month spaceflights, with differential responses between mitogens suggesting an activation threshold shift. The percentage of CD4 + T cells capable of producing IL-2 was depressed after landing. Significant reductions in mitogen-stimulated production of IFNγ, IL-10, IL-5, TNFα, and IL-6 persisted during spaceflight. Following lipopolysaccharide (LPS) stimulation, production of IL-10 was reduced, whereas IL-8 production was increased during flight. The data indicated that immune alterations persist during long-duration spaceflight. This phenomenon, in the absence of appropriate countermeasures, has the potential to increase specific clinical risks for crewmembers during exploration-class deep space missions.

Alterations in adaptive immunity persist during long-duration spaceflight

PubMed Central

Crucian, Brian; Stowe, Raymond P; Mehta, Satish; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

2015-01-01

Background: It is currently unknown whether immune system alterations persist during long-duration spaceflight. In this study various adaptive immune parameters were assessed in astronauts at three intervals during 6-month spaceflight on board the International Space Station (ISS). AIMS: To assess phenotypic and functional immune system alterations in astronauts participating in 6-month orbital spaceflight. Methods: Blood was collected before, during, and after flight from 23 astronauts participating in 6-month ISS expeditions. In-flight samples were returned to Earth within 48 h of collection for immediate analysis. Assays included peripheral leukocyte distribution, T-cell function, virus-specific immunity, and mitogen-stimulated cytokine production profiles. Results: Redistribution of leukocyte subsets occurred during flight, including an elevated white blood cell (WBC) count and alterations in CD8+ T-cell maturation. A reduction in general T-cell function (both CD4+ and CD8+) persisted for the duration of the 6-month spaceflights, with differential responses between mitogens suggesting an activation threshold shift. The percentage of CD4+ T cells capable of producing IL-2 was depressed after landing. Significant reductions in mitogen-stimulated production of IFNγ, IL-10, IL-5, TNFα, and IL-6 persisted during spaceflight. Following lipopolysaccharide (LPS) stimulation, production of IL-10 was reduced, whereas IL-8 production was increased during flight. Conclusions: The data indicated that immune alterations persist during long-duration spaceflight. This phenomenon, in the absence of appropriate countermeasures, has the potential to increase specific clinical risks for crewmembers during exploration-class deep space missions. PMID:28725716

Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus

PubMed Central

Op den Brouw, Marjoleine L; Binda, Rekha S; van Roosmalen, Mark H; Protzer, Ulrike; Janssen, Harry L A; van der Molen, Renate G; Woltman, Andrea M

2009-01-01

Chronic hepatitis B virus (HBV) infection is the result of an inadequate immune response towards the virus. Myeloid dendritic cells (mDC) of patients with chronic HBV are impaired in their maturation and function, resulting in more tolerogenic rather than immunogenic responses, which may contribute to viral persistence. The mechanism responsible for altered mDC function remains unclear. The HBV-infected patients display large amounts of HBV particles and viral proteins in their circulation, especially the surface antigen HBsAg, which allows multiple interactions between the virus, its viral proteins and DC. To assess whether HBV directly influences mDC function, the effects of HBV and HBsAg on human mDC maturation and function were investigated in vitro. As already described for internalization of HBV by DC, the present study shows that peripheral blood-derived mDC of healthy controls also actively take up HBsAg in a time-dependent manner. Cytokine-induced maturation in the presence of HBV or HBsAg resulted in a significantly more tolerogenic mDC phenotype as demonstrated by a diminished up-regulation of costimulatory molecules and a decreased T-cell stimulatory capacity, as assessed by T-cell proliferation and interferon-γ production. In addition, the presence of HBV significantly reduced interleukin-12 production by mDC. These results show that both HBV particles and purified HBsAg have an immune modulatory capacity and may directly contribute to the dysfunction of mDC in patients with chronic HBV. The direct immune regulatory effect of HBV and circulating HBsAg particles on the function of DC can be considered as part of the mechanism by which HBV escapes immunity. PMID:18624732

Induction of regulatory T cells in Th1-/Th17-driven experimental autoimmune encephalomyelitis by zinc administration.

PubMed

Rosenkranz, Eva; Maywald, Martina; Hilgers, Ralf-Dieter; Brieger, Anne; Clarner, Tim; Kipp, Markus; Plümäkers, Birgit; Meyer, Sören; Schwerdtle, Tanja; Rink, Lothar

2016-03-01

The essential trace element zinc is indispensable for proper immune function as zinc deficiency accompanies immune defects and dysregulations like allergies, autoimmunity and an increased presence of transplant rejection. This point to the importance of the physiological and dietary control of zinc levels for a functioning immune system. This study investigates the capacity of zinc to induce immune tolerance. The beneficial impact of physiological zinc supplementation of 6 μg/day (0.3mg/kg body weight) or 30 μg/day (1.5mg/kg body weight) on murine experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis with a Th1/Th17 (Th, T helper) cell-dominated immunopathogenesis, was analyzed. Zinc administration diminished EAE scores in C57BL/6 mice in vivo (P<.05), reduced Th17 RORγT(+) cells (P<.05) and significantly increased inducible iTreg cells (P<.05). While Th17 cells decreased systemically, iTreg cells accumulated in the central nervous system. Cumulatively, zinc supplementation seems to be capable to induce tolerance in unwanted immune reactions by increasing iTreg cells. This makes zinc a promising future tool for treating autoimmune diseases without suppressing the immune system. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Temperature fluctuations during deep temperature cryopreservation reduce PBMC recovery, viability and T-cell function.

PubMed

Germann, Anja; Oh, Young-Joo; Schmidt, Tomm; Schön, Uwe; Zimmermann, Heiko; von Briesen, Hagen

2013-10-01

The ability to analyze cryopreserved peripheral blood mononuclear cell (PBMC) from biobanks for antigen-specific immunity is necessary to evaluate response to immune-based therapies. To ensure comparable assay results, collaborative research in multicenter trials needs reliable and reproducible cryopreservation that maintains cell viability and functionality. A standardized cryopreservation procedure is comprised of not only sample collection, preparation and freezing but also low temperature storage in liquid nitrogen without any temperature fluctuations, to avoid cell damage. Therefore, we have developed a storage approach to minimize suboptimal storage conditions in order to maximize cell viability, recovery and T-cell functionality. We compared the influence of repeated temperature fluctuations on cell health from sample storage, sample sorting and removal in comparison to sample storage without temperature rises. We found that cyclical temperature shifts during low temperature storage reduce cell viability, recovery and immune response against specific-antigens. We showed that samples handled under a protective hood system, to avoid or minimize such repeated temperature rises, have comparable cell viability and cell recovery rates to samples stored without any temperature fluctuations. Also T-cell functionality could be considerably increased with the use of the protective hood system compared to sample handling without such a protection system. This data suggests that the impact of temperature fluctuation on cell integrity should be carefully considered in future clinical vaccine trials and consideration should be given to optimal sample storage conditions. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Accelerated aging versus rejuvenation of the immune system in heterochronic parabiosis.

PubMed

Pishel, Iryna; Shytikov, Dmytro; Orlova, Tatiana; Peregudov, Alex; Artyuhov, Igor; Butenko, Gennadij

2012-04-01

The emergence of immune disorders in aging is explained by many factors, including thymus dysfunction, decrease in the proportion and function of naïve T cells, and so forth. There are several approaches to preventing these changes, such as thymus rejuvenation, stem cells recovery, modulation of hormone production, and others. Our investigations of heterochronic parabiosis have shown that benefits of a young immune system, e.g., actively working thymus and regular migration of young hematopoietic stem cells between parabiotic partners, appeared unable to restore the immune system of the old partner. At the same time, we have established a progressive immune impairment in the young heterochronic partners. The mechanism of age changes in the immune system in this model, which may lead to reduced life expectancy, has not been fully understood. The first age-related manifestation in the young partners observed 3 weeks after the surgery was a dramatic increase of CD8(+)44(+) cells population in the spleen. A detailed analysis of further changes revealed a progressive decline of most immunological functions observable for up to 3 months after the surgery. This article reviews possible mechanisms of induction of age-related changes in the immune system of young heterochronic partners. The data obtained suggest the existence of certain factors in the old organisms that trigger aging, thus preventing the rejuvenation process.

Broad modulation of tissue responses (immune activation) by celacade may favorably influence pathologic processes associated with heart failure progression.

PubMed

Torre-Amione, Guillermo; Sestier, François; Radovancevic, Branislav; Young, James

2005-06-06

Immune activation and inflammation contribute to the progression of chronic heart failure (CHF), but therapeutic approaches directed against these processes have been largely unsuccessful. This clinical study evaluated a novel, nonpharmacologic immune modulation therapy, shown experimentally to reduce inflammatory and increase anti-inflammatory cytokines. A total of 75 patients with New York Heart Association (NYHA) functional class III or IV CHF were randomized to receive either Celacade (immune modulation therapy) or placebo (n = 38 and n = 37, respectively) in a double-blind trial for 6 months, during which standard therapy for CHF was maintained. Patients were evaluated using the 6-minute walk test, changes in NYHA class, cardiac function, and quality-of-life assessments, and were observed for the occurrence of death and hospitalization. There was no between-treatment difference in the 6-minute walk test results, but 15 Celacade-treated patients (compared with 9 placebo-treated patients) improved NYHA classification by > or = 1 class (p = 0.140). Kaplan-Meier survival analysis showed that Celacade significantly reduced the risk of death (p = 0.022) and hospitalization (p = 0.008). Analysis of a clinical composite score demonstrated a significant between-group difference (p = 0.006). There was no difference in left ventricular ejection fraction between groups, but there was a trend toward improved quality of life favoring the Celacade-treated group (p = 0.110). These preliminary findings are consistent with the hypothesis that immune activation is important in the pathogenesis of CHF, and they establish the basis for a phase 3 trial to define the benefit of Celacade in CHF.

Modulation of macrophage functions by sheeppox virus provides clues to understand interaction of the virus with host immune system.

PubMed

Abu-El-Saad, Abdel-Aziz S; Abdel-Moneim, Ahmed S

2005-03-22

Poxviruses encode a range of immunomodulatory genes to subvert or evade the challenges posed by the innate and adaptive immune responses. However, the inactivated poxviruses possessed immunostimulating capacity and were used as a prophylactic or metaphylactic application that efficiently reduced susceptibility to infectious diseases in different species. This fact is intensively studied in different genera of poxviruses. However, little is known about the basic mechanisms adopted by sheeppox virus (SPPV). SPPV causes an acute disease of sheep that recently, has been observed to reinfect its host in spite of vaccination. By injecting inactivated or attenuated sheeppox virus SPPV vaccine in adult male Swiss mice, SPPV was found to reduce macrophages' functions in a local event that occurs at the site of application 12 h after vaccine administration as indicated by increased level of IL-10 and decreased level of SOD from cultured peritoneal macrophages. In contrast increased levels of IL-12, and SOD activity from cultured splenic macrophages, lymphocyte response to PHA-P, and in-vivo response to T-dependant Ag were detected. These effects were observed in both attenuated and inactivated SPPV, but more prominent in attenuated one. The results of this study help to elucidate, the phenomenon of existence natural SPPV infections in sheep instead of vaccination and the basic mechanisms responsible for the immunostimulating capacity of sheeppox virus. Locally, SPPV shows evidence for an immune escape mechanism that alleviates the host's immune response. Later and systemically, the virus protects the host from any fatal consequences of the immune system suppression.

Functional and quantitative changes of immune cells of ageing NZB mice treated with nandrolone decanoate. I. Effect on survival and autoantibody development.

PubMed Central

Bruley-Rosset, M; Dardenne, M; Schuurs, A

1985-01-01

We analysed the effect of nandrolone decanoate (ND) on functional and quantitative changes in immune cell populations, on survival, and on autoantibody production of female New Zealand Black (NZB) mice. Our results confirmed that, with increasing age, untreated NZB mice display a lower natural killer (NK) cell activity, an impaired T-cell function as evidenced by a reduced mitogen lymphoproliferative response, IL-2 production and generation of cytotoxic lymphocytes, a lower level of thymic serum factor (TSF), a reduced percentage of Thy-1+ cells; we also observed an increased incidence of mice with abnormally high levels of anti-DNA in the serum. In addition, we demonstrated an important defect in the IL-1 production by LPS-stimulated macrophages. ND administered to female NZB mice increased the survival time of the animals and reduced the anti-DNA titres. This favourable effect was associated with improved immune responses, especially those mediated by T cells; these included increased IL-2 production, complete recovery of cytotoxic T lymphocytes (CTL), a significant augmentation of the percentage of Lyt-2+ cells and enhanced TSF level. Moreover IL-1 production by macrophages returned to normal. These results suggest that ND acts on T-cell differentiation, either by a direct effect on thymic epithelial cells resulting in an increased TSF release, and/or via macrophage regulatory activity. The protective effect of ND may also be attributed in part to the higher number of Lyt-2+ (suppressor) T cells present in the spleen after treatment. PMID:3878753

Suppression of innate inflammation and immunity by interleukin-37.

PubMed

Dinarello, Charles A; Nold-Petry, Claudia; Nold, Marcel; Fujita, Mayumi; Li, Suzhao; Kim, Soohyun; Bufler, Philip

2016-05-01

IL-37 is unique in the IL-1 family in that unlike other members of the family, IL-37 broadly suppresses innate immunity. IL-37 can be elevated in humans with inflammatory and autoimmune diseases where it likely functions to limit inflammation. Transgenic mice expressing human IL-37 (IL37-tg) exhibit less severe inflammation in models of endotoxin shock, colitis, myocardial infarction, lung, and spinal cord injury. IL37-tg mice have reduced antigen-specific responses and dendritic cells (DCs) from these mice exhibit characteristics of tolerogenic DCs. Compared to aging wild-type (WT) mice, aging IL37-tg mice are protected against B-cell leukemogenesis and heart failure. Treatment of WT mice with recombinant human IL-37 has been shown to be protective in several models of inflammation and injury. IL-37 binds to the IL-18 receptor but then recruits the orphan IL-1R8 (formerly TIR8 or SIGIRR) in order to function as an inhibitor. Here, we review the discovery of IL-37, its production, release, and mechanisms by which IL-37 reduces inflammation and suppresses immune responses. The data reviewed here suggest a therapeutic potential for IL-37. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Letting Our Cells Do the Fighting: Flight-Induced Changes in the Immune Response

NASA Technical Reports Server (NTRS)

Pierson, Duane; Bloomberg, Jacob; Lee, Angie (Technical Monitor)

2002-01-01

The organisms that make us ill, such as bacteria, viruses, and fungi, are like attacking armies. We now know a great deal more about this unseen world of microscopic invaders. Fortunately for us, the human immune system is ever vigilant against them. Microorganisms such as bacteria, viruses, and fungi occupy almost every corner of the Earth, and even parts of the human body. Some organisms are beneficial to us, helping to produce milk, cheese or yogurt. Others are potentially harmful, yet we don#t always develop illnesses from them; they are kept in check by the sentinels of our immune system. Our immune system is routinely challenged by these organisms every day. When the immune response is diminished, our ability to fight off these "bugs" is lowered. And that's when we become ill. Space flight presents a challenge to the immune system. Scientists believe that the stressful conditions of space flight - launch into orbit, adapting to microgravity, heavy workloads, and isolation from family and friends, to name but a few - reduce the astronauts' immunity. This immune suppression makes them more susceptible to common illnesses from bacteria and to re-infections from latent viruses in the body. In addition, risk of spreading illness in the confined environment of the Space Shuttle is high. Understanding changes in immune function will help scientists develop ways to keep astronauts healthy in space. This knowledge can also benefit earthbound populations. This experiment will give scientists insight into the immune system by comparing how certain cells of astronauts' innate immune system - the first line of defense against invaders - function after flight compared to before flight.

Preserved dendritic cell HLA-DR expression and reduced regulatory T cell activation in asymptomatic Plasmodium falciparum and P. vivax infection.

PubMed

Kho, Steven; Marfurt, Jutta; Noviyanti, Rintis; Kusuma, Andreas; Piera, Kim A; Burdam, Faustina H; Kenangalem, Enny; Lampah, Daniel A; Engwerda, Christian R; Poespoprodjo, Jeanne R; Price, Ric N; Anstey, Nicholas M; Minigo, Gabriela; Woodberry, Tonia

2015-08-01

Clinical illness with Plasmodium falciparum or Plasmodium vivax compromises the function of dendritic cells (DC) and expands regulatory T (Treg) cells. Individuals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. The role of DC and Treg cells during asymptomatic Plasmodium infection is unclear. During a cross-sectional household survey in Papua, Indonesia, we examined the number and activation of blood plasmacytoid DC (pDC), CD141(+), and CD1c(+) myeloid DC (mDC) subsets and Treg cells using flow cytometry in 168 afebrile children (of whom 15 had P. falciparum and 36 had P. vivax infections) and 162 afebrile adults (of whom 20 had P. falciparum and 20 had P. vivax infections), alongside samples from 16 patients hospitalized with uncomplicated malaria. Unlike DC from malaria patients, DC from children and adults with asymptomatic, microscopy-positive P. vivax or P. falciparum infection increased or retained HLA-DR expression. Treg cells in asymptomatic adults and children exhibited reduced activation, suggesting increased immune responsiveness. The pDC and mDC subsets varied according to clinical immunity (asymptomatic or symptomatic Plasmodium infection) and, in asymptomatic infection, according to host age and parasite species. In conclusion, active control of asymptomatic infection was associated with and likely contingent upon functional DC and reduced Treg cell activation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Malaria epidemiology and economics: the effect of delayed immune acquisition on the cost-effectiveness of insecticide-treated bednets.

PubMed Central

Guyatt, H L; Snow, R W; Evans, D B

1999-01-01

An understanding of the epidemiology of a disease is central in evaluating the health impact and cost-effectiveness of control interventions. The epidemiology of life-threatening malaria is receiving renewed interest, with concerns that the implementation of preventive measures such as insecticide-treated bednets (ITNs) while protecting young children might in fact increase the risks of mortality and morbidity in older ages by delaying the acquisition of functional immunity. This paper aims to illustrate how a combined approach of epidemiology and economics can be used to (i) explore the long-term impact of changes in epidemiological profiles, and (ii) identify those variables that are critical in determining whether an intervention will be an efficient use of resources. The key parameters for determining effectiveness are the protective efficacy of ITNs (reduction in all-cause mortality), the malaria attributable mortality and the increased malaria-specific mortality risk due to delays in the acquisition of functional immunity. In particular, the analysis demonstrates that delayed immune acquisition is not a problem per se, but that the critical issue is whether it occurs immediately following the implementation of an ITN programme or whether it builds up slowly over time. In the 'worst case' scenario where ITNs immediately increase malaria-specific mortality due to reduced immunity, the intervention might actually cost lives. In other words, it might be better to not use ITNs. On the other hand, if reduced immunity takes two years to develop, ITNs would still fall into the category of excellent value for money compared to other health interventions, saving a year of life (YLL) at a cost of between US$25-30. These types of calculations are important in identifying the parameters which field researchers should be seeking to measure to address the important question of the net impact of delaying the acquisition of immunity through preventive control measures. PMID:10365407

Nutritional strategies to optimize dairy cattle immunity.

PubMed

Sordillo, L M

2016-06-01

Dairy cattle are susceptible to increased incidence and severity of both metabolic and infectious diseases during the periparturient period. A major contributing factor to increased health disorders is alterations in bovine immune mechanisms. Indeed, uncontrolled inflammation is a major contributing factor and a common link among several economically important infectious and metabolic diseases including mastitis, retained placenta, metritis, displaced abomasum, and ketosis. The nutritional status of dairy cows and the metabolism of specific nutrients are critical regulators of immune cell function. There is now a greater appreciation that certain mediators of the immune system can have a reciprocal effect on the metabolism of nutrients. Thus, any disturbances in nutritional or immunological homeostasis can provide deleterious feedback loops that can further enhance health disorders, increase production losses, and decrease the availability of safe and nutritious dairy foods for a growing global population. This review will discuss the complex interactions between nutrient metabolism and immune functions in periparturient dairy cattle. Details of how either deficiencies or overexposure to macro- and micronutrients can contribute to immune dysfunction and the subsequent development of health disorders will be presented. Specifically, the ways in which altered nutrient metabolism and oxidative stress can interact to compromise the immune system in transition cows will be discussed. A better understanding of the linkages between nutrition and immunity may facilitate the design of nutritional regimens that will reduce disease susceptibility in early lactation cows. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers.

PubMed

Martin-Gayo, Enrique; Buzon, Maria Jose; Ouyang, Zhengyu; Hickman, Taylor; Cronin, Jacqueline; Pimenova, Dina; Walker, Bruce D; Lichterfeld, Mathias; Yu, Xu G

2015-06-01

The majority of HIV-1 elite controllers (EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells (cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes.

Electrotransfer of the epinecidin-1 gene into skeletal muscle enhances the antibacterial and immunomodulatory functions of a marine fish, grouper (Epinephelus coioides).

PubMed

Lee, Lin-Han; Hui, Cho-Fat; Chuang, Chi-Mu; Chen, Jyh-Yih

2013-11-01

Electrotransfer of plasmid DNA into skeletal muscle is a common non-viral delivery system for the study of gene function and for gene therapy. However, the effects of epinecidin-1 (epi) on bacterial growth and immune system modulation following its electrotransfer into the muscle of grouper (Epinephelus coioides), a marine fish species, have not been addressed. In this study, pCMV-gfp-epi plasmid was electroporated into grouper muscle, and its effect on subsequent infection with Vibrio vulnificus was examined. Over-expression of epi efficiently reduced bacterial numbers at 24 and 48 h after infection, and augmented the expression of immune-related genes in muscle and liver, inducing a moderate innate immune response associated with pro-inflammatory infiltration. Furthermore, electroporation of pCMV-gfp-epi plasmid without V. vulnificus infection induced moderate expression of certain immune-related genes, particularly innate immune genes. These data suggest that electroporation-mediated gene transfer of epi into the muscle of grouper may hold potential as an antimicrobial therapy for pathogen infection in marine fish. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genetics Home Reference: anhidrotic ectodermal dysplasia with immune deficiency

MedlinePlus

... The proteins produced from these two genes regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related ... proteins with impaired function, which reduces activation of nuclear factor-kappa-B. These changes disrupt certain signaling ...

Redox sensitivity of the MyD88 immune signaling adapter.

PubMed

Stottmeier, Benjamin; Dick, Tobias P

2016-12-01

The transcription factor nuclear factor-κB (NF-κB) mediates expression of key genes involved in innate immunity and inflammation. NF-κB activation has been repeatedly reported to be modulated by hydrogen peroxide (H 2 O 2 ). Here, we show that the NF-κB-activating signaling adapter myeloid differentiation primary response gene 88 (MyD88) is highly sensitive to oxidation by H 2 O 2 and may be redox-regulated in its function, thus facilitating an influence of H 2 O 2 on the NF-κB signaling pathway. Upon oxidation, MyD88 forms distinct disulfide-linked conjugates which are reduced by the MyD88-interacting oxidoreductase nucleoredoxin (Nrx). MyD88 cysteine residues functionally modulate MyD88-dependent NF-κB activation, suggesting a link between MyD88 thiol oxidation state and immune signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

Decline in Early Childhood Respiratory Tract Infections in the Norwegian Mother and Child Cohort Study after Introduction of Pneumococcal Conjugate Vaccination

PubMed Central

Magnus, Maria C.; Vestrheim, Didrik F.; Nystad, Wenche; Håberg, Siri Eldevik; Stigum, Hein; London, Stephanie J.; Bergsaker, Marianne A. R.; Caugant, Dominique A.; Aaberge, Ingeborg S.; Nafstad, Per

2012-01-01

BACKGROUND The seven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the Norwegian Childhood Immunization Program in 2006. A substantial effectiveness of PCV7 immunization against invasive pneumococcal disease has been demonstrated, while evidence of the impact on respiratory tract infections are less consistent. METHODS This study included children participating in the Norwegian Mother and Child Cohort Study, which recruited pregnant women between 1999 and 2008. Maternal report of acute otitis media (AOM), lower respiratory tract infections (LRTIs) and asthma in the child was compared with PCV7 immunization status, as obtained from the Norwegian Immunization Registry. Generalized linear models with the log link function were used to report adjusted relative risks (RR) and 95% confidence intervals (CI). RESULTS For children who had received three or more PCV7 immunizations by 12 months of age, the adjusted relative risks of AOM and LRTIs between 12 and 18 months were 0.86 [95% CI: 0.81, 0.91] and 0.78 [95% CI: 0.70, 0.87] respectively, when compared with non-immunized children. A reduced risk of AOM, RR 0.92 [95% CI: 0.90, 0.94], and LRTIs, RR 0.75 [95%CI: 0.71, 0.80], between 18 and 36 months of age was also identified among children who had received 3 or more immunizations by 18 months. No association was seen between PCV7 immunization and asthma at 36 months of age. CONCLUSION Reduced incidence proportions of AOM and LRTIs before 36 months of age were observed among children immunized with PCV7 through the childhood immunization program. PMID:22627867

BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Impact of mineral and vitamin status on beef cattle immune function and health.

PubMed

Kegley, E B; Ball, J J; Beck, P A

2016-12-01

The importance of optimal mineral and vitamin nutrition on improving immune function and health has been recognized in the preceding decades. In the southeast, beef cattle are raised predominantly on forages that may be limiting in nutrients for optimal health, especially trace minerals such as Cu, Zn, and Se. Clinical deficiencies of these nutrients produce classic symptoms that are common to several nutrient deficiencies (e.g., slow growth and unthrifty appearance); however, subclinical deficiencies are more widespread and more difficult to detect, yet may result in broader economic losses. Dietary mineral concentrations often considered adequate for maximum growth, reproductive performance, or optimal immune function have been found to be insufficient at times of physiological stress (weaning, transport, comingling, etc.), when feed intake is reduced. The impacts of these deficiencies on beef cattle health are not apparent until calves have been subjected to these stressors. Health problems that are exacerbated by mineral or vitamin deficiencies include bovine respiratory disease, footrot, retained placenta, metritis, and mastitis. Many micronutrients have antioxidant properties through being components of enzymes and proteins that benefit animal health. In dairy cattle, high levels of supplemental Zn are generally associated with reduced somatic cell counts and improved foot health, possibly reflecting the importance of Zn in maintaining effective epithelial barriers. Neutrophils isolated from ruminants deficient in Cu or Se have reduced ability to kill ingested bacteria in vitro. Supplemental vitamin E, in its role as an intracellular antioxidant has been shown to decrease morbidity in stressed calves. There is more understanding of the important biological role that these nutrients play in the functioning of the complex and multifaceted immune system. However, there is still much to be learned about determining the micronutrient status of herds (and hence when supplementation will be beneficial), requirements for different genetic and environmental conditions, understanding the bioavailability of these nutrients from feedstuffs and forages, quantifying the bioavailability of different supplemental sources of these nutrients, and identifying the impact of dietary antagonists on these nutrients.

Neutrophil and Monocyte Bactericidal Responses to 10 Weeks of Low-Volume High-Intensity Interval or Moderate-Intensity Continuous Training in Sedentary Adults

PubMed Central

Shepherd, Sam O.; Wilson, Oliver J.; Adlan, Ahmed M.; Wagenmakers, Anton J. M.; Shaw, Christopher S.; Lord, Janet M.

2017-01-01

Neutrophils and monocytes are key components of the innate immune system that undergo age-associated declines in function. This study compared the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on immune function in sedentary adults. Twenty-seven (43 ± 11 years) healthy sedentary adults were randomized into ten weeks of either a HIIT (>90% maximum heart rate) or MICT (70% maximum heart rate) group training program. Aerobic capacity (VO2peak), neutrophil and monocyte bacterial phagocytosis and oxidative burst, cell surface receptor expression, and systemic inflammation were measured before and after the training. Total exercise time commitment was 57% less for HIIT compared to that for MICT while both significantly improved VO2peak similarly. Neutrophil phagocytosis and oxidative burst and monocyte phagocytosis and percentage of monocytes producing an oxidative burst were improved by training similarly in both groups. Expression of monocyte but not neutrophil CD16, TLR2, and TLR4 was reduced by training similarly in both groups. No differences in systemic inflammation were observed for training; however, leptin was reduced in the MICT group only. With similar immune-enhancing effects for HIIT compared to those for MICT at 50% of the time commitment, our results support HIIT as a time efficient exercise option to improve neutrophil and monocyte function. PMID:28656073

SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways.

PubMed

Chen, Shuliang; Bonifati, Serena; Qin, Zhihua; St Gelais, Corine; Kodigepalli, Karthik M; Barrett, Bradley S; Kim, Sun Hee; Antonucci, Jenna M; Ladner, Katherine J; Buzovetsky, Olga; Knecht, Kirsten M; Xiong, Yong; Yount, Jacob S; Guttridge, Denis C; Santiago, Mario L; Wu, Li

2018-04-17

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-κB (NF-κB) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF-κB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-κB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-κB activation by interacting with NF-κB1/2 and reducing phosphorylation of the NF-κB inhibitory protein IκBα. SAMHD1 also interacts with the inhibitor-κB kinase ε (IKKε) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKε-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-κB and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-κB activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity.

GABAergic neurons in cerebellar interposed nucleus modulate cellular and humoral immunity via hypothalamic and sympathetic pathways.

PubMed

Lu, Jian-Hua; Wang, Xiao-Qin; Huang, Yan; Qiu, Yi-Hua; Peng, Yu-Ping

2015-06-15

Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3-MP), a glutamic acid decarboxylase antagonist that reduces γ-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

The bradykinin B2 receptor in the early immune response against Listeria infection.

PubMed

Kaman, Wendy E; Wolterink, Arthur F W M; Bader, Michael; Boele, Linda C L; van der Kleij, Desiree

2009-02-01

The endogenous danger signal bradykinin was recently found implicated in the development of immunity against parasites via dendritic cells. We here report an essential role of the B(2) (B(2)R) bradykinin receptor in the early immune response against Listeria infection. Mice deficient in B(2)R (B(2)R(-/-) mice) were shown to suffer from increased hepatic bacterial burden and concomitant dramatic weight loss during infection with Listeria monocytogenes. Levels of cytokines known to play a pivotal role in the early phase immune response against L. monocytogenes, IL-12p70 and IFN-gamma, were reduced in B(2)R(-/-) mice. To extend these findings to the human system, we show that bradykinin potentiates the production of IL-12p70 in human monocyte-derived dendritic cells. Thus, we show that bradykinin and the B(2)R play a role in early innate immune functions during bacterial infection.

Reduced Expression of SARM in Mouse Spleen during Polymicrobial Sepsis.

PubMed

Gong, Yu; Zou, Lin; Cen, Dongzhi; Chao, Wei; Chen, Dunjin

2016-12-01

Objective Immune dysfunction, including prominent apoptosis of immune cells and decreased functioning of the remaining immune cells, plays a central role in the pathogenesis of sepsis. Sterile α and HEAT/armadillo motif-containing protein (SARM) is implicated in the regulation of immune cell apoptosis. This study aimed to elucidate SARM contributes to sepsis-induced immune cell death and immunosuppression. Methods A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). SARM gene and protein expression, caspase 3 cleavage and intracellular ATP production were measured in the mouse spleens. Results CLP-induced polymicrobial sepsis specifically attenuated both the gene and protein expression of SARM in the spleens. Moreover, the attenuation of SARM expression synchronized with splenocyte apoptosis, as evidenced by increased caspase 3 cleavage and ATP depletion. Conclusions These findings suggest that SARM is a potential regulator of sepsis-induced splenocyte apoptosis.

Improving the Nation's Health. Step One: Reduce Toxic Stress in Early Childhood. Perspectives

ERIC Educational Resources Information Center

Louv, Richard

2006-01-01

To reduce risk factors for adult disease in our society, we must tackle the problem of toxic stress in early childhood. This condition is associated with the excessive release of a stream of hormones whose persistent elevation can disrupt the wiring of the developing brain and the functioning of the immune system. Children who experience toxic…

Perioperative recombinant human granulocyte colony-stimulating factor (Filgrastim) treatment prevents immunoinflammatory dysfunction associated with major surgery.

PubMed

Schneider, Christian; von Aulock, Sonja; Zedler, Siegfried; Schinkel, Christian; Hartung, Thomas; Faist, Eugen

2004-01-01

To examine the effects of perioperative rhG-CSF administration on immune function in patients subjected to major surgery. Severe trauma, such as major surgery, initiates acute immunodysfunction which predisposes the patient towards infectious complications. Sixty patients undergoing elective surgery received either recombinant human granulocyte colony-stimulating factor/rh G-CSF (Filgrastim) or a placebo perioperatively. At several time points before and after the surgical intervention immunofunctional parameters were assessed. RESULTS Leukocyte counts and serum levels of anti-inflammatory mediators (IL-1ra and TNF-R) were increased in Filgrastim-treated patients, while the post-operative acute phase response was attenuated. Monocyte deactivation (reduced TNF-alpha release and HLA-DR expression) and lymphocyte anergy (impaired mitogenic proliferation and reduced TH1 lymphokine release) were blunted and the incidence and severity of infectious complications were reduced. These results suggest that Filgrastim treatment reinforces innate immunity, enabling better prevention of infection. Thus, this unique combination of hematopoietic, anti-inflammatory and anti-infectious effects on the innate immune system warrants further study of clinical efficacy and sepsis prophylaxis.

Perioperative Recombinant Human Granulocyte Colony-Stimulating Factor (Filgrastim) Treatment Prevents Immunoinflammatory Dysfunction Associated With Major Surgery

PubMed Central

Schneider, Christian; von Aulock, Sonja; Zedler, Siegfried; Schinkel, Christian; Hartung, Thomas; Faist, Eugen

2004-01-01

Objective: To examine the effects of perioperative rhG-CSF administration on immune function in patients subjected to major surgery. Summary Background Data: Severe trauma, such as major surgery, initiates acute immunodysfunction which predisposes the patient towards infectious complications. Methods: Sixty patients undergoing elective surgery received either recombinant human granulocyte colony-stimulating factor/rh G-CSF (Filgrastim) or a placebo perioperatively. At several time points before and after the surgical intervention immunofunctional parameters were assessed. Results: Leukocyte counts and serum levels of anti-inflammatory mediators (IL-1ra and TNF-R) were increased in Filgrastim-treated patients, while the post-operative acute phase response was attenuated. Monocyte deactivation (reduced TNF-α release and HLA-DR expression) and lymphocyte anergy (impaired mitogenic proliferation and reduced TH1 lymphokine release) were blunted and the incidence and severity of infectious complications were reduced. Conclusions: These results suggest that Filgrastim treatment reinforces innate immunity, enabling better prevention of infection. Thus, this unique combination of hematopoietic, anti-inflammatory and anti-infectious effects on the innate immune system warrants further study of clinical efficacy and sepsis prophylaxis. PMID:14685103

The RpoB H₄₈₁Y rifampicin resistance mutation and an active stringent response reduce virulence and increase resistance to innate immune responses in Staphylococcus aureus.

PubMed

Gao, Wei; Cameron, David R; Davies, John K; Kostoulias, Xenia; Stepnell, Justin; Tuck, Kellie L; Yeaman, Michael R; Peleg, Anton Y; Stinear, Timothy P; Howden, Benjamin P

2013-03-15

The occurrence of mutations in methicillin-resistant Staphylococcus aureus (MRSA) during persistent infection leads to antimicrobial resistance but may also impact host-pathogen interactions. Here, we investigate the host-pathogen consequences of 2 mutations arising in clinical MRSA during persistent infection: RpoB H₄₈₁Y, which is linked to rifampicin resistance, and RelA F₁₂₈Y, which is associated with an active stringent response. Allelic exchange experiments showed that both mutations cause global transcriptional changes, leading to upregulation of capsule production, with attenuated virulence in a murine bacteremia model and reduced susceptibility to both antimicrobial peptides and whole-blood killing. Disruption of capsule biosynthesis reversed these impacts on innate immune function. These data clearly link MRSA persistence and reduced virulence to the same mechanisms that alter antimicrobial susceptibility. Our study highlights the wider consequences of suboptimal antimicrobial use, where drug resistance and immune escape mechanisms coevolve, thus increasing the likelihood of treatment failure.

Effects of various LED light spectra on antioxidant and immune response in juvenile rock bream, Oplegnathus fasciatus exposed to bisphenol A.

PubMed

Choi, Ji Yong; Kim, Tae Hwan; Choi, Young Jae; Kim, Na Na; Oh, Sung-Yong; Choi, Cheol Young

2016-07-01

Bisphenol A (BPA) is a monomer used in plastics and plasticizers. As an environmental toxin included in industrial wastewater, it contaminates the aquatic environment and is known to cause endocrine disruption in fish. Particular wavelengths of light-emitting diodes (LEDs) are known to affect the endocrine regulation of fish. The present study aimed to investigate the effects of green and red LED light on the antioxidant and immune systems in juvenile rock bream (Oplegnathus fasciatus) exposed to BPA. We used green and red LED exposure at two intensities (0.3 and 0.5W/m(2)) for 1, 3, and 5 days. We measured liver mRNA expression and plasma levels of antioxidant enzyme superoxide dismutase (SOD) and caspase-3. Furthermore, we measured plasma levels of hydrogen peroxide (H2O2), lipid peroxidation (LPO), melatonin, and immunoglobulin M (IgM). DNA damage and apoptotic activity were measured using comet and terminal transferase dUTP nick end labeling (TUNEL) assays, respectively. We found that SOD, H2O2, and LPO increased significantly, whereas melatonin and IgM decreased significantly, suggesting that BPA induces oxidative stress and reduces immune function. Likewise, both DNA damage and apoptotic activity increased following BPA exposure. However, we found that exposure to green LED light effectively reduced the detrimental effects induced by BPA, including decreasing DNA damage, apoptotic activity, SOD mRNA expression, and plasma levels of SOD, H2O2, and LPO. Likewise, the plasma levels of melatonin and IgM increased. Thus, our results indicate that green light conditions effectively reduces oxidative stress and promotes the immune function in juvenile rock bream. Copyright © 2016 Elsevier B.V. All rights reserved.

Sodium butyrate improved performance while modulating the cecal microbiota and regulating the expression of intestinal immune-related genes of broiler chickens.

PubMed

Bortoluzzi, C; Pedroso, A A; Mallo, J J; Puyalto, M; Kim, W K; Applegate, T J

2017-09-01

This study evaluated the effect of sodium butyrate (SB) on performance, expression of immune-related genes in the cecal tonsils, and cecal microbiota of broiler chickens when dietary energy and amino acids concentrations were reduced. Day-old male Ross 708 broiler chicks were fed dietary treatments in a 3 × 2 factorial design (8 pens per treatment) with 3 dietary formulations (control diet; reduction of 2.3% of amino acids and 60 kcal/kg; and reduction of 4.6% of amino acids and 120 kcal/kg) with or without the inclusion of 0.1% of SB. Feed intake (FI), body weight gain (BW gain), and feed conversion ratio (FCR) were recorded until 28 d of age. From 14 to 28 d, there was an interaction of nutrient density by SB (P = 0.003) wherein BW gain of birds fed SB was impaired less by the energy/amino acids reduction than unsupplemented birds. A similar result was obtained from 1 to 28 d (P = 0.004). No interaction (P < 0.05) between nutrient density by SB was observed for FCR. Nutritional density of the diets and SB modified the structure, composition, and predicted function of the cecal microbiota. The nutritionally reduced diet altered the imputed function performed by the microbiota and the SB supplementation reduced these variations, keeping the microbial function similar to that observed in chickens fed a control diet. The frequency of bacterial species presenting the butyryl-CoA: acetate CoA-transferase gene increased in the microbiota of chickens fed a nutritionally reduced diet without SB supplementation, and was not changed by nutrient density of the diet when supplemented with SB (interaction; P = 0.01). SB modulated the expression of immune related genes in the cecal tonsils; wherein SB upregulated the expression of A20 in broilers fed control diets (P < 0.05) and increased IL-6 expression (P < 0.05). These results show that SB had positive effects on the productive performance of broilers fed nutritionally reduced diets, partially by modulating the cecal microbiota and exerting immune-modulatory effects. © 2017 Poultry Science Association Inc.

Influence of cattle temperament on blood serum fatty acid content

USDA-ARS?s Scientific Manuscript database

Cattle temperament has been reported to influence blood metabolites. Specifically, temperament was related with increased circulation of serum NEFA, decreased blood urea nitrogen, and reduced insulin sensitivity. Metabolic alterations such as these may impact cattle immune function, performance trai...

Single-cell mass cytometry and transcriptome profiling reveal the impact of graphene on human immune cells.

PubMed

Orecchioni, Marco; Bedognetti, Davide; Newman, Leon; Fuoco, Claudia; Spada, Filomena; Hendrickx, Wouter; Marincola, Francesco M; Sgarrella, Francesco; Rodrigues, Artur Filipe; Ménard-Moyon, Cécilia; Cesareni, Gianni; Kostarelos, Kostas; Bianco, Alberto; Delogu, Lucia G

2017-10-24

Understanding the biomolecular interactions between graphene and human immune cells is a prerequisite for its utilization as a diagnostic or therapeutic tool. To characterize the complex interactions between graphene and immune cells, we propose an integrative analytical pipeline encompassing the evaluation of molecular and cellular parameters. Herein, we use single-cell mass cytometry to dissect the effects of graphene oxide (GO) and GO functionalized with amino groups (GONH 2 ) on 15 immune cell populations, interrogating 30 markers at the single-cell level. Next, the integration of single-cell mass cytometry with genome-wide transcriptome analysis shows that the amine groups reduce the perturbations caused by GO on cell metabolism and increase biocompatibility. Moreover, GONH 2 polarizes T-cell and monocyte activation toward a T helper-1/M1 immune response. This study describes an innovative approach for the analysis of the effects of nanomaterials on distinct immune cells, laying the foundation for the incorporation of single-cell mass cytometry on the experimental pipeline.

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.

Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults.

PubMed

Tran, Thanh; Guardigni, Viola; Pencina, Karol M; Amato, Anthony A; Floyd, Michael; Brawley, Brooke; Mozeleski, Brian; McKinnon, Jennifer; Woodbury, Erin; Heckel, Emily; Li, Zhuoying; Storer, Tom; Sax, Paul E; Montano, Monty

2018-06-01

Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions. NCT03011957.

Characteristics of human dendritic cells generated in a microgravity analog culture system

NASA Technical Reports Server (NTRS)

Savary, C. A.; Grazziuti, M. L.; Przepiorka, D.; Tomasovic, S. P.; McIntyre, B. W.; Woodside, D. G.; Pellis, N. R.; Pierson, D. L.; Rex, J. H.; McIntire, L. V. (Principal Investigator)

2001-01-01

Generation of an effective immune response requires that antigens be processed and presented to T lymphocytes by antigen-presenting cells, the most efficient of which are dendritic cells (DC). Because of their influence on both the innate and the acquired arms of immunity, a defect in DC would be expected to result in a broad impairment of immune function, not unlike that observed in astronauts during or after space flight. In the study reported here, we investigated whether DC generation and function are altered in a culture environment that models microgravity, i.e., the rotary-cell culture system (RCCS). We observed that RCCS supported the generation of DC identified by morphology, phenotype (HLA-DR+ and lacking lineage-associated markers), and function (high allostimulatory activity). However, the yield of DC from RCCS was significantly lower than that from static cultures. RCCS-generated DC were less able to phagocytose Aspergillus fumigatus conidia and expressed a lower density of surface HLA-DR. The proportion of DC expressing CD80 was also significantly reduced in RCCS compared to static cultures. When exposed to fungal antigens, RCCS-generated DC produced lower levels of interleukin-12 and failed to upregulate some costimulatory/adhesion molecules involved in antigen presentation. These data suggest that DC generation, and some functions needed to mount an effective immune response to pathogens, may be disturbed in the microgravity environment of space.

Plasma Cytokine Levels During Long-Duration Spaceflight

NASA Technical Reports Server (NTRS)

Crucian, Brian E.; Zwart, Sara R.; Quiriarte, Heather A.; Smith, Scott M.; Sams, Clarence F.

2012-01-01

Determine the in-flight status of immunity, physiological stress, viral immunity/reactivation. Specific measurements include leukocyte distribution, T cell function, cytokine production profiles (mRNA, intracellular, secreted, plasma), virus-specific T cell number/function, latent herpesvirus reactivation, stress hormone levels. Determine the clinical risk related to immune dysregulation for exploration class spaceflight, as well as an appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures. Specific Study Objectives: Determine the nutritional status of astronauts before, during, and after spaceflight ensure adequate intake of energy, protein, and vitamins during missions. The Clinical Nutritional Status Assessment measures dietary intake, body composition, protein, bone, iron, mineral, vitamin, and antioxidant status (60 total analytes). Currently, it is a medical requirement for U.S. crewmembers on-board the ISS. The results of data analysis are used both to understand the connections between nutrition and human health during space flight, and to develop effective dietary strategies to reduce adverse health impacts (including bone loss, loss of important vitamins and minerals, and increased genetic damage from radiation).

Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response

PubMed Central

Yang, Jinming; Hawkins, Oriana E.; Barham, Whitney; Gilchuk, Pavlo; Boothby, Mark; Ayers, Gregory D.; Joyce, Sebastian; Karin, Michael; Yull, Fiona E.; Richmond, Ann

2015-01-01

Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a BRAFV600E/PTEN−/− allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8+ T cell–mediated tumor cell lysis. Depleting macrophages or CD8+ T cells in mice with wild-type IKKβ myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8+ T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβCA) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance. PMID:25336190

Boron Affects Immune Function Through Modulation of Splenic T Lymphocyte Subsets, Cytokine Secretion, and Lymphocyte Proliferation and Apoptosis in Rats.

PubMed

Jin, Erhui; Li, Shenghe; Ren, Man; Hu, Qianqian; Gu, Youfang; Li, Kui

2017-08-01

This study demonstrated the mechanisms of boron effects in a rat model and provided a scientific basis for the rational of boron use. These findings were achieved by investigating the effects of boron (10, 20, 40, 80, 160, 320, and 640 mg/L in drinking water or 1.5, 3, 6, 12, 24, 48, and 96 mg/kg BW) on rat serum immunoglobulins (IgGs), splenic cytokines, lymphocyte subsets, as well as on lymphocyte proliferation and apoptosis. Addition of 20 (3) and 40 (6) mg/L (mg/kg BW) of boron to drinking water significantly increased rat serum IgG concentrations, splenic IFN-γ and IL-4 expression as well as the number of splenic CD3 + , CD4 + and proliferating cell nuclear antigen (PCNA) + cells. Supplementation of drinking water with 40 mg/L (6 mg/kg BW) boron also markedly increased splenic IL-2 expression and the CD4 + /CD8 + cell ratio and reduced splenic CD8 + cell number. Supplementation with 80 mg/L (12 mg/kg BW) boron significantly increased CD3 + and PCNA + cell numbers (P < 0.05) and decreased the IL-10 expression in the spleen. Addition of 320 (48) and 640 (96) mg/L (mg/kg BW) boron markedly reduced the serum IgG concentrations; splenic IL-2 and IL-10 expression; the number of CD3 + , CD4 + and PCNA + cells; and increased the number of splenic CD8 + and caspase-3 + cells and promoted caspase-3 expression in CD3 + cells. In conclusion, these findings suggest that the supplementation of rat drinking water with 20(3) and 40(6) mg/L (mg/kg BW) boron can markedly enhance humoral and cellular immune functions, while boron concentrations above 320 mg/L (48 mg/kg BW) can have an inhibitory effect or even toxicity on immune functions. These results exhibit a U-shaped response characteristic of low and high doses of boron supplementation on immune function and imply that proper boron supplementation in food for humans and animals could be used as an immunity regulator.

mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer

PubMed Central

Cash, Harrison; Shah, Sujay; Moore, Ellen; Caruso, Andria; Uppaluri, Ravindra; Van Waes, Carter; Allen, Clint

2015-01-01

We investigated the effects of mTOR and MEK1/2 inhibition on tumor growth and the tumor microenvironment in immunogenic and poorly immunogenic models of murine oral cancer. In vitro, rapamycin and PD901 inhibited signaling through expected downstream targets, but only PD901 reduced viability and altered function of MOC cells. Following transplantation of MOC cells into immune-competent mice, effects on both cancer and infiltrating immune cells were characterized following rapamycin and/or PD901 treatment for 21 days. In vivo, both rapamycin and PD901 inhibition reduced primary growth of established MOC tumors on treatment. Following withdrawal of PD901, rapid rebound of tumor growth limited survival, whereas durable tumor control was observed following rapamycin treatment in immunogenic MOC1 tumors despite more robust inhibition of oncogenic signaling by PD901. Characterization of the immune microenvironment revealed diminished infiltration and activation of antigen-specific CD8+ T-cells and other immune cells following PD901 but not rapamycin in immunogenic tumors. Subsequent in vitro T-cell assays validated robust inhibition of T-cell expansion and activation following MEK inhibition compared to mTOR inhibition. CD8 cell depletion abrogated rapamycin-induced primary tumor growth inhibition in MOC1 mice. These data have critical implications in the design of combination targeted and immune therapies in oral cancer. PMID:26506415

Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells In Vitro and In Vivo

PubMed Central

Roux, Clémence; Saviane, Gaëlle; Pini, Jonathan; Belaïd, Nourhène; Dhib, Gihen; Voha, Christine; Ibáñez, Lidia; Boutin, Antoine; Mazure, Nathalie M.; Wakkach, Abdelilah; Blin-Wakkach, Claudine; Rouleau, Matthieu

2018-01-01

Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4+ FoxP3+ regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3+-Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo. They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance. PMID:29422893

Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells In Vitro and In Vivo.

PubMed

Roux, Clémence; Saviane, Gaëlle; Pini, Jonathan; Belaïd, Nourhène; Dhib, Gihen; Voha, Christine; Ibáñez, Lidia; Boutin, Antoine; Mazure, Nathalie M; Wakkach, Abdelilah; Blin-Wakkach, Claudine; Rouleau, Matthieu

2017-01-01

Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4 + FoxP3 + regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3 + -Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo . They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance.

Effects of methylmercury exposure on the immune function of juvenile common loons (Gavia immer)

USGS Publications Warehouse

Kenow, K.P.; Grasman, K.A.; Hines, R.K.; Meyer, M.W.; Gendron-Fitzpatrick, A.; Spalding, M.G.; Gray, B.R.

2007-01-01

We conducted a dose-response laboratory study to quantify the level of exposure to dietary Hg, delivered as methylmercury chloride (CH3HgCl), that is associated with suppressed immune function in captive-reared common loon (Gavia immer) chicks. We used the phytohemagglutinin (PHA) skin test to assess T-lymphocyte function and the sheep red blood cell (SRBC) hemagglutination test to measure antibody-mediated immunity. The PHA stimulation index among chicks receiving dietary Hg treatment did not differ significantly from those of chicks on the control diet (p = 0.15). Total antibody (immunoglobulin [Ig] M [primary antibody] + IgG [secondary response]) production to the SRBC antigen in chicks treated with dietary methylmercury (MeHg), however, was suppressed (p = 0.04) relative to chicks on control diets. Analysis indicated suppression of total Ig production (p = 0.025 with comparisonwise ?? level = 0.017) between control and 0.4 ??g Hg/g wet food intake treatment groups. Furthermore, the control group exhibited a higher degree of variability in antibody response compared to the Hg groups, suggesting that in addition to reducing the mean response, Hg treatment reduced the normal variation attributable to other biological factors. We observed bursal lymphoid depletion in chicks receiving the 1.2 ??g Hg/g treatment (p = 0.017) and a marginally significant effect (p = 0.025) in chicks receiving the 0.4 ??g Hg/g diet. These findings suggest that common loon chick immune systems may be compromised at an ecologically relevant dietary exposure concentration (0.4 ??g Hg/g wet wt food intake). We also found that chicks hatched from eggs collected from low-pH lakes exhibited higher levels of lymphoid depletion in bursa tissue relative to chicks hatched from eggs collected from neutral-pH lakes. ?? 2007 SETAC.

Exercise and Human Immunodeficiency Virus (HIV-1) Infection

NASA Technical Reports Server (NTRS)

Lawless, DeSales; Jackson, Catherine G. R.; Greenleaf, John E.

1995-01-01

The human immune system is highly efficient and remarkably protective when functioning properly. Similar to other physiological systems, it functions best when the body is maintained with a balanced diet, sufficient rest and a moderately stress-free lifestyle. It can be disrupted by inappropriate drug use and extreme emotion or exertion. The functioning of normal or compromised immune systems can be enhanced by properly prescribed moderate exercise conditioning regimens in healthy people, and in some human immunodeficiency virus (HIV-1)-infected patients but not in others who unable to complete an interval training program. Regular exercise conditioning in healthy people reduces cardiovascular risk factors, increases stamina, facilitates bodyweight control, and reduces stress by engendering positive feelings of well-being. Certain types of cancer may also be suppressed by appropriate exercise conditioning. Various exercise regimens are being evaluated as adjunct treatments for medicated patients with the HIV-1 syndrome. Limited anecdotal evidence from patients suggests that moderate exercise conditioning is per se responsible for their survival well beyond expectancy. HIV-1-infected patients respond positively, both physiologically and psychologically, to moderate exercise conditioning. However, the effectiveness of any exercise treatment programme depends on its mode, frequency, intensity and duration when prescribed o complement the pathological condition of the patient. The effectiveness of exercise conditioning regimens in patients with HIV-1 infection is reviewed in this article. In addition, we discuss mechanisms and pathways, involving the interplay of psychological and physiological factors, through which the suppressed immune system can be enhanced. The immune modulators discussed are endogenous opioids, cytokines, neurotransmitters and other hormones. Exercise conditioning treatment appears to be more effective when combined with other stress management procedures.

Crude oil impairs immune function and increases susceptibility to pathogenic bacteria in southern flounder

PubMed Central

Bayha, Keith M.; Ortell, Natalie; Ryan, Caitlin N.; Griffitt, Kimberly J.; Krasnec, Michelle; Sena, Johnny; Ramaraj, Thiruvarangan; Takeshita, Ryan; Mayer, Gregory D.; Schilkey, Faye; Griffitt, Robert J.

2017-01-01

Exposure to crude oil or its individual constituents can have detrimental impacts on fish species, including impairment of the immune response. Increased observations of skin lesions in northern Gulf of Mexico fish during the 2010 Deepwater Horizon oil spill indicated the possibility of oil-induced immunocompromisation resulting in bacterial or viral infection. This study used a full factorial design of oil exposure and bacterial challenge to examine how oil exposure impairs southern flounder (Paralichthys lethostigma) immune function and increases susceptibility to the bacteria Vibrio anguillarum, a causative agent of vibriosis. Fish exposed to oil prior to bacterial challenge exhibited 94.4% mortality within 48 hours of bacterial exposure. Flounder challenged with V. anguillarum without prior oil exposure had <10% mortality. Exposure resulted in taxonomically distinct gill and intestine bacterial communities. Mortality strongly correlated with V. anguillarum levels, where it comprised a significantly higher percentage of the microbiome in Oil/Pathogen challenged fish and was nearly non-existent in the No Oil/Pathogen challenged fish bacterial community. Elevated V. anguillarum levels were a direct result of oil exposure-induced immunosuppression. Oil-exposure reduced expression of immunoglobulin M, the major systemic fish antibody, and resulted in an overall downregulation in transcriptome response, particularly in genes related to immune function, response to stimulus and hemostasis. Ultimately, sediment-borne oil exposure impairs immune function, leading to increased incidences of bacterial infections. This type of sediment-borne exposure may result in long-term marine ecosystem effects, as oil-bound sediment in the northern Gulf of Mexico will likely remain a contamination source for years to come. PMID:28464028

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

PubMed

Zaidman-Rémy, Anna; Poidevin, Mickael; Hervé, Mireille; Welchman, David P; Paredes, Juan C; Fahlander, Carina; Steiner, Hakan; Mengin-Lecreulx, Dominique; Lemaitre, Bruno

2011-02-18

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

Modulation of Roquin function in myeloid cells reduces Mycobacterium tuberculosis induced inflammation

PubMed Central

Nagalingam, Gayathri; Vinuesa, Carola G.; Britton, Warwick J; Saunders, Bernadette M.

2017-01-01

Damaging inflammation is a hallmark of Mycobacterium tuberculosis infection, and understanding how this is regulated is important for the development of new therapies to limit excessive inflammation. The E3 ubiquitin ligase, Roquin, is involved in immune regulation, however its role in immunity to M. tuberculosis is unknown. To address this we infected mice with a point mutation in Roquin1/Rc3h1 (sanroque). Aerosol-infected sanroque mice showed enhanced control of M. tuberculosis infection associated with delayed bacterial dissemination and upregulated TNF production in the lung after 2 weeks. However, this early control of infection was not maintained, and by 8 weeks post-infection sanroque mice demonstrated increased bacterial burden and dysregulated inflammation in the lung. As the inflammation in the lung of the sanroque mice could have been influenced by emerging autoimmune conditions that are characteristic of aging sanroque mice, the function of Roquin was examined in immune cell subsets in the absence of autoimmune complications. Mycobacterium bovis BCG-primed sanroque T cells transferred into Rag1-/- mice provided equivalent protection in the spleen and liver. Interestingly, the transfer of mycobacteria-specific (P25 CD4+ TCR transgenic) wild-type spleen cells into sanroque.Rag1-/- mice actually led to enhanced protection with reduced bacterial load, decreased chemokine expression and reduced inflammation in the lung compared with transfers into Rag1-/- mice expressing intact Roquin. These studies suggest that modulation of Roquin in myeloid cells may reduce both inflammation and bacterial growth during the chronic phase of M. tuberculosis infection. PMID:28747346

The NLRP3 Inflammasome Suppresses Protective Immunity to Gastrointestinal Helminth Infection.

PubMed

Alhallaf, Rafid; Agha, Zainab; Miller, Catherine M; Robertson, Avril A B; Sotillo, Javier; Croese, John; Cooper, Matthew A; Masters, Seth L; Kupz, Andreas; Smith, Nicholas C; Loukas, Alex; Giacomin, Paul R

2018-04-24

Inflammasomes promote immunity to microbial pathogens by regulating the function of IL-1-family cytokines such as IL-18 and IL-1β. However, the roles for inflammasomes during parasitic helminth infections remain unclear. We demonstrate that mice and humans infected with gastrointestinal nematodes display increased IL-18 secretion, which in Trichuris-infected or worm antigen-treated mice and in macrophages co-cultured with Trichuris antigens or exosome-like vesicles was dependent on the NLRP3 inflammasome. NLRP3-deficient mice displayed reduced pro-inflammatory type 1 cytokine responses and augmented protective type 2 immunity, which was reversed by IL-18 administration. NLRP3-dependent suppression of immunity partially required CD4 + cells but was apparent even in Rag1 -/- mice that lack adaptive immune cells, suggesting that NLRP3 influences both innate and adaptive immunity. These data highlight a role for NLRP3 in limiting protective immunity to helminths, suggesting that targeting the NLRP3 inflammasome may be an approach for limiting the disease burden associated with helminth infections. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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.

Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice.

PubMed

Zhang, Qian; Luan, Hong; Wang, Le; He, Fan; Zhou, Huan; Xu, Xiaoli; Li, Xingai; Xu, Qing; Niki, Toshiro; Hirashima, Mitsuomi; Xu, Gang; Lv, Yongman; Yuan, Jin

2014-04-15

Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4(+)Tim-3(+) T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury, and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the downregulation of CCL-20, CXCL-9, and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-γ and IL-17A declined in Gal-9-treated nephritic mice at days 21 and 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney.

Massage Therapy Research

ERIC Educational Resources Information Center

Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria

2007-01-01

Massage therapy has been notably effective in preventing prematurity, enhancing growth of infants, increasing attentiveness, decreasing depression and aggression, alleviating motor problems, reducing pain, and enhancing immune function. This review covers massage therapy research from the last decade, as an update to the American Psychologist 1998…

Very Good Medicine: Indigenous Humor and Laughter

ERIC Educational Resources Information Center

Mala, Cynthia Lindquist

2016-01-01

Humor is not only instinctive and a basic human need, but it also is very good medicine. Laughter boosts the immune system, lowers blood pressure, reduces stress hormones, and is linked to healthy functioning organs. [This article was written with Mylo Redwater Smith.

Functional defect in regulatory T cells in myasthenia gravis

PubMed Central

Thiruppathi, Muthusamy; Rowin, Julie; Jiang, Qin Li; Sheng, Jian Rong; Prabhakar, Bellur S.; Meriggioli, Matthew N.

2012-01-01

Forkhead box P3 (FOXP3)+ is a transcription factor necessary for the function of regulatory T cells (Treg cells). Treg cells maintain immune homeostasis and self-tolerance, and play an important role in the prevention of autoimmune disease. Here, we discuss the role of Treg cells in the pathogenesis of myasthenia gravis (MG) and review evidence indicating that a significant defect in Treg cell in vitro suppressive function exists in MG patients, without an alteration in circulating frequency. This functional defect is associated with a reduced expression of key functional molecules such as FOXP3 on isolated Treg cells and appears to be more pronounced in immunosuppression-naive MG patients. In vitro administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced the suppressive function of Treg cells and up-regulated FOXP3 expression. These findings indicate a clinically relevant Treg cell–intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target. PMID:23252899

Obesity: impact of infections and response to vaccines.

PubMed

Tagliabue, C; Principi, N; Giavoli, C; Esposito, S

2016-03-01

Obesity is a common condition that has rapidly increased in both the industrialised and developing world in recent decades. Obese individuals show increased risk factors for severe infections and significant immune system dysregulation that may impair the immune response to vaccines. The main aim of this paper was to review the current knowledge regarding the association between obesity and the risk and outcome of infections as well as immune response to vaccines. The results showed that obesity is a highly complex clinical condition in which the functions of several organ and body systems, including the immune system, are modified. However, only a small minority of the biological mechanisms that lead to reduced host defences have been elucidated. Relevant efforts for future research should focus on obese children, as the available data on this population are scarce compared with the adult population. Even if most vaccines are given in the first months of life when obesity is rare, some vaccines require booster doses at preschool age, and other vaccines, such as the influenza vaccine, are recommended yearly in the obese population, but it is not known whether response to vaccines of obese patients is impaired. The reduced immune response of obese patients to vaccination can be deleterious not only for the patient but also for the community.

Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract

PubMed Central

Patras, Kathryn A.; Coady, Alison; Olson, Joshua; Ali, Syed Raza; RamachandraRao, Satish P.; Kumar, Satish; Varki, Ajit; Nizet, Victor

2017-01-01

Urinary tract infections (UTI) are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm-Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic E. coli (UPEC) as well host immune cells. In addition to its well-studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation. Using isolated human neutrophils, we found that THP binds neutrophils and that this interaction reduces reactive oxygen species generation, chemotaxis, and killing of UPEC. We discovered that THP engages the inhibitory neutrophil receptor sialic acid-binding Ig-like lectin-9 (Siglec-9), and mouse functional ortholog Siglec-E, in a manner dependent on sialic acid on its N-glycan moieties. THP-null mice have significantly more neutrophils present in the urine compared to WT mice, both with and without the presence of inflammatory stimuli. These data support THP as an important negative regulator of neutrophil activation in the urinary tract, with dual functions to counteract bacterial colonization and suppress excessive inflammation within the urinary tract. PMID:28829050

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.

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

PubMed Central

Gross, Catharina C.; Schulte-Mecklenbeck, Andreas; Rünzi, Anna; Kuhlmann, Tanja; Posevitz-Fejfár, Anita; Schwab, Nicholas; Schneider-Hohendorf, Tilman; Herich, Sebastian; Held, Kathrin; Konjević, Matea; Hartwig, Marvin; Dornmair, Klaus; Hohlfeld, Reinhard; Ziemssen, Tjalf; Klotz, Luisa; Meuth, Sven G.; Wiendl, Heinz

2016-01-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood–brain barrier, CD56bright NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4+ T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4+ T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor’s ligand CD155 on CD4+ T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4+ T cells and the cytolytic activity of NK cells. PMID:27162345

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

Maternal obesity alters immune cell frequencies and responses in umbilical cord blood samples.

PubMed

Wilson, Randall M; Marshall, Nicole E; Jeske, Daniel R; Purnell, Jonathan Q; Thornburg, Kent; Messaoudi, Ilhem

2015-06-01

Maternal obesity is one of the several key factors thought to modulate neonatal immune system development. Data from murine studies demonstrate worse outcomes in models of infection, autoimmunity, and allergic sensitization in offspring of obese dams. In humans, children born to obese mothers are at increased risk for asthma. These findings suggest a dysregulation of immune function in the children of obese mothers; however, the underlying mechanisms remain poorly understood. The aim of this study was to examine the relationship between maternal body weight and the human neonatal immune system. Umbilical cord blood samples were collected from infants born to lean, overweight, and obese mothers. Frequency and function of major innate and adaptive immune cell populations were quantified using flow cytometry and multiplex analysis of circulating factors. Compared to babies born to lean mothers, babies of obese mothers had fewer eosinophils and CD4 T helper cells, reduced monocyte and dendritic cell responses to Toll-like receptor ligands, and increased plasma levels of IFN-α2 and IL-6 in cord blood. These results support the hypothesis that maternal obesity influences programming of the neonatal immune system, providing a potential link to increased incidence of chronic inflammatory diseases such as asthma and cardiovascular disease in the offspring. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions.

PubMed

Ginwala, Rashida; McTish, Emily; Raman, Chander; Singh, Narendra; Nagarkatti, Mitzi; Nagarkatti, Prakash; Sagar, Divya; Jain, Pooja; Khan, Zafar K

2016-03-01

Apigenin, a natural flavonoid, found in several plants, fruits, vegetables, herbs, and spices, is known to have anti-oxidant and anti-inflammatory properties that are evident in the use of these substances for centuries as medicinal approaches to treat asthma, insomnia, Parkinson's disease, neuralgia, and shingles. However, there is a considerable dearth of information regarding its effect on immune cells, especially dendritic cells (DC) that maintain the critical balance between an immunogenic and tolerogenic immune response, in an immunospecialized location like the central nervous system (CNS). In this paper we looked at the anti-inflammatory properties of Apigenin in restoration of immune function and the resultant decrease in neuroinflammation. In vivo, a significant reduction in severity of experimental autoimmune encephalomyelitis (EAE) progression and relapse was observed in C57BL/6 (progressive) and SJL/J (relapse-remitting) mouse models of multiple sclerosis upon treatment with Apigenin. Apigenin treated EAE mice show decreased expression of α4 integrin and CLEC12A on splenic DCs and an increased retention of immune cells in the periphery compared to untreated EAE mice. This correlated consequently with immunohistochemistry findings of decreased immune cell infiltration and reduced demyelination in the CNS. These results indicate a protective role of Apigenin against the neurodegenerative effects resulting from the entry of DC stimulated pathogenic T cells into the CNS thus implicating a potential therapy for neuroinflammatory disease.

Immune, inflammatory and cardiovascular consequences of sleep restriction and recovery.

PubMed

Faraut, Brice; Boudjeltia, Karim Zouaoui; Vanhamme, Luc; Kerkhofs, Myriam

2012-04-01

In addition to its effects on cognitive function, compelling evidence links sleep loss to alterations in the neuroendocrine, immune and inflammatory systems with potential negative public-health ramifications. The evidence to suggest that shorter sleep is associated with detrimental health outcomes comes from both epidemiological and experimental sleep deprivation studies. This review will focus on the post-sleep deprivation and recovery changes in immune and inflammatory functions in well-controlled sleep restriction laboratory studies. The data obtained indicate non-specific activation of leukocyte populations and a state of low-level systemic inflammation after sleep loss. Furthermore, one night of recovery sleep does not allow full recovery of a number of these systemic immune and inflammatory markers. We will speculate on the mechanism(s) that link(s) sleep loss to these responses and to the progression of cardiovascular disease. The immune and inflammatory responses to chronic sleep restriction suggest that chronic exposure to reduced sleep (<6 h/day) and insufficient time for recovery sleep could have gradual deleterious effects, over years, on cardiovascular pathogenesis with a heightened risk in women and in night and shift workers. Finally, we will examine countermeasures, e.g., napping or sleep extension, which could improve the recovery processes, in terms of alertness and immune and inflammatory parameters, after sleep restriction. Copyright © 2011 Elsevier Ltd. All rights reserved.

Engineering Vaccines to Reprogram Immunity against Head and Neck Cancer.

PubMed

Tan, Y S; Sansanaphongpricha, K; Prince, M E P; Sun, D; Wolf, G T; Lei, Y L

2018-06-01

The recent Food and Drug Administration's approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8 + T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines.

Developing Extracellular Matrix Technology to Treat Retinal or Optic Nerve Injury

PubMed Central

van der Merwe, Yolandi

2015-01-01

Abstract Adult mammalian CNS neurons often degenerate after injury, leading to lost neurologic functions. In the visual system, retinal or optic nerve injury often leads to retinal ganglion cell axon degeneration and irreversible vision loss. CNS axon degeneration is increasingly linked to the innate immune response to injury, which leads to tissue-destructive inflammation and scarring. Extracellular matrix (ECM) technology can reduce inflammation, while increasing functional tissue remodeling, over scarring, in various tissues and organs, including the peripheral nervous system. However, applying ECM technology to CNS injuries has been limited and virtually unstudied in the visual system. Here we discuss advances in deriving fetal CNS-specific ECMs, like fetal porcine brain, retina, and optic nerve, and fetal non-CNS-specific ECMs, like fetal urinary bladder, and the potential for using tissue-specific ECMs to treat retinal or optic nerve injuries in two platforms. The first platform is an ECM hydrogel that can be administered as a retrobulbar, periocular, or even intraocular injection. The second platform is an ECM hydrogel and polymer “biohybrid” sheet that can be readily shaped and wrapped around a nerve. Both platforms can be tuned mechanically and biochemically to deliver factors like neurotrophins, immunotherapeutics, or stem cells. Since clinical CNS therapies often use general anti-inflammatory agents, which can reduce tissue-destructive inflammation but also suppress tissue-reparative immune system functions, tissue-specific, ECM-based devices may fill an important need by providing naturally derived, biocompatible, and highly translatable platforms that can modulate the innate immune response to promote a positive functional outcome. PMID:26478910

Effect of reducing milk production using a prolactin-release inhibitor or a glucocorticoid on metabolism and immune functions in cows subjected to acute nutritional stress.

PubMed

Ollier, S; Beaudoin, F; Vanacker, N; Lacasse, P

2016-12-01

When cows are unable to consume enough feed to support milk production, they often fall into severe negative energy balance. This leads to a weakened immune system and increases their susceptibility to infectious diseases. Reducing the milk production of cows subjected to acute nutritional stress decreases their energy deficit. The aim of this study was to compare the effects on metabolism and immune function of reducing milk production using quinagolide (a prolactin-release inhibitor) or dexamethasone in feed-restricted cows. A total of 23 cows in early/mid-lactation were fed for 5 d at 55.9% of their previous dry matter intake to subject them to acute nutritional stress. After 1 d of feed restriction and for 4 d afterward (d 2 to 5), cows received twice-daily i.m. injections of water (control group; n=8), 2mg of quinagolide (QN group; n=7), or water after a first injection of 20mg of dexamethasone (DEX group; n=8). Feed restriction decreased milk production, but the decrease was greater in the QN and DEX cows than in the control cows on d 2 and 3. As expected, feed restriction reduced the energy balance, but the reduction was lower in the QN cows than in the control cows. Feed restriction decreased plasma glucose concentration and increased plasma nonesterified fatty acid (NEFA) and β-hydroxybutyrate (BHB) concentrations. The QN cows had higher glucose concentration and lower BHB concentration than the control cows. The NEFA concentration was also lower in the QN cows than in the control cows on d 2. Dexamethasone injection induced transient hyperglycemia concomitant with a reduction in milk lactose concentration; it also decreased BHB concentration and decreased NEFA initially but increased it later. Feed restriction and quinagolide injections did not affect the blood concentration or activity of polymorphonuclear leukocytes (PMN), whereas dexamethasone injection increased PMN blood concentration but decreased the proportion of PMN capable of inducing oxidative burst. Incubation of peripheral blood mononuclear cells in serum harvested on d 2 of the restriction period reduced their ability to react to mitogen-induced proliferation, and injection of quinagolide or dexamethasone could not alleviate this effect. This experiment shows that prolactin-release inhibition could be an alternative to dexamethasone for reducing milk production and energy deficit in cows under acute nutritional stress, without disturbing immune function. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Can Probiotics Reduce Inflammation and Enhance Gut Immune Health in People Living with HIV: Study Designs for the Probiotic Visbiome for Inflammation and Translocation (PROOV IT) Pilot Trials.

PubMed

Kim, Connie J; Walmsley, Sharon L; Raboud, Janet M; Kovacs, Colin; Coburn, Bryan; Rousseau, Rodney; Reinhard, Robert; Rosenes, Ron; Kaul, Rupert

2016-07-01

Despite substantial improvements in HIV outcomes with combination antiretroviral therapy (cART), morbidity and mortality remain above population norms. The gut mucosal immune system is not completely restored by cART, and the resultant microbial translocation may contribute to chronic inflammation, inadequate CD4 T-cell recovery, and increased rates of serious non-AIDS events. Since the microbial environment surrounding a CD4 T cell may influence its development and function, we hypothesize that probiotics provided during cART might reduce inflammation and improve gut immune health in HIV-positive treatment-naïve individuals (PROOV IT I) and individuals with suboptimal CD4 recovery on cART (PROOV IT II). These prospective, double-blinded, randomized, placebo-controlled, multicenter pilot studies will assess the impact of the probiotic Visbiome at 900 billion bacteria daily. Forty HIV positive cART-naïve men will be randomized in the PROOV IT I study, coincident with antiretroviral initiation, and be followed for 24 weeks. In PROOV IT II, 36 men on cART, but with a CD4 T-cell count below 350 cells/mm(3) will be followed for 48 weeks. The primary outcome for both studies is the comparison of blood CD8 T-cell immune activation. Secondary analyses will include comparison of blood inflammatory biomarkers, microbial translocation, blood and gut immunology and HIV levels, the bacterial community composition, diet, intestinal permeability, and the safety, adherence and tolerability of the study product. These studies will evaluate the ability of probiotics as a safe and tolerable therapeutic intervention to reduce systemic immune activation and to accelerate gut immune restoration in people living with HIV.

Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy.

PubMed

Zhao, Limei; Shao, Shuai; Chen, Yi; Sun, Ximeng; Sun, Ran; Huang, Jingjing; Zhan, Bin; Zhu, Xinping

2017-01-01

As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin ( Ts -CRT), a Ca 2+ -binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts -CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts -CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody-sensitized sheep erythrocytes. Moreover, recombinant Ts -CRT (r Ts -CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte-macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts -CRT on the surface of newborn larvae (NBL) of T. spiralis with anti- Ts -CRT antibody increased the C1q-mediated adherence of monocyte-macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis -expressed Ts -CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q-induced non-complement activation of macrophages.

Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy

PubMed Central

Zhao, Limei; Shao, Shuai; Chen, Yi; Sun, Ximeng; Sun, Ran; Huang, Jingjing; Zhan, Bin; Zhu, Xinping

2017-01-01

As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin (Ts-CRT), a Ca2+-binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts-CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts-CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody-sensitized sheep erythrocytes. Moreover, recombinant Ts-CRT (rTs-CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte–macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts-CRT on the surface of newborn larvae (NBL) of T. spiralis with anti-Ts-CRT antibody increased the C1q-mediated adherence of monocyte–macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis-expressed Ts-CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q-induced non-complement activation of macrophages. PMID:28620388

Inducible nitric oxide synthase in T cells regulates T cell death and immune memory

PubMed Central

Vig, Monika; Srivastava, Smita; Kandpal, Usha; Sade, Hadassah; Lewis, Virginia; Sarin, Apurva; George, Anna; Bal, Vineeta; Durdik, Jeannine M.; Rath, Satyajit

2004-01-01

The progeny of T lymphocytes responding to immunization mostly die rapidly, leaving a few long-lived survivors functioning as immune memory. Thus, control of this choice of death versus survival is critical for immune memory. There are indications that reactive radicals may be involved in this death pathway. We now show that, in mice lacking inducible nitric oxide synthase (iNOS), higher frequencies of both CD4 and CD8 memory T cells persist in response to immunization, even when iNOS+/+ APCs are used for immunization. Postactivation T cell death by neglect is reduced in iNOS–/– T cells, and levels of the antiapoptotic proteins Bcl-2 and Bcl-xL are increased. Inhibitors of the iNOS-peroxynitrite pathway also enhance memory responses and block postactivation death by neglect in both mouse and human T cells. However, early primary immune responses are not enhanced, which suggests that altered survival, rather than enhanced activation, is responsible for the persistent immunity observed. Thus, in primary immune responses, iNOS in activated T cells autocrinely controls their susceptibility to death by neglect to determine the level of persisting CD4 and CD8 T cell memory, and modulation of this pathway can enhance the persistence of immune memory in response to vaccination. PMID:15199408

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.

Progress in Childhood Vaccination Data in Immunization Information Systems - United States, 2013-2016.

PubMed

Murthy, Neil; Rodgers, Loren; Pabst, Laura; Fiebelkorn, Amy Parker; Ng, Terence

2017-11-03

In 2016, 55 jurisdictions in 49 states and six cities in the United States* used immunization information systems (IISs) to collect and manage immunization data and support vaccination providers and immunization programs. To monitor progress toward achieving IIS program goals, CDC surveys jurisdictions through an annual self-administered IIS Annual Report (IISAR). Data from the 2013-2016 IISARs were analyzed to assess progress made in four priority areas: 1) data completeness, 2) bidirectional exchange of data with electronic health record systems, 3) clinical decision support for immunizations, and 4) ability to generate childhood vaccination coverage estimates. IIS participation among children aged 4 months through 5 years increased from 90% in 2013 to 94% in 2016, and 33 jurisdictions reported ≥95% of children aged 4 months through 5 years participating in their IIS in 2016. Bidirectional messaging capacity in IISs increased from 25 jurisdictions in 2013 to 37 in 2016. In 2016, nearly all jurisdictions (52 of 55) could provide automated provider-level coverage reports, and 32 jurisdictions reported that their IISs could send vaccine forecasts to providers via Health Level 7 (HL7) messaging, up from 17 in 2013. Incremental progress was made in each area since 2013, but continued effort is needed to implement these critical functionalities among all IISs. Success in these priority areas, as defined by the IIS Functional Standards (1), bolsters clinicians' and public health practitioners' ability to attain high vaccination coverage in pediatric populations, and prepares IISs to develop more advanced functionalities to support state/local immunization services. Success in these priority areas also supports the achievement of federal immunization objectives, including the use of IISs as supplemental sampling frames for vaccination coverage surveys like the National Immunization Survey (NIS)-Child, reducing data collection costs, and supporting increased precision of state-level estimates.

Association of T-cell reactivity with beta-cell function in recent onset type 1 diabetes patients.

PubMed

Pfleger, Christian; Meierhoff, Guido; Kolb, Hubert; Schloot, Nanette C

2010-03-01

The aim of the current study was to investigate whether autoantigen directed T-cell reactivity relates to beta-cell function during the first 78 weeks after diagnosis of type 1 diabetes. 50 adults and 49 children (mean age 27.3 and 10.9 years respectively) with recent onset type 1 diabetes who participated in a placebo-controlled trial of immune intervention with DiaPep277 were analyzed. Secretion of interferon (IFN)-gamma, interleukin (IL)-5, IL-13 and IL-10 by single peripheral mononuclear cells (PBMC) upon stimulation with islet antigens GAD65, heat shock protein 60 (Hsp60) protein-tyrosine-phosphatase-like-antigen (pIA2) or tetanus toxoid (TT) was determined applying ELISPOT; beta-cell function was evaluated by glucagon stimulated C-peptide. Multivariate regression analysis was applied. In general, number of islet antigen-reactive cells decreased over 78 weeks in both adults and children, whereas reactivity to TT was not reduced. In addition, there was an association between the quality of immune cell responses and beta-cell function. Overall, increased responses by IFN-gamma secreting cells were associated with lower beta-cell function whereas IL-5, IL-13 and IL-10 cytokine responses were positively associated with beta-cell function in adults and children. Essentially, the same results were obtained with three different models of regression analysis. The number of detectable islet-reactive immune cells decreases within 1-2 years after diagnosis of type 1 diabetes. Cytokine production by antigen-specific PBMC reactivity is related to beta-cell function as measured by stimulated C-peptide. Cellular immunity appears to regress soon after disease diagnosis and begin of insulin therapy. Copyright 2009 Elsevier Ltd. All rights reserved.

Influences of Plant Traits on Immune Responses of Specialist and Generalist Herbivores

PubMed Central

Lampert, Evan

2012-01-01

Specialist and generalist insect herbivore species often differ in how they respond to host plant traits, particularly defensive traits, and these responses can include weakened or strengthened immune responses to pathogens and parasites. Accurate methods to measure immune response in the presence and absence of pathogens and parasites are necessary to determine whether susceptibility to these natural enemies is reduced or increased by host plant traits. Plant chemical traits are particularly important in that host plant metabolites may function as antioxidants beneficial to the immune response, or interfere with the immune response of both specialist and generalist herbivores. Specialist herbivores that are adapted to process and sometimes accumulate specific plant compounds may experience high metabolic demands that may decrease immune response, whereas the metabolic demands of generalist species differ due to more broad-substrate enzyme systems. However, the direct deleterious effects of plant compounds on generalist herbivores may weaken their immune responses. Further research in this area is important given that the ecological relevance of plant traits to herbivore immune responses is equally important in natural systems and agroecosystems, due to potential incompatibility of some host plant species and cultivars with biological control agents of herbivorous pests. PMID:26466545

Role of the immune system in cardiac tissue damage and repair following myocardial infarction.

PubMed

Saparov, Arman; Ogay, Vyacheslav; Nurgozhin, Talgat; Chen, William C W; Mansurov, Nurlan; Issabekova, Assel; Zhakupova, Jamilya

2017-09-01

The immune system plays a crucial role in the initiation, development, and resolution of inflammation following myocardial infarction (MI). The lack of oxygen and nutrients causes the death of cardiomyocytes and leads to the exposure of danger-associated molecular patterns that are recognized by the immune system to initiate inflammation. At the initial stage of post-MI inflammation, the immune system further damages cardiac tissue to clear cell debris. The excessive production of reactive oxygen species (ROS) by immune cells and the inability of the anti-oxidant system to neutralize ROS cause oxidative stress that further aggravates inflammation. On the other hand, the cells of both innate and adaptive immune system and their secreted factors are critically instrumental in the very dynamic and complex processes of regulating inflammation and mediating cardiac repair. It is important to decipher the balance between detrimental and beneficial effects of the immune system in MI. This enables us to identify better therapeutic targets for reducing the infarct size, sustaining the cardiac function, and minimizing the likelihood of heart failure. This review discusses the role of both innate and adaptive immune systems in cardiac tissue damage and repair in experimental models of MI.

Carboxyl-functionalized polyurethane nanoparticles with immunosuppressive properties as a new type of anti-inflammatory platform

NASA Astrophysics Data System (ADS)

Huang, Yen-Jang; Hung, Kun-Che; Hsieh, Fu-Yu; Hsu, Shan-Hui

2015-12-01

The interaction of nanoparticles (NPs) with the body immune system is critically important for their biomedical applications. Most NPs stimulate the immune response of macrophages. Here we show that synthetic polyurethane nanoparticles (PU NPs, diameter 34-64 nm) with rich surface COO- functional groups (zeta potential -70 to -50 mV) can suppress the immune response of macrophages. The specially-designed PU NPs reduce the gene expression levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) for endotoxin-treated macrophages. The PU NPs increase the intracellular calcium of macrophages (4.5-6.5 fold) and activate autophagy. This is in contrast to the autophagy dysfunction generally observed upon NP exposure. These PU NPs may further decrease the nuclear factor-κB-related inflammation via autophagy pathways. The immunosuppressive activities of PU NPs can prevent animal death by inhibiting the macrophage recruitment and proinflammatory responses, confirmed by an in vivo zebrafish model. Therefore, the novel biodegradable PU NPs demonstrate COO- dependent immunosuppressive properties without carrying any anti-inflammatory agents. This study suggests that NP surface chemistry may regulate the immune response, which provides a new paradigm for potential applications of NPs in anti-inflammation and immunomodulation.The interaction of nanoparticles (NPs) with the body immune system is critically important for their biomedical applications. Most NPs stimulate the immune response of macrophages. Here we show that synthetic polyurethane nanoparticles (PU NPs, diameter 34-64 nm) with rich surface COO- functional groups (zeta potential -70 to -50 mV) can suppress the immune response of macrophages. The specially-designed PU NPs reduce the gene expression levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) for endotoxin-treated macrophages. The PU NPs increase the intracellular calcium of macrophages (4.5-6.5 fold) and activate autophagy. This is in contrast to the autophagy dysfunction generally observed upon NP exposure. These PU NPs may further decrease the nuclear factor-κB-related inflammation via autophagy pathways. The immunosuppressive activities of PU NPs can prevent animal death by inhibiting the macrophage recruitment and proinflammatory responses, confirmed by an in vivo zebrafish model. Therefore, the novel biodegradable PU NPs demonstrate COO- dependent immunosuppressive properties without carrying any anti-inflammatory agents. This study suggests that NP surface chemistry may regulate the immune response, which provides a new paradigm for potential applications of NPs in anti-inflammation and immunomodulation. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06379e

Does Oil Rich in Alpha-Linolenic Fatty Acid Cause the Same Immune Modulation as Fish Oil in Walker 256 Tumor-Bearing Rats?

PubMed

Schiessel, Dalton Luiz; Yamazaki, Ricardo K; Kryczyk, Marcelo; Coelho de Castro, Isabela; Yamaguchi, Adriana A; Pequito, Danielle C T; Brito, Gleisson A P; Borghetti, Gina; Aikawa, Júlia; Nunes, Everson A; Naliwaiko, Kátia; Fernandes, Luiz C

2016-01-01

Polyunsaturated fatty acids n-3 (PUFA n-3) have shown effects in reducing tumor growth, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) abundantly present in fish oil (FO). When these fatty acids are provided in the diet, they alter the functions of the cells, particularly in tumor and immune cells. However, the effects of α-linolenic fatty acid (ALA), which is the precursor of EPA and DHA, are controversial. Thus, our objective was to test the effect of this parental fatty acid. Non-tumor-bearing and tumor-bearing Wistar rats (70 days) were supplemented with 1 g/kg body weight of FO or Oro Inca® (OI) oil (rich in ALA). Immune cells function, proliferation, cytokine production, and subpopulation profile were evaluated. We have shown that innate immune cells enhanced phagocytosis capacity, and increased processing and elimination of antigens. Moreover, there was a decrease in production of pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)) by macrophages. Lymphocytes showed decreased proliferation capacity, increased cluster of differentiation 8 (CD8 + ) subpopulation, and increased TNF-α production. Oil rich in ALA caused similar immune modulation in cancer when compared with FO.

Immunotoxicity of trenbolone acetate in Japanese quail

USGS Publications Warehouse

Quinn, M.J.; McKernan, M.; Lavoie, E.T.; Ottinger, M.A.

2007-01-01

Trenbolone acetate is a synthetic androgen that is currently used as a growth promoter in many meat-exporting countries. Despite industry laboratories classifying trenbolone as nonteratogenic, data showed that embryonic exposure to this androgenic chemical altered development of the immune system in Japanese quail. Trenbolone is lipophilic, persistent, and released into the environment in manure used as soil fertilizer. This is the first study to date to assess this chemical's immunotoxic effects in an avian species. A one-time injection of trenbolone into yolks was administered to mimic maternal deposition, and subsequent effects on the development and function of the immune system were determined in chicks and adults. Development of the bursa of Fabricius, an organ responsible for development of the humoral arm of the immune system, was disrupted, as indicated by lower masse, and smaller and fewer follicles at day 1 of hatch. Morphological differences in the bursas persisted in adults, although no differences in either two measures of immune function were observed. Total numbers of circulating leukocytes were reduced and heterophil-lymphocyte ratios were elevated in chicks but not adults. This study shows that trenbolone acetate is teratogenic and immunotoxic in Japanese quail, and provides evidence that the quail immune system may be fairly resilient to embryonic endocrine-disrupting chemical-induced alterations following no further exposure posthatch.

Single-walled carbon nanotubes as delivery vehicles enhance the immunoprotective effects of a recombinant vaccine against Aeromonas hydrophila.

PubMed

Gong, Yu-Xin; Zhu, Bin; Liu, Guang-Lu; Liu, Lei; Ling, Fei; Wang, Gao-Xue; Xu, Xin-Gang

2015-01-01

To reduce the economic losses caused by diseases in aquaculture industry, more efficient and economic prophylactic measures should be urgently investigated. In this research, the effects of a novel functionalized single-walled carbon nanotubes (SWCNTs) applied as a delivery vehicle for recombinant Aeromonas hydrophila vaccine administration via bath or injection in juvenile grass carp were studied. The results showed that SWCNT as a vector for the recombinant protein aerA, augmented the production of specific antibodies, apparently stimulated the induction of immune-related genes, and induced higher level of survival rate compared with free aerA subunit vaccine. Furthermore, we compared the routes of bath and intramuscular injection immunization by SWCNTs-aerA vaccine, and found that similar antibody levels induced by SWCNTs-aerA were observed in both immunization routes. Meanwhile, a similar relative percentage survival (approximately 80%) was found in both a 40 mg/L bath immunization group, and a 20 μg injection group. The results indicate that functionalized SWCNTs could be a promising delivery vehicle to potentiate the immune response of recombinant vaccines, and might be used to vaccinate juvenile fish by bath administration method. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity.

PubMed

Chng, Song Hui; Kundu, Parag; Dominguez-Brauer, Carmen; Teo, Wei Ling; Kawajiri, Kaname; Fujii-Kuriyama, Yoshiaki; Mak, Tak Wah; Pettersson, Sven

2016-04-12

Diet and microbiome derived indole derivatives are known to activate the ligand induced transcription factor, the Aryl hydrocarbon Receptor (AhR). While the current understanding of AhR biology has confirmed its role in mucosal lymphocytes, its function in intestinal antigen presenting cells (APCs) is poorly understood. Here, we report that Cre-mediated deletion of AhR in CD11c-expressing cells in C57/BL6 mice is associated with altered intestinal epithelial morphogenesis in vivo. Moreover, when co-cultured with AhR-deficient DCs ex vivo, intestinal organoids showed reduced SRY (sex determining region Y)-box 9 and increased Mucin 2 expression, which correlates with reduced Paneth cells and increased goblet cell differentiation, similar to the data obtained in vivo. Further, characterization of intestinal APC subsets, devoid of AhR, revealed an expression pattern associated with aberrant intrinsic Wnt pathway regulation. At a functional level, the loss of AhR in APCs resulted in a dysfunctional epithelial barrier, associated with a more aggressive chemically induced colitis compared to wild type animals. Our results are consistent with a model whereby the AhR signalling pathway may participate in the regulation of innate immunity through intestinal epithelium development and mucosal immunity.

The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer.

PubMed

Khan, Mohammad W; Saadalla, Abdulrahman; Ewida, Ahmed H; Al-Katranji, Khalid; Al-Saoudi, Ghadier; Giaccone, Zachary T; Gounari, Fotini; Zhang, Ming; Frank, David A; Khazaie, Khashayarsha

2018-01-01

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8 + T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

Absence of γ-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment.

PubMed

Nowak, Karolin; Linzner, Daniela; Thrasher, Adrian J; Lambert, Paul F; Di, Wei-Li; Burns, Siobhan O

2017-10-01

Loss-of-function mutations in the common gamma (γc) chain cytokine receptor subunit give rise to severe combined immunodeficiency characterized by lack of T and natural killer cells and infant death from infection. Hematopoietic stem cell transplantation or gene therapy offer a cure, but despite successful replacement of lymphoid immune lineages, a long-term risk of severe cutaneous human papilloma virus infections persists, possibly related to persistent γc-deficiency in other cell types. Here we show that keratinocytes, the only cell type directly infected by human papilloma virus, express functional γc and its co-receptors. After stimulation with the γc-ligand IL-15, γc-deficient keratinocytes show significantly impaired secretion of specific chemokines including CXCL1, CXCL8, and CCL20, resulting in reduced chemotaxis of dendritic cells and CD4 + T cells. Furthermore, γc-deficient keratinocytes also exhibit defective induction of T-cell chemotaxis in a model of stable human papilloma virus-18 infection. These findings suggest that persistent γc-deficiency in keratinocytes alters immune cell recruitment to the skin, which may contribute to the development and persistence of warts in this condition and would require different treatment approaches. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cardiovascular disease and type 2 diabetes in evolutionary perspective: A critical role for helminths?

PubMed Central

Gurven, Michael D.; Trumble, Benjamin C.; Stieglitz, Jonathan; Blackwell, Aaron D.; Michalik, David E.; Finch, Caleb E.; Kaplan, Hillard S.

2016-01-01

Heart disease and type 2 diabetes are commonly believed to be rare among contemporary subsistence-level human populations, and by extension prehistoric populations. Although some caveats remain, evidence shows these diseases to be unusual among well-studied hunter-gatherers and other subsistence populations with minimal access to healthcare. Here we expand on a relatively new proposal for why these and other populations may not show major signs of these diseases. Chronic infections, especially helminths, may offer protection against heart disease and diabetes through direct and indirect pathways. As part of a strategy to insure their own survival and reproduction, helminths exert multiple cardio-protective effects on their host through their effects on immune function and blood lipid metabolism. Helminths consume blood lipids and glucose, alter lipid metabolism, and modulate immune function towards Th-2 polarization—which combined can lower blood cholesterol, reduce obesity, increase insulin sensitivity, decrease atheroma progression, and reduce likelihood of atherosclerotic plaque rupture. Traditional cardiometabolic risk factors, coupled with the mismatch between our evolved immune systems and modern, hygienic environments may interact in complex ways. In this review, we survey existing studies in the non-human animal and human literature, highlight unresolved questions and suggest future directions to explore the role of helminths in the etiology of cardio-metabolic disease. PMID:27666719

Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer

PubMed Central

Liang, Shuzhen; Xu, Kecheng; Niu, Lizhi; Wang, Xiaohua; Liang, Yingqing; Zhang, Mingjie; Chen, Jibing; Lin, Mao

2017-01-01

In the present study, we aimed to compare the clinical outcome of autogeneic and allogeneic natural killer (NK) cells immunotherapy for the treatment of recurrent breast cancer. Between July 2016 and February 2017, 36 patients who met the enrollment criteria were randomly assigned to two groups: autogeneic NK cells immunotherapy group (group I, n=18) and allogeneic NK cells immunotherapy group (group II, n=18). The clinical efficacy, quality of life, immune function, circulating tumor cell (CTC) level, and other related indicators were evaluated. We found that allogeneic NK cells immunotherapy has better clinical efficacy than autogeneic therapy. Moreover, allogeneic NK cells therapy improves the quality of life, reduces the number of CTCs, reduces carcinoembryonic antigen and cancer antigen 15-3 (CA15-3) expression, and significantly enhances immune function. To our knowledge, this is the first clinical trial to compare the clinical outcome of autogeneic and allogeneic NK cells immunotherapy for recurrent breast cancer. PMID:28894383

Interactions of Gut Microbiota, Endotoxemia, Immune Function, and Diet in Exertional Heatstroke

PubMed Central

Lee, Elaine C.; Armstrong, Elizabeth M.

2018-01-01

Exertional heatstroke (EHS) is a medical emergency that cannot be predicted, requires immediate whole-body cooling to reduce elevated internal body temperature, and is influenced by numerous host and environmental factors. Widely accepted predisposing factors (PDF) include prolonged or intense exercise, lack of heat acclimatization, sleep deprivation, dehydration, diet, alcohol abuse, drug use, chronic inflammation, febrile illness, older age, and nonsteroidal anti-inflammatory drug use. The present review links these factors to the human intestinal microbiota (IM) and diet, which previously have not been appreciated as PDF. This review also describes plausible mechanisms by which these PDF lead to EHS: endotoxemia resulting from elevated plasma lipopolysaccharide (i.e., a structural component of the outer membrane of Gram-negative bacteria) and tissue injury from oxygen free radicals. We propose that recognizing the lifestyle and host factors which are influenced by intestine-microbial interactions, and modifying habitual dietary patterns to alter the IM ecosystem, will encourage efficient immune function, optimize the intestinal epithelial barrier, and reduce EHS morbidity and mortality. PMID:29850597

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.

Leptin receptor signaling in T cells is required for Th17 differentiation.

PubMed

Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H; Mascaraque, Cristina; Amoury, Manal; Cohn, Lillian B; Rogoz, Aneta; Dallner, Olof S; Moraes-Vieira, Pedro M; Domingos, Ana I; Mucida, Daniel

2015-06-01

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. Copyright © 2015 by The American Association of Immunologists, Inc.

Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice.

PubMed

MacPherson, Kathryn P; Sompol, Pradoldej; Kannarkat, George T; Chang, Jianjun; Sniffen, Lindsey; Wildner, Mary E; Norris, Christopher M; Tansey, Malú G

2017-06-01

Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII + , CD45 high , and Ly6C high ) myeloid-derived CD11b + immune cells are decreased while CD3 + T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 + T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD. Immune cells and cytokines perform specialized functions inside and outside the brain to maintain optimal brain health; but the extent to which their activities change in response to neuronal dysfunction and degeneration is not well understood. Our findings indicate that neutralization of sTNF reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4 + T cells. In addition, impaired long-term potentiation (LTP) was rescued by XPro1595 in association with decreased hippocampal Aβ plaques. Selective targeting of sTNF holds translational potential to modulate brain immune cell infiltration, dampen neuroinflammation, and prevent or delay neuronal dysfunction in AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Preserved immune functionality and high CMV-specific T-cell responses in HIV-infected individuals with poor CD4+ T-cell immune recovery.

PubMed

Gómez-Mora, Elisabet; García, Elisabet; Urrea, Victor; Massanella, Marta; Puig, Jordi; Negredo, Eugenia; Clotet, Bonaventura; Blanco, Julià; Cabrera, Cecilia

2017-09-15

Poor CD4 + T-cell recovery after cART has been associated with skewed T-cell maturation, inflammation and immunosenescence; however, T-cell functionality in those individuals has not been fully characterized. In the present study, we assessed T-cell function by assessing cytokine production after polyclonal, CMV and HIV stimulations of T-cells from ART-suppressed HIV-infected individuals with CD4 + T-cell counts >350 cells/μL (immunoconcordants) or <350 cells/μL (immunodiscordants). A group of HIV-uninfected individuals were also included as controls. Since CMV co-infection significantly affected T-cell maturation and polyfunctionality, only CMV + individuals were analyzed. Despite their reduced and skewed CD4 + T-cell compartment, immunodiscordant individuals showed preserved polyclonal and HIV-specific responses. However, CMV response in immunodiscordant participants was significantly different from immunoconcordant or HIV-seronegative individuals. In immunodiscordant subjects, the magnitude of IFN-γ + CD8 + and IL-2 + CD4 + T-cells in response to CMV was higher and differently associated with the CD4 + T-cell maturation profile., showing an increased frequency of naïve, central memory and EMRA CMV-specific CD4 + T-cells. In conclusion, CD4 + and CD8 + T-cell polyfunctionality was not reduced in immunodiscordant individuals, although heightened CMV-specific immune responses, likely related to subclinical CMV reactivations, may be contributing to the skewed T-cell maturation and the higher risk of clinical progression observed in those individuals.

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions.

PubMed

Frerker, Nadine; Raber, Kerstin; Bode, Felix; Skripuletz, Thomas; Nave, Heike; Klemann, Christian; Pabst, Reinhard; Stephan, Michael; Schade, Jutta; Brabant, Georg; Wedekind, Dirk; Jacobs, Roland; Jörns, Anne; Forssmann, Ulf; Straub, Rainer H; Johannes, Sigrid; Hoffmann, Torsten; Wagner, Leona; Demuth, Hans-Ulrich; von Hörsten, Stephan

2009-01-01

Treatment of diabetes type 2 using chronic pharmacological inhibition of dipeptidyl peptidase 4 (DP4) still requires an in-depth analysis of models for chronic DP4 deficiency, because adverse reactions induced by some DP4 inhibitors have been described. In the present study, a novel congenic rat model of DP4 deficiency on a "DP4-high" DA rat genetic background was generated (DA.F344-Dpp4(m)/ SvH rats) and comprehensively phenotyped. Similar to chronic pharmacological inhibition of DP4, DP4 deficient rats exhibited a phenotype involving reduced diet-induced body weight gain and improved glucose tolerance associated with increased levels of glucagon-like peptide-1 (GLP-1) and bound leptin as well as decreased aminotransferases and triglycerides. Additionally, DA.F344-Dpp4(m)/SvH rats showed anxiolytic-like and reduced stress-like responses, a phenomenon presently not targeted by DP4 inhibitors. However, several immune alterations, such as differential leukocyte subset composition at baseline, blunted natural killer cell and T-cell functions, and altered cytokine levels were observed. While this animal model confirms a critical role of DP4 in GLP-1-dependent glucose regulation, genetically induced chronic DP4 deficiency apparently also affects stress-regulatory and immuneregulatory systems, indicating that the use of chronic DP4 inhibitors might have the potential to interfere with central nervous system and immune functions in vivo.

Immunosuppressive effects of factor IX products: an in vitro study.

PubMed

Grosset, A B; McGregor, J R; Samlowski, W E; Rodgers, G M

1999-11-01

The effects of a recombinant factor IX product (BeneFix), and of five plasma-derived factor IX products, AlphaNine, Immunine, Konyne, Mononine and Replinine on in vitro peripheral blood mononuclear cell (PBMC) immune function were compared in a blinded study. We assessed the effects of these products on Con-A-induced lymphocyte proliferation and interleukin-2 and interleukin-10 secretion, expression of lymphocyte activation markers, and nitric oxide secretion by stimulated mouse peritoneal macrophages. At 1 mL-1 for 48 h, Konyne reduced Con-A-induced mitogenesis by 50% (P < 0.05); AlphaNine, Mononine and BeneFix had no effect. At 10 IU mL-1, Con-A-induced mi- togenesis was at control levels with Mononine and BeneFix, but was reduced to <15% (P < 0.05) with each of the other products. IL-2 and IL-10 secretion by Con-A-stimulated lymphocytes was also markedly depressed by all the products tested except Mononine and BeneFix. Dialysis of these products did not substantially affect these results. Flow cytometric analysis of lymphocyte activation markers following Con-A stimulation showed that Konyne also decreased IL-2 receptor alpha and beta chain (CD25 and CD122) induction on PBMC. Konyne also inhibited nitric oxide secretion to levels <18% of controls. These results indicate that certain factor IX products, including some of purported higher purity, substantially depress in vitro immune function. The importance of these findings to in vivo immune function in haemophilia B patients remains to be established.

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.

Therapeutic Touch Has Significant Effects on Mouse Breast Cancer Metastasis and Immune Responses but Not Primary Tumor Size

PubMed Central

Gronowicz, Gloria; Secor, Eric R.; Flynn, John R.; Jellison, Evan R.; Kuhn, Liisa T.

2015-01-01

Evidence-based integrative medicine therapies have been introduced to promote wellness and offset side-effects from cancer treatment. Energy medicine is an integrative medicine technique using the human biofield to promote well-being. The biofield therapy chosen for study was Therapeutic Touch (TT). Breast cancer tumors were initiated in mice by injection of metastatic 66cl4 mammary carcinoma cells. The control group received only vehicle. TT or mock treatments were performed twice a week for 10 minutes. Two experienced TT practitioners alternated treatments. At 26 days, metastasis to popliteal lymph nodes was determined by clonogenic assay. Changes in immune function were measured by analysis of serum cytokines and by fluorescent activated cells sorting (FACS) of immune cells from the spleen and lymph nodes. No significant differences were found in body weight gain or tumor size. Metastasis was significantly reduced in the TT-treated mice compared to mock-treated mice. Cancer significantly elevated eleven cytokines. TT significantly reduced IL-1-a, MIG, IL-1b, and MIP-2 to control/vehicle levels. FACS demonstrated that TT significantly reduced specific splenic lymphocyte subsets and macrophages were significantly elevated with cancer. Human biofield therapy had no significant effect on primary tumor but produced significant effects on metastasis and immune responses in a mouse breast cancer model. PMID:26113869

The effect of a probiotic Escherichia coli strain on regulatory T-cells in six year-old children.

PubMed

Hrdý, J; Kocourková, I; Lodinová-Žádníková, R; Kolářová, L; Prokešová, L

2016-11-30

Probiotics are believed to prevent or reduce allergy development but the mechanism of their beneficial effect is still poorly understood. Immune characteristics of regulatory T cells (Tregs) in peripheral blood of perinatally probiotic-supplemented children of allergic mothers (51 children), non-supplemented children of allergic mothers (42 children), and non-supplemented children of healthy mothers (28 children) were compared at the age of 6-7 years. A first dose of a probiotic Escherichia coli strain (E. coli O83:K24:H31) was administered within 2 days after the birth and then 12 times during the first months of life and children were followed longitudinally. Proportion and functional properties of Tregs were estimated by flow cytometry in relation to the children's allergy status. Proportion of Tregs in the peripheral blood of children suffering from allergy tends to be higher whereas median of fluorescence intensity (MFI) of FoxP3 was significantly decreased in allergic group. Intracellular presence of regulatory cytokine interleukin (IL)-10 was also lower in allergic children. Immune functions of Tregs reflected by both MFI of FoxP3 and IL-10 in the group of probiotic-supplemented children of allergic mothers were nearly comparable with children of healthy mothers while probiotic non-supplemented children of allergic mothers have decreased immune function of Tregs. Supplementation by probiotic E. coli strain decreases allergy incidence in high-risk children. In contrast to our expectation, proportion of Tregs has not been increased in probiotic supplemented children. Beneficial effect of probiotics on newborn immature immune system could be, at least partially, explained by the modulating immune function of Tregs. In summary, we detected increased proportion of Tregs in peripheral blood of allergic children, their functional properties were decreased in comparison with the Tregs of healthy children. A unifying hypothesis for these findings is that Treg numbers in allergic children are increased in order to compensate for decreased function.

[COMBINED IMMUNOTHERAPY OF RECONDITIONAL CHRONIC NON-SPECIFIC VULVOVAGINITIS IN IMMUNOCOMPROMISED GIRLS].

PubMed

Nesterova, I; Kovaleva, S; Chudilova, G; Lomtatidze, L; Krutova, V; Aslanian, I; Tulendinova, A; Malinovskaya, V

2017-05-01

Nonspecific chronic vulvovaginitis (CNV) is often a clinical indicator of immune deficiency, especially in young girls. The established violations of the functioning of various parts of the immune system (IS) in this pathology dictate the need to include in the complex of immunomodulatory therapy. The developed program of combined immunotherapy for immunocompromised girls allows to reduce the severity and duration of exacerbation of CNV, their frequency against the background of a significant reduction in the incidence of ARVI. Positive clinical effects were observed against the background of the restoration of the functioning of the IS. A protective effect was obtained (observation in a catamnesis for 1 year) - the duration of a clinically safe period increased from 6 to 11-11,5 months per year.

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.

PubMed

Curiel, Tyler J; Coukos, George; Zou, Linhua; Alvarez, Xavier; Cheng, Pui; Mottram, Peter; Evdemon-Hogan, Melina; Conejo-Garcia, Jose R; Zhang, Lin; Burow, Matthew; Zhu, Yun; Wei, Shuang; Kryczek, Ilona; Daniel, Ben; Gordon, Alan; Myers, Leann; Lackner, Andrew; Disis, Mary L; Knutson, Keith L; Chen, Lieping; Zou, Weiping

2004-09-01

Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.

β-Endorphin Neuronal Cell Transplant Reduces Corticotropin Releasing Hormone Hyperresponse to Lipopolysaccharide and Eliminates Natural Killer Cell Functional Deficiencies in Fetal Alcohol Exposed Rats

PubMed Central

Boyadjieva, Nadka I.; Ortigüela, María; Arjona, Alvaro; Cheng, Xiaodong; Sarkar, Dipak K.

2010-01-01

Background Natural killer (NK) cell dysfunction is associated with hyperresponse of corticotropin releasing hormone (CRH) to immune challenge and with a loss of β-endorphin (BEP) neurons in fetal alcohol exposed animals. Recently, we established a method to differentiate neural stem cells into BEP neurons using cyclic adenosine monophosphate (cAMP)-elevating agents in cultures. Hence, we determined whether in vitro differentiated BEP neurons could be used for reversing the compromised stress response and immune function in fetal alcohol exposed rats. Methods To determine the effect of BEP neuron transplants on NK cell function, we implanted in vitro differentiated BEP neurons into the paraventricular nucleus of pubertal and adult male rats exposed to ethanol or control in utero. The functionality of transplanted BEP neurons was determined by measuring proopiomelanocortin (POMC) gene expression in these cells and their effects on CRH gene expression under basal and after lipopolysaccaride (LPS) challenge. In addition, the effectiveness of BEP neurons in activating NK cell functions is determined by measuring NK cell cytolytic activity and interferon-γ (IFN-γ) production in the spleen and in the peripheral blood mononuclear cell (PBMC) following cell transplantation. Results We showed here that when these in vitro differentiated BEP neurons were transplanted into the hypothalamus, they maintain biological functions by producing POMC and reducing the CRH neuronal response to the LPS challenge. BEP neuronal transplants significantly increased NK cell cytolytic activity in the spleen and in the PBMC and increased plasma levels of IFN-γ in control and fetal alcohol exposed rats. Conclusions These data further establish the BEP neuronal regulatory role in the control of CRH and NK cell cytolytic function and identify a possible novel therapy to treat stress hyper-response and immune deficiency in fetal alcohol exposed subjects. PMID:19320628

Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer

PubMed Central

Murray, Shannon; Witt, Kristina; Seitz, Christina; Wallerius, Majken; Xie, Hanjing; Ullén, Anders; Harmenberg, Ulrika; Lidbrink, Elisabet; Rolny, Charlotte; Andersson, John

2017-01-01

ABSTRACT Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer. PMID:28920001

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.

Apps for immunization: Leveraging mobile devices to place the individual at the center of care.

PubMed

Wilson, Kumanan; Atkinson, Katherine M; Westeinde, Jacqueline

2015-01-01

Mobile technology and applications (apps) have disrupted several industries including healthcare. The advantage of apps, being personally focused and permitting bidirectional communication, make them well suited to address many immunization challenges. As of April 25, 2015 searching the Android app store with the words 'immunize app' and 'immunization app' in Canada yielded 225 apps. On the Apple App Store a similar search produced 98 results. These include apps that provide immunization related information, permit vaccine tracking both for individuals and for animals, assist with the creation of customized schedules and identification of vaccine clinics and serve as sources of education. The diverse functionality of mobile apps creates the potential for transformation of immunization practice both at a personal level and a system level. For individuals, mobile apps offer the opportunity for better record keeping, assistance with the logistics of vaccination, and novel ways of communicating with and receiving information from public health officials. For the system, mobile apps offer the potential to improve the quality of information residing in immunization information systems and program evaluation, facilitate harmonization of immunization information between individuals, health care providers and public health as well as reduce vaccine hesitancy. As mobile technology continues to rapidly evolve there will emerge new ways in which apps can enhance immunization practice.

Experimental evolution reveals differences between phenotypic and evolutionary responses to population density.

PubMed

McNamara, K B; Simmons, L W

2017-09-01

Group living can select for increased immunity, given the heightened risk of parasite transmission. Yet, it also may select for increased male reproductive investment, given the elevated risk of female multiple mating. Trade-offs between immunity and reproduction are well documented. Phenotypically, population density mediates both reproductive investment and immune function in the Indian meal moth, Plodia interpunctella. However, the evolutionary response of populations to these traits is unknown. We created two replicated populations of P. interpunctella, reared and mated for 14 generations under high or low population densities. These population densities cause plastic responses in immunity and reproduction: at higher numbers, both sexes invest more in one index of immunity [phenoloxidase (PO) activity] and males invest more in sperm. Interestingly, our data revealed divergence in PO and reproduction in a different direction to previously reported phenotypic responses. Males evolving at low population densities transferred more sperm, and both males and females displayed higher PO than individuals at high population densities. These positively correlated responses to selection suggest no apparent evolutionary trade-off between immunity and reproduction. We speculate that the reduced PO activity and sperm investment when evolving under high population density may be due to the reduced population fitness predicted under increased sexual conflict and/or to trade-offs between pre- and post-copulatory traits. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

The early stages of the immune response of the European abalone Haliotis tuberculata to a Vibrio harveyi infection.

PubMed

Cardinaud, Marion; Dheilly, Nolwenn M; Huchette, Sylvain; Moraga, Dario; Paillard, Christine

2015-08-01

Vibrio harveyi is a marine bacterial pathogen responsible for episodic abalone mortalities in France, Japan and Australia. In the European abalone, V. harveyi invades the circulatory system in a few hours after exposure and is lethal after 2 days of infection. In this study, we investigated the responses of European abalone immune cells over the first 24 h of infection. Results revealed an initial induction of immune gene expression including Rel/NF-kB, Mpeg and Clathrin. It is rapidly followed by a significant immuno-suppression characterized by reduced cellular hemocyte parameters, immune response gene expressions and enzymatic activities. Interestingly, Ferritin was overexpressed after 24 h of infection suggesting that abalone attempt to counter V. harveyi infection using soluble effectors. Immune function alteration was positively correlated with V. harveyi concentration. This study provides the evidence that V. harveyi has a hemolytic activity and an immuno-suppressive effect in the European abalone. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characteristics of the early immune response following transplantation of mouse ES cell derived insulin-producing cell clusters.

PubMed

Boyd, Ashleigh S; Wood, Kathryn J

2010-06-04

The fully differentiated progeny of ES cells (ESC) may eventually be used for cell replacement therapy (CRT). However, elements of the innate immune system may contribute to damage or destruction of these tissues when transplanted. Herein, we assessed the hitherto ill-defined contribution of the early innate immune response in CRT after transplantation of either ESC derived insulin producing cell clusters (IPCCs) or adult pancreatic islets. Ingress of neutrophil or macrophage cells was noted immediately at the site of IPCC transplantation, but this infiltration was attenuated by day three. Gene profiling identified specific inflammatory cytokines and chemokines that were either absent or sharply reduced by three days after IPCC transplantation. Thus, IPCC transplantation provoked less of an early immune response than pancreatic islet transplantation. Our study offers insights into the characteristics of the immune response of an ESC derived tissue in the incipient stages following transplantation and suggests potential strategies to inhibit cell damage to ensure their long-term perpetuation and functionality in CRT.

Aging of the T cell compartment in mice and humans: from no naïve expectations to foggy memories

PubMed Central

Nikolich-Žugich, Janko

2014-01-01

Until the mid-20th century, infectious diseases were the major cause of morbidity and mortality in humans. Massive vaccination campaigns, antibiotics, antivirals and advanced public health measures drastically reduced sickness and death of infections in children and younger adults. Older adults (>65yr of age), however, remain vulnerable to infections, and to date infectious diseases remain amongst the top 5–10 causes of death in this population. The aging of the immune system, often referred to as immune senescence, is the key phenomenon underlying this vulnerability. This review centers on age-related changes in T cells, which are dramatically and reproducibly altered with aging. I will discuss changes in T cell production, maintenance, function and response to latent persistent infection, particularly against the cytomegalovirus (CMV), that exerts profound influence on the aging T cell pool, concluding with a brief list of measures to improve immune function in older adults. PMID:25193936

Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function

PubMed Central

Chen, Edward P.; Markosyan, Nune; Connolly, Emma; Lawson, John A.; Li, Xuanwen; Grant, Gregory R.; Grosser, Tilo; FitzGerald, Garret A.; Smyth, Emer M.

2014-01-01

Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast cancer. The contribution of tumor cell-derived COX-2 to tumorigenesis has been examined in numerous studies; however, the role of stromal-derived COX-2 is ill-defined. Here, we examined how COX-2 in myeloid cells, an immune cell subset that includes macrophages, influences mammary tumor progression. In mice engineered to selectively lack myeloid cell COX-2 [myeloid-COX-2 knockout (KO) mice], spontaneous neu oncogene-induced tumor onset was delayed, tumor burden reduced, and tumor growth slowed compared with wild-type (WT). Similarly, growth of neu-transformed mammary tumor cells as orthotopic tumors in immune competent syngeneic myeloid-COX-2 KO host mice was reduced compared with WT. By flow cytometric analysis, orthotopic myeloid-COX-2 KO tumors had lower tumor-associated macrophage (TAM) infiltration consistent with impaired colony stimulating factor-1-dependent chemotaxis by COX-2 deficient macrophages in vitro. Further, in both spontaneous and orthotopic tumors, COX-2-deficient TAM displayed lower immunosuppressive M2 markers and this was coincident with less suppression of CD8+ cytotoxic T lymphocytes (CTLs) in myeloid-COX-2 KO tumors. These studies suggest that reduced tumor growth in myeloid-COX-2 KO mice resulted from disruption of M2-like TAM function, thereby enhancing T-cell survival and immune surveillance. Antibody-mediated depletion of CD8+, but not CD4+ cells, restored tumor growth in myeloid-COX-2 KO to WT levels, indicating that CD8+ CTLs are dominant antitumor effectors in myeloid-COX-2 KO mice. Our studies suggest that inhibition of myeloid cell COX-2 can potentiate CTL-mediated tumor cytotoxicity and may provide a novel therapeutic approach in breast cancer therapy. PMID:24590894

Dectin-1 is required for β-glucan recognition and control of fungal infection

PubMed Central

Taylor, Philip R; Tsoni, S Vicky; Willment, Janet A; Dennehy, Kevin M; Rosas, Marcela; Findon, Helen; Haynes, Ken; Steele, Chad; Botto, Marina; Gordon, Siamon; Brown, Gordon D

2007-01-01

β-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for β-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for β-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non–Toll-like pattern-recognition receptor required for the induction of protective immune responses. PMID:17159984

[Magneto-peloidotherapy and hydrogen sulfide baths for the correction of dyslipidemia and immune inflammation in patients with ischemic heart disease during resort treatment].

PubMed

Bykov, A T; Konovalova, M P; Khodasevich, L S

2009-01-01

A total of 55 patients with angina of effort (functional classes I-II) were treated by magneto-peloidotherapy and hydrogen sulfide baths. Effectiveness of he treatment was evaluated based on the lipid profile (total cholesterol, triglycerides, high and low density lipoproteides), atherogenicity index, lipid peroxidation, reactivity of the antioxidative defense system, and immune characteristics. Results of the study indicate that combination of magneto-peloidotherapy and hydrogen sulfide baths has hypolipidemic effect and reduces lipid peroxidation in the absence of activation of the antioxidative defense system and correction of the disbalanced immune system. Taken together, these effects decrease severity of the systemic inflammatory reaction and facilitate remission of the atherosclerotic process.

Enhanced clearance of herpes simplex virus type 1 and reduced herpetic eye disease in STAT6 knockout mice is associated with increased IL-2.

PubMed

Ghiasi, Homayon; Osorio, Yanira; Nesburn, Anthony B; Wechsler, Steven L

2002-10-25

STAT6 (signal transducers and activators of transcription 6)-deficient (STAT6-/-) mice have defects in IL-4- and IL-13-mediated functions and thus have a reduced T(H)2-mediated immune response. Conversely, they have elevated levels of IL-2 and thus an increased T(H)1-mediated immune response. To assess the relative impact of reduced T(H)2- and elevated T(H)1-dependent immune responses on HSV-1 infection, vaccinated and mock-vaccinated STAT6-/- mice were challenged ocularly with HSV-1. Mock-vaccinated STAT6-/- mice were as susceptible to lethal HSV-1 infection as parental BALB/c mice. Mock-vaccinated STAT6-/- mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Furthermore, mock-vaccinated STAT6-/- mice had significantly less corneal scarring than their BALB/c counterparts. Vaccination induced significantly higher serum-neutralizing antibody titers in STAT6-/- mice compared to BALB/c mice, while completely protecting both types of mice against HSV-1-induced death and corneal scarring. Vaccinated STAT6-/- mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Lymphocytes from both vaccinated and mock-vaccinated STAT6-/- mice secreted higher amounts of IL-2 than lymphocytes from BALB/c mice, in the presence or absence of stimulation with UV-inactivated HSV-1. Finally, depletion of IL-2 increased ocular virus replication in STAT6-/- mice to levels similar to that measured in BALB/c mice. Our results suggest that in the absence of the STAT6 pathway, IL-2-mediated immune responses are up-regulated. This, in turn, leads to faster viral clearance and, consequently, lower levels of eye disease.

Innate Immunity and Biomaterials at the Nexus: Friends or Foes.

PubMed

Christo, Susan N; Diener, Kerrilyn R; Bachhuka, Akash; Vasilev, Krasimir; Hayball, John D

2015-01-01

Biomaterial implants are an established part of medical practice, encompassing a broad range of devices that widely differ in function and structural composition. However, one common property amongst biomaterials is the induction of the foreign body response: an acute sterile inflammatory reaction which overlaps with tissue vascularisation and remodelling and ultimately fibrotic encapsulation of the biomaterial to prevent further interaction with host tissue. Severity and clinical manifestation of the biomaterial-induced foreign body response are different for each biomaterial, with cases of incompatibility often associated with loss of function. However, unravelling the mechanisms that progress to the formation of the fibrotic capsule highlights the tightly intertwined nature of immunological responses to a seemingly noncanonical "antigen." In this review, we detail the pathways associated with the foreign body response and describe possible mechanisms of immune involvement that can be targeted. We also discuss methods of modulating the immune response by altering the physiochemical surface properties of the biomaterial prior to implantation. Developments in these areas are reliant on reproducible and effective animal models and may allow a "combined" immunomodulatory approach of adapting surface properties of biomaterials, as well as treating key immune pathways to ultimately reduce the negative consequences of biomaterial implantation.

No Detectable Trade-Offs Among Immune Function, Fecundity, and Survival via a Juvenile Hormone Analog in the House Cricket.

PubMed

Nava-Sánchez, A; Munguía-Steyer, R; Córdoba-Aguilar, A

2014-08-01

Hormones are key regulators of resource allocation among functions and thus play an important role in resource-based trade-offs. The juvenile hormone (JH) is an insect hormone that mediates resource allocation between immunity and life history components. Here, we have tested whether this is the case using the house cricket. We investigated whether increased levels of JH (using methoprene, a JH analog) enable an enhanced survival and fecundity (via egg number) at the cost of reduced hemocyte number (a trait that is associated with immune response in insects) in the house cricket, Acheta domesticus L. We had three groups of adult crickets of both sexes: experimental (methoprene and acetone), positive control (methoprene), and negative control (no manipulation). Prior to and after experimental treatments, we counted the number of hemocytes (for the case of both sexes) and recorded the number of eggs laid and survival of females after the manipulation. There was no difference in hemocyte number, egg number, and survival. These results do not support a JH-mediated trade-off among immune ability, survival, and fecundity. We provide arguments to explain the lack of JH-mediated trade-offs in the house cricket.

The importance of vitamins D and K for the bone health and immune function in inflammatory bowel disease.

PubMed

Iijima, Hideki; Shinzaki, Shinichiro; Takehara, Tetsuo

2012-11-01

This review summarizes the recent literature about the roles of vitamins D and K in bone metabolism and immunity-mediated inflammatory processes in inflammatory bowel diseases (IBDs). The levels of vitamins D and K are lower than normal in patients with IBD, especially in Crohn's disease. Although vitamins D and K are important for the maintenance of bone mineral density in non-IBD patients, an association between vitamins D or K and bone metabolism is not apparent in IBD patients. Recent studies showed that vitamins D and K are suggested to have immune-suppressive effects, both in animal models of colitis and human trials. In particular, vitamin D suppresses dendritic and T-cell functions by inhibiting the production of proinflammatory cytokines. Insufficiency of vitamin D is associated with the activated phenotype of IBD. Vitamins D and K potentially contribute to the maintenance of bone health in IBD, but this effect may be diminished by other factors such as steroid use, reduced exposure to sunlight, and inflammatory cytokines. Vitamin D and possibly vitamin K are suggested to be involved in the suppression of immune-mediated inflammation and modulation of disease activity.

Macrophage function in murine allogeneic bone marrow radiation chimeras in the early phase after transplantation

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

Roesler, J.; Baccarini, M.; Vogt, B.

1989-08-01

We tested several of the functions of macrophages (M phi) in the early phase after allogeneic bone marrow transfer to get information about this important aspect of the nonspecific immune system in the T-cell-deficient recipient. On days 3-5 after transfer, the number of M phi was reduced in the spleen, liver, lungs, and peritoneal cavity (Pe). The phagocytosis of sheep red blood cells (SRBC) by these M phi was normal or even enhanced, as in the case of Pe-M phi. Already on days 8-12 after transfer, the number of M phi in spleen and liver exceeded that of controls, whereasmore » the number was still reduced in lungs and Pe. We examined their ability to kill P815 tumor cells, to produce tumor necrosis factor-alpha (TNF alpha), to phagocytose SRBC, to produce reactive oxygen intermediates (ROI) in vitro and to kill Listeria monocytogenes in vivo. Most functions were normal and often even enhanced, depending on the organ origin, but the ability of Pe-M phi to produce ROI was reduced. Proliferative response to macrophage colony-stimulating factor (M-CSF) and killing of YAC-1 tumor cells revealed a high frequency of macrophage precursor cells in the spleen and liver and a high natural killer (NK) activity in the liver. Altogether, enhanced nonspecific immune function, especially preactivated M phi, may enable chimeras to survive attacks by opportunistic pathogens.« less

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.

The Role of Sphingolipids on Innate Immunity to Intestinal Salmonella Infection.

PubMed

Huang, Fu-Chen

2017-08-07

Salmonella spp. remains a major public health problem for the whole world. To reduce the use of antimicrobial agents and drug-resistant Salmonella , a better strategy is to explore alternative therapy rather than to discover another antibiotic. Sphingolipid- and cholesterol-enriched lipid microdomains attract signaling proteins and orchestrate them toward cell signaling and membrane trafficking pathways. Recent studies have highlighted the crucial role of sphingolipids in the innate immunity against infecting pathogens. It is therefore mandatory to exploit the role of the membrane sphingolipids in the innate immunity of intestinal epithelia infected by this pathogen. In the present review, we focus on the role of sphingolipids in the innate immunity of intestinal epithelia against Salmonella infection, including adhesion, autophagy, bactericidal effect, barrier function, membrane trafficking, cytokine and antimicrobial peptide expression. The intervention of sphingolipid-enhanced foods to make our life healthy or pharmacological agents regulating sphingolipids is provided at the end.

Effects of Malignant Melanoma Initiating Cells on T-Cell Activation

PubMed Central

Schatton, Tobias; Schütte, Ute; Frank, Markus H.

2016-01-01

Although human malignant melanoma is a highly immunogenic cancer, both the endogenous antitumor immune response and melanoma immunotherapy often fail to control neoplastic progression. Accordingly, characterizing melanoma cell subsets capable of evading antitumor immunity could unravel optimized treatment strategies that might reduce morbidity and mortality from melanoma. By virtue of their preferential capacity to modulate antitumor immune responses and drive inexorable tumor growth and progression, malignant melanoma-initiating cells (MMICs) warrant closer investigation to further elucidate the cellular and molecular mechanisms underlying melanoma immune evasion and immunotherapy resistance. Here we describe methodologies that enable the characterization of immunoregulatory effects of purified MMICs versus melanoma bulk populations in coculture with syngeneic or allogeneic lymphocytes, using [3H] thymidine incorporation, enzyme-linked immunosorbent spot (ELISPOT), or ELISA assays. These assays were traditionally developed to analyze alloimmune processes and we successfully adapted them for the study of tumor-mediated immunomodulatory functions. PMID:26786883

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.

Predictors and immunological correlates of sublethal mercury exposure in vampire bats

PubMed Central

Chumchal, Matthew M.; Platt, Steven G.; Czirják, Gábor Á.; Rainwater, Thomas R.; Altizer, Sonia; Streicker, Daniel G.

2017-01-01

Mercury (Hg) is a pervasive heavy metal that often enters the environment from anthropogenic sources such as gold mining and agriculture. Chronic exposure to Hg can impair immune function, reducing the ability of animals to resist or recover from infections. How Hg influences immunity and susceptibility remains unknown for bats, which appear immunologically distinct from other mammals and are reservoir hosts of many pathogens of importance to human and animal health. We here quantify total Hg (THg) in hair collected from common vampire bats (Desmodus rotundus), which feed on blood and are the main reservoir hosts of rabies virus in Latin America. We examine how diet, sampling site and year, and bat demography influence THg and test the consequences of this variation for eight immune measures. In two populations from Belize, THg concentrations in bats were best explained by an interaction between long-term diet inferred from stable isotopes and year. Bats that foraged more consistently on domestic animals exhibited higher THg. However, relationships between diet and THg were evident only in 2015 but not in 2014, which could reflect recent environmental perturbations associated with agriculture. THg concentrations were low relative to values previously observed in other bat species but still correlated with bat immunity. Bats with higher THg had more neutrophils, weaker bacterial killing ability and impaired innate immunity. These patterns suggest that temporal variation in Hg exposure may impair bat innate immunity and increase susceptibility to pathogens such as bacteria. Unexpected associations between low-level Hg exposure and immune function underscore the need to better understand the environmental sources of Hg exposure in bats and the consequences for bat immunity and susceptibility. PMID:28484633

The role of innate immunity in acute allograft rejection after lung transplantation.

PubMed

Palmer, Scott M; Burch, Lauranell H; Davis, R Duane; Herczyk, Walter F; Howell, David N; Reinsmoen, Nancy L; Schwartz, David A

2003-09-15

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.

Adjuvants for veterinary vaccines--types and modes of action.

PubMed

Gerdts, Volker

2015-01-01

Adjuvants are used to improve the immune response to vaccines. Formulation with adjuvants can result in an earlier onset of immunity, an overall stronger immune response, a specific type of immunity, or a longer duration of immunity to the vaccine. Adjuvants were discovered empirically, and for decades, have been used in both humans and animals without understanding the mechanisms of action. With an improved understanding of the immune system, and in particular the interplay between innate and adaptive immunity, we are now getting better insight into the function of adjuvants. As a result, new adjuvants are being developed that are safe and highly effective for common use in humans and animals, as well as for use in high risk populations such as immunocompromised animals, neonates or very old animals. Furthermore, adjuvants can help to reduce the amount of antigen needed in the vaccine, increase the stability of the vaccine and enable alternatiye administration routes such as needle-free delivery of the vaccine. Here, I will provide an over view of the existing adjuvant technologies for veterinary vaccines and provide an outlook into some of the new technologies in preclinical and clinical development.

Immune function monitoring in lung transplantation using adenosine triphosphate production: time trends and relationship to postoperative infection.

PubMed

Takahashi, Mamoru; Ohsumi, Akihiro; Ohata, Keiji; Kondo, Takeshi; Motoyama, Hideki; Hijiya, Kyoko; Aoyama, Akihiro; Date, Hiroshi; Chen-Yoshikawa, Toyofumi F

2017-06-01

The ImmuKnow (IK) assay is a comprehensive immune function test that involves measuring adenosine triphosphate produced by the cluster of differentiation 4+ T lymphocytes in peripheral blood. The aim of this study was to analyze the time trends of IK values and assess the relationship between IK values and infections in lung transplants. We prospectively collected 178 blood samples from 22 deceased-donor lung transplant (DDLT) recipients and 17 living-donor lobar lung transplant (LDLLT) recipients. A surveillance IK assay was performed postoperatively, then after 1 week and 1, 3, 6, and 12 months. Time trends of IK values in stable recipients peaked 1 week after DDLT (477 ± 247 ATP ng/ml), and 1 month after LDLLT (433 ± 134 ng/ml), followed by a gradual decline over 1 year. The mean IK values in infections were significantly lower than those in the stable state (119 vs 312 ATP ng/ml, p = 0.0002). IK values increased sharply after lung transplantation and then decreased gradually over time in the first year, suggesting a natural history of immune function. IK values were also significantly reduced during infections. These results may provide new insights into the utility of immune monitoring after lung transplantation.

Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity

PubMed Central

Anel, Alberto; Aguiló, Juan I.; Catalán, Elena; Garaude, Johan; Rathore, Moeez G.; Pardo, Julián; Villalba, Martín

2012-01-01

The protein kinase C-θ (PKCθ), which is essential for T cell function and survival, is also required for efficient anti-tumor immune surveillance. Natural killer (NK) cells, which express PKCθ, play a prominent role in this process, mainly by elimination of tumor cells with reduced or absent major histocompatibility complex class-I (MHC-I) expression. This justifies the increased interest of the use of activated NK cells in anti-tumor immunotherapy in the clinic. The in vivo development of MHC-I-deficient tumors is much favored in PKCθ−/− mice compared with wild-type mice. Recent data offer some clues on the mechanism that could explain the important role of PKCθ in NK cell-mediated anti-tumor immune surveillance: some studies show that PKCθ is implicated in signal transduction and anti-tumoral activity of NK cells elicited by interleukin (IL)-12 or IL-15, while others show that it is implicated in NK cell functional activation mediated by certain killer-activating receptors. Alternatively, the possibility that PKCθ is involved in NK cell degranulation is discussed, since recent data indicate that it is implicated in microtubule-organizing center polarization to the immune synapse in CD4+ T cells. The implication of PKC isoforms in degranulation has been more extensively studied in cytotoxic T lymphocyte, and these studies will be also summarized. PMID:22783260

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.

Immunological aspects of sport nutrition.

PubMed

Gleeson, Michael

2016-02-01

Prolonged bouts of exercise and heavy training regimens are associated with depression of immune system functions that can increase the risk of picking up opportunistic infections such as the common cold and influenza. Some common sport nutrition practices including high-carbohydrate diets and carbohydrate ingestion during exercise, training with low-glycogen stores, intentional dieting for weight loss, ingestion of high-dose antioxidant supplements and protein ingestion post exercise may influence immune system status in athletes. In order to maintain robust immunity, athletes need to consume a well-balanced diet that is sufficient to meet their requirements for energy, carbohydrate, protein and micronutrients. Dietary deficiencies of protein and specific micronutrients are well known to be potential causes of immune dysfunction and an adequate intake of some essential minerals including iron and zinc and the vitamins A, D, E, B6 and B12 are important to maintain a healthy immune function. Vitamin D may be a particular concern as recent studies have emphasised its importance in limiting infection episode incidence and duration in both the general population and in athletes and many individuals exhibit inadequate vitamin D status during the winter months. There is only limited evidence that individual amino acids, β-glucans, herbal extracts and zinc are capable of boosting immunity or reducing infection risk in athletes. The ingestion of carbohydrate during exercise and daily consumption of probiotics, vitamin D3, bovine colostrum and plant polyphenol containing supplements or foodstuffs currently offer the best chance of success, particularly for those individuals who are prone to illness.

Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions

PubMed Central

Ginwala, Rashida; McTish, Emily; Raman, Chander; Singh, Narendra; Nagarkatti, Mitzi; Nagarkatti, Prakash; Sagar, Divya

2016-01-01

Apigenin, a natural flavonoid, found in several plants, fruits, vegetables, herbs, and spices, is known to have anti-oxidant and anti-inflammatory properties that are evident in the use of these substances for centuries as medicinal approaches to treat asthma, insomnia, Parkinson’s disease, neuralgia, and shingles. However, there is a considerable dearth of information regarding its effect on immune cells, especially dendritic cells (DC) that maintain the critical balance between an immunogenic and tolerogenic immune response, in an immunospecialized location like the central nervous system (CNS). In this paper we looked at the anti-inflammatory properties of Apigenin in restoration of immune function and the resultant decrease in neuroinflammation. In vivo, a significant reduction in severity of experimental autoimmune encephalomyelitis (EAE) progression and relapse was observed in C57BL/6 (progressive) and SJL/J (relapse-remitting) mouse models of multiple sclerosis upon treatment with Apigenin. Apigenin treated EAE mice show decreased expression of α4 integrin and CLEC12A on splenic DCs and an increased retention of immune cells in the periphery compared to untreated EAE mice. This correlated consequently with immunohistochemistry findings of decreased immune cell infiltration and reduced demyelination in the CNS. These results indicate a protective role of Apigenin against the neurodegenerative effects resulting from the entry of DC stimulated pathogenic T cells into the CNS thus implicating a potential therapy for neuroinflammatory disease. PMID:26040501

PCSK9 at the crossroad of cholesterol metabolism and immune function during infections.

PubMed

Paciullo, Francesco; Fallarino, Francesca; Bianconi, Vanessa; Mannarino, Massimo R; Sahebkar, Amirhossein; Pirro, Matteo

2017-09-01

Sepsis, a complex and dynamic syndrome resulting from microbial invasion and immune system dysregulation, is associated with an increased mortality, reaching up to 35% worldwide. Cholesterol metabolism is often disturbed during sepsis, with low plasma cholesterol levels being associated with poor prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of the low-density lipoprotein receptor (LDLR), thus regulating intracellular and plasma cholesterol levels. PCSK9 is often upregulated during sepsis and might have a detrimental effect on immune host response and survival. Accordingly, PCSK9 reduces lipopolysaccharide uptake and clearance by human hepatocytes. Moreover, PCSK9 upregulation exacerbates organ dysfunction and tissue inflammation during sepsis, whereas a protective effect of PCSK9 deficiency has been documented in septic patients. Although a possible detrimental impact of PCSK9 on survival has been described, some beneficial effects of PCSK9 on immune response may be hypothesized. First, PCSK9 is associated with increased plasma cholesterol levels, which might be protective during sepsis. Second, PCSK9, by stimulating LDLR degradation and inhibiting reverse cholesterol transport (RCT), might promote preferential cholesterol accumulation in macrophages and other immune cells; these events might improve lipid raft composition and augment toll-like receptor function thus supporting inflammatory response. Hence, a more clear definition of the role of PCSK9 in septic states might provide additional insight in the understanding of the sepsis-associated immune dysregulation and enhance therapeutic outcomes. © 2017 Wiley Periodicals, Inc.

Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia

PubMed Central

Shouval, Roni; Eldror, Shiran; Lev, Atar; Davidson, Jacqueline; Rosenthal, Esther; Volchek, Yulia; Shem-Tov, Noga; Yerushalmi, Ronit; Shimoni, Avichai; Somech, Raz; Nagler, Arnon

2017-01-01

Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation. PMID:27880933

Biochemical Principles and Functional Aspects of Pipecolic Acid Biosynthesis in Plant Immunity1[OPEN

PubMed Central

Kim, Denis; Schreiber, Stefan; Zeier, Tatyana; Schuck, Stefan; Reichel-Deland, Vanessa

2017-01-01

The nonprotein amino acid pipecolic acid (Pip) regulates plant systemic acquired resistance and basal immunity to bacterial pathogen infection. In Arabidopsis (Arabidopsis thaliana), the lysine (Lys) aminotransferase AGD2-LIKE DEFENSE RESPONSE PROTEIN1 (ALD1) mediates the pathogen-induced accumulation of Pip in inoculated and distal leaf tissue. Here, we show that ALD1 transfers the α-amino group of l-Lys to acceptor oxoacids. Combined mass spectrometric and infrared spectroscopic analyses of in vitro assays and plant extracts indicate that the final product of the ALD1-catalyzed reaction is enaminic 2,3-dehydropipecolic acid (DP), whose formation involves consecutive transamination, cyclization, and isomerization steps. Besides l-Lys, recombinant ALD1 transaminates l-methionine, l-leucine, diaminopimelate, and several other amino acids to generate oxoacids or derived products in vitro. However, detailed in planta analyses suggest that the biosynthesis of 2,3-DP from l-Lys is the major in vivo function of ALD1. Since ald1 mutant plants are able to convert exogenous 2,3-DP into Pip, their Pip deficiency relies on the inability to form the 2,3-DP intermediate. The Arabidopsis reductase ornithine cyclodeaminase/μ-crystallin, alias SYSTEMIC ACQUIRED RESISTANCE-DEFICIENT4 (SARD4), converts ALD1-generated 2,3-DP into Pip in vitro. SARD4 significantly contributes to the production of Pip in pathogen-inoculated leaves but is not the exclusive reducing enzyme involved in Pip biosynthesis. Functional SARD4 is required for proper basal immunity to the bacterial pathogen Pseudomonas syringae. Although SARD4 knockout plants show greatly reduced accumulation of Pip in leaves distal to P. syringae inoculation, they display a considerable systemic acquired resistance response. This suggests a triggering function of locally accumulating Pip for systemic resistance induction. PMID:28330936

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

Armc5 deletion causes developmental defects and compromises T-cell immune responses

PubMed Central

Hu, Yan; Lao, Linjiang; Mao, Jianning; Jin, Wei; Luo, Hongyu; Charpentier, Tania; Qi, Shijie; Peng, Junzheng; Hu, Bing; Marcinkiewicz, Mieczyslaw Martin; Lamarre, Alain; Wu, Jiangping

2017-01-01

Armadillo repeat containing 5 (ARMC5) is a cytosolic protein with no enzymatic activities. Little is known about its function and mechanisms of action, except that gene mutations are associated with risks of primary macronodular adrenal gland hyperplasia. Here we map Armc5 expression by in situ hybridization, and generate Armc5 knockout mice, which are small in body size. Armc5 knockout mice have compromised T-cell proliferation and differentiation into Th1 and Th17 cells, increased T-cell apoptosis, reduced severity of experimental autoimmune encephalitis, and defective immune responses to lymphocytic choriomeningitis virus infection. These mice also develop adrenal gland hyperplasia in old age. Yeast 2-hybrid assays identify 16 ARMC5-binding partners. Together these data indicate that ARMC5 is crucial in fetal development, T-cell function and adrenal gland growth homeostasis, and that the functions of ARMC5 probably depend on interaction with multiple signalling pathways. PMID:28169274

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.

The stress response and immune system share, borrow, and reconfigure their physiological network elements: Evidence from the insects.

PubMed

Adamo, Shelley A

2017-02-01

The classic biomedical view is that stress hormone effects on the immune system are largely pathological, especially if the stress is chronic. However, more recent interpretations have focused on the potential adaptive function of these effects. This paper examines stress response-immune system interactions from a physiological network perspective, using insects because of their simpler physiology. For example, stress hormones can reduce disease resistance, yet activating an immune response results in the release of stress hormones in both vertebrates and invertebrates. From a network perspective, this phenomenon is consistent with the 'sharing' of the energy-releasing ability of stress hormones by both the stress response and the immune system. Stress-induced immunosuppression is consistent with the stress response 'borrowing' molecular components from the immune system to increase the capacity of stress-relevant physiological processes (i.e. a trade off). The insect stress hormones octopamine and adipokinetic hormone can also 'reconfigure' the immune system to help compensate for the loss of some of the immune system's molecular resources (e.g. apolipophorin III). This view helps explain seemingly maladaptive interactions between the stress response and immune system. The adaptiveness of stress hormone effects on individual immune components may be apparent only from the perspective of the whole organism. These broad principles will apply to both vertebrates and invertebrates. Copyright © 2016 Elsevier Inc. All rights reserved.

A T-cell response to a liver-stage Plasmodium antigen is not boosted by repeated sporozoite immunizations

PubMed Central

Murphy, Sean C.; Kas, Arnold; Stone, Brad C.; Bevan, Michael J.

2013-01-01

Development of an antimalarial subunit vaccine inducing protective cytotoxic T lymphocyte (CTL)-mediated immunity could pave the way for malaria eradication. Experimental immunization with sporozoites induces this type of protective response, but the extremely large number of proteins expressed by Plasmodium parasites has so far prohibited the identification of sufficient discrete T-cell antigens to develop subunit vaccines that produce sterile immunity. Here, using mice singly immunized with Plasmodium yoelii sporozoites and high-throughput screening, we identified a unique CTL response against the parasite ribosomal L3 protein. Unlike CTL responses to the circumsporozoite protein (CSP), the population of L3-specific CTLs was not expanded by multiple sporozoite immunizations. CSP is abundant in the sporozoite itself, whereas L3 expression does not increase until the liver stage. The response induced by a single immunization with sporozoites reduces the parasite load in the liver so greatly during subsequent immunizations that L3-specific responses are only generated during the primary exposure. Functional L3-specific CTLs can, however, be expanded by heterologous prime-boost regimens. Thus, although repeat sporozoite immunization expands responses to preformed antigens like CSP that are present in the sporozoite itself, this immunization strategy may not expand CTLs targeting parasite proteins that are synthesized later. Heterologous strategies may be needed to increase CTL responses across the entire spectrum of Plasmodium liver-stage proteins. PMID:23530242

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.

Early-life inflammation, immune response and ageing.

PubMed

Khan, Imroze; Agashe, Deepa; Rolff, Jens

2017-03-15

Age-related diseases are often attributed to immunopathology, which results in self-damage caused by an inappropriate inflammatory response. Immunopathology associated with early-life inflammation also appears to cause faster ageing, although we lack direct experimental evidence for this association. To understand the interactions between ageing, inflammation and immunopathology, we used the mealworm beetle Tenebrio molitor as a study organism. We hypothesized that phenoloxidase, an important immune effector in insect defence, may impose substantial immunopathological costs by causing tissue damage to Malpighian tubules (MTs; functionally equivalent to the human kidney), in turn accelerating ageing. In support of this hypothesis, we found that RNAi knockdown of phenoloxidase (PO) transcripts in young adults possibly reduced inflammation-induced autoreactive tissue damage to MTs, and increased adult lifespan. Our work thus suggests a causative link between immunopathological costs of early-life inflammation and faster ageing. We also reasoned that if natural selection weakens with age, older individuals should display increased immunopathological costs associated with an immune response. Indeed, we found that while old infected individuals cleared infection faster than young individuals, possibly they also displayed exacerbated immunopathological costs (larger decline in MT function) and higher post-infection mortality. RNAi-mediated knockdown of PO response partially rescued MTs function in older beetles and resulted in increased lifespan after infection. Taken together, our data are consistent with a direct role of immunopathological consequences of immune response during ageing in insects. Our work is also the first report that highlights the pervasive role of tissue damage under diverse contexts of ageing and immune response. © 2017 The Author(s).

B and T lymphocyte attenuator restricts the protective immune response against experimental malaria.

PubMed

Adler, Guido; Steeg, Christiane; Pfeffer, Klaus; Murphy, Theresa L; Murphy, Kenneth M; Langhorne, Jean; Jacobs, Thomas

2011-11-15

The immune response against the blood stage of malaria has to be tightly regulated to allow for vigorous antiplasmodial activity while restraining potentially lethal immunopathologic damage to the host like cerebral malaria. Coinhibitory cell surface receptors are important modulators of immune activation. B and T lymphocyte attenuator (BTLA) (CD272) is a coinhibitory receptor expressed by most leukocytes, with the highest expression levels on T and B cells, and is involved in the maintenance of peripheral tolerance by dampening the activation of lymphocytes. The function of BTLA is described in several models of inflammatory disorders and autoimmunity, but its function in infectious diseases is less well characterized. Also, little is known about the influence of BTLA on non-T cells. In this study, we analyzed the function of BTLA during blood-stage malaria infection with the nonlethal Plasmodium yoelii strain 17NL. We show that BTLA knockout mice exhibit strongly reduced parasitemia and clear the infection earlier compared with wild-type mice. This increased resistance was seen before the onset of adaptive immune mechanisms and even in the absence of T and B cells but was more pronounced at later time points when activation of T and B cells was observed. We demonstrate that BTLA regulates production of proinflammatory cytokines in a T cell-intrinsic way and B cell intrinsically regulates the production of P. yoelii 17NL-specific Abs. These results indicate that the coinhibitory receptor BTLA plays a critical role during experimental malaria and attenuates the innate as well as the subsequent adaptive immune response.

Early-life inflammation, immune response and ageing

PubMed Central

2017-01-01

Age-related diseases are often attributed to immunopathology, which results in self-damage caused by an inappropriate inflammatory response. Immunopathology associated with early-life inflammation also appears to cause faster ageing, although we lack direct experimental evidence for this association. To understand the interactions between ageing, inflammation and immunopathology, we used the mealworm beetle Tenebrio molitor as a study organism. We hypothesized that phenoloxidase, an important immune effector in insect defence, may impose substantial immunopathological costs by causing tissue damage to Malpighian tubules (MTs; functionally equivalent to the human kidney), in turn accelerating ageing. In support of this hypothesis, we found that RNAi knockdown of phenoloxidase (PO) transcripts in young adults possibly reduced inflammation-induced autoreactive tissue damage to MTs, and increased adult lifespan. Our work thus suggests a causative link between immunopathological costs of early-life inflammation and faster ageing. We also reasoned that if natural selection weakens with age, older individuals should display increased immunopathological costs associated with an immune response. Indeed, we found that while old infected individuals cleared infection faster than young individuals, possibly they also displayed exacerbated immunopathological costs (larger decline in MT function) and higher post-infection mortality. RNAi-mediated knockdown of PO response partially rescued MTs function in older beetles and resulted in increased lifespan after infection. Taken together, our data are consistent with a direct role of immunopathological consequences of immune response during ageing in insects. Our work is also the first report that highlights the pervasive role of tissue damage under diverse contexts of ageing and immune response. PMID:28275145

Immune biomarkers for chronic inflammation related complications in non-cancerous and cancerous diseases.

PubMed

Meirow, Yaron; Baniyash, Michal

2017-08-01

Chronic inflammation arising in a diverse range of non-cancerous and cancerous diseases, dysregulates immunity and exposes patients to a variety of complications. These include immunosuppression, tissue damage, cardiovascular diseases and more. In cancer, chronic inflammation and related immunosuppression can directly support tumor growth and dramatically reduce the efficacies of traditional treatments, as well as novel immune-based therapies, which require a functional immune system. Nowadays, none of the immune biomarkers, regularly used by clinicians can sense a developing chronic inflammation, thus complications can only be detected upon their appearance. This review focuses on the necessity for such immune status biomarkers, which could predict complications prior to their appearance. Herein we bring examples for the use of cellular and molecular biomarkers in diagnosis, prognosis and follow-up of patients suffering from various cancers, for prediction of response to immune-based anti-cancer therapy and for prediction of cardiovascular disease in type 2 diabetes patients. Monitoring such biomarkers is expected to have a major clinical impact in addition to unraveling of the entangled complexity underlying dysregulated immunity in chronic inflammation. Thus, newly discovered biomarkers and those that are under investigation are projected to open a new era towards combating the silent damage induced by chronic inflammation.

Metformin, A New Era for an Old Drug in the Treatment of Immune Mediated Disease?

PubMed

Schuiveling, Mark; Vazirpanah, Nadia; Radstake, Timothy R D J; Zimmermann, Maili; Broen, Jasper C A

2018-01-01

Metformin, a widely prescribed blood glucose normalizing antidiabetic drug, is now beginning to receive increasing attention due to its anti-inflammatory properties. To provide a critical and comprehensive review of the available literature describing the effects of metformin on the immune system and on auto-inflammatory diseases. Based on the available scientific literature, metformin suppresses immune responses mainly through its direct effect on the cellular functions of various immune cell types by induction of AMPK and subsequent inhibition of mTORC1, and by inhibition of mitochondrial ROS production. Among key immune events, this results in inhibited monocyte to macrophage differentiation and restrained inflammatory capacity of activated macrophages. In addition, metformin treatment increases differentiation of T cells into both regulatory and memory T cells, as well as decreasing the capacity of neutrophils to commence in NETosis. Due to its inhibitory effect on the proinflammatory phenotype of immune cells, metformin seems to reduce auto-immune disease burden not only in several animal models, but has also shown beneficial results in some human trials. Based on its immunomodulatory properties and high tolerability as a drug, metformin is an interesting add-on drug for future trials in treatment of immune mediated inflammatory diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

PubMed

Bernsmeier, Christine; Triantafyllou, Evangelos; Brenig, Robert; Lebosse, Fanny J; Singanayagam, Arjuna; Patel, Vishal C; Pop, Oltin T; Khamri, Wafa; Nathwani, Rooshi; Tidswell, Robert; Weston, Christopher J; Adams, David H; Thursz, Mark R; Wendon, Julia A; Antoniades, Charalambos Gustav

2018-06-01

Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14 + HLA-DR - myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14 + CD15 - CD11b + HLA-DR - cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. Circulating CD14 + CD15 - CD11b + HLA-DR - M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. Immunosuppressive CD14 + HLA-DR - M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Ibrutinib treatment improves T cell number and function in CLL patients.

PubMed

Long, Meixiao; Beckwith, Kyle; Do, Priscilla; Mundy, Bethany L; Gordon, Amber; Lehman, Amy M; Maddocks, Kami J; Cheney, Carolyn; Jones, Jeffrey A; Flynn, Joseph M; Andritsos, Leslie A; Awan, Farrukh; Fraietta, Joseph A; June, Carl H; Maus, Marcela V; Woyach, Jennifer A; Caligiuri, Michael A; Johnson, Amy J; Muthusamy, Natarajan; Byrd, John C

2017-08-01

Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. The National Cancer Institute.

Hydrogen-rich Water Exerting a Protective Effect on Ovarian Reserve Function in a Mouse Model of Immune Premature Ovarian Failure Induced by Zona Pellucida 3

PubMed Central

He, Xin; Wang, Shu-Yu; Yin, Cheng-Hong; Wang, Tong; Jia, Chan-Wei; Ma, Yan-Min

2016-01-01

Background: Premature ovarian failure (POF) is a disease that affects female fertility but has few effective treatments. Ovarian reserve function plays an important role in female fertility. Recent studies have reported that hydrogen can protect male fertility. Therefore, we explored the potential protective effect of hydrogen-rich water on ovarian reserve function through a mouse immune POF model. Methods: To set up immune POF model, fifty female BALB/c mice were randomly divided into four groups: Control (mice consumed normal water, n = 10), hydrogen (mice consumed hydrogen-rich water, n = 10), model (mice were immunized with zona pellucida glycoprotein 3 [ZP3] and consumed normal water, n = 15), and model-hydrogen (mice were immunized with ZP3 and consumed hydrogen-rich water, n = 15) groups. After 5 weeks, mice were sacrificed. Serum anti-Müllerian hormone (AMH) levels, granulosa cell (GC) apoptotic index (AI), B-cell leukemia/lymphoma 2 (Bcl-2), and BCL2-associated X protein (Bax) expression were examined. Analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) software. Results: Immune POF model, model group exhibited markedly reduced serum AMH levels compared with those of the control group (5.41 ± 0.91 ng/ml vs. 16.23 ± 1.97 ng/ml, P = 0.033) and the hydrogen group (19.65 ± 7.82 ng/ml, P = 0.006). The model-hydrogen group displayed significantly higher AMH concentrations compared with that of the model group (15.03 ± 2.75 ng/ml vs. 5.41 ± 0.91 ng/ml, P = 0.021). The GC AI was significantly higher in the model group (21.30 ± 1.74%) than those in the control (7.06 ± 0.27%), hydrogen (5.17 ± 0.41%), and model-hydrogen groups (11.24 ± 0.58%) (all P < 0.001). The GC AI was significantly higher in the model-hydrogen group compared with that of the hydrogen group (11.24 ± 0.58% vs. 5.17 ± 0.41%, P = 0.021). Compared with those of the model group, ovarian tissue Bcl-2 levels increased (2.18 ± 0.30 vs. 3.01 ± 0.33, P = 0.045) and the Bax/Bcl-2 ratio decreased in the model-hydrogen group. Conclusions: Hydrogen-rich water may improve serum AMH levels and reduce ovarian GC apoptosis in a mouse immune POF model induced by ZP3. PMID:27647193

Intrinsic and extrinsic contributors to defective CD8+ T cell responses with aging.

PubMed

Jergović, Mladen; Smithey, Megan J; Nikolich-Žugich, Janko

2018-05-01

Aging has a profound effect on the immune system, and both innate and adaptive arms of the immune system show functional decline with age. In response to infection with intracellular microorganisms, old animals mobilize decreased numbers of antigen-specific CD8+ T cells with reduced production of effector molecules and impaired cytolytic activity. However, the CD8+ T cell-intrinsic contribution to, and molecular mechanisms behind, these defects remain unclear. In this review we will discuss the mechanistic contributions of age related changes in the CD8+ T cell pool and the relative roles of intrinsic functional defects in aged CD8+ T cells vs. defects in the aged environment initiating the CD8+ T cell response. Copyright © 2018 Elsevier Inc. All rights reserved.

Depressive symptoms are associated with reduced neutrophil function in hip fracture patients☆

PubMed Central

Duggal, Niharika Arora; Upton, Jane; Phillips, Anna C.; Hampson, Peter; Lord, Janet M.

2013-01-01

Hip fracture is a common trauma in older adults with a high incidence of depression, which relates to poorer prognosis including increased risk of infection. Ageing is accompanied by reduced immunity, termed immunesenescence, resulting in increased susceptibility to infection. We examined whether physical trauma (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system that might contribute to poor outcomes after injury. Neutrophil function was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and 43 healthy age-matched controls (28 female). Thirty eight fracture patients had depressive symptoms at 6 weeks. No difference in neutrophil phagocytosis of Escherichia coli was observed between controls and hip fracture patients, but superoxide production was significantly reduced in hip fracture patients with depressive symptoms compared with patients without symptoms (p = .001) or controls (p = .004) at 6 weeks. Superoxide production improved 6 months following fracture to the level seen in controls. We detected elevated serum cortisol, reduced dehydroepiandrosterone sulphate (DHEAS) and an increased cortisol:DHEAS ratio in fracture patients with depressive symptoms compared with patients without depressive symptoms or controls at 6 weeks and 6 months after injury. Serum IL6, TNFα and IL10 were higher among patients with depressive symptoms at 6 weeks. The cortisol:DHEAS ratio and IL6 levels related to depressive symptom scores but not to neutrophil function. In conclusion, depressive symptoms related to poorer neutrophil function after hip fracture, but this was not driven by changes in stress hormone or cytokine levels. PMID:23876747

Sustained Partial Sleep Deprivation: Effects on Immune Modulation and Growth Factors

NASA Technical Reports Server (NTRS)

Mullington, Janet M.

1999-01-01

The vulnerability to medical emergencies is greatest in space where there are real limits to the availability or effectiveness of ground based assistance. Moreover, astronaut safety and health maintenance will be of increasing importance as we venture out into space for extended periods of time. It is therefore critical to understand the mechanisms of the regulatory physiology of homeostatic systems (sleep, circadian, neuroendocrine, fluid and nutritional balance) and the key roles played in adaptation. This synergy project has combined aims of the "Human Performance Factors, Sleep and Chronobiology Team"; the "Immunology, Infection and Hematology Team"; and the "Muscle Alterations and Atrophy Team", to broadly address the effects of long term sleep reduction, as is frequently encountered in space exploration, on neuroendocrine, neuroimmune and circulating growth factors. Astronaut sleep is frequently curtailed to averages of between 4- 6.5 hours per night. There is evidence that this amount of sleep is inadequate for maintaining optimal daytime functioning. However, there is a lack of information concerning the effects of chronic sleep restriction, or reduction, on regulatory physiology in general, and there have been no controlled studies of the cumulative effects of chronic sleep reduction on neuroendocrine and neuroimmune parameters. This synergy project represents a pilot study designed to characterize the effects of chronic partial sleep deprivation (PSD) on neuroendocrine, neuroimmune and growth factors. This project draws its subjects from two (of 18) conditions of the larger NSBRI project, "Countermeasures to Neurobehavioral Deficits from Cumulative Partial Sleep Deprivation During Space Flight", one of the projects on the "Human Performance Factors, Sleep and Chronobiology Team ". For the purposes of this study, to investigate the effects of chronic sleep loss on neuroendocrine and neuroimmune function, we have focused on the two extreme sleep conditions from this larger study: a 4.2 hour per night condition, and a 8.2 hour per night condition. During space flight, muscle mass and bone density are reduced, apparently due to loss of GH and IGF-I, associated with microgravity. Since >70% of growth hormone (GH) is secreted at night in normal adults, we hypothesized that the chronic sleep restriction to 4 hours per night would reduce GH levels as measured in the periphery. In this synergy project, in collaboration with the "Muscle Alterations and Atrophy Team ", we are measuring insulin-like growth factor-I (IGF-I) in peripheral circulation to test the prediction that it will be reduced by chronic sleep restriction. In addition to stress modulation of immune function, recent research suggests that sleep is also involved. While we all have the common experience of being sleepy when suffering from infection, and being susceptible to infection when not getting enough sleep, the mechanisms involved in this process are not understood and until recently have gone largely overlooked. We believe that the immune function changes seen in spaceflight may also be related to the cumulative effects of sleep loss. Moreover, in space flight, the possibility of compromised immune function or of the reactivation of latent viruses are serious potential hazards for the success of long term missions. Confined living conditions, reduced sleep, altered diet and stress are all factors that may compromise immune function, thereby increasing the risks of developing and transmitting disease. Medical complications, which would not pose serious problems on earth, may be disastrous if they emerged in space.

Prediction of selenoprotein T structure and its response to selenium deficiency in chicken immune organs.

PubMed

You, Lu; Liu, Ci; Yang, Zi-Jiang; Li, Ming; Li, Shu

2014-08-01

Selenoprotein T (SelT) is associated with the regulation of calcium homeostasis and neuroendocrine secretion. SelT can also change cell adhesion and is involved in redox regulation and cell fixation. However, the structure and function of chicken SelT and its response to selenium (Se) remains unclear. In the present study, 150 1-day-old chickens were randomly divided into a low Se group (L group, fed a Se-deficient diet containing 0.020 mg/kg Se) and a control group (C group, fed a diet containing sodium selenite at 0.2 mg/kg Se). The immune organs (spleen, thymus, and bursa of Fabricius) were collected at 15, 25, 35, 45, and 55 days of age. We performed a sequence analysis and predicted the structure and function of SelT. We also investigated the effects of Se deficiency on the expression of SelT, selenophosphate synthetase-1 (SPS1), and selenocysteine synthase (SecS) using RT-PCR and the oxidative stress in the chicken immune organs. The data showed that the coding sequence (CDS) and deduced amino acid sequence of SelT were highly similar to those of 17 other animals. Se deficiency induced lower (P < 0.05) levels of SelT, SPS1, and SecS, reduced the catalase (CAT) activity, and increased the levels of hydrogen peroxide (H2O2) and hydroxyl radical (-OH) in immune organs. In conclusion, the CDS and deduced amino acid sequence of chicken SelT are highly homologous to those of various mammals. The redox function and response to the Se deficiency of chicken SelT may be conserved. A Se-deficient diet led to a decrease in SelT, SecS, and SPS1 and induced oxidative stress in the chicken immune organs. To our knowledge, this is the first report of predictions of chicken SelT structure and function. The present study demonstrated the relationship between the selenoprotein synthases (SPS1, SecS) and SelT expression in the chicken immune organs and further confirmed oxidative stress caused by Se deficiency. Thus, the information presented in this study is helpful to understand chicken SelT structure and function. Meanwhile, the present research also confirmed the negative effects of Se deficiency on chicken immune organs.

Effect of Lactobacillus johnsonii La1 on immune function and serum albumin in aged and malnourished aged mice.

PubMed

Kaburagi, Tomoko; Yamano, Toshihiko; Fukushima, Yoichi; Yoshino, Haruka; Mito, Natsuko; Sato, Kazuto

2007-04-01

Protein-energy malnutrition (PEM) is a serious nutritional problem that causes immune dysfunction in elderly people. Probiotic lactic acid bacteria may potentially modify immunity; however, there is little evidence to elucidate the influence of these bacteria on PEM in the elderly. The immune modulation effects of lactic acid bacterium Lactobacillus johnsonii La1 (La1) were examined in aged mice and aged mice with PEM. Twenty-month-old male 57BL6/n mice (n = 28) were divided into four groups and received the following diet for 14 d: a complete diet (20% protein) without Lal (control) or with Lal or a low-protein diet (5% protein) to induce PEM, with or without La1. All mice were immunized with diphtheria toxin (DT) with alfacalciferol at 7 d and sacrificed 14 d after starting the experimental diets. Serum albumin concentrations and body weight, both of which were reduced by the low-protein diet, were ameliorated by La1 intake and were the same as in mice receiving the control diet. Anti-DT immunoglobulin (Ig) A in fecal extract was increased by La1 intake in mice receiving the complete and low-protein diets. Serum anti-DT IgA, IgG, splenocyte proliferation, and CD8(+) T cells were reduced by the low-protein diet and restored by La1 intake. La1 enhances intestinal IgA production and helps recover nutritional status and systemic immune responses in aged mice with PEM. It is possible that La1 may contribute to immune system recovery in immunocompromised hosts such as elderly humans with PEM.

Yoga clinical research review.

PubMed

Field, Tiffany

2011-02-01

In this paper recent research is reviewed on the effects of yoga poses on psychological conditions including anxiety and depression, on pain syndromes, cardiovascular, autoimmune and immune conditions and on pregnancy. Further, the physiological effects of yoga including decreased heartrate and blood pressure and the physical effects including weight loss and increased muscle strength are reviewed. Finally, potential underlying mechanisms are proposed including the stimulation of pressure receptors leading to enhanced vagal activity and reduced cortisol. The reduction in cortisol, in turn, may contribute to positive effects such as enhanced immune function and a lower prematurity rate. Copyright © 2010 Elsevier Ltd. All rights reserved.

Combination of selenium-enriched green tea polysaccharides and Huo-ji polysaccharides synergistically enhances antioxidant and immune activity in mice.

PubMed

Yuan, Chengfu; Li, Zhihong; Peng, Fan; Xiao, Fangxiang; Ren, Dongming; Xue, Hui; Chen, Tao; Mushtaq, Gohar; Kamal, Mohammad Amjad

2015-12-01

The aim of this study was to investigate the influence of a combination of selenium-enriched green tea polysaccharides (Se-GTP) and Huo-ji polysaccharides (HJP) on the immune function and antioxidant activity in mice. The results showed that the indices of spleen and thymus were markedly increased, and the activity of natural killer (NK) cell was promoted in mice treated with the combination of Se-GTP and HJP. The combined treatment of Se-GTP and HJP also reduced the content of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in splenocytes. In addition, the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) were remarkably enhanced, and malondialdehyde (MDA) levels were significantly reduced in mice treated with combination of Se-GTP and HJP. Furthermore, the combined treatment of Se-GTP and HJP increased nuclear factor erythroid 2-related factor (Nrf2) expression at mRNA and protein levels in splenocytes. The effects of the combination treatment of Se-GTP and HJP in mice were stronger than with Se-GTP or HJP treatment alone. Our study suggests that the combined administration of Se-GTP and HJP can synergistically improve immune function and decrease the oxidative stress by enhancing the mechanisms involved in the clearance of free radicals. © 2015 Society of Chemical Industry.

Red ginseng and vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus/H1N1 infection.

PubMed

Kim, Hyemin; Jang, Mirim; Kim, Yejin; Choi, Jiyea; Jeon, Jane; Kim, Jihoon; Hwang, Young-Il; Kang, Jae Seung; Lee, Wang Jae

2016-03-01

Because red ginseng and vitamin C have immunomodulatory function and anti-viral effect, we investigated whether red ginseng and vitamin C synergistically regulate immune cell function and suppress viral infection. Red ginseng and vitamin C were treated to human peripheral blood mononuclear cells (PBMCs) or sarcoma-associated herpesvirus (KSHV)-infected BCBL-1, and administrated to Gulo(-/-) mice, which are incapable of synthesizing vitamin C, with or without influenza A virus/H1N1 infection. Red ginseng and vitamin C increased the expression of CD25 and CD69 of PBMCs and natural killer (NK) cells. Co-treatment of them decreased cell viability and lytic gene expression in BCBL-1. In Gulo(-/-) mice, red ginseng and vitamin C increased the expression of NKp46, a natural cytotoxic receptor of NK cells and interferon (IFN)-γ production. Influenza infection decreased the survival rate, and increased inflammation and viral plaque accumulation in the lungs of vitamin C-depleted Gulo(-/-) mice, which were remarkably reduced by red ginseng and vitamin C supplementation. Administration of red ginseng and vitamin C enhanced the activation of immune cells like T and NK cells, and repressed the progress of viral lytic cycle. It also reduced lung inflammation caused by viral infection, which consequently increased the survival rate. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

Opiate antagonist prevents μ- and δ-opiate receptor dimerization to facilitate ability of agonist to control ethanol-altered natural killer cell functions and mammary tumor growth.

PubMed

Sarkar, Dipak K; Sengupta, Amitabha; Zhang, Changqing; Boyadjieva, Nadka; Murugan, Sengottuvelan

2012-05-11

In the natural killer (NK) cells, δ-opiate receptor (DOR) and μ-opioid receptor (MOR) interact in a feedback manner to regulate cytolytic function with an unknown mechanism. Using RNK16 cells, a rat NK cell line, we show that MOR and DOR monomer and dimer proteins existed in these cells and that chronic treatment with a receptor antagonist reduced protein levels of the targeted receptor but increased levels of opposing receptor monomer and homodimer. The opposing receptor-enhancing effects of MOR and DOR antagonists were abolished following receptor gene knockdown by siRNA. Ethanol treatment increased MOR and DOR heterodimers while it decreased the cellular levels of MOR and DOR monomers and homodimers. The opioid receptor homodimerization was associated with an increased receptor binding, and heterodimerization was associated with a decreased receptor binding and the production of cytotoxic factors. Similarly, in vivo, opioid receptor dimerization, ligand binding of receptors, and cell function in immune cells were promoted by chronic treatment with an opiate antagonist but suppressed by chronic ethanol feeding. Additionally, a combined treatment of an MOR antagonist and a DOR agonist was able to reverse the immune suppressive effect of ethanol and reduce the growth and progression of mammary tumors in rats. These data identify a role of receptor dimerization in the mechanism of DOR and MOR feedback interaction in NK cells, and they further elucidate the potential for the use of a combined opioid antagonist and agonist therapy for the treatment of immune incompetence and cancer and alcohol-related diseases.

Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection

PubMed Central

Cubas, Rafael; van Grevenynghe, Julien; Wills, Saintedym; Kardava, Lela; Santich, Brian H.; Buckner, Clarisa M.; Muir, Roshell; Tardif, Virginie; Nichols, Carmen; Procopio, Francesco; He, Zhong; Metcalf, Talibah; Ghneim, Khader; Locci, Michela; Ancuta, Petronella; Routy, Jean-Pierre; Trautmann, Lydie; Li, Yuxing; McDermott, Adrian B.; Koup, Rick A.; Petrovas, Constantinos; Migueles, Steven A.; Connors, Mark; Tomaras, Georgia D.; Moir, Susan; Crotty, Shane

2015-01-01

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2–responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART. PMID:26546609

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

Specific Amyloid β Clearance by a Catalytic Antibody Construct*

PubMed Central

Planque, Stephanie A.; Nishiyama, Yasuhiro; Sonoda, Sari; Lin, Yan; Taguchi, Hiroaki; Hara, Mariko; Kolodziej, Steven; Mitsuda, Yukie; Gonzalez, Veronica; Sait, Hameetha B. R.; Fukuchi, Ken-ichiro; Massey, Richard J.; Friedland, Robert P.; O'Nuallain, Brian; Sigurdsson, Einar M.; Paul, Sudhir

2015-01-01

Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid β (Aβ)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aβ C terminus noncovalently and hydrolyzed Aβ rapidly, with no reactivity to the Aβ precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Aβ dipeptide unit. The catabody dissolved preformed Aβ aggregates and inhibited Aβ aggregation more potently than an Aβ-binding IgG. Intravenous catabody treatment reduced brain Aβ deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Aβ hydrolysis appears to be an innate immune function that could be applied for therapeutic Aβ removal. PMID:25724648

Innate scavenger receptor-A regulates adaptive T helper cell responses to pathogen infection

PubMed Central

Xu, Zhipeng; Xu, Lei; Li, Wei; Jin, Xin; Song, Xian; Chen, Xiaojun; Zhu, Jifeng; Zhou, Sha; Li, Yong; Zhang, Weiwei; Dong, Xiaoxiao; Yang, Xiaowei; Liu, Feng; Bai, Hui; Chen, Qi; Su, Chuan

2017-01-01

The pattern recognition receptor (PRR) scavenger receptor class A (SR-A) has an important function in the pathogenesis of non-infectious diseases and in innate immune responses to pathogen infections. However, little is known about the role of SR-A in the host adaptive immune responses to pathogen infection. Here we show with mouse models of helminth Schistosoma japonicum infection and heat-inactivated Mycobacterium tuberculosis stimulation that SR-A is regulated by pathogens and suppresses IRF5 nuclear translocation by direct interaction. Reduced abundance of nuclear IRF5 shifts macrophage polarization from M1 towards M2, which subsequently switches T-helper responses from type 1 to type 2. Our study identifies a role for SR-A as an innate PRR in regulating adaptive immune responses. PMID:28695899

[Transrectal magnetotherapy of the prostate from Intramag device in prophylaxis of postoperative complications of transurethral resection of prostatic adenoma].

PubMed

Neĭmark, A I; Snegirev, I V; Neĭmark, B A

2006-01-01

The authors analyse preoperative preparation of 91 patients with benign prostatic hyperplasia (BPH). Two groups of patients received conventional preparation (group 1) and magnetotherapy (group 2) before TUR of the prostate. The examination covered immune system, bacteriological indices of urine and prostatic tissue. Infection of the urinary tract is a main risk factor of complications after TUR. Conventional preoperative preparation fails to correct immunity, to change bacterial urine flora, to improve hemodynamics in the prostate. Transrectal magnetotherapy with running magnetic field eliminates deficiency of T- and B-cell immunity, raises functional activity of B-lymphocytes and phagocytic ability of neutrophils, reduces endogenic intoxication, tissue edema, bacterial contamination, number of thrombohemorrhagic complications. This leads to a decrease in the number of postoperative complications.

5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis

PubMed Central

Grace, Marcy B.; Singh, Vijay K.; Rhee, Juong G.; Jackson, William E.; Kao, Tzu-Cheg; Whitnall, Mark H.

2012-01-01

The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis. PMID:22843381

5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.

PubMed

Grace, Marcy B; Singh, Vijay K; Rhee, Juong G; Jackson, William E; Kao, Tzu-Cheg; Whitnall, Mark H

2012-11-01

The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.

Apps for immunization: Leveraging mobile devices to place the individual at the center of care

PubMed Central

Wilson, Kumanan; Atkinson, Katherine M; Westeinde, Jacqueline

2015-01-01

Mobile technology and applications (apps) have disrupted several industries including healthcare. The advantage of apps, being personally focused and permitting bidirectional communication, make them well suited to address many immunization challenges. As of April 25, 2015 searching the Android app store with the words ‘immunize app’ and ‘immunization app’ in Canada yielded 225 apps. On the Apple App Store a similar search produced 98 results. These include apps that provide immunization related information, permit vaccine tracking both for individuals and for animals, assist with the creation of customized schedules and identification of vaccine clinics and serve as sources of education. The diverse functionality of mobile apps creates the potential for transformation of immunization practice both at a personal level and a system level. For individuals, mobile apps offer the opportunity for better record keeping, assistance with the logistics of vaccination, and novel ways of communicating with and receiving information from public health officials. For the system, mobile apps offer the potential to improve the quality of information residing in immunization information systems and program evaluation, facilitate harmonization of immunization information between individuals, health care providers and public health as well as reduce vaccine hesitancy. As mobile technology continues to rapidly evolve there will emerge new ways in which apps can enhance immunization practice. PMID:26110351

big bang gene modulates gut immune tolerance in Drosophila.

PubMed

Bonnay, François; Cohen-Berros, Eva; Hoffmann, Martine; Kim, Sabrina Y; Boulianne, Gabrielle L; Hoffmann, Jules A; Matt, Nicolas; Reichhart, Jean-Marc

2013-02-19

Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases.

Leptin Metabolically Licenses T Cells for Activation to Link Nutrition and Immunity

PubMed Central

Saucillo, Donte C.; Gerriets, Valerie A.; Sheng, John; Rathmell, Jeffrey C.; MacIver, Nancie J.

2013-01-01

Immune responses are highly energy dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. While it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show here that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell-intrinsic and specific to activated effector T cells, as naïve T cells and Treg did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency. PMID:24273001

Dairy Cows Naturally Infected with Bovine Leukemia Virus Exhibit Abnormal B- and T-Cell Phenotypes after Primary and Secondary Exposures to Keyhole Limpet Hemocyanin

PubMed Central

Frie, Meredith C.; Sporer, Kelly R. B.; Benitez, Oscar J.; Wallace, Joseph C.; Droscha, Casey J.; Bartlett, Paul C.; Coussens, Paul M.

2017-01-01

Bovine leukemia virus (BLV) is a retrovirus that is highly prevalent in US dairy herds: over 83% are BLV infected and the within-herd infection rate can be almost 50% on average. While BLV is known to cause lymphosarcomas, only 5% or fewer infected cattle will develop lymphoma; this low prevalence of cancer has historically not been a concern to dairy producers. However, more recent research has found that BLV+ cows without lymphoma produce less milk and have shorter lifespans than uninfected herdmates. It has been hypothesized that BLV infection interferes with normal immune function in infected cattle, and this could lead to reduced dairy production. To assess how naturally infected BLV+ cows responded to a primary and secondary immune challenge, 10 BLV+ and 10 BLV− cows were injected subcutaneously with keyhole limpet hemocyanin (KLH) and dimethyldioctadecylammonium bromide. B- and T-cell responses were characterized over the following 28 days. A total of 56 days after primary KLH exposure, cows were re-injected with KLH and B- and T-cell responses were characterized again over the following 28 days. BLV+ cows produced less KLH-specific IgM after primary immune stimulation; demonstrated fewer CD45R0+ B cells, altered proportions of CD5+ B cells, altered expression of CD5 on CD5+ B cells, and reduced MHCII surface expression on B cells ex vivo; exhibited reduced B-cell activation in vitro; and displayed an increase in BLV proviral load after KLH exposure. In addition, BLV+ cows had a reduced CD45R0+γδ+ T-cell population in the periphery and demonstrated a greater prevalence of IL4-producing T cells in vitro. All together, our results demonstrate that both B- and T-cell immunities are disrupted in BLV+ cows and that antigen-specific deficiencies can be detected in BLV+ cows even after a primary immune exposure. PMID:28770217

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

Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates

PubMed Central

Messaoudi, Ilhem; Warner, Jessica; Fischer, Miranda; Park, Buyng; Hill, Brenna; Mattison, Julie; Lane, Mark A.; Roth, George S.; Ingram, Donald K.; Picker, Louis J.; Douek, Daniel C.; Mori, Motomi; Nikolich-Žugich, Janko

2006-01-01

Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decreases mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. In rodents, CR was reported to delay the aging of the immune system (immune senescence), which is believed to be largely responsible for a dramatic increase in age-related susceptibility to infectious diseases. However, it is unclear whether CR can exert similar effects in long-lived organisms. Previous studies involving 2- to 4-year CR treatment of long-lived primates failed to find a CR effect or reported effects on the immune system opposite to those seen in CR-treated rodents. Here we show that long-term CR delays the adverse effects of aging on nonhuman primate T cells. CR effected a marked improvement in the maintenance and/or production of naïve T cells and the consequent preservation of T cell receptor repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells. Our results provide evidence that CR can delay immune senescence in nonhuman primates, potentially contributing to an extended lifespan by reducing susceptibility to infectious disease. PMID:17159149

Fast food fever: reviewing the impacts of the Western diet on immunity

PubMed Central

2014-01-01

While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet’s impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today’s modern diet may provide beneficial protection from micro- and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease. PMID:24939238

Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation▿

PubMed Central

Allen, Sariah J.; Mott, Kevin R.; Wechsler, Steven L.; Flavell, Richard A.; Town, Terrence; Ghiasi, Homayon

2011-01-01

Innate and adaptive immunity play important protective roles by combating herpes simplex virus 1 (HSV-1) infection. Transforming growth factor β (TGF-β) is a key negative cytokine regulator of both innate and adaptive immune responses. Yet, it is unknown whether TGF-β signaling in either immune compartment impacts HSV-1 replication and latency. We undertook genetic approaches to address these issues by infecting two different dominant negative TGF-β receptor type II transgenic mouse lines. These mice have specific TGF-β signaling blockades in either T cells or innate cells. Mice were ocularly infected with HSV-1 to evaluate the effects of restricted innate or adaptive TGF-β signaling during acute and latent infections. Limiting innate cell but not T cell TGF-β signaling reduced virus replication in the eyes of infected mice. On the other hand, blocking TGF-β signaling in either innate cells or T cells resulted in decreased latency in the trigeminal ganglia of infected mice. Furthermore, inhibiting TGF-β signaling in T cells reduced cell lysis and leukocyte infiltration in corneas and trigeminal ganglia during primary HSV-1 infection of mice. These findings strongly suggest that TGF-β signaling, which generally functions to dampen immune responses, results in increased HSV-1 latency. PMID:21880769

The Immune System and Developmental Programming of Brain and Behavior

PubMed Central

Bilbo, Staci D.; Schwarz, Jaclyn M.

2012-01-01

The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone-behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition. PMID:22982535

Silencing of the Rice Gene LRR1 Compromises Rice Xa21 Transcript Accumulation and XA21-Mediated Immunity.

PubMed

Caddell, Daniel F; Park, Chang-Jin; Thomas, Nicholas C; Canlas, Patrick E; Ronald, Pamela C

2017-12-01

The rice immune receptor XA21 confers resistance to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. We previously demonstrated that an auxilin-like protein, XA21 BINDING PROTEIN 21 (XB21), positively regulates resistance to Xoo. To further investigate the function of XB21, we performed a yeast two-hybrid screen. We identified 22 unique XB21 interacting proteins, including LEUCINE-RICH REPEAT PROTEIN 1 (LRR1), which we selected for further analysis. Silencing of LRR1 in the XA21 genetic background (XA21-LRR1Ri) compromises resistance to Xoo compared with control XA21 plants. XA21-LRR1Ri plants have reduced Xa21 transcript levels and reduced expression of genes that serve as markers of XA21-mediated activation. Overexpression of LRR1 is insufficient to alter resistance to Xoo in rice lines lacking XA21. Taken together, our results indicate that LRR1 is required for wild-type Xa21 transcript expression and XA21-mediated immunity.

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.

Changing expression of vertebrate immunity genes in an anthropogenic environment: a controlled experiment.

PubMed

Hablützel, Pascal I; Brown, Martha; Friberg, Ida M; Jackson, Joseph A

2016-09-01

The effect of anthropogenic environments on the function of the vertebrate immune system is a problem of general importance. For example, it relates to the increasing rates of immunologically-based disease in modern human populations and to the desirability of identifying optimal immune function in domesticated animals. Despite this importance, our present understanding is compromised by a deficit of experimental studies that make adequately matched comparisons between wild and captive vertebrates. We transferred post-larval fishes (three-spined sticklebacks), collected in the wild, to an anthropogenic (captive) environment. We then monitored, over 11 months, how the systemic expression of immunity genes changed in comparison to cohort-matched wild individuals in the originator population (total n = 299). We found that a range of innate (lyz, defbl2, il1r-like, tbk1) and adaptive (cd8a, igmh) immunity genes were up-regulated in captivity, accompanied by an increase in expression of the antioxidant enzyme, gpx4a. For some genes previously known to show seasonality in the wild, this appeared to be reduced in captive fishes. Captive fishes tended to express immunity genes, including igzh, foxp3b, lyz, defbl2, and il1r-like, more variably. Furthermore, although gene co-expression patterns (analyzed through gene-by-gene correlations and mutual information theory based networks) shared common structure in wild and captive fishes, there was also significant divergence. For one gene in particular, defbl2, high expression was associated with adverse health outcomes in captive fishes. Taken together, these results demonstrate widespread regulatory changes in the immune system in captive populations, and that the expression of immunity genes is more constrained in the wild. An increase in constitutive systemic immune activity, such as we observed here, may alter the risk of immunopathology and contribute to variance in health in vertebrate populations exposed to anthropogenic environments.

Comprehensive Astronaut Immune Assessment Following a Short-Duration Space Flight

NASA Technical Reports Server (NTRS)

Crucian, Brian; Stowe, Raymond; Yetman, Deborah; Pierson, Duane; Sams, Clarence

2006-01-01

Immune system dysregulation has been demonstrated to occur during spaceflight and has the potential to cause serious health risks to crewmembers participating in exploration class missions. As a part of an ongoing NASA flight experiment assessing viral immunity (DSO-500), a generalized immune assessment was performed on 3 crewmembers who participated in the recent STS-114 Space Shuttle mission. The following assays were performed: (1) comprehensive immunophenotype analysis; (2) T cell function/intracellular cytokine profiles; (4) secreted Th1/Th2 cytokine profiles via cytometric bead array. Immunophenotype analysis included a leukocyte differential, lymphocyte subsets, T cell subsets, cytotoxic/effector CD8+ T cells, memory/naive T cell subsets and constitutively activated T cells. Study timepoints were L-180, L-65, L-10, R+0, R+3 and R+14. Detailed data are presented in the poster text. As expected from a limited number of human subjects, data tended to vary with respect to most parameters. Specific post-flight alterations were as follows (subject number in parentheses): Granulocytosis (2/3), reduced NK cells (3/3), elevated CD4/CD8 ratio (3/3), general CD8+ phenotype shift to a less differentiated phenotype (3/3), elevated levels of memory CD4+ T cells (3/3), loss of L-selectin on T cell subsets (3/3), increased levels of activated T cells (2/3), reduced IL-2 producing T cell subsets (3/3), levels of IFNg producing T cells were unchanged. CD8+ T cell expression of the CD69 activation markers following whole blood stimulation with SEA+SEB were dramatically reduced postflight (3/3), whereas other T cell function assessments were largely unchanged. Cytometric bead array assessment of secreted T cell cytokines was performed, following whole blood stimulation with either CD3/CD28 antibodies or PMA+ionomycin for 48 hours. Specific cytokines assessed were IFNg, TNFa, IL-2, IL-4, IL-5, IL-10. Following CD3/CD28 stimulation, all three crewmembers had a mission-associated reduction in the levels of secreted IFNg. One crewmember had a post-flight inversion in the IFNg/IL-10 ratio postflight, which trended back to baseline by R+14. Detailed cytokine data are presented in the poster text. This testing regimen was designed to correlate immunophenotype changes (thought to correspond to specific in-vivo immune responses or pathogenesis), against altered leukocyte function and cytokine profiles. In-flight studies are required to determine if post-flight alterations are reflective of the in-flight condition, or are a response to landing and readaptation.

Associations between male testosterone and immune function in a pathogenically stressed forager-horticultural population

PubMed Central

Trumble, Benjamin C; Blackwell, Aaron D; Stieglitz, Jonathan; Thompson, Melissa Emery; Suarez, Ivan Maldonado; Kaplan, Hillard; Gurven, Michael

2016-01-01

Objectives Despite well-known fitness advantages to males who produce and maintain high endogenous testosterone levels, such phenotypes may be costly if testosterone-mediated investment in reproductive effort trade-off against investment in somatic maintenance. Previous studies of androgen-mediated trade-offs in human immune function find mixed results, in part because most studies either focus on a few indicators of immunity, are confounded by phenotypic correlation, or are observational. Here the association between male endogenous testosterone and 13 circulating cytokines are examined before and after ex vivo antigen stimulation with phytohaemagglutinin (PHA) and lipopolysaccharides (LPS) in a high pathogen population of Bolivian forager-horticulturalists. Materials and Methods A Milliplex 13-plex cytokine panel measured cytokine concentration in whole blood samples from 109 Tsimane men aged 40–89 (median=50 years) before and after antigen stimulation with PHA and LPS. Urinary testosterone was measured via enzyme immunoassay; demographic and anthropometric data were collected as part of the Tsimane Health and Life History Project. Results Higher endogenous testosterone was associated with down-regulated responses in all cytokines after PHA stimulation (but significantly in only 2/13 cytokines), controlling for age and body mass index. In contrast, testosterone was not significantly associated with down-regulation of cytokines after LPS stimulation. MANOVAs indicate that men with higher testosterone showed reduced cytokine responses to PHA compared to LPS (p=0.0098). Discussion Endogenous testosterone appears to be immunomodulatory rather than immunosuppressive. Potentially costlier forms of immune activation like those induced by PHA (largely T-cell biased immune activation) are down-regulated in men with higher testosterone, but testosterone has less impact on potentially less costly immune activation following LPS stimulation (largely B-cell mediated immunity). PMID:27465811

Attenuation of Pathogenic Immune Responses during Infection with Human and Simian Immunodeficiency Virus (HIV/SIV) by the Tetracycline Derivative Minocycline

PubMed Central

Drewes, Julia L.; Szeto, Gregory L.; Engle, Elizabeth L.; Liao, Zhaohao; Shearer, Gene M.; Zink, M. Christine; Graham, David R.

2014-01-01

HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo. PMID:24732038

Interleukin-17A Promotes CD8+ T Cell Cytotoxicity To Facilitate West Nile Virus Clearance.

PubMed

Acharya, Dhiraj; Wang, Penghua; Paul, Amber M; Dai, Jianfeng; Gate, David; Lowery, Jordan E; Stokic, Dobrivoje S; Leis, A Arturo; Flavell, Richard A; Town, Terrence; Fikrig, Erol; Bai, Fengwei

2017-01-01

CD8 + T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 + T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a -/- ) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 + T cells isolated from Il17a -/- mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8 + T cell cytotoxicity, which may have broad implications in other microbial infections and cancers. Interleukin-17A (IL-17A) and CD8 + T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8 + T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8 + T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8 + T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A-CD8 + T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8 + T cell functions are crucial. Copyright © 2016 American Society for Microbiology.

Early Life Wildfire Smoke Exposure Is Associated with Immune Dysregulation and Lung Function Decrements in Adolescence.

PubMed

Black, Carolyn; Gerriets, Joan E; Fontaine, Justin H; Harper, Richart W; Kenyon, Nicholas J; Tablin, Fern; Schelegle, Edward S; Miller, Lisa A

2017-05-01

The long-term health effects of wildfire smoke exposure in pediatric populations are not known. The objectives of this study were to determine if early life exposure to wildfire smoke can affect parameters of immunity and airway physiology that are detectable with maturity. We studied a mixed-sex cohort of rhesus macaque monkeys that were exposed as infants to ambient wood smoke from a series of Northern California wildfires in the summer of 2008. Peripheral blood mononuclear cells (PBMCs) and pulmonary function measures were obtained when animals were approximately 3 years of age. PBMCs were cultured with either LPS or flagellin, followed by measurement of secreted IL-8 and IL-6 protein. PBMCs from a subset of female animals were also evaluated by Toll-like receptor (TLR) pathway mRNA analysis. Induction of IL-8 protein synthesis with either LPS or flagellin was significantly reduced in PBMC cultures from wildfire smoke-exposed female monkeys. In contrast, LPS- or flagellin-induced IL-6 protein synthesis was significantly reduced in PBMC cultures from wildfire smoke-exposed male monkeys. Baseline and TLR ligand-induced expression of the transcription factor, RelB, was globally modulated in PBMCs from wildfire smoke-exposed monkeys, with additional TLR pathway genes affected in a ligand-dependent manner. Wildfire smoke-exposed monkeys displayed significantly reduced inspiratory capacity, residual volume, vital capacity, functional residual capacity, and total lung capacity per unit of body weight relative to control animals. Our findings suggest that ambient wildfire smoke exposure during infancy results in sex-dependent attenuation of systemic TLR responses and reduced lung volume in adolescence.

Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer.

PubMed

Borcherding, Nicholas; Kolb, Ryan; Gullicksrud, Jodi; Vikas, Praveen; Zhu, Yuwen; Zhang, Weizhou

2018-07-06

Immune checkpoints are a diverse set of inhibitory signals to the immune system that play a functional role in adaptive immune response and self-tolerance. Dysregulation of these pathways is a vital mechanism in the avoidance of immune destruction by tumor cells. Immune checkpoint blockade (ICB) refers to targeted strategies to disrupt the tumor co-opted immune suppression to enhance anti-tumor immunity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are two immune checkpoints that have the widest range of antibody-based therapies. These therapies have gone from promising approaches to Food and Drug Administration-approved first- and second-line agents for a number of immunogenic cancers. The burgeoning investigations of ICB efficacy in blood and solid cancers have underscored the importance of identifying the predictors of response and resistance to ICB. Identification of response correlates is made complicated by the observations of mixed reactions, or different responses in multiple lesions from the same patient, and delayed responses that can occur over a year after the induction therapy. Factors that can influence response and resistance in ICB can illuminate underlying molecular mechanisms of immune activation and suppression. These same response predictors can guide the identification of patients who would benefit from ICB, reduce off-target immune-relate adverse events, and facilitate the use of combinatorial therapies to increase efficacy. Here we review the underlying principles of immune checkpoint therapy and results of single-agent ICB clinical trials, and summarize the predictors of response and resistance. Copyright © 2018 Elsevier Ltd. All rights reserved.

Abscisic Acid-Cytokinin Antagonism Modulates Resistance Against Pseudomonas syringae in Tobacco.

PubMed

Großkinsky, Dominik K; van der Graaff, Eric; Roitsch, Thomas

2014-12-01

Phytohormones are known as essential regulators of plant defenses, with ethylene, jasmonic acid, and salicylic acid as the central immunity backbone, while other phytohormones have been demonstrated to interact with this. Only recently, a function of the classic phytohormone cytokinin in plant immunity has been described in Arabidopsis, rice, and tobacco. Although interactions of cytokinins with salicylic acid and auxin have been indicated, the complete network of cytokinin interactions with other immunity-relevant phytohormones is not yet understood. Therefore, we studied the interaction of kinetin and abscisic acid as a negative regulator of plant immunity to modulate resistance in tobacco against Pseudomonas syringae. By analyzing infection symptoms, pathogen proliferation, and accumulation of the phytoalexin scopoletin as a key mediator of kinetin-induced resistance in tobacco, antagonistic interaction of these phytohormones in plant immunity was identified. Kinetin reduced abscisic acid levels in tobacco, while increased abscisic acid levels by exogenous application or inhibition of abscisic acid catabolism by diniconazole neutralized kinetin-induced resistance. Based on these results, we conclude that reduction of abscisic acid levels by enhanced abscisic acid catabolism strongly contributes to cytokinin-mediated resistance effects. Thus, the identified cytokinin-abscisic acid antagonism is a novel regulatory mechanism in plant immunity.

As we age: Does slippage of quality control in the immune system lead to collateral damage?

PubMed

Müller, Ludmila; Pawelec, Graham

2015-09-01

The vertebrate adaptive immune system is remarkable for its possession of a very broad range of antigen receptors imbuing the system with exquisite specificity, in addition to the phagocytic and inflammatory cells of the innate system shared with invertebrates. This system requires strict control both at the level of the generation the cells carrying these receptors and at the level of their activation and effector function mediation in order to avoid autoimmunity and mitigate immune pathology. Thus, quality control checkpoints are built into the system at multiple nodes in the response, relying on clonal selection and regulatory networks to maximize pathogen-directed effects and minimize collateral tissue damage. However, these checkpoints are compromised with age, resulting in poorer immune control manifesting as tissue-damaging autoimmune and inflammatory phenomena which can cause widespread systemic disease, paradoxically compounding the problems associated with increased susceptibility to infectious disease and possibly cancer in the elderly. Better understanding the reasons for slippage of immune control will pave the way for developing rational strategies for interventions to maintain appropriate immunity while reducing immunopathology. Copyright © 2015 Elsevier B.V. All rights reserved.

Host protective roles of type 2 immunity: Parasite killing and tissue repair, flip sides of the same coin

PubMed Central

Allen, Judith E.; Sutherland, Tara E.

2014-01-01

Metazoan parasites typically induce a type 2 immune response, characterized by T helper 2 (Th2) cells that produce the cytokines IL-4, IL-5 and IL-13 among others. The type 2 response is host protective, reducing the number of parasites either through direct killing in the tissues, or expulsion from the intestine. Type 2 immunity also protects the host against damage mediated by these large extracellular parasites as they migrate through the body. At the center of both the innate and adaptive type 2 immune response, is the IL-4Rα that mediates many of the key effector functions. Here we highlight the striking overlap between the molecules, cells and pathways that mediate both parasite control and tissue repair. We have proposed that adaptive Th2 immunity evolved out of our innate repair pathways to mediate both accelerated repair and parasite control in the face of continual assault from multicellular pathogens. Type 2 cytokines are involved in many aspects of mammalian physiology independent of helminth infection. Therefore understanding the evolutionary relationship between helminth killing and tissue repair should provide new insight into immune mechanisms of tissue protection in the face of physical injury. PMID:25028340

EDA-Fibronectin Originating from Osteoblasts Inhibits the Immune Response against Cancer

PubMed Central

Rossnagl, Stephanie; Altrock, Eva; Sens, Carla; Kraft, Sabrina; Rau, Katrin; Giese, Thomas; Samstag, Yvonne; Nakchbandi, Inaam A.

2016-01-01

Osteoblasts lining the inner surface of bone support hematopoietic stem cell differentiation by virtue of proximity to the bone marrow. The osteoblasts also modify their own differentiation by producing various isoforms of fibronectin (FN). Despite evidence for immune regulation by osteoblasts, there is limited knowledge of how osteoblasts modulate cells of the immune system. Here, we show that extra domain A (EDA)-FN produced by osteoblasts increases arginase production in myeloid-derived cells, and we identify α5β1 as the mediating receptor. In different mouse models of cancer, osteoblasts or EDA-FN was found to up-regulate arginase-1 expression in myeloid-derived cells, resulting in increased cancer growth. This harmful effect can be reduced by interfering with the integrin α5β1 receptor or inhibiting arginase. Conversely, in tissue injury, the expression of arginase-1 is normally beneficial as it dampens the immune response to allow wound healing. We show that EDA-FN protects against excessive fibrotic tissue formation in a liver fibrosis model. Our results establish an immune regulatory function for EDA-FN originating from the osteoblasts and identify new avenues for enhancing the immune reaction against cancer. PMID:27653627

An essential complementary role of NF-kappaB pathway to microbicidal oxidants in Drosophila gut immunity.

PubMed

Ryu, Ji-Hwan; Ha, Eun-Mi; Oh, Chun-Taek; Seol, Jae-Hong; Brey, Paul T; Jin, Ingnyol; Lee, Dong Gun; Kim, Jaesang; Lee, Daekee; Lee, Won-Jae

2006-08-09

In the Drosophila gut, reactive oxygen species (ROS)-dependent immunity is critical to host survival. This is in contrast to the NF-kappaB pathway whose physiological function in the microbe-laden epithelia has yet to be convincingly demonstrated despite playing a critical role during systemic infections. We used a novel in vivo approach to reveal the physiological role of gut NF-kappaB/antimicrobial peptide (AMP) system, which has been 'masked' in the presence of the dominant intestinal ROS-dependent immunity. When fed with ROS-resistant microbes, NF-kappaB pathway mutant flies, but not wild-type flies, become highly susceptible to gut infection. This high lethality can be significantly reduced by either re-introducing Relish expression to Relish mutants or by constitutively expressing a single AMP to the NF-kappaB pathway mutants in the intestine. These results imply that the local 'NF-kappaB/AMP' system acts as an essential 'fail-safe' system, complementary to the ROS-dependent gut immunity, during gut infection with ROS-resistant pathogens. This system provides the Drosophila gut immunity the versatility necessary to manage sporadic invasion of virulent pathogens that somehow counteract or evade the ROS-dependent immunity.

Gestational Hypothyroxinemia Affects Its Offspring With a Reduced Suppressive Capacity Impairing the Outcome of the Experimental Autoimmune Encephalomyelitis.

PubMed

Haensgen, Henny; Albornoz, Eduardo; Opazo, María C; Bugueño, Katherinne; Jara Fernández, Evelyn Liliana; Binzberger, Rebecca; Rivero-Castillo, Tomás; Venegas Salas, Luis F; Simon, Felipe; Cabello-Verrugio, Claudio; Elorza, Alvaro A; Kalergis, Alexis M; Bueno, Susan M; Riedel, Claudia A

2018-01-01

Hypothyroxinemia (Hpx) is a thyroid hormone deficiency (THD) condition highly frequent during pregnancy, which although asymptomatic for the mother, it can impair the cognitive function of the offspring. Previous studies have shown that maternal hypothyroidism increases the severity of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis (MS). Here, we analyzed the immune response after EAE induction in the adult offspring gestated in Hpx. Mice gestated in Hpx showed an early appearance of EAE symptoms and the increase of all parameters of the disease such as: the pathological score, spinal cord demyelination, and immune cell infiltration in comparison to the adult offspring gestated in euthyroidism. Isolated CD4 + CD25 + T cells from spleen of the offspring gestated in Hpx that suffer EAE showed reduced capacity to suppress proliferation of effector T cells (T Eff ) after being stimulated with anti-CD3 and anti-CD28 antibodies. Moreover, adoptive transfer experiments of CD4 + CD25 + T cells from the offspring gestated in Hpx suffering EAE to mice that were induced with EAE showed that the receptor mice suffer more intense EAE pathological score. Even though, no significant differences were detected in the frequency of T reg cells and IL-10 content in the blood, spleen, and brain between mice gestated in Hpx or euthyroidism, T cells CD4 + CD25 + from spleen have reduced capacity to differentiate in vitro to T reg and to produce IL-10. Thus, our data support the notion that maternal Hpx can imprint the immune response of the offspring suffering EAE probably due to a reduced capacity to trigger suppression. Such "imprints" on the immune system could contribute to explaining as to why adult offspring gestated in Hpx suffer earlier and more intense EAE.

Reduced PU.1 expression underlies aberrant neutrophil maturation and function in β-thalassemia mice and patients.

PubMed

Siwaponanan, Panjaree; Siegers, Jurre Ynze; Ghazali, Razi; Ng, Thian; McColl, Bradley; Ng, Garrett Zhen-Wei; Sutton, Philip; Wang, Nancy; Ooi, Isabelle; Thiengtavor, Chayada; Fucharoen, Suthat; Chaichompoo, Pornthip; Svasti, Saovaros; Wijburg, Odilia; Vadolas, Jim

2017-06-08

β-Thalassemia is associated with several abnormalities of the innate immune system. Neutrophils in particular are defective, predisposing patients to life-threatening bacterial infections. The molecular and cellular mechanisms involved in impaired neutrophil function remain incompletely defined. We used the Hbb th3/+ β-thalassemia mouse and hemoglobin E (HbE)/β-thalassemia patients to investigate dysregulated neutrophil activity. Mature neutrophils from Hbb th3/+ mice displayed a significant reduction in chemotaxis, opsonophagocytosis, and production of reactive oxygen species, closely mimicking the defective immune functions observed in β-thalassemia patients. In Hbb th3/+ mice, the expression of neutrophil CXCR2, CD11b, and reduced NAD phosphate oxidase components (p22phox, p67phox, and gp91phox) were significantly reduced. Morphological analysis of Hbb th3/+ neutrophils showed that a large percentage of mature phenotype neutrophils (Ly6G hi Ly6C low ) appeared as band form cells, and a striking expansion of immature (Ly6G low Ly6C low ) hyposegmented neutrophils, consisting mainly of myelocytes and metamyelocytes, was noted. Intriguingly, expression of an essential mediator of neutrophil terminal differentiation, the ets transcription factor PU.1, was significantly decreased in Hbb th3/+ neutrophils. In addition, in vivo infection with Streptococcus pneumoniae failed to induce PU.1 expression or upregulate neutrophil effector functions in Hbb th3/+ mice. Similar changes to neutrophil morphology and PU.1 expression were observed in splenectomized and nonsplenectomized HbE/β-thalassemia patients. This study provides a mechanistic insight into defective neutrophil maturation in β-thalassemia patients, which contributes to deficiencies in neutrophil effector functions. © 2017 by The American Society of Hematology.

Characteristics of the Early Immune Response Following Transplantation of Mouse ES Cell Derived Insulin-Producing Cell Clusters

PubMed Central

Boyd, Ashleigh S.; Wood, Kathryn J.

2010-01-01

Background The fully differentiated progeny of ES cells (ESC) may eventually be used for cell replacement therapy (CRT). However, elements of the innate immune system may contribute to damage or destruction of these tissues when transplanted. Methodology/Principal Findings Herein, we assessed the hitherto ill-defined contribution of the early innate immune response in CRT after transplantation of either ESC derived insulin producing cell clusters (IPCCs) or adult pancreatic islets. Ingress of neutrophil or macrophage cells was noted immediately at the site of IPCC transplantation, but this infiltration was attenuated by day three. Gene profiling identified specific inflammatory cytokines and chemokines that were either absent or sharply reduced by three days after IPCC transplantation. Thus, IPCC transplantation provoked less of an early immune response than pancreatic islet transplantation. Conclusions/Significance Our study offers insights into the characteristics of the immune response of an ESC derived tissue in the incipient stages following transplantation and suggests potential strategies to inhibit cell damage to ensure their long-term perpetuation and functionality in CRT. PMID:20532031

Practical immunoregulation: neonatal immune response variation and prophylaxis of experimental food allergy in pigs.

PubMed

Wilkie, Bruce N; Rupa, Prithy; Schmied, Julie

2012-07-15

The importance of environment in immune response is identified and the increase in prevalence of allergic, autoimmune and chronic inflammatory diseases reviewed. In particular, altered opportunity to acquire evolutionarily anticipated commensal microbiota is associated through the "hygiene hypothesis" with defective developmental and response signals to the innate and adaptive immune systems. Evidence of the detrimental effects of such environments is reviewed as is evidence for remediation using controlled exposure to bacteria or their active components such as LPS or peptidoglycan ligands for TLR and NOD-like receptors. Occurrence of major environmentally associated changes in porcine immune response phenotype are described. The prophylactic effects of heat-killed Escherichia coli given intramuscularly or of oral Lactococcus lactis on experimental ovomucoid-induced allergy in piglets are described in the context of altered immune response bias favouring reduced type-2 phenotypes. The high frequency of clinical tolerance to developing allergic signs even in the face of classical sensitization indicates possible function in this pig model of regulatory effectors such as Treg cells. Copyright © 2011 Elsevier B.V. All rights reserved.

Trichomonas vaginalis Lipophosphoglycan Exploits Binding to Galectin-1 and -3 to Modulate Epithelial Immunity*

PubMed Central

Fichorova, Raina N.; Yamamoto, Hidemi S.; Fashemi, Titilayo; Foley, Evan; Ryan, Stanthia; Beatty, Noah; Dawood, Hassan; Hayes, Gary R.; St-Pierre, Guillaume; Sato, Sachiko; Singh, Bibhuti N.

2016-01-01

Trichomoniasis is the most common non-viral sexually transmitted infection caused by the vaginotropic extracellular protozoan parasite Trichomonas vaginalis. The infection is recurrent, with no lasting immunity, often asymptomatic, and linked to pregnancy complications and risk of viral infection. The molecular mechanisms of immune evasion by the parasite are poorly understood. We demonstrate that galectin-1 and -3 are expressed by the human cervical and vaginal epithelial cells and act as pathogen-recognition receptors for the ceramide phosphoinositol glycan core (CPI-GC) of the dominant surface protozoan lipophosphoglycan (LPG). We used an in vitro model with siRNA galectin knockdown epithelial clones, recombinant galectins, clinical Trichomonas isolates, and mutant protozoan derivatives to dissect the function of galectin-1 and -3 in the context of Trichomonas infection. Galectin-1 suppressed chemokines that facilitate recruitment of phagocytes, which can eliminate extracellular protozoa (IL-8) or bridge innate to adaptive immunity (MIP-3α and RANTES (regulated on activation normal T cell expressed and secreted)). Silencing galectin-1 increased and adding exogenous galectin-1 suppressed chemokine responses to Trichomonas or CPI-GC/LPG. In contrast, silencing galectin-3 reduced IL-8 response to LPG. Live Trichomonas depleted the extracellular levels of galectin-3. Clinical isolates and mutant Trichomonas CPI-GC that had reduced affinity to galectin-3 but maintained affinity to galectin-1 suppressed chemokine expression. Thus via CPI-GC binding, Trichomonas is capable of regulating galectin bioavailability and function to the benefit of its parasitic survival. These findings suggest novel approaches to control trichomoniasis and warrant further studies of galectin-binding diversity among clinical isolates as a possible source for symptom disparity in parasitic infections. PMID:26589797

NASA 14 Day Undersea Missions: A Short-Duration Spaceflight Analog for Immune System Dysregulation

NASA Technical Reports Server (NTRS)

Crucian, B. E.; Stowe, R. P.; Mehta, S. K.; Quiriarte, H.; Pierson, D. L.; Sams, C. F.

2010-01-01

BACKGROUND Spaceflight-associated immune dysregulation (SAID) occurs during spaceflight and may represent specific clinical risks for exploration-class missions. An appropriate ground analog for spaceflight-associated immune dysregulation would offer a platform for ground-evaluation of various potential countermeasures. This study evaluated the NASA Undersea Mission Operations ( NEEMO ), consisting of 14 day undersea deployment at the Aquarius station, as an analog for SAID. Sixteen Aquanauts from missions NEEMO-12, 13 and 14 participated in the study. RESULTS Mid-mission alterations leukocyte distribution occurred, including granulocytosis and elevations in central-memory CD8+ T-cells. General T cell function was reduced during NEEMO missions in roughly 50% of subjects. Secreted cytokines profiles were evaluated following whole blood stimulation with CD3/CD28 (T cells) or LPS (monocytes). T cell production of IFNg, IL-5, IL-10, IL-2, TNFa and IL-6 were all reduced before and during the mission. Conversely, monocyte production of TNFa, IL-10, IL-6, IL-1b and IL-8 were elevated during mission, moreso at the MD-14 timepoint. Antibodies to Epstein-Barr virus (EBV) viral capsid antigen and early antigen were increased in approximately 40% of the subjects. Changes in EBV tetramer-positive CD8+ T-cells exhibited a variable pattern. Antibodies against Cytomegalovirus (CMV) were marginally increased during the mission. Herpesvirus reactivation was determined by PCR. EBV viral load was generally elevated at L-6. Higher levels of salivary EBV were found during the NEEMO mission than before and after as well as than the healthy controls. No VZV or CMV was found in any pre, during and after NEEMO mission or control samples. Plasma cortisol was elevated at L-6. CONCLUSION Unfortunately, L-6 may be too near to mission start to be an appropriate baseline measurement. The general immune changes in leukocyte distribution, T cell function, cytokine production, virus specific immunity and viral reactivation are similar to those observed during or following spaceflight. The NEEMO platform may thus have utility for short-duration, ground-based spaceflight-immune research, such as investigations of mechanism or countermeasures validation.

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

Symposium review: Modulating adipose tissue lipolysis and remodeling to improve immune function during the transition period and early lactation of dairy cows.

PubMed

Contreras, G Andres; Strieder-Barboza, Clarissa; De Koster, Jenne

2018-03-01

Despite major advances in our understanding of transition and early lactation cow physiology and the use of advanced dietary, medical, and management tools, at least half of early lactation cows are reported to develop disease and over half of cow deaths occur during the first week of lactation. Excessive lipolysis, usually measured as plasma concentrations of free fatty acids (FFA), is a major risk factor for the development of displaced abomasum, ketosis, fatty liver, and metritis, and may also lead to poor lactation performance. Lipolysis triggers adipose tissue (AT) remodeling that is characterized by enhanced humoral and cell-mediated inflammatory responses and changes in its distribution of cellular populations and extracellular matrix composition. Uncontrolled AT inflammation could perpetuate lipolysis, as we have observed in cows with displaced abomasum, especially in those animals with genetic predisposition for excessive lipolysis responses. Efficient transition cow management ensures a moderate rate of lipolysis that is rapidly reduced as lactation progresses. Limiting FFA release from AT benefits immune function as several FFA are known to promote dysregulation of inflammation. Adequate formulation of pre- and postpartum diet reduces the intensity of AT lipolysis. Additionally, supplementation with niacin, monensin, and rumen-protected methyl donors (choline and methionine) during the transition period is reported to minimize FFA release into systemic circulation. Targeted supplementation of energy sources during early lactation improves energy balance and increases insulin concentration, which limits AT lipolytic responses. This review elaborates on the mechanisms by which uncontrolled lipolysis triggers inflammatory disorders. Details on current nutritional and pharmacological interventions that aid the modulation of FFA release from AT and their effect on immune function are provided. Understanding the inherent characteristics of AT biology in transition and early lactation cows will reduce disease incidence and improve lactation performance. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation

PubMed Central

Wong, Carmen P.; Rinaldi, Nicole A.; Ho, Emily

2015-01-01

Scope Zinc deficiency results in immune dysfunction and promotes systemic inflammation. The objective of this study was to examine the effects of zinc deficiency on cellular immune activation and epigenetic mechanisms that promote inflammation. This work is potentially relevant to the aging population given that age-related immune defects, including chronic inflammation, coincide with declining zinc status. Methods and results An in vitro cell culture system and the aged mouse model were used to characterize immune activation and DNA methylation profiles that may contribute to the enhanced proinflammatory response mediated by zinc deficiency. Zinc deficiency up-regulated cell activation markers ICAM1, MHC class II, and CD86 in THP1 cells, that coincided with increased IL1β and IL6 responses following LPS stimulation. A decreased zinc status in aged mice was similarly associated with increased ICAM1 and IL6 gene expression. Reduced IL6 promoter methylation was observed in zinc deficient THP1 cells, as well as in aged mice and human lymphoblastoid cell lines derived from aged individuals. Conclusion Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Our results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation. PMID:25656040

Innate Immunity and Biomaterials at the Nexus: Friends or Foes

PubMed Central

Christo, Susan N.; Diener, Kerrilyn R.; Bachhuka, Akash; Vasilev, Krasimir; Hayball, John D.

2015-01-01

Biomaterial implants are an established part of medical practice, encompassing a broad range of devices that widely differ in function and structural composition. However, one common property amongst biomaterials is the induction of the foreign body response: an acute sterile inflammatory reaction which overlaps with tissue vascularisation and remodelling and ultimately fibrotic encapsulation of the biomaterial to prevent further interaction with host tissue. Severity and clinical manifestation of the biomaterial-induced foreign body response are different for each biomaterial, with cases of incompatibility often associated with loss of function. However, unravelling the mechanisms that progress to the formation of the fibrotic capsule highlights the tightly intertwined nature of immunological responses to a seemingly noncanonical “antigen.” In this review, we detail the pathways associated with the foreign body response and describe possible mechanisms of immune involvement that can be targeted. We also discuss methods of modulating the immune response by altering the physiochemical surface properties of the biomaterial prior to implantation. Developments in these areas are reliant on reproducible and effective animal models and may allow a “combined” immunomodulatory approach of adapting surface properties of biomaterials, as well as treating key immune pathways to ultimately reduce the negative consequences of biomaterial implantation. PMID:26247017

Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis.

PubMed

Brenu, Ekua Weba; Huth, Teilah K; Hardcastle, Sharni L; Fuller, Kirsty; Kaur, Manprit; Johnston, Samantha; Ramos, Sandra B; Staines, Don R; Marshall-Gradisnik, Sonya M

2014-04-01

Perturbations in immune processes are a hallmark of a number of autoimmune and inflammatory disorders. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is an inflammatory disorder with possible autoimmune correlates, characterized by reduced NK cell activity, elevations in regulatory T cells (Tregs) and dysregulation in cytokine levels. The purpose of this article is to examine innate and adaptive immune cell phenotypes and functional characteristics that have not been previously examined in CFS/ME patients. Thirty patients with CFS/ME and 25 non-fatigued controls were recruited for this study. Whole blood samples were collected from all participants for the assessment of cell phenotypes, functional properties, receptors, adhesion molecules, antigens and intracellular proteins using flow cytometric protocols. The cells investigated included NK cells, dendritic cells, neutrophils, B cells, T cells, γδT cells and Tregs. Significant changes were observed in B-cell subsets, Tregs, CD4(+)CD73(+)CD39(+) T cells, cytotoxic activity, granzyme B, neutrophil antigens, TNF-α and IFN-γ in the CFS/ME patients in comparison with the non-fatigued controls. Alterations in B cells, Tregs, NK cells and neutrophils suggest significant impairments in immune regulation in CFS/ME and these may have similarities to a number of autoimmune disorders.

OsSERK1 regulates rice development but not immunity to Xanthomonas oryzae pv. oryzae or Magnaporthe oryzae.

PubMed

Zuo, Shimin; Zhou, Xiaogang; Chen, Mawsheng; Zhang, Shilu; Schwessinger, Benjamin; Ruan, Deling; Yuan, Can; Wang, Jing; Chen, Xuewei; Ronald, Pamela C

2014-12-01

Somatic embryogenesis receptor kinase (SERK) proteins play pivotal roles in regulation of plant development and immunity. The rice genome contains two SERK genes, OsSerk1 and OsSerk2. We previously demonstrated that OsSerk2 is required for rice Xa21-mediated resistance to Xanthomonas oryzae pv. oryzae (Xoo) and for normal development. Here we report the molecular characterization of OsSerk1. Overexpression of OsSerk1 results in a semi-dwarf phenotype whereas silencing of OsSerk1 results in a reduced angle of the lamina joint. OsSerk1 is not required for rice resistance to Xoo or Magnaporthe oryzae. Overexpression of OsSerk1 in OsSerk2-silenced lines complements phenotypes associated with brassinosteroid (BR) signaling defects, but not the disease resistance phenotype mediated by Xa21. In yeast, OsSERK1 interacts with itself forming homodimers, and also interacts with the kinase domains of OsSERK2 and BRI1, respectively. OsSERK1 is a functional protein kinase capable of auto-phosphorylation in vitro. We conclude that, whereas OsSERK2 regulates both rice development and immunity, OsSERK1 functions in rice development but not immunity to Xoo and M. oryzae. © 2014 Institute of Botany, Chinese Academy of Sciences.

The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

PubMed Central

Ojanen, Markus J. T.; Turpeinen, Hannu; Cordova, Zuzet M.; Hammarén, Milka M.; Harjula, Sanna-Kaisa E.; Parikka, Mataleena; Rämet, Mika

2015-01-01

Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinAtd204e/+ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinum-infected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinAtd204e/+ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinAtd204e/+ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection. PMID:25624351

Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis.

PubMed

Margoles, Lindsay M; Mittal, Rohit; Klingensmith, Nathan J; Lyons, John D; Liang, Zhe; Serbanescu, Mara A; Wagener, Maylene E; Coopersmith, Craig M; Ford, Mandy L

2016-01-01

Sepsis is the leading cause of death in intensive care units in the US, and it is known that chronic alcohol use is associated with higher incidence of sepsis, longer ICU stays, and higher mortality from sepsis. Both sepsis and chronic alcohol use are associated with immune deficits such as decreased lymphocyte numbers, impaired innate immunity, delayed-type hypersensitivity reactions, and susceptibility to infections; however, understanding of specific pathways of interaction or synergy between these two states of immune dysregulation is lacking. This study therefore sought to elucidate mechanisms underlying the immune dysregulation observed during sepsis in the setting of chronic alcohol exposure. Using a murine model of chronic ethanol ingestion followed by sepsis induction via cecal ligation and puncture, we determined that while CD4+ and CD8+ T cells isolated from alcohol fed mice eventually expressed the same cellular activation markers (CD44, CD69, and CD43) and effector molecules (IFN-γ, TNF) as their water fed counterparts, there was an overall delay in the acquisition of these phenotypes. This early lag in T cell activation was associated with significantly reduced IL-2 production at a later timepoint in both the CD4+ and CD8+ T cell compartments in alcohol sepsis, as well as with a reduced accumulation of CD8dim activated effectors. Taken together, these data suggest that delayed T cell activation may result in qualitative differences in the immune response to sepsis in the setting of chronic alcohol ingestion.

Fluoride reduced the immune privileged function of mouse Sertoli cells via the regulation of Fas/FasL system.

PubMed

Sun, Zilong; Nie, Qingli; Zhang, Lianjie; Niu, Ruiyan; Wang, Jundong; Wang, Shaolin

2017-02-01

Previous investigations have demonstrated the adverse impacts of fluoride on Sertoli cells (SCs), such as oxidative stress and apoptosis. SCs are the crucial cellular components that can create the immune privileged environment in testis. However, the effect of fluoride on SCs immune privilege is unknown. In this study, mouse SCs were exposed to sodium fluoride with varying concentrations of 10 -5 , 10 -4 , and 10 -3  mol/L to establish the model of fluoride-treated SCs (F-SCs) in vitro. After 48 h of incubation, F-SCs were transplanted underneath the kidney capsule of mice for 21 days, or cocultured with spleen lymphocytes for another 48 h. Immunohistochemical analysis of GATA4 in SCs grafts underneath kidney capsule presented less SCs distribution and obvious immune cell infiltration in F-SCs groups. In addition, the levels of FasL protein and mRNA in non-cocultured F-SCs decreased with the increase of fluoride concentration. When cocultured with F-SCs, lymphocytes presented significantly high cell viability and low apoptosis in F-SCs groups. Protein and mRNA expressions of FasL in cocultured F-SCs and Fas in lymphocytes were reduced, and the caspase 8 and caspase 3 mRNA levels were also decreased in fluoride groups in a dose-dependent manner. These findings indicated that fluoride influenced the testicular immune privilege through disturbing the Fas/FasL system. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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

A functional antigen in a practical crop: LT-B producing maize protects mice against Escherichia coli heat labile enterotoxin (LT) and cholera toxin (CT).

PubMed

Chikwamba, Rachel; Cunnick, Joan; Hathaway, Diane; McMurray, Jennifer; Mason, Hugh; Wang, Kan

2002-10-01

We have produced a functional heat labile enterotoxin (LT-) B subunit of Escherichia coli in maize. LT-B is a multimeric protein that presents an ideal model for an edible vaccine, displaying stability in the gut and inducing mucosal and systemic immune responses. Transgenic maize was engineered to synthesize the LT-B polypeptides, which assembled into oligomeric structures with affinity for G(M1) gangliosides. We orally immunized BALB/c mice by feeding transgenic maize meal expressing LT-B or non-transgenic maize meal spiked with bacterial LT-B. Both treatments stimulated elevated IgA and IgG antibodies against LT-B and the closely related cholera toxin B subunit (CT-B) in serum, and elevated IgA in fecal pellets. The transgenic maize induced a higher anti-LT-B and anti-CT-B mucosal and serum IgA response compared to the equivalent amount of bacterial LT-B spiked into maize. Following challenge by oral administration of the diarrhea inducing toxins LT and CT, transgenic maize-fed mice displayed reduced fluid accumulation in the gut compared to non-immunized mice. Moreover, the gut to carcass ratio of immunized mice was not significantly different from the PBS (non-toxin) challenged control group. We concluded that maize-synthesized LT-B had features of the native bacterial LT-B such as molecular weight, G(M1) binding ability, and induction of serum and mucosal immunity. We have demonstrated that maize, a major food and feed ingredient, can be efficiently transformed to produce, accumulate, and store a fully assembled and functional candidate vaccine antigen.

Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.

PubMed

Keiser, Nicholas W; Birket, Susan E; Evans, Idil A; Tyler, Scott R; Crooke, Adrianne K; Sun, Xingshen; Zhou, Weihong; Nellis, Joseph R; Stroebele, Elizabeth K; Chu, Kengyeh K; Tearney, Guillermo J; Stevens, Mark J; Harris, J Kirk; Rowe, Steven M; Engelhardt, John F

2015-06-01

Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.

Defective Innate Immunity and Hyperinflammation in Newborn Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferret Lungs

PubMed Central

Keiser, Nicholas W.; Birket, Susan E.; Evans, Idil A.; Tyler, Scott R.; Crooke, Adrianne K.; Sun, Xingshen; Zhou, Weihong; Nellis, Joseph R.; Stroebele, Elizabeth K.; Chu, Kengyeh K.; Tearney, Guillermo J.; Stevens, Mark J.; Harris, J. Kirk; Rowe, Steven M.

2015-01-01

Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography–tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals. PMID:25317669

Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity.

PubMed

Botelho, Danielle J; Leo, Bey Fen; Massa, Christopher B; Sarkar, Srijata; Tetley, Terry D; Chung, Kian Fan; Chen, Shu; Ryan, Mary P; Porter, Alexandra E; Zhang, Junfeng; Schwander, Stephan K; Gow, Andrew J

2016-01-01

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 μg/g body weight) 20 and 110 nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110 nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

Immune System Dysfunction in the Elderly.

PubMed

Fuentes, Eduardo; Fuentes, Manuel; Alarcón, Marcelo; Palomo, Iván

2017-01-01

Human aging is characterized by both physical and physiological frailty that profoundly affects the immune system. In this context aging is associated with declines in adaptive and innate immunity established as immunosenescence. Immunosenescence is a new concept that reflects the age-associated restructuring changes of innate and adaptive immune functions. Thus elderly individuals usually present chronic low-level inflammation, higher infection rates and chronic diseases. A study of alterations in the immune system during aging could provide a potentially useful biomarker for the evaluation of immune senescence treatment. The immune system is the result of the interplay between innate and adaptive immunity, yet the impact of aging on this function is unclear. In this article the function of the immune system during aging is explored.

Use of a priori statistics to minimize acquisition time for RFI immune spread spectrum systems

NASA Technical Reports Server (NTRS)

Holmes, J. K.; Woo, K. T.

1978-01-01

The optimum acquisition sweep strategy was determined for a PN code despreader when the a priori probability density function was not uniform. A psuedo noise spread spectrum system was considered which could be utilized in the DSN to combat radio frequency interference. In a sample case, when the a priori probability density function was Gaussian, the acquisition time was reduced by about 41% compared to a uniform sweep approach.

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.

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

An Extracellular Subtilase Switch for Immune Priming in Arabidopsis

PubMed Central

Mauch-Mani, Brigitte; Gil, Ma José; Vera, Pablo

2013-01-01

In higher eukaryotes, induced resistance associates with acquisition of a priming state of the cells for a more effective activation of innate immunity; however, the nature of the components for mounting this type of immunological memory is not well known. We identified an extracellular subtilase from Arabidopsis, SBT3.3, the overexpression of which enhances innate immune responses while the loss of function compromises them. SBT3.3 expression initiates a durable autoinduction mechanism that promotes chromatin remodeling and activates a salicylic acid(SA)-dependent mechanism of priming of defense genes for amplified response. Moreover, SBT3.3 expression-sensitized plants for enhanced expression of the OXI1 kinase gene and activation of MAP kinases following pathogen attack, providing additional clues for the regulation of immune priming by SBT3.3. Conversely, in sbt3.3 mutant plants pathogen-mediated induction of SA-related defense gene expression is drastically reduced and activation of MAP kinases inhibited. Moreover, chromatin remodeling of defense-related genes normally associated with activation of an immune priming response appear inhibited in sbt3.3 plants, further indicating the importance of the extracellular SBT3.3 subtilase in the establishment of immune priming. Our results also point to an epigenetic control in the regulation of plant immunity, since SBT3.3 is up-regulated and priming activated when epigenetic control is impeded. SBT3.3 represents a new regulator of primed immunity. PMID:23818851

An extracellular subtilase switch for immune priming in Arabidopsis.

PubMed

Ramírez, Vicente; López, Ana; Mauch-Mani, Brigitte; Gil, Ma José; Vera, Pablo

2013-01-01

In higher eukaryotes, induced resistance associates with acquisition of a priming state of the cells for a more effective activation of innate immunity; however, the nature of the components for mounting this type of immunological memory is not well known. We identified an extracellular subtilase from Arabidopsis, SBT3.3, the overexpression of which enhances innate immune responses while the loss of function compromises them. SBT3.3 expression initiates a durable autoinduction mechanism that promotes chromatin remodeling and activates a salicylic acid(SA)-dependent mechanism of priming of defense genes for amplified response. Moreover, SBT3.3 expression-sensitized plants for enhanced expression of the OXI1 kinase gene and activation of MAP kinases following pathogen attack, providing additional clues for the regulation of immune priming by SBT3.3. Conversely, in sbt3.3 mutant plants pathogen-mediated induction of SA-related defense gene expression is drastically reduced and activation of MAP kinases inhibited. Moreover, chromatin remodeling of defense-related genes normally associated with activation of an immune priming response appear inhibited in sbt3.3 plants, further indicating the importance of the extracellular SBT3.3 subtilase in the establishment of immune priming. Our results also point to an epigenetic control in the regulation of plant immunity, since SBT3.3 is up-regulated and priming activated when epigenetic control is impeded. SBT3.3 represents a new regulator of primed immunity.

The Effect of Physicochemical Modification on the Function of Antibodies Induced by Anti-Nicotine Vaccine in Mice

PubMed Central

Thorn, Jennifer M.; Bhattacharya, Keshab; Crutcher, Renata; Sperry, Justin; Isele, Colleen; Kelly, Barbara; Yates, Libbey; Zobel, James; Zhang, Ningli; Davis, Heather L.; McCluskie, Michael J.

2017-01-01

Smoking remains one of the major causes of morbidity and mortality worldwide. One approach to assisting smoking cessation is via anti-nicotine vaccines, composed of nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). We have previously shown that the carrier, hapten, linker, hapten load, degree of conjugate aggregation, and presence of adducts can each influence the function (nicotine-binding capacity) of the antibody (Ab) induced. Herein, we extend those findings and show that tertiary structure is also critical to the induction of functional immune responses and that this can be influenced by conjugation conditions. We evaluated immunogenicity in mice using six lots of NIC7-CRM, a conjugate of 5-aminoethoxy-nicotine (Hapten 7), and a single point (glycine 52 to glutamic acid) mutant nontoxic form of diphtheria toxin, cross-reactive material 197 (CRM197), which were synthesized under different reaction conditions resulting in conjugates with equivalent molecular characteristics (hapten load, aggregates, adducts), but a different tertiary structure. When tested in mice, better functional responses (reduced nicotine in the brain of immunized animals relative to non-immunized controls) were obtained with conjugates with a more closed structure than those with an open conformation. These studies highlight the need for a better understanding of the physicochemical properties of small molecule conjugate vaccines. PMID:28513561

The role of psychoneuroendocrine factors on spaceflight-induced immunological alterations

NASA Technical Reports Server (NTRS)

Meehan, R.; Whitson, P.; Sams, C.

1993-01-01

This paper summarizes previous in-flight infections and novel conditions of spaceflight that may suppress immune function. Granulocytosis, monocytosis, and lymphopenia are routinely observed following short duration orbital flights. Subtle changes within the monocyte and T cell populations can also be noted by flow cytometric analysis. The similarity between the immunological changes observed after spaceflight and other diverse environmental stressors suggest that most of these alterations may be neuroendocrine-mediated. Available data support the hypothesis that spaceflight and other environmental stressors modulate normal immune regulation via stress hormones, other than exclusively glucocorticoids. It will be essential to simultaneously collect in-flight endocrine, immunologic, and infectious illness data to determine the clinical significance of these results. Additional research that delineates the neuroendocrine mechanisms of stress-induced changes in normal immune regulation will allow clinicians in the future to initiate prophylactic immunomodulator therapy to restore immune competence altered by the stress of long-duration spaceflight and therefore reduce morbidity from infectious illness, autoimmune disease, or malignancy.

Candida innate immunity at the mucosa.

PubMed

Richardson, Jonathan P; Moyes, David L; Ho, Jemima; Naglik, Julian R

2018-03-09

The tremendous diversity in microbial species that colonise the mucosal surfaces of the human body is only now beginning to be fully appreciated. Distinguishing between the behaviour of commensal microbes and harmful pathogens that reside at mucosal sites in the body is a complex, and exquisitely fine-tuned process central to mucosal health. The fungal pathobiont Candida albicans is frequently isolated from mucosal surfaces with an asymptomatic carriage rate of approximately 60% in the human population. While normally a benign member of the microbiota, overgrowth of C. albicans often results in localised mucosal infection causing morbidity in otherwise healthy individuals, and invasive infection that often causes death in the absence of effective immune defence. C. albicans triggers numerous innate immune responses at mucosal surfaces, and detection of C. albicans hyphae in particular, stimulates the production of antimicrobial peptides, danger-associated molecular patterns and cytokines that function to reduce fungal burdens during infection. This review will summarise our current understanding of innate immune responses to C. albicans at mucosal surfaces. Copyright © 2018. Published by Elsevier Ltd.

dOCRL maintains immune cell quiescence by regulating endosomal traffic

PubMed Central

Del Signore, Steven J.; Biber, Sarah A.; Lehmann, Katherine S.; Heimler, Stephanie R.; Rosenfeld, Benjamin H.; Eskin, Tania L.

2017-01-01

Lowe Syndrome is a developmental disorder characterized by eye, kidney, and neurological pathologies, and is caused by mutations in the phosphatidylinositol-5-phosphatase OCRL. OCRL plays diverse roles in endocytic and endolysosomal trafficking, cytokinesis, and ciliogenesis, but it is unclear which of these cellular functions underlie specific patient symptoms. Here, we show that mutation of Drosophila OCRL causes cell-autonomous activation of hemocytes, which are macrophage-like cells of the innate immune system. Among many cell biological defects that we identified in docrl mutant hemocytes, we pinpointed the cause of innate immune cell activation to reduced Rab11-dependent recycling traffic and concomitantly increased Rab7-dependent late endosome traffic. Loss of docrl amplifies multiple immune-relevant signals, including Toll, Jun kinase, and STAT, and leads to Rab11-sensitive mis-sorting and excessive secretion of the Toll ligand Spåtzle. Thus, docrl regulation of endosomal traffic maintains hemocytes in a poised, but quiescent state, suggesting mechanisms by which endosomal misregulation of signaling may contribute to symptoms of Lowe syndrome. PMID:29028801

Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment.

PubMed

Kryczek, Ilona; Wei, Shuang; Zou, Linhua; Altuwaijri, Saleh; Szeliga, Wojciech; Kolls, Jay; Chang, Alfred; Zou, Weiping

2007-06-01

Th17 cells play an active role in inflammation and autoimmune diseases. However, the nature and regulation of Th17 in the context of tumor immunity remain unknown. In this study, we show that parallel to regulatory T (Treg) cells, IL-17(+) CD4(+) and CD8(+) T cells are kinetically induced in multiple tumor microenvironments in mice and humans. Treg cells play a crucial role in tumor immune pathogenesis and temper immune therapeutic efficacy. IL-2 is crucial for the production and function of Treg cells. We now show that IL-2 reduces IL-17(+) T cell differentiation in the tumor microenvironment accompanied with an enhanced Treg cell compartment in vitro and in vivo. Altogether, our work demonstrates a dynamic differentiation of IL-17(+) T cells in the tumor microenvironment, reveals a novel role for IL-2 in controlling the balance between IL-17(+) and Treg cells, and provides new insight of IL-17(+) T cells in tumor immune pathology and therapy.

Activating Transcription Factor 3 Regulates Immune and Metabolic Homeostasis

PubMed Central

Rynes, Jan; Donohoe, Colin D.; Frommolt, Peter; Brodesser, Susanne; Jindra, Marek

2012-01-01

Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-κB/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins. PMID:22851689

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.

Seasonal benefits of a natural propolis envelope to honey bee immunity and colony health.

PubMed

Borba, Renata S; Klyczek, Karen K; Mogen, Kim L; Spivak, Marla

2015-11-01

Honey bees, as social insects, rely on collective behavioral defenses that produce a colony-level immune phenotype, or social immunity, which in turn impacts the immune response of individuals. One behavioral defense is the collection and deposition of antimicrobial plant resins, or propolis, in the nest. We tested the effect of a naturally constructed propolis envelope within standard beekeeping equipment on the pathogen and parasite load of large field colonies, and on immune system activity, virus and storage protein levels of individual bees over the course of a year. The main effect of the propolis envelope was a decreased and more uniform baseline expression of immune genes in bees during summer and autumn months each year, compared with the immune activity in bees with no propolis envelope in the colony. The most important function of the propolis envelope may be to modulate costly immune system activity. As no differences were found in levels of bacteria, pathogens and parasites between the treatment groups, the propolis envelope may act directly on the immune system, reducing the bees' need to activate the physiologically costly production of humoral immune responses. Colonies with a natural propolis envelope had increased colony strength and vitellogenin levels after surviving the winter in one of the two years of the study, despite the fact that the biological activity of the propolis diminished over the winter. A natural propolis envelope acts as an important antimicrobial layer enshrouding the colony, benefiting individual immunity and ultimately colony health. © 2015. Published by The Company of Biologists Ltd.

Ibrutinib treatment improves T cell number and function in CLL patients

PubMed Central

Long, Meixiao; Do, Priscilla; Mundy, Bethany L.; Gordon, Amber; Lehman, Amy M.; Maddocks, Kami J.; Cheney, Carolyn; Jones, Jeffrey A.; Flynn, Joseph M.; Andritsos, Leslie A.; Fraietta, Joseph A.; June, Carl H.; Maus, Marcela V.; Woyach, Jennifer A.; Caligiuri, Michael A.; Johnson, Amy J.

2017-01-01

BACKGROUND. Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton’s tyrosine kinase (BTK) and IL-2–inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. FUNDING. The National Cancer Institute. PMID:28714866

Myeloid-derived suppressor cells express Bruton’s tyrosine kinase and can be depleted in tumor bearing hosts by ibrutinib treatment

PubMed Central

Stiff, Andrew; Trikha, Prashant; Wesolowski, Robert; Kendra, Kari; Hsu, Vincent; Uppati, Sarvani; McMichael, Elizabeth; Duggan, Megan; Campbell, Amanda; Keller, Karen; Landi, Ian; Zhong, Yiming; Dubovsky, Jason; Howard, John Harrison; Yu, Lianbo; Harrington, Bonnie; Old, Matthew; Reiff, Sean; Mace, Thomas; Tridandapani, Susheela; Muthusamy, Natarajan; Caligiuri, Michael A.; Byrd, John C.; Carson, William E.

2016-01-01

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells that expand in tumor bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wildtype mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo. Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. PMID:26880800

Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment.

PubMed

Stiff, Andrew; Trikha, Prashant; Wesolowski, Robert; Kendra, Kari; Hsu, Vincent; Uppati, Sarvani; McMichael, Elizabeth; Duggan, Megan; Campbell, Amanda; Keller, Karen; Landi, Ian; Zhong, Yiming; Dubovsky, Jason; Howard, John Harrison; Yu, Lianbo; Harrington, Bonnie; Old, Matthew; Reiff, Sean; Mace, Thomas; Tridandapani, Susheela; Muthusamy, Natarajan; Caligiuri, Michael A; Byrd, John C; Carson, William E

2016-04-15

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. Cancer Res; 76(8); 2125-36. ©2016 AACR. ©2016 American Association for Cancer Research.

Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function.

PubMed

Hemingway, Cheryl; Berk, Maurice; Anderson, Suzanne T; Wright, Victoria J; Hamilton, Shea; Eleftherohorinou, Hariklia; Kaforou, Myrsini; Goldgof, Greg M; Hickman, Katy; Kampmann, Beate; Schoeman, Johan; Eley, Brian; Beatty, David; Pienaar, Sandra; Nicol, Mark P; Griffiths, Michael J; Waddell, Simon J; Newton, Sandra M; Coin, Lachlan J; Relman, David A; Montana, Giovanni; Levin, Michael

2017-01-01

The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.

[Effect of Yishen capsule on serum vascular endothelial growth factor and cell immunity in patients with chronic glomerulonephritis].

PubMed

Wu, Xi-li; Sun, Wan-sen; Zhang, Wang-gang; Qiao, Cheng-lin; Wang, Zhu; Wang, Juan

2007-11-01

To explore the effect of Yishen capsule on the serum vascular endothelial growth factor (VEGF), the cell immunity and the theraphic. Serum VEGF and T cell subsets were studied in 30 normal subjects and 83 patients before and after treatment. Compare with normal subjects, CD3, CD4, CD4/CD8 were decreased, CD8 and serum VEGF were increased obviously (P <0. 05 or P <0. 01). After three months treatment with YiShen capsule, CD4/CD8 was increased, CD8 and serum VEGF were decreased significantly (P <0.05 or P <0.01). Yishen capsule can reduce the proteinuria, increase the function of immunity and improve the clinical symptom of patients with chronic glomerulonephritis, achieved the effects of allevating chronic glomerular sclerosis ultimately.

HIV therapeutic vaccines: moving towards a functional cure.

PubMed

Mylvaganam, Geetha H; Silvestri, Guido; Amara, Rama Rao

2015-08-01

Anti-viral T-cell and B-cell responses play a crucial role in suppressing HIV and SIV replication during chronic infection. However, these infections are rarely controlled by the host immune response, and most infected individuals need lifelong antiretroviral therapy (ART). Recent advances in our understanding of how anti-HIV immune responses are elicited and regulated prompted a surge of interest in harnessing these responses to reduce the HIV 'residual disease' that is present in ART-treated HIV-infected individuals. Novel approaches that are currently explored include both conventional therapeutic vaccines (i.e., active immunization strategies using HIV-derived immunogens) as well as the use of checkpoint blockers such as anti-PD-1 antibodies. These approaches appear promising as key components of complex therapeutic strategies aimed at curing HIV infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Specific amyloid β clearance by a catalytic antibody construct.

PubMed

Planque, Stephanie A; Nishiyama, Yasuhiro; Sonoda, Sari; Lin, Yan; Taguchi, Hiroaki; Hara, Mariko; Kolodziej, Steven; Mitsuda, Yukie; Gonzalez, Veronica; Sait, Hameetha B R; Fukuchi, Ken-ichiro; Massey, Richard J; Friedland, Robert P; O'Nuallain, Brian; Sigurdsson, Einar M; Paul, Sudhir

2015-04-17

Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid β (Aβ)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aβ C terminus noncovalently and hydrolyzed Aβ rapidly, with no reactivity to the Aβ precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Aβ dipeptide unit. The catabody dissolved preformed Aβ aggregates and inhibited Aβ aggregation more potently than an Aβ-binding IgG. Intravenous catabody treatment reduced brain Aβ deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Aβ hydrolysis appears to be an innate immune function that could be applied for therapeutic Aβ removal. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Exercise immunology: practical applications.

PubMed

Nieman, D C

1997-03-01

During the last 95 years, 629 papers (60% in the 1990s) dealing specifically with exercise and immunology have been published. Major findings of practical importance in terms of public health and athletic endeavor include: (a) In response to acute exercise (the most frequently studied area of exercise immunology), a rapid interchange of immune cells between peripheral lymphoid tissues and the circulation occurs. The response depends on many factors, including the intensity, duration, and mode of exercise, concentrations of hormones and cytokines, change in body temperature, blood flow, hydration status, and body position. Of all immune cells, natural killer (NK) cells, neutrophils, and macrophages (of the innate immune system) appear to be most responsive to the effects of acute exercise, both in terms of numbers and function. In general, acute exercise bouts of moderate duration (< 60 min) and intensity (< 60% VO2max) are associated with fewer perturbations and less stress to the immune system than are prolonged, high-intensity sessions. (b) In response to long-term exercise training, the only finding to date reported with some congruity between investigators is a significant elevation in NK cell activity. Changes in the function of neutrophils, macrophages, and T and B cells in response to training have been reported inconsistently, but there is some indication that neutrophil function is suppressed during periods of heavy training. (c) Limited data suggest that unusually heavy acute or chronic exercise may increase the risk of upper respiratory tract infection (URTI), while regular moderate physical activity may reduce URTI symptomatology. (d) Work performance tends to diminish with most systemic infectious, and clinical case studies and animal data suggest that infection severity, relapse, and myocarditis may result when patients exercise vigorously. (e) Although regular exercise has many benefits for HIV-infected individuals, helper T cell counts and other immune measures are not enhanced significantly. (f) Data suggest that the incidence and mortality rates for certain types of cancer are lower among active subjects. The role of the immune system may be limited, however, depending on the sensitivity of the specific tumor to cytolysis, the stage of cancer, the type of exercise program, and many other complex factors. (g) As individuals age, they experience a decline in most cell- mediated and humoral immune responses. Two human studies suggest that immune function is superior in highly conditioned versus sedentary elderly subjects. (h) Mental stress, undernourishment, quick weight loss, and improper hygiene have each been associated with impaired immunity. Athletes who are undergoing heavy training regimens should realize that each of these factors has the potential to compound the effect that exercise stress is having on their immune systems.

Measuring the immune system: a comprehensive approach for the analysis of immune functions in humans.

PubMed

Claus, Maren; Dychus, Nicole; Ebel, Melanie; Damaschke, Jürgen; Maydych, Viktoriya; Wolf, Oliver T; Kleinsorge, Thomas; Watzl, Carsten

2016-10-01

The immune system is essential to provide protection from infections and cancer. Disturbances in immune function can therefore directly affect the health of the affected individual. Many extrinsic and intrinsic factors such as exposure to chemicals, stress, nutrition and age have been reported to influence the immune system. These influences can affect various components of the immune system, and we are just beginning to understand the causalities of these changes. To investigate such disturbances, it is therefore essential to analyze the different components of the immune system in a comprehensive fashion. Here, we demonstrate such an approach which provides information about total number of leukocytes, detailed quantitative and qualitative changes in the composition of lymphocyte subsets, cytokine levels in serum and functional properties of T cells, NK cells and monocytes. Using samples from a cohort of 24 healthy volunteers, we demonstrate the feasibility of our approach to detect changes in immune functions.

Interplay between the gut microbiota and immune responses of ayu (Plecoglossus altivelis) during Vibrio anguillarum infection.

PubMed

Nie, Li; Zhou, Qian-Jin; Qiao, Yan; Chen, Jiong

2017-09-01

Gut microbiota plays fundamental roles in protection against pathogen invasion. However, the mechanism and extent of responses of gut microbiota to pathogenic infection are poorly understood. This study investigated the gut bacterial communities and immune responses of ayu (Plecoglossus altivelis) upon exposure to Vibrio anguillarum. The succession of V. anguillarum infection was evidenced by increased expression of immune genes and bacterial loads in ayu tissues, which in turn altered the composition and predicted functions of gut bacterial community. The dynamics of gut bacterial diversity and evenness were temporally stable in control ayu but were reduced in infected subjects, particularly at the late stages of infection. Variations in the gut microbiota were significantly associated with the expression levels of TNF-α (P = 0.019) and IL-1 β (P = 0.013). The profiles of certain gut bacterial taxa were indicative of V. anguillarum infection. Compared with healthy controls, the ayu infected with V. anguillarum possessed less complex, fewer connected, and lower cooperative gut bacterial interspecies interaction, coinciding with significant shifts in keystone species. These findings imply that V. anguillarum infection substantially disrupted the compositions and interspecies interaction of ayu gut bacterial community, thereby altering gut microbial-mediated functions and inducing host immune responses. This study provides an integrated overview on the interaction between the gut microbiota and host immune responses to pathogen infection from an ecological perspective. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interleukin-Encoding Adenoviral Vectors as Genetic Adjuvant for Vaccination against Retroviral Infection

PubMed Central

Ohs, Inga; Windmann, Sonja; Wildner, Oliver; Dittmer, Ulf; Bayer, Wibke

2013-01-01

Interleukins (IL) are cytokines with stimulatory and modulatory functions in the immune system. In this study, we have chosen interleukins which are involved in the enhancement of TH2 responses and B cell functions to analyze their potential to improve a prophylactic adenovirus-based anti-retroviral vaccine with regard to antibody and virus-specific CD4+ T cell responses. Mice were vaccinated with an adenoviral vector which encodes and displays the Friend Virus (FV) surface envelope protein gp70 (Ad.pIXgp70) in combination with adenoviral vectors encoding the interleukins IL4, IL5, IL6, IL7 or IL23. Co-application of Ad.pIXgp70 with Ad.IL5, Ad.IL6 or Ad.IL23 resulted in improved protection with high control over FV-induced splenomegaly and reduced viral loads. Mice co-immunized with adenoviral vectors encoding IL5 or IL23 showed increased neutralizing antibody responses while mice co-immunized with Ad.IL6 or Ad.IL23 showed improved FV-specific CD4+ T cell responses compared to mice immunized with Ad.pIXgp70 alone. We show that the co-application of adenoviral vectors encoding specific interleukins is suitable to improve the vaccination efficacy of an anti-retroviral vaccine. Improved protection correlated with improved CD4+ T cell responses and especially with higher neutralizing antibody titers. The co-application of selected interleukin-encoding adenoviral vectors is a valuable tool for vaccination with regard to enhancement of antibody mediated immunity. PMID:24349306

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 dysfunction in cirrhosis.

PubMed

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-03-14

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.

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 dysfunction in cirrhosis

PubMed Central

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-01-01

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID:24627592

Influence of fish oil supplementation and strength training on some functional aspects of immune cells in healthy elderly women.

PubMed

de Lourdes Nahhas Rodacki, Cintia; Rodacki, André Luiz Felix; Coelho, Isabela; Pequito, Daniele; Krause, Maressa; Bonatto, Sandro; Naliwaiko, Katya; Fernandes, Luiz Cláudio

2015-07-14

Immune function changes with ageing and is influenced by physical activity (strength training, ST) and diet (fish oil, FO). The present study investigated the effect of FO and ST on the immune system of elderly women. Forty-five women (64 (sd 1.4) years) were assigned to ST for 90 d (ST; n 15), ST plus 2 g/d FO for 90 d (ST90; n 15) or 2 g/d FO for 60 d followed by ST plus FO for 90 d (ST150; n 15). Training was performed three times per week, for 12 weeks. A number of innate (zymosan phagocytosis, lysosomal volume, superoxide anion, peroxide of hydrogen) and adaptive (cluster of differentiation 4 (CD4), CD8, TNF-α, interferon-γ (IFN-γ), IL-2, IL-6 and IL-10 produced by lymphocytes) immune parameters were assessed before supplementation (base), before (pre-) and after (post-) training. ST induced no immune changes. FO supplementation caused increased phagocytosis (48 %), lysosomal volume (100 %) and the production of superoxide anion (32 %) and H₂O₂(70 %) in the ST90. Additional FO supplementation (ST150) caused no additive influence on the immune system, as ST150 and ST90 did not differ, but caused greater changes when compared to the ST (P< 0·05). FO increased CD4+ and CD8+ lymphocytes in the ST150, which remained unchanged when training was introduced. The combination of ST and FO reduced TNF-α in the ST150 from base to post-test. FO supplementation (ST150, base-pre) when combined with exercise (ST150, pre-post) increased IFN-γ, IL-2, IL-6 and IL-10 production. The immune parameters improved in response to FO supplementation; however, ST alone did not enhance the immune system.

A Strong Immune Response in Young Adult Honeybees Masks Their Increased Susceptibility to Infection Compared to Older Bees

PubMed Central

Bull, James C.; Ryabov, Eugene V.; Prince, Gill; Mead, Andrew; Zhang, Cunjin; Baxter, Laura A.; Pell, Judith K.; Osborne, Juliet L.; Chandler, Dave

2012-01-01

Honeybees, Apis mellifera, show age-related division of labor in which young adults perform maintenance (“housekeeping”) tasks inside the colony before switching to outside foraging at approximately 23 days old. Disease resistance is an important feature of honeybee biology, but little is known about the interaction of pathogens and age-related division of labor. We tested a hypothesis that older forager bees and younger “house” bees differ in susceptibility to infection. We coupled an infection bioassay with a functional analysis of gene expression in individual bees using a whole genome microarray. Forager bees treated with the entomopathogenic fungus Metarhizium anisopliae s.l. survived for significantly longer than house bees. This was concomitant with substantial differences in gene expression including genes associated with immune function. In house bees, infection was associated with differential expression of 35 candidate immune genes contrasted with differential expression of only two candidate immune genes in forager bees. For control bees (i.e. not treated with M. anisopliae) the development from the house to the forager stage was associated with differential expression of 49 candidate immune genes, including up-regulation of the antimicrobial peptide gene abaecin, plus major components of the Toll pathway, serine proteases, and serpins. We infer that reduced pathogen susceptibility in forager bees was associated with age-related activation of specific immune system pathways. Our findings contrast with the view that the immunocompetence in social insects declines with the onset of foraging as a result of a trade-off in the allocation of resources for foraging. The up-regulation of immune-related genes in young adult bees in response to M. anisopliae infection was an indicator of disease susceptibility; this also challenges previous research in social insects, in which an elevated immune status has been used as a marker of increased disease resistance and fitness without considering the effects of age-related development. PMID:23300441

Molecular Steps in the Immune Signaling Pathway Evoked by Plant Elicitor Peptides: Ca2+-Dependent Protein Kinases, Nitric Oxide, and Reactive Oxygen Species Are Downstream from the Early Ca2+ Signal1[OPEN

PubMed Central

Ma, Yi; Zhao, Yichen; Walker, Robin K.; Berkowitz, Gerald A.

2013-01-01

Endogenous plant elicitor peptides (Peps) can act to facilitate immune signaling and pathogen defense responses. Binding of these peptides to the Arabidopsis (Arabidopsis thaliana) plasma membrane-localized Pep receptors (PEPRs) leads to cytosolic Ca2+ elevation, an early event in a signaling cascade that activates immune responses. This immune response includes the amplification of signaling evoked by direct perception of pathogen-associated molecular patterns by plant cells under assault. Work included in this report further characterizes the Pep immune response and identifies new molecular steps in the signal transduction cascade. The PEPR coreceptor BRASSINOSTEROID-INSENSITIVE1 Associated Kinase1 contributes to generation of the Pep-activated Ca2+ signal and leads to increased defense gene expression and resistance to a virulent bacterial pathogen. Ca2+-dependent protein kinases (CPKs) decode the Ca2+ signal, also facilitating defense gene expression and enhanced resistance to the pathogen. Nitric oxide and reduced nicotinamide adenine dinucleotide phosphate oxidase-dependent reactive oxygen species generation (due to the function of Respiratory Burst Oxidase Homolog proteins D and F) are also involved downstream from the Ca2+ signal in the Pep immune defense signal transduction cascade, as is the case with BRASSINOSTEROID-INSENSITIVE1 Associated Kinase1 and CPK5, CPK6, and CPK11. These steps of the pathogen defense response are required for maximal Pep immune activation that limits growth of a virulent bacterial pathogen in the plant. We find a synergism between function of the PEPR and Flagellin Sensing2 receptors in terms of both nitric oxide and reactive oxygen species generation. Presented results are also consistent with the involvement of the secondary messenger cyclic GMP and a cyclic GMP-activated Ca2+-conducting channel in the Pep immune signaling pathway. PMID:24019427

Reduced immune responses to purified protein derivative and Candida albicans in oral lichen planus.

PubMed

Simark-Mattsson, Charlotte; Eklund, Christina

2013-10-01

Impairment of cellular immunity is reported in lichen planus, an autoimmune disease affecting mucosae and skin. Our aim was to investigate immune responses directed against a set of microbial antigens in patients with oral lichen planus and in matched controls. Venous blood was obtained, and the mononuclear cells were enriched by density gradient centrifugation. The proliferation of peripheral blood mononuclear cells was assessed, following stimulation with purified protein derivative (PPD), Candida albicans, phytohemagglutinin or when cells were left unstimulated, after three or six days of cell culture. The production of interleukin-1ß (IL-1ß), IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), G-CSF, GM-CSF, MCP-1, MIP-ß was assessed in supernatants using the Bio-plex(®) assay and was complemented with ELISA for selected cytokines. Patients with oral lichen planus demonstrated reduced proliferative responses against PPD (P < 0.05) and C. albicans (P < 0.05). The majority of investigated cytokines, including the pro-inflammatory, IFN-γ and TNF-α were expressed at reduced levels in PPD-stimulated supernatants from patients with oral lichen planus. Collectively, the findings suggested that memory lymphocytes from patients with oral lichen planus (OLP) may have an impaired functional ability to react against certain recall antigens, as part of a generalized response, which may reflect immune regulatory processes. Further studies are needed to clarify the mechanisms of down-regulation in OLP pathogenesis and progression. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dim light at night interferes with the development of the short-day phenotype and impairs cell-mediated immunity in Siberian hamsters (Phodopus sungorus).

PubMed

Aubrecht, Taryn G; Weil, Zachary M; Nelson, Randy J

2014-10-01

Winter is a challenging time to survive and breed outside of the tropics. Animals use day length (photoperiod) to regulate seasonally appropriate adaptations in anticipation of challenging winter conditions. The net result of these photoperiod-mediated adjustments is enhanced immune function and increased survival. Thus, the ability to discriminate day length information is critical for survival and reproduction in small animals. However, during the past century, urban and suburban development has rapidly expanded and filled the night sky with light from various sources, obscuring crucial light-dark signals, which alters physiological interpretation of day lengths. Furthermore, reduced space, increased proximity to people, and the presence of light at night may act as stressors for small animals. Whereas acute stressors typically enhance immune responses, chronic exposure to stressors often impairs immune responses. Therefore, we hypothesized that the combination of dim light at night and chronic stress interferes with enhanced cell-mediated immunity observed during short days. Siberian hamsters (Phodopus sungorus) were assigned to short or long days with dark nights (0 lux) or dim (5 lux) light at night for 10 weeks. Following 2 weeks of chronic restraint (6 hr/day), a model of chronic stress, delayed type hypersensitivity (DTH) responses were assessed. Both dim light at night and restraint reduced the DTH response. Dim light at night during long nights produced an intermediate short day phenotype. These results suggest the constant presence of light at night could negatively affect survival of photoperiodic rodents by disrupting the timing of breeding and immune responses. © 2014 Wiley Periodicals, Inc.

Hydroxyurea and Zileuton Differentially Modulate Cell Proliferation and Interleukin-2 Secretion by Murine Spleen Cells: Possible Implication on the Immune Function and Risk of Pain Crisis in Patients with Sickle Cell Disease

PubMed Central

Kuvibidila, Solo; Warrier, Rajasekharan P.; Haynes, Johnson; Baliga, Surendra B.

2015-01-01

Background Hydroxyurea (HU) reduces major complications associated with sickle cell disease in part because of the induction of fetal hemoglobin. However, because of its antiproliferative property, its long-term use may impair immunity. Zileuton, a derivative of HU, also induces fetal hemoglobin and has antiinflammatory properties, a feature that can reduce the risk of sickling. Our goal was to investigate the capacity of both drugs to modulate the secretion of interleukin-2 (IL-2), a regulatory cytokine for immune responses. Methods Spleen cells obtained from 11 4-month-old C57BL/6 female mice were incubated without and with 10 μg/mL HU or zileuton, 2.5 μg/mL concanavalin A (ConA), 20 μg/mL phytohemagglutinin (PHA), and 50 ng/mL anti-CD3 antibody for 12-48 h. IL-2 was measured in the supernatant by enzyme-linked immunosorbent assay and cell proliferation by 3H-thymidine uptake. Results While HU reduced lymphocyte proliferation in response to mitogens (P<0.05), zileuton did not. Baseline IL-2 concentration and PHA-induced IL-2 were not significantly affected by either drug. Contrary to what we expected, while HU increased IL-2 supernatant levels 1.17-fold to 6.5-fold in anti-CD3 antibody–treated cells (P<0.05), zileuton decreased them 35%-65% (P<0.05). Zileuton likely reduced IL-2 levels by inhibiting 5-lipoxygenase, hence leukotriene B4 production, an IL-2 inducer. HU did not decrease IL-2 secretion likely because of its lack of effect on mRNA and protein synthesis. Conclusion Modulation of IL-2 secretion by zileuton and/or reduced lymphocyte proliferation by HU may impair the immune response of patients with sickle cell disease but may also be beneficial by attenuating inflammation independently of fetal hemoglobin induction. PMID:26412995

Regulatory T cells in human disease and their potential for therapeutic manipulation

PubMed Central

Taams, Leonie S; Palmer, Donald B; Akbar, Arne N; Robinson, Douglas S; Brown, Zarin; Hawrylowicz, Catherine M

2006-01-01

Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7–8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity. PMID:16630018

Factors influencing African-American mothers' concerns about immunization safety: a summary of focus group findings.

PubMed Central

Shui, Irene; Kennedy, Allison; Wooten, Karen; Schwartz, Benjamin; Gust, Deborah

2005-01-01

OBJECTIVE: To examine the vaccine safety concerns of African-American mothers who, despite concerns, have their children immunized. METHODS: Six focus groups of Atlanta-area African-American mothers who were very concerned about vaccine safety but whose children were fully vaccinated were conducted. RESULTS: Major factors influencing participants' concerns about immunizations included: lack of information and mistrust of the medical community and government. Factors that convinced parents to have their child immunized despite their concerns included social norms and/or laws supporting immunization and fear of the consequences of not immunizing. Suggestions given to reduce concerns included improving available information that addressed their concerns and provider-patient communication. CONCLUSIONS: Addressing mothers' concerns about immunization is important both from an ethical perspective, in assuring that they are fully informed of the risks and benefits of immunizations, as well as from a practical one, in reducing the possibility that they will decide not to immunize their child. Changes in the childhood immunization process should be made to reduce parental concern about vaccine safety. Some changes that may be considered include improved provider communication about immunizations and additional tailored information about the necessity and safety of vaccines. PMID:15926642

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.

Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality.

PubMed

Bancos, Irina; Hazeldine, Jon; Chortis, Vasileios; Hampson, Peter; Taylor, Angela E; Lord, Janet M; Arlt, Wiebke

2017-04-01

Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection. We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis ( n =  37) or bilateral adrenalectomy ( n =  5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects. Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P  < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P  < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients ( P  < 0.01). Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI. © 2017 The authors.

Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlβ (RELMβ) Null Mice: A Model of Intestinal Immune System Dysfunction in Disease Susceptibility.

PubMed

Wernstedt Asterholm, Ingrid; Kim-Muller, Ja Young; Rutkowski, Joseph M; Crewe, Clair; Tao, Caroline; Scherer, Philipp E

2016-09-01

Resistin, and its closely related homologs, the resistin-like molecules (RELMs) have been implicated in metabolic dysregulation, inflammation, and cancer. Specifically, RELMβ, expressed predominantly in the goblet cells in the colon, is released both apically and basolaterally, and is hence found in both the intestinal lumen in the mucosal layer as well as in the circulation. RELMβ has been linked to both the pathogenesis of colon cancer and type 2 diabetes. RELMβ plays a complex role in immune system regulation, and the impact of loss of function of RELMβ on colon cancer and metabolic regulation has not been fully elucidated. We therefore tested whether Retnlβ (mouse ortholog of human RETNLβ) null mice have an enhanced or reduced susceptibility for colon cancer as well as metabolic dysfunction. We found that the lack of RELMβ leads to increased colonic expression of T helper cell type-2 cytokines and IL-17, associated with a reduced ability to maintain intestinal homeostasis. This defect leads to an enhanced susceptibility to the development of inflammation, colorectal cancer, and glucose intolerance. In conclusion, the phenotype of the Retnlβ null mice unravels new aspects of inflammation-mediated diseases and strengthens the notion that a proper intestinal barrier function is essential to sustain a healthy phenotype. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies

PubMed Central

Haselmayer, Philipp; Camps, Montserrat; Muzerelle, Mathilde; El Bawab, Samer; Waltzinger, Caroline; Bruns, Lisa; Abla, Nada; Polokoff, Mark A.; Jond-Necand, Carole; Gaudet, Marilène; Benoit, Audrey; Bertschy Meier, Dominique; Martin, Catherine; Gretener, Denise; Lombardi, Maria Stella; Grenningloh, Roland; Ladel, Christoph; Petersen, Jørgen Søberg; Gaillard, Pascale; Ji, Hong

2014-01-01

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T–B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP®) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis. PMID:24904582

Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.

PubMed

Haselmayer, Philipp; Camps, Montserrat; Muzerelle, Mathilde; El Bawab, Samer; Waltzinger, Caroline; Bruns, Lisa; Abla, Nada; Polokoff, Mark A; Jond-Necand, Carole; Gaudet, Marilène; Benoit, Audrey; Bertschy Meier, Dominique; Martin, Catherine; Gretener, Denise; Lombardi, Maria Stella; Grenningloh, Roland; Ladel, Christoph; Petersen, Jørgen Søberg; Gaillard, Pascale; Ji, Hong

2014-01-01

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.

Impaired airway mucociliary function reduces antigen-specific IgA immune response to immunization with a claudin-4-targeting nasal vaccine in mice.

PubMed

Suzuki, Hidehiko; Nagatake, Takahiro; Nasu, Ayaka; Lan, Huangwenxian; Ikegami, Koji; Setou, Mitsutoshi; Hamazaki, Yoko; Kiyono, Hiroshi; Yagi, Kiyohito; Kondoh, Masuo; Kunisawa, Jun

2018-02-13

Vaccine delivery is an essential element for the development of mucosal vaccine, but it remains to be investigated how physical barriers such as mucus and cilia affect vaccine delivery efficacy. Previously, we reported that C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) targeted claudin-4, which is expressed by the epithelium associated with nasopharynx-associated lymphoid tissue (NALT), and could be effective as a nasal vaccine delivery. Mice lacking tubulin tyrosine ligase-like family, member 1 (Ttll1-KO mice) showed mucus accumulation in nasal cavity due to the impaired motility of respiratory cilia. Ttll1-KO mice nasally immunized with C-CPE fused to pneumococcal surface protein A (PspA-C-CPE) showed reduced PspA-specific nasal IgA responses, impaired germinal center formation, and decreased germinal center B-cells and follicular helper T cells in the NALT. Although there was no change in the expression of claudin-4 in the NALT epithelium in Ttll1-KO mice, the epithelium was covered by a dense mucus that prevented the binding of PspA-C-CPE to NALT. However, administration of expectorant N-acetylcysteine removed the mucus and rescued the PspA-specific nasal IgA response. These results show that the accumulation of mucus caused by impaired respiratory cilia function is an interfering factor in the C-CPE-based claudin-4-targeting nasal vaccine.

E3L and F1L Gene Functions Modulate the Protective Capacity of Modified Vaccinia Virus Ankara Immunization in Murine Model of Human Smallpox.

PubMed

Volz, Asisa; Jany, Sylvia; Freudenstein, Astrid; Lantermann, Markus; Ludwig, Holger; Sutter, Gerd

2018-01-04

The highly attenuated Modified Vaccinia virus Ankara (MVA) lacks most of the known vaccinia virus (VACV) virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in the MVA genome, such as the apoptosis inhibitor genes F1L and E3L . Here, we tested MVA vaccine preparations on the basis of the deletion mutant viruses MVA-ΔF1L and MVA-ΔE3L for efficacy against ectromelia virus (ECTV) challenge infections in mice. In non-permissive human tissue culture the MVA deletion mutant viruses produced reduced levels of the VACV envelope antigen B5. Upon mousepox challenge at three weeks after vaccination, MVA-ΔF1L and MVA-ΔE3L exhibited reduced protective capacity in comparison to wildtype MVA. Surprisingly, however, all vaccines proved equally protective against a lethal ECTV infection at two days after vaccination. Accordingly, the deletion mutant MVA vaccines induced high levels of virus-specific CD8+ T cells previously shown to be essential for rapidly protective MVA vaccination. These results suggest that inactivation of the anti-apoptotic genes F1L or E3L modulates the protective capacity of MVA vaccination most likely through the induction of distinct orthopoxvirus specific immunity in the absence of these viral regulatory proteins.

Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?

PubMed

Gurven, Michael D; Trumble, Benjamin C; Stieglitz, Jonathan; Blackwell, Aaron D; Michalik, David E; Finch, Caleb E; Kaplan, Hillard S

2016-09-25

Heart disease and type 2 diabetes are commonly believed to be rare among contemporary subsistence-level human populations, and by extension prehistoric populations. Although some caveats remain, evidence shows these diseases to be unusual among well-studied hunter-gatherers and other subsistence populations with minimal access to healthcare. Here we expand on a relatively new proposal for why these and other populations may not show major signs of these diseases. Chronic infections, especially helminths, may offer protection against heart disease and diabetes through direct and indirect pathways. As part of a strategy to insure their own survival and reproduction, helminths exert multiple cardio-protective effects on their host through their effects on immune function and blood lipid metabolism. Helminths consume blood lipids and glucose, alter lipid metabolism, and modulate immune function towards Th-2 polarization - which combined can lower blood cholesterol, reduce obesity, increase insulin sensitivity, decrease atheroma progression, and reduce likelihood of atherosclerotic plaque rupture. Traditional cardiometabolic risk factors, coupled with the mismatch between our evolved immune systems and modern, hygienic environments may interact in complex ways. In this review, we survey existing studies in the non-human animal and human literature, highlight unresolved questions and suggest future directions to explore the role of helminths in the etiology of cardio-metabolic disease. © The Author(s) 2016. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.

Prostaglandin-mediated recovery from bacteremia delays larval development in fall armyworm, Spodoptera frugiperda.

PubMed

Zhang, Lei; Ringbauer, Joseph A; Goodman, Cynthia L; Reall, Tamra; Jiang, Xing-Fu; Stanley, David

2018-04-01

Insect immunity includes a surveillance system that detects and signals infections, coupled with hemocytic and humoral immune functions. These functions are signaled and coordinated by several biochemicals, including biogenic amines, insect cytokines, peptides, and prostaglandins (PGs). The actions of these mediators are coordinated within cells by various forms of cross-talk among the signaling systems and they result in effective reactions to infection. While this is well understood, we lack information on how immune-mediated recovery influences subsequent juvenile development in surviving insects. We investigated this point by posing the hypothesis that PG signaling is necessary for larval recovery, although the recovery imposes biological costs, registered in developmental delays and failures in surviving individuals. Here, we report that nodulation responses to infections by the bacterium, Serratia marcescens, increased over time up to 5 h postinfection, with no further nodulation; it increased in a linear manner with increasing bacterial dosages. Larval survivorship decreased with increasing bacterial doses. Treating larvae with the PG-biosynthesis inhibitor, indomethacin, led to sharply decreased nodulation reactions to infection, which were rescued in larvae cotreated with indomethacin and the PG-precursor, arachidonic acid. Although nodulation was fully rescued, all bacterial challenged larvae suffered reduced survivorship compared to controls. Bacterial infection led to reduced developmental rates in larvae, but not pupae. Adult emergence from pupae that developed from experimental larvae was also decreased. Taken together, our data potently bolster our hypothesis. © 2018 Wiley Periodicals, Inc.

[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.

Right ventricular systolic pressure measurements in combination with harvest of lung and immune tissue samples in mice.

PubMed

Chen, Wen-Chi; Park, Sung-Hyun; Hoffman, Carol; Philip, Cecil; Robinson, Linda; West, James; Grunig, Gabriele

2013-01-16

The function of the right heart is to pump blood through the lungs, thus linking right heart physiology and pulmonary vascular physiology. Inflammation is a common modifier of heart and lung function, by elaborating cellular infiltration, production of cytokines and growth factors, and by initiating remodeling processes. Compared to the left ventricle, the right ventricle is a low-pressure pump that operates in a relatively narrow zone of pressure changes. Increased pulmonary artery pressures are associated with increased pressure in the lung vascular bed and pulmonary hypertension. Pulmonary hypertension is often associated with inflammatory lung diseases, for example chronic obstructive pulmonary disease, or autoimmune diseases. Because pulmonary hypertension confers a bad prognosis for quality of life and life expectancy, much research is directed towards understanding the mechanisms that might be targets for pharmaceutical intervention. The main challenge for the development of effective management tools for pulmonary hypertension remains the complexity of the simultaneous understanding of molecular and cellular changes in the right heart, the lungs and the immune system. Here, we present a procedural workflow for the rapid and precise measurement of pressure changes in the right heart of mice and the simultaneous harvest of samples from heart, lungs and immune tissues. The method is based on the direct catheterization of the right ventricle via the jugular vein in close-chested mice, first developed in the late 1990s as surrogate measure of pressures in the pulmonary artery. The organized team-approach facilitates a very rapid right heart catheterization technique. This makes it possible to perform the measurements in mice that spontaneously breathe room air. The organization of the work-flow in distinct work-areas reduces time delay and opens the possibility to simultaneously perform physiology experiments and harvest immune, heart and lung tissues. The procedural workflow outlined here can be adapted for a wide variety of laboratory settings and study designs, from small, targeted experiments, to large drug screening assays. The simultaneous acquisition of cardiac physiology data that can be expanded to include echocardiography and harvest of heart, lung and immune tissues reduces the number of animals needed to obtain data that move the scientific knowledge basis forward. The procedural workflow presented here also provides an ideal basis for gaining knowledge of the networks that link immune, lung and heart function. The same principles outlined here can be adapted to study other or additional organs as needed.

Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22

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

Waseda, Masazumi; Arimura, Sumimasa; Shimura, Eri

Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 singlemore » KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. - Highlights: • Dok-1 and Dok-2 play a cooperative role in protection against DSS-induced colitis. • Dok-1/-2 double KO (DKO) mice show extensive ulceration of the colon after DSS treatment. • Proliferation of colonic epithelium is inhibited in DSS-treated Dok-1/-2 DKO mice. • Expression of IL-17A and IL-22 is reduced in the colon of DSS-treated Dok-1/-2 DKO mice.« less

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.

Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

PubMed

Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

2018-06-01

As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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.

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.

Plasma Cytokine Levels During Long-Duration Spaceflight

NASA Technical Reports Server (NTRS)

Crucian, Brian E.; Zwart, Sara R.; Quiriarte, Heather A.; Smith, Scott M.; Sams, Clarence F.

2011-01-01

Reduced T cell, granulocyte, NK and monocyte function have all been reported following both long and short duration spaceflight, however these data indicate crews are generally not experiencing inflammatory or adaptive immune activation during spaceflight. There appear to be varied individual crew responses, and specific relationships between cytokines and markers of iron status and muscle turnover that warrant further evaluation. Increases in growth factors and chemokines may indicate other types of adaptation occurring during spaceflight, such as attempts to overcome diminished immunocyte function.

Immunomodulatory properties of carbon nanotubes are able to compensate immune function dysregulation caused by microgravity conditions

NASA Astrophysics Data System (ADS)

Crescio, Claudia; Orecchioni, Marco; Ménard-Moyon, Cécilia; Sgarrella, Francesco; Pippia, Proto; Manetti, Roberto; Bianco, Alberto; Delogu, Lucia Gemma

2014-07-01

Spaceflights lead to dysregulation of the immune cell functionality affecting the expression of activation markers and cytokine production. Short oxidized multi-walled carbon nanotubes functionalized by 1,3-dipolar cycloaddition have been reported to activate immune cells. In this Communication we have performed surface marker assays and multiplex ELISA on primary monocytes and T cells under microgravity. We have discovered that carbon nanotubes, through their immunostimulatory properties, are able to fight spaceflight immune system dysregulations.Spaceflights lead to dysregulation of the immune cell functionality affecting the expression of activation markers and cytokine production. Short oxidized multi-walled carbon nanotubes functionalized by 1,3-dipolar cycloaddition have been reported to activate immune cells. In this Communication we have performed surface marker assays and multiplex ELISA on primary monocytes and T cells under microgravity. We have discovered that carbon nanotubes, through their immunostimulatory properties, are able to fight spaceflight immune system dysregulations. Electronic supplementary information (ESI) available: Experimental section, structures of f-MWCNTs and uptake by human primary immune cells. See DOI: 10.1039/c4nr02711f

Glycogen synthase kinase 3β promotes liver innate immune activation by restraining AMP-activated protein kinase activation.

PubMed

Zhou, Haoming; Wang, Han; Ni, Ming; Yue, Shi; Xia, Yongxiang; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

2018-07-01

Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo. We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model. Compared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients. Gsk3β promotes innate proinflammatory immune activation by restraining AMPK activation. Glycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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.

Vitamin A supplementation increases ratios of proinflammatory to anti-inflammatory cytokine responses in pregnancy and lactation

PubMed Central

Cox, S E; Arthur, P; Kirkwood, B R; Yeboah-Antwi, K; Riley, E M

2006-01-01

Vitamin A supplementation reduces child mortality in populations at risk of vitamin A deficiency and may also reduce maternal mortality. One possible explanation for this is that vitamin A deficiency is associated with altered immune function and cytokine dysregulation. Vitamin A deficiency in pregnancy may thus compound the pregnancy-associated bias of cellular immune responses towards Th-2-like responses and exacerbate susceptibility to intracellular pathogens. We assessed mitogen and antigen-induced cytokine responses during pregnancy and lactation in Ghanaian primigravidae receiving either vitamin A supplementation or placebo. This was a double-blind, randomized, placebo-controlled trial of weekly vitamin A supplementation in pregnant and lactating women. Pregnancy compared to postpartum was associated with a suppression of cytokine responses, in particular of the proinflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α. Mitogen-induced TNF-α responses were associated with a decreased risk of peripheral parasitaemia during pregnancy. Furthermore, vitamin A supplementation was significantly associated with an increased ratio of mitogen-induced proinflammatory cytokine (IFN-γ) to anti-inflammatory cytokine (IL-10) during pregnancy and in the postpartum period. The results of this study indicate that suppression of proinflammatory type 1 immune responses and hence immunity to intracellular infections, resulting from the combined effects of pregnancy and vitamin A deficiency, might be ameliorated by vitamin A supplementation. PMID:16734607

Characteristics of social drinkers with and without a hangover after heavy alcohol consumption.

PubMed

Hogewoning, A; Van de Loo, Ajae; Mackus, M; Raasveld, S J; De Zeeuw, R; Bosma, E R; Bouwmeester, N H; Brookhuis, K A; Garssen, J; Verster, J C

2016-01-01

A number of social drinkers claim that they do not experience next-day hangovers despite consuming large quantities of alcohol. The aim of this study was to investigate the characteristics of drinkers who claim to be hangover immune and compare them with drinkers who do report having hangovers. A total of 36 social drinkers participated in a naturalistic study consisting of a hangover day (alcohol consumed) and a control day (no alcohol consumed). Data were collected on alcohol consumption, demographics, sleep, next-day adverse effects, and mood. Data from drinkers with a hangover (N=18) were compared with data from drinkers who claim to be hangover immune (N=18). Drinkers with a hangover reported drowsiness-related symptoms, symptoms related to reduced cognitive functioning, and classic hangover symptoms such as headache, nausea, dizziness, weakness, and stomach pain. Corresponding mood changes comprised increased feelings of depression, anger-hostility, fatigue, and reduced vigor-activity. In contrast, hangover-immune drinkers reported relatively few hangover symptoms, with only mild corresponding severity scores. The reported symptoms were limited to drowsiness-related symptoms such as sleepiness and being tired. The classic hangover symptoms were usually not reported by these drinkers. In contrast to drinkers with a hangover, for those who claim to be hangover immune, next-day adverse effects of alcohol consumption are limited to a mild increase in drowsiness-related symptoms.

The receptor-like cytoplasmic kinase PCRK1 contributes to pattern-triggered immunity against Pseudomonas syringae in Arabidopsis thaliana.

PubMed

Sreekanta, Suma; Bethke, Gerit; Hatsugai, Noriyuki; Tsuda, Kenichi; Thao, Amanda; Wang, Lin; Katagiri, Fumiaki; Glazebrook, Jane

2015-07-01

In this paper we describe PATTERN-TRIGGERED IMMUNITY (PTI) COMPROMISED RECEPTOR-LIKE CYTOPLASMIC KINASE 1 (PCRK1) of Arabidopsis thaliana, an RLCK that is important for defense against the pathogen Pseudomonas syringae pv. maculicola ES4326 (Pma ES4326). We examined defense responses such as bacterial growth, production of reactive oxygen species (ROS) and callose deposition in pcrk1 mutant plants to determine the role of PCRK1 during pathogen infection. Expression of PCRK1 was induced following pathogen infection. Pathogen growth was significantly higher in pcrk1 mutant lines than in wild-type Col-0. Mutant pcrk1 plants showed reduced pattern-triggered immunity (PTI) against Pma ES4326 after pretreatment with peptides derived from flagellin (flg22), elongation factor-Tu (elf18), or an endogenous protein (pep1). Deposition of callose was reduced in pcrk1 plants, indicating a role of PCRK1 in activation of early immune responses. A PCRK1 transgene containing a mutation in a conserved lysine residue important for phosphorylation activity of kinases (K118E) failed to complement a pcrk1 mutant for the Pma ES4326 growth phenotype. Our study shows that PCRK1 plays an important role during PTI and that a conserved lysine residue in the putative kinase domain is important for PCRK1 function. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

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.

State-dependent physiological maintenance in a long-lived ectotherm, the painted turtle (Chrysemys picta).

PubMed

Schwanz, Lisa; Warner, Daniel A; McGaugh, Suzanne; Di Terlizzi, Roberta; Bronikowski, Anne

2011-01-01

Energy allocation among somatic maintenance, reproduction and growth varies not only among species, but among individuals according to states such as age, sex and season. Little research has been conducted on the somatic (physiological) maintenance of long-lived organisms, particularly ectotherms such as reptiles. In this study, we examined sex differences and age- and season-related variation in immune function and DNA repair efficiency in a long-lived reptile, the painted turtle (Chrysemys picta). Immune components tended to be depressed during hibernation, in winter, compared with autumn or spring. Increased heterophil count during hibernation provided the only support for winter immunoenhancement. In juvenile and adult turtles, we found little evidence for senescence in physiological maintenance, consistent with predictions for long-lived organisms. Among immune components, swelling in response to phytohemagglutinin (PHA) and control injection increased with age, whereas basophil count decreased with age. Hatchling turtles had reduced basophil counts and natural antibodies, indicative of an immature immune system, but demonstrated higher DNA repair efficiency than older turtles. Reproductively mature turtles had reduced lymphocytes compared with juvenile turtles in the spring, presumably driven by a trade-off between maintenance and reproduction. Sex had little influence on physiological maintenance. These results suggest that components of physiological maintenance are modulated differentially according to individual state and highlight the need for more research on the multiple components of physiological maintenance in animals of variable states.

Early Life Wildfire Smoke Exposure Is Associated with Immune Dysregulation and Lung Function Decrements in Adolescence

PubMed Central

Black, Carolyn; Gerriets, Joan E.; Fontaine, Justin H.; Harper, Richart W.; Kenyon, Nicholas J.; Tablin, Fern; Schelegle, Edward S.

2017-01-01

The long-term health effects of wildfire smoke exposure in pediatric populations are not known. The objectives of this study were to determine if early life exposure to wildfire smoke can affect parameters of immunity and airway physiology that are detectable with maturity. We studied a mixed-sex cohort of rhesus macaque monkeys that were exposed as infants to ambient wood smoke from a series of Northern California wildfires in the summer of 2008. Peripheral blood mononuclear cells (PBMCs) and pulmonary function measures were obtained when animals were approximately 3 years of age. PBMCs were cultured with either LPS or flagellin, followed by measurement of secreted IL-8 and IL-6 protein. PBMCs from a subset of female animals were also evaluated by Toll-like receptor (TLR) pathway mRNA analysis. Induction of IL-8 protein synthesis with either LPS or flagellin was significantly reduced in PBMC cultures from wildfire smoke–exposed female monkeys. In contrast, LPS- or flagellin-induced IL-6 protein synthesis was significantly reduced in PBMC cultures from wildfire smoke–exposed male monkeys. Baseline and TLR ligand–induced expression of the transcription factor, RelB, was globally modulated in PBMCs from wildfire smoke–exposed monkeys, with additional TLR pathway genes affected in a ligand-dependent manner. Wildfire smoke–exposed monkeys displayed significantly reduced inspiratory capacity, residual volume, vital capacity, functional residual capacity, and total lung capacity per unit of body weight relative to control animals. Our findings suggest that ambient wildfire smoke exposure during infancy results in sex-dependent attenuation of systemic TLR responses and reduced lung volume in adolescence. PMID:28208028

Tranexamic Acid Attenuates The Loss of Lung Barrier Function in a Rat Model of Polytrauma And Hemorrhage With Resuscitation.

PubMed

Wu, Xiaowu; Dubick, Michael A; Schwacha, Martin G; Cap, Andrew P; Darlington, Daniel N

2017-04-01

Severe trauma, hemorrhage, and resuscitation can lead to a trauma-related acute lung injury that involves rapid infiltration of immune cells and platelets. This infiltration involves exymatic degradation of matrix proteins, including plasmin, and causes loss of barrier function. Since tranexamic acid (TXA) inhibits plasminogen/ plasmin binding to target substrates, it may attenuate loss of barrier function after severe trauma, hemorrhage, and resuscitation. Sprague-Dawley rats were subjected to polytrauma (laparotomy, and trauma to intestines, liver, right leg skeletal muscle, and right femur fracture), then bled 40% of their blood volume. One hour after completion of polytrauma and hemorrhage, resuscitation was begun with fresh whole blood (FWB) or FWB with prior bolus administration of TXA (10 mg/kg in 0.2 mL). Polytrauma, hemorrhage, and resuscitation with FWB led to an elevation in lung water content that was significantly reduced with TXA administration. Polytrauma and hemorrhage led to rise in the number of neutrophils/monocytes and platelets in the lungs, and a rise in myeloperoxidase (MPO), neutrophil elastase and complement C5a content. While resuscitation with FWB significantly reduced the cellular infiltrate and MPO, FWB/TXA further reduced the levels of neutrophil/monocytes, neutrophil elastase, and complement C5a. Polytrauma and hemorrhage led to rise in lung plasmin activity that was significantly reduced with either FWB or FWB/TXA resuscitation. Severe trauma and hemorrhage leads to increases in lung water content, and immune cell, platelets, MPO, elastase, and C5a content in lung tissue, all markers of inflammation and acute lung injury. The addition of TXA to FWB resuscitation markedly attenuated the rise in these parameters suggesting its utility in treating acute lung injury.

HTLV-1 Tax-Specific CTL Epitope-Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax.

PubMed

Ando, Satomi; Hasegawa, Atsuhiko; Murakami, Yuji; Zeng, Na; Takatsuka, Natsuko; Maeda, Yasuhiro; Masuda, Takao; Suehiro, Youko; Kannagi, Mari

2017-02-01

Adult T cell leukemia/lymphoma (ATL), a CD4 + T cell malignancy with a poor prognosis, is caused by human T cell leukemia virus type 1 (HTLV-1) infection. High proviral load (PVL) is a risk factor for the progression to ATL. We previously reported that some asymptomatic carriers had severely reduced functions of CTLs against HTLV-1 Tax, the major target Ag. Furthermore, the CTL responses tended to be inversely correlated with PVL, suggesting that weak HTLV-1-specific CTL responses may be involved in the elevation of PVL. Our previous animal studies indicated that oral HTLV-1 infection, the major route of infection, caused persistent infection with higher PVL in rats compared with other routes. In this study, we found that Tax-specific CD8 + T cells were present, but not functional, in orally infected rats as observed in some human asymptomatic carriers. Even in the infected rats with immune unresponsiveness against Tax, Tax-specific CTL epitope-pulsed dendritic cell (DC) therapy reduced the PVL and induced Tax-specific CD8 + T cells capable of proliferating and producing IFN-γ. Furthermore, we found that monocyte-derived DCs from most infected individuals still had the capacity to stimulate CMV-specific autologous CTLs in vitro, indicating that DC therapy may be applicable to most infected individuals. These data suggest that peptide-pulsed DC immunotherapy will be useful to induce functional HTLV-1-specific CTLs and decrease PVL in infected individuals with high PVL and impaired HTLV-1-specific CTL responses, thereby reducing the risk of the development of ATL. Copyright © 2017 by The American Association of Immunologists, Inc.

Differential Regulatory Role of Pituitary Adenylate Cyclase–Activating Polypeptide in the Serum-Transfer Arthritis Model

PubMed Central

Botz, Bálint; Bölcskei, Kata; Kereskai, László; Kovács, Miklós; Németh, Tamás; Szigeti, Krisztián; Horváth, Ildikó; Máthé, Domokos; Kovács, Noémi; Hashimoto, Hitoshi; Reglődi, Dóra; Szolcsányi, János; Pintér, Erika; Mócsai, Attila; Helyes, Zsuzsanna

2014-01-01

Objective Pituitary adenylate cyclase–activating polypeptide (PACAP) expressed in capsaicin-sensitive sensory neurons and immune cells has divergent functions in inflammatory and pain processes. This study was undertaken to investigate the involvement of PACAP in a mouse model of rheumatoid arthritis. Methods Arthritis was induced in PACAP−/− and wild-type (PACAP+/+) mice by K/BxN serum transfer. General features of the disease were investigated by semiquantitative scoring, plethysmometry, and histopathologic analysis. Mechano- and thermonociceptive thresholds and motor functions were also evaluated. Metabolic activity was assessed by positron emission tomography. Bone morphology was measured by in vivo micro–computed tomography, myeloperoxidase activity and superoxide production by bioluminescence imaging with luminol and lucigenin, respectively, and vascular permeability by fluorescent indocyanine green dye study. Results PACAP+/+ mice developed notable joint swelling, reduced grasping ability, and mechanical (but not thermal) hyperalgesia after K/BxN serum transfer. In PACAP−/− mice clinical scores and edema were significantly reduced, and mechanical hyperalgesia and motor impairment were absent, throughout the 2-week period of observation. Metabolic activity and superoxide production increased in the tibiotarsal joints of wild-type mice but were significantly lower in PACAP−/− animals. Myeloperoxidase activity in the ankle joints of PACAP−/− mice was significantly reduced in the early phase of arthritis, but increased in the late phase. Synovial hyperplasia was also significantly increased, and progressive bone spur formation was observed in PACAP-deficient mice only. Conclusion In PACAP-deficient mice with serum-transfer arthritis, joint swelling, vascular leakage, hyperalgesia, and early inflammatory cell accumulation are reduced; in the later phase of the disease, immune cell function and bone neoformation are increased. Elucidation of the underlying pathways of PACAP activity may open promising new avenues for development of therapy in inflammatory arthritis. PMID:25048575

Splenectomy Fails to Provide Long-Term Protection Against Ischemic Stroke.

PubMed

Ran, Yuanyuan; Liu, Zongjian; Huang, Shuo; Shen, Jiamei; Li, Fengwu; Zhang, Wenxiu; Chen, Chen; Geng, Xiaokun; Ji, Zhili; Du, Huishan; Hu, Xiaoming

2018-06-01

Splenectomy before or immediately after stroke provides early brain protection. This study aims to explore the effect of splenectomy on long-term neurological recovery after stroke, which is currently lacking in the field. Adult male rats were randomized into splenectomy or sham groups and then subjected to 90 min of middle cerebral artery occlusion (MCAO). Spleen was removed right upon reperfusion or 3d after MCAO. Infarct volume, neurological functions, and peripheral immune cell populations were assessed up to 28d after stroke. The results show that delayed removal of spleen did not reduce brain tissue loss and showed no effect on sensorimotor function (Rotarod, beam balance, forelimb placing, grid walk, and adhesive removal tests) or cognitive function (Morris water maze). Spleen removal immediately upon reperfusion, although significantly reduced the infarct size and immune cell infiltration 3d after MCAO, also failed to promote long-term recovery. Flow cytometry analysis demonstrated that immediate splenectomy after MCAO resulted in a prolonged decrease in the percentage of CD3 + CD4 + and CD3 + CD8 + T cells in total lymphocytes as compared to non-splenectomy MCAO rats. In contrast, the percentage of CD3 - CD45RA + B cells was significantly elevated after splenectomy. As a result, the ratio of T/B cells was significantly reduced in stroke rats with splenectomy. In conclusion, delayed splenectomy failed to provide long-term protection to the ischemic brain or improve functional recovery. The acute neuroprotective effect achieved by early splenectomy after stroke cannot last for long term. This loss of neuroprotection might be related to the prolonged disturbance in the T cell to B cell ratio.

Adenovirus-mediated Foxp3 expression in lung epithelial cells reduces airway inflammation in ovalbumin and cockroach-induced asthma model

PubMed Central

Park, Soojin; Chung, Hwan-Suck; Shin, Dasom; Jung, Kyung-Hwa; Lee, Hyunil; Moon, Junghee; Bae, Hyunsu

2016-01-01

Foxp3 is a master regulator of CD4+CD25+ regulatory T-cell (Treg) function and is also a suppressor of SKP2 and HER2/ErbB2. There are an increasing number of reports describing the functions of Foxp3 in cell types other than Tregs. In this context, we evaluated the functions of Foxp3 in ovalbumin- and cockroach-induced asthma models. Foxp3-EGFP-expressing adenovirus or EGFP control adenovirus was administered intratracheally (i.t.), followed by challenge with ovalbumin (OVA) or cockroach extract to induce asthma. Th2 cytokine and immune cell profiles of bronchoalveolar lavage fluid (BALF), as well as serum IgE levels, were analyzed. Histological analyses were also conducted to demonstrate the effects of Foxp3 expression on airway remodeling, goblet cell hyperplasia and inflammatory responses in the lung. Adenoviral Foxp3 was expressed only in lung epithelial cells, and not in CD4+ or CD8+ cells. BALF from Foxp3 gene-delivered mice showed significantly reduced numbers of total immune cells, eosinophils, neutrophils, macrophages and lymphocytes in response to cockroach allergen or OVA. In addition, Foxp3 expression in the lung reduced the levels of Th2 cytokines and IgE in BALF and serum, respectively. Moreover, histopathological analysis also showed that Foxp3 expression substantially inhibited eosinophil infiltration into the airways, goblet cell hyperplasia and smooth muscle cell hypertrophy. Furthermore, when Tregs were depleted by diphtheria toxin in Foxp3DTR mice, the anti-asthmatic functions of Foxp3 were not altered in OVA-challenged asthma models. In this study, our results suggest that Foxp3 expression in lung epithelial cells, and not in Tregs, inhibited OVA- and cockroach extract-induced asthma. PMID:27633092

Contrasting Effects of Human, Canine, and Hybrid Adenovirus Vectors on the Phenotypical and Functional Maturation of Human Dendritic Cells: Implications for Clinical Efficacy▿

PubMed Central

Perreau, Matthieu; Mennechet, Franck; Serratrice, Nicolas; Glasgow, Joel N.; Curiel, David T.; Wodrich, Harald; Kremer, Eric J.

2007-01-01

Antipathogen immune responses create a balance between immunity, tolerance, and immune evasion. However, during gene therapy most viral vectors are delivered in substantial doses and are incapable of expressing gene products that reduce the host's ability to detect transduced cells. Gene transfer efficacy is also modified by the in vivo transduction of dendritic cells (DC), which notably increases the immunogenicity of virions and vector-encoded genes. In this study, we evaluated parameters that are relevant to the use of canine adenovirus serotype 2 (CAV-2) vectors in the clinical setting by assaying their effect on human monocyte-derived DC (hMoDC). We compared CAV-2 to human adenovirus (HAd) vectors containing the wild-type virion, functional deletions in the penton base RGD motif, and the CAV-2 fiber knob. In contrast to the HAd type 5 (HAd5)-based vectors, CAV-2 poorly transduced hMoDC, provoked minimal upregulation of major histocompatibility complex class I/II and costimulatory molecules (CD40, CD80, and CD86), and induced negligible morphological changes indicative of DC maturation. Functional maturation assay results (e.g., reduced antigen uptake; tumor necrosis factor alpha, interleukin-1β [IL-1β], gamma interferon [IFN-γ], IL-10, IL-12, and IFN-α/β secretion; and stimulation of heterologous T-cell proliferation) were also significantly lower for CAV-2. Our data suggested that this was due, in part, to the use of an alternative receptor and a block in vesicular escape. Additionally, HAd5 vector-induced hMoDC maturation was independent of the aforementioned cytokines. Paradoxically, an HAd5/CAV-2 hybrid vector induced the greatest phenotypical and functional maturation of hMoDC. Our data suggest that CAV-2 and the HAd5/CAV-2 vector may be the antithesis of Adenoviridae immunogenicity and that each may have specific clinical advantages. PMID:17229706

Distinct Effects of Monophosphoryl Lipid A, Oligodeoxynucleotide CpG, and Combination Adjuvants on Modulating Innate and Adaptive Immune Responses to Influenza Vaccination.

PubMed

Ko, Eun-Ju; Lee, Young-Tae; Lee, Youri; Kim, Ki-Hye; Kang, Sang-Moo

2017-10-01

Monophosphoryl lipid A (MPL) and oligodeoxynucleotide CpG are toll-like receptor (TLR) 4 and 9 agonist, respectively. Here, we investigated the effects of MPL, CpG, and combination adjuvants on stimulating in vitro dendritic cells (DCs), in vivo innate and adaptive immune responses, and protective efficacy of influenza vaccination. Combination of MPL and CpG was found to exhibit distinct effects on stimulating DCs in vitro to secrete IL-12p70 and tumor necrosis factor (TNF)-α and proliferate allogeneic CD8 T cells. Prime immunization of mice with inactivated split influenza vaccine in the presence of low dose MPL+CpG adjuvants increased the induction of virus-specific IgG and IgG2a isotype antibodies. MPL and CpG adjuvants contribute to improving the efficacy of prime influenza vaccination against lethal influenza challenge as determined by body weight monitoring, lung function, viral titers, and histology. A combination of MPL and CpG adjuvants was effective in improving vaccine efficacy as well as in reducing inflammatory immune responses locally and in inducing cellular immune responses upon lethal influenza virus challenge. This study demonstrates unique adjuvant effects of MPL, CpG, and combination adjuvants on modulating innate and adaptive immune responses to influenza prime vaccination.

Pineal-adrenal-immune system relationship under thermal stress: effect on physiological, endocrine, and non-specific immune response in goats.

PubMed

Sejian, Veerasamy; Srivastava, Rajendra Swaroop

2010-12-01

The purpose of the investigation was to observe the pineal-adrenal-immune system relationships and their influence on non-specific immune response in female goats under short-term thermal stress. Six female goats had been exposed to 40°C and 60% relative humidity in the psychrometric chamber for 17 days. Blood samples were obtained on days 0 and 10 to establish control and thermal stress effects, respectively. Chemical adrenalectomy was achieved by injecting metyrapone (100 mg/kg body weight) followed by exogenous melatonin treatment (0.1 mg/kg body weight) from 11th to 17th day of experiment. Thermal stress significantly (P≤0.05) altered the physiological responses. Metyrapone and melatonin treatment significantly (P≤0.05) reduced the thermal-stress-induced increase in plasma concentrations of cortisol and corticosterone while significantly (P≤0.05) increased the plasma melatonin on days 11 and 17. Furthermore, these treatments significantly (P<0.05) increased the phagocytic activity of neutrophils as compared to both control and thermal exposure values from 11-17 days of experiment. The data generated from this study help us to understand the functional relationship between pineal, adrenal, and immune system, and how this relationship modifies the non-specific immune response for the well being of goats during thermal stress.

Heat killed Saccharomyces cerevisiae as an adjuvant for the induction of vaccine-mediated immunity against infection with Mycobacterium tuberculosis.

PubMed

Grover, Ajay; McLean, Jennifer L; Troudt, JoLynn M; Foster, Chad; Izzo, Linda; Creissen, Elisabeth; MacDonald, Elisabeth; Troy, Amber; Izzo, Angelo A

2016-05-27

The use of novel vaccine delivery systems allows for the manipulation of the adaptive immune systems through the use of molecular adjuvants that target specific innate pathways. Such strategies have been used extensively for vaccines against cancer and multiple pathogens such as Mycobacterium tuberculosis. In the current study we used heat killed non-pathogenic recombinant Saccharomyces cerevisiae expressing M. tuberculosis antigen Rv1886c (fbpB, mpt59, Ag85B) as a delivery system in conjunction with its ability to stimulate innate immunity to determine its ability to induce immunity. We established that the recombinant yeast induced activated antigen specific T cells are capable of reducing the mycobacterial burden. Inoculation of the recombinant yeast after vaccination with BCG resulted in a systemic alteration of the phenotype of the immune response although this was not reflected in an increase in the reduction of the mycobacterial burden. Taken together the data suggest that heat killed yeast can induce multiple cytokines required for induction of protective immunity and can function as a vehicle for delivery of M. tuberculosis antigens in a vaccine formulation. In addition, while it can enhance the effector memory response induced by BCG, it had little effect on central memory responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Therapeutic application of human leukocyte antigen-G1 improves atopic dermatitis-like skin lesions in mice.

PubMed

Maeda, Naoyoshi; Yamada, Chisato; Takahashi, Ami; Kuroki, Kimiko; Maenaka, Katsumi

2017-09-01

Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that plays critical roles in immune response and in triggering inhibitory signaling to immune cells such as T cells, natural killer cells, and antigen-presenting cells. Thus, the application of HLA-G can be considered for treating immune response-related inflammatory disorders. We have previously reported that treatment with HLA-G1 and HLA-G2 ameliorates the joint swelling associated with collagen-induced arthritis of DBA/1 mice, an animal model for rheumatoid arthritis. In this study, we further investigated the effects of HLA-G1 on atopic dermatitis (AD), the most common inflammatory skin disorder. AD-like lesions were induced with the extract of the house dust mite Dermatophagoides farinae in NC/Nga mice. Continuous administration of HLA-G1 ameliorated the AD-like skin lesions in the mice. Furthermore, production of immunoglobulin E, interleukin (IL)-13, and IL-17A was significantly reduced in HLA-G1-treated mice, suggesting a Th2/Th17-mediated immune-inhibitory function of HLA-G1 in vivo. Our studies shed light on novel therapeutic strategies with recombinant HLA-G proteins for immune reaction-mediated chronic inflammatory disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Dual Proteolytic Pathways Govern Glycolysis and Immune Competence

PubMed Central

Lu, Wei; Zhang, Yu; McDonald, David O.; Jing, Huie; Carroll, Bernadette; Robertson, Nic; Zhang, Qian; Griffin, Helen; Sanderson, Sharon; Lakey, Jeremy H.; Morgan, Neil V.; Reynard, Louise N.; Zheng, Lixin; Murdock, Heardley M.; Turvey, Stuart E.; Hackett, Scott J.; Prestidge, Tim; Hall, Julie M.; Cant, Andrew J.; Matthews, Helen F.; Santibanez Koref, Mauro F.; Simon, Anna Katharina; Korolchuk, Viktor I.; Lenardo, Michael J.; Hambleton, Sophie; Su, Helen C.

2014-01-01

SUMMARY Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels, and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health. PMID:25525876

Independent and interactive effects of immune activation and larval diet on adult immune function, growth and development in the greater wax moth (Galleria mellonella).

PubMed

Kangassalo, Katariina; Valtonen, Terhi M; Sorvari, Jouni; Kecko, Sanita; Pölkki, Mari; Krams, Indrikis; Krama, Tatjana; Rantala, Markus J

2018-06-29

Organisms in the wild are likely to face multiple immune challenges as well as additional ecological stressors, yet their interactive effects on immune function are poorly understood. Insects are found to respond to cues of increased infection risk by enhancing their immune capacity. However, such adaptive plasticity in immune function may be limited by physiological and environmental constraints. Here, we investigated the effects of two environmental stressors - poor larval diet and an artificial parasite-like immune challenge at the pupal stage - on adult immune function, growth and development in the greater wax moth (Galleria mellonella). Males whose immune system was activated with an artificial parasite-like immune challenge had weaker immune response - measured as strength of encapsulation response - as adults compared to the control groups, but only when raised in high-nutrition larval diet. Immune activation did not negatively affect adult immune response in males reared in low-nutrition larval diet, indicating that poor larval diet improved the capacity of the insects to respond to repeated immune challenges. Low-nutrition larval diet also had a positive independent effect on immune capacity in females, yet it negatively affected development time and adult body mass in both sexes. As in the nature immune challenges are rarely isolated, and adverse nutritional environment may indicate an elevated risk of infection, resilience to repeated immune challenges as a response to poor nutritional environment could provide a significant fitness advantage. The present study highlights the importance of considering environmental context when investigating effects of immune activation in insects. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Longitudinal study of cellular and systemic cytokines signatures define the dynamics of a balanced immune environment in disease manifestation in Zika virus-infected patients.

PubMed

Lum, Fok-Moon; Lye, David C B; Tan, Jeslin J L; Lee, Bernett; Chia, Po-Ying; Chua, Tze-Kwang; Amrun, Siti N; Kam, Yiu-Wing; Yee, Wearn-Xin; Ling, Wei-Ping; Lim, Vanessa W X; Pang, Vincent J X; Lee, Linda K; Mok, Esther W H; Chong, Chia-Yin; Leo, Yee-Sin; Ng, Lisa F P

2018-04-16

The unexpected re-emergence of Zika virus (ZIKV) has caused numerous outbreaks globally. This study characterized the host immune responses during ZIKV infection. Patient samples were collected longitudinally during the acute, convalescence and recovery phases of ZIKV infection over 6 months during the Singapore outbreak in late 2016. Plasma immune mediators were profiled via multiplex micro-bead assay, while changes in blood cell numbers were determined with immune-phenotyping. Data showed the involvement of various immune mediators during acute ZIKV infection accompanied by a general reduction in blood cell numbers for all immune subsets except CD14+ monocytes. Importantly, viremic patients experiencing moderate symptoms had significantly higher quantities of IP-10, MCP-1, IL-1RA, IL-8 and PIGF-1, accompanied by reduced numbers of peripheral CD8+, CD4+ and DNT cells. Levels of T-cell associated mediators including IP-10, IFNγ, and IL-10 were high in recovery phases of ZIKV infection, suggesting a functional role for T-cells. The identification of different markers at specific disease phases emphasizes the dynamics of a balanced cytokine environment in disease progression. This is the first comprehensive study that highlights specific cellular changes and immune signatures during ZIKV disease progression and provides valuable insights into ZIKV immuno-pathogenesis.

A key requirement for CD300f in innate immune responses of eosinophils in colitis.

PubMed

Moshkovits, I; Reichman, H; Karo-Atar, D; Rozenberg, P; Zigmond, E; Haberman, Y; Ben Baruch-Morgenstern, N; Lampinen, M; Carlson, M; Itan, M; Denson, L A; Varol, C; Munitz, A

2017-01-01

Eosinophils are traditionally studied in the context of type 2 immune responses. However, recent studies highlight key innate immune functions for eosinophils especially in colonic inflammation. Surprisingly, molecular pathways regulating innate immune activities of eosinophil are largely unknown. We have recently shown that the CD300f is highly expressed by colonic eosinophils. Nonetheless, the role of CD300f in governing innate immune eosinophil activities is ill-defined. RNA sequencing of 162 pediatric Crohn's disease patients revealed upregulation of multiple Cd300 family members, which correlated with the presence of severe ulcerations and inflammation. Increased expression of CD300 family receptors was also observed in active ulcerative colitis (UC) and in mice following induction of experimental colitis. Specifically, the expression of CD300f was dynamically regulated in monocytes and eosinophils. Dextran sodium sulfate (DSS)-treated Cd300f -/- mice exhibit attenuated disease activity and histopathology in comparison with DSS-treated wild type (WT). Decreased disease activity in Cd300f -/- mice was accompanied with reduced inflammatory cell infiltration and nearly abolished production of pro-inflammatory cytokines. Monocyte depletion and chimeric bone marrow transfer experiments revealed a cell-specific requirement for CD300f in innate immune activation of eosinophils. Collectively, we uncover a new pathway regulating innate immune activities of eosinophils, a finding with significant implications in eosinophil-associated gastrointestinal diseases.

Curdlan blocks the immune suppression by myeloid-derived suppressor cells and reduces tumor burden.

PubMed

Rui, Ke; Tian, Jie; Tang, Xinyi; Ma, Jie; Xu, Ping; Tian, Xinyu; Wang, Yungang; Xu, Huaxi; Lu, Liwei; Wang, Shengjun

2016-08-01

Tumor-elicited immunosuppression is one of the essential mechanisms for tumor evasion of immune surveillance. It is widely thought to be one of the main reasons for the failure of tumor immunotherapy. Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of cells that play an important role in tumor-induced immunosuppression. These cells expand in tumor-bearing individuals and suppress T cell responses via various mechanisms. Curdlan, the linear (1 → 3)-β-glucan from Agrobacterium, has been applied in the food industry and other sectors. The anti-tumor property of curdlan has been recognized for a long time although the underlying mechanism still needs to be explored. In this study, we investigated the effect of curdlan on MDSCs and found that curdlan could promote MDSCs to differentiate into a more mature state and then significantly reduce the suppressive function of MDSCs, decrease the MDSCs in vivo and down-regulate the suppression in tumor-bearing mice, thus leading to enhanced anti-tumor immune responses. We, therefore, increase the understanding of further mechanisms by which curdlan achieves anti-tumor effects.

Divergent response profile in activated cord blood T cells from first-born child implies birth-order-associated in utero immune programming.

PubMed

Kragh, M; Larsen, J M; Thysen, A H; Rasmussen, M A; Wolsk, H M; Bisgaard, H; Brix, S

2016-03-01

First-born children are at higher risk of developing a range of immune-mediated diseases. The underlying mechanism of 'birth-order effects' on disease risk is largely unknown, but in utero programming of the child's immune system may play a role. We studied the association between birth order and the functional response of stimulated cord blood T cells. Purified cord blood T cells were polyclonally activated with anti-CD3-/anti-CD28-coated beads in a subgroup of 28 children enrolled in the COPSAC2010 birth cohort. Expression levels of seven activation markers on helper and cytotoxic T cells as well as the percentage of CD4(+) CD25(+) T cells were assessed by flow cytometry. Production of IFN-γ, TNF-α, IL-17, IL-4, IL-5, IL-13, and IL-10 was measured in the supernatants. IL-10 secretion (P = 0.007) and CD25 expression on CD4(+) helper T cells (P = 0.0003) in the activated cord blood T cells were selectively reduced in first-born children, while the percentage of circulating CD4(+) CD25(+) cord blood T cells was independent of birth order. First-born infants display a reduced anti-inflammatory profile in T cells at birth. This possible in utero 'birth-order' T-cell programming may contribute to later development of immune-mediated diseases by increasing overall immune reactivity in first-born children as compared to younger siblings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immune response to 60-day head-down bed rest

NASA Astrophysics Data System (ADS)

Song, Jinping; Guo, Aihua; Zhong, Ping; Zhang, Hongyu; Wu, Feng; Wan, Yumin; Bai, Yanqiang; Chen, Shanguang; Li, Yinghui

Introduction: Exposure of humans to spaceflight has resulted in disregulation of the immune system. Head-down bed rest (HDBR) has been extensively used as an earth-bound analog to study physiologic effects mimicking those occurring in weightlessness during spaceflight. It is uncertain how a prolonged period of bed rest affect human immune responses. The objective of this study was to investigate the effects of 60-day HDBR on immune function and EB virus reactivation in seven male volunteers. Methods: There were seven healthy male volunteers who were subjected to HDBR for 60d. Immunological parameters including leukocyte subset distribution, lymphocyte proliferation to mitogens, secreted cytokine profiles and EB virus reactivation were monitored. Results: Total WBC conunts increased significantly 10d post-HDBR as compared with pre-HDBR. At the same time, the relative percentage of neutrophils was also higher than pre-HDBR but not significant. MFI of CD11b in neutrophils was reduced obviously at thd end of HDBR. T Lymphocyte proliferations to PHA reduced at HDBR 30, HDBR 60 and 10d post-HDBR while IL-2 production decreased significantly at the same time. IFN-and IL-4 production trended to decrease at HDBR 30 and HDBR 60. The relative percentage of T lymphocyte subset, B lymphocyte and NK cells were not altered. EBV EA (early antigen) were negative and EBV VCA titers had no changes through HDBR. Conclusion: The results indicate that several immunological parameters (mainly cellular immunity) are altered significantly by prolonged HDBR, and these changes were similar to those happened in spaceflight.

Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications.

PubMed

Ish-Shalom, Eliran; Meirow, Yaron; Sade-Feldman, Moshe; Kanterman, Julia; Wang, Lynn; Mizrahi, Olga; Klieger, Yair; Baniyash, Michal

2016-01-01

Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases. Copyright © 2015 by The American Association of Immunologists, Inc.

Effects of prenatal yoga on women's stress and immune function across pregnancy: A randomized controlled trial.

PubMed

Chen, Pao-Ju; Yang, Luke; Chou, Cheng-Chen; Li, Chia-Chi; Chang, Yu-Cune; Liaw, Jen-Jiuan

2017-04-01

The effects of prenatal yoga on biological indicators have not been widely studied. Thus, we compared changes in stress and immunity salivary biomarkers from 16 to 36 weeks' gestation between women receiving prenatal yoga and those receiving routine prenatal care. For this longitudinal, prospective, randomized controlled trial, we recruited 94 healthy pregnant women at 16 weeks' gestation through convenience sampling from a prenatal clinic in Taipei. Participants were randomly assigned to intervention (n=48) or control (n=46) groups using Clinstat block randomization. The 20-week intervention comprised two weekly 70-min yoga sessions led by a midwife certified as a yoga instructor; the control group received only routine prenatal care. In both groups, participants' salivary cortisol and immunoglobulin A levels were collected before and after yoga every 4 weeks from 16 to 36 weeks' gestation. The intervention group had lower salivary cortisol (p<0.001) and higher immunoglobulin A (p<0.001) levels immediately after yoga than the control group. Specifically, the intervention group had significantly higher long-term salivary immunoglobulin A levels than the control group (p=0.018), and infants born to women in the intervention group weighed more than those born to the control group (p<0.001). Prenatal yoga significantly reduced pregnant women's stress and enhanced their immune function. Clinicians should learn the mechanisms of yoga and its effects on pregnant women. Our findings can guide clinicians to help pregnant women alleviate their stress and enhance their immune function. Copyright © 2017. Published by Elsevier Ltd.

Balance of flora, galt, and mucosal integrity.

PubMed

Hanaway, Patrick

2006-01-01

It is clear that there is a dynamic relationship involving the gastrointestinal flora, environmental inputs (food and other nutrients), and the health of the immune system. Recent research has taught us a great deal about the role of diet and commensal bacteria in promoting health. It appears that Nobel Laureate Eli Metchnikov may have been correct in his assertion that live bacterial cultures are "the elixir of life". We are unlocking a number of secrets about immune system functioning, but we keep coming back to a simple intervention that has an ever-expanding opus of research to support it, and an extremely low toxicity ratio. Future studies will help us to clarify the best strains and the best dosages for individual patients and specific conditions. Assessment of commensal flora and a genomic scan for markers of immunologic dysregulation will be more accurate and more widely available. It appears, however, that the diagnostic and therapeutic tools we have to work with today can make a tremendous difference in reducing the burden of suffering for our patients. If "form follows function," as Buckminster Fuller was fond of saying, then the form of our immune system may be following the precise functions that our commensal flora is dictating. We have the opportunity to encourage breastfeeding, decrease unnecessary antibiotic and antimicrobial usage (especially in the first two years of life), improve oral tolerance with a healthy n-6/n-3 fatty acid ratio, and support the development of a healthy commensal flora. These actions on behalf of our immune systems will pay dividends for years to come.

A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system.

PubMed

St Pierre, Cristina; Guo, Jane; Shin, John D; Engstrom, Laura W; Lee, Hyun-Hee; Herbert, Alan; Surdi, Laura; Baker, James; Salmon, Michael; Shah, Sanjiv; Ellis, J Michael; Houshyar, Hani; Crackower, Michael A; Kleinschek, Melanie A; Jones, Dallas C; Hicks, Alexandra; Zaller, Dennis M; Alves, Stephen E; Ramadas, Ravisankar A

2017-01-01

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.

Identification of Immune Traits Correlated with Dairy Cow Health, Reproduction and Productivity

PubMed Central

Banos, Georgios; Wall, Eileen; Coffey, Michael P.; Bagnall, Ainsley; Gillespie, Sandra; Russell, George C.; McNeilly, Tom N.

2013-01-01

Detailed biological analyses (e.g. epidemiological, genetic) of animal health and fitness in the field are limited by the lack of large-scale recording of individual animals. An alternative approach is to identify immune traits that are associated with these important functions and can be subsequently used in more detailed studies. We have used an experimental dairy herd with uniquely dense phenotypic data to identify a range of potentially useful immune traits correlated with enhanced (or depressed) health and fitness. Blood samples from 248 dairy cows were collected at two-monthly intervals over a 10-month period and analysed for a number of immune traits, including levels of serum proteins associated with the innate immune response and circulating leukocyte populations. Immune measures were matched to individual cow records related to productivity, fertility and disease. Correlations between traits were calculated using bivariate analyses based on animal repeatability and random regression models with a Bonferroni correction to account for multiple testing. A number of significant correlations were found between immune traits and other recorded traits including: CD4+:CD8+ T lymphocyte ratio and subclinical mastitis; % CD8+ lymphocytes and fertility; % CD335+ natural killer cells and lameness episodes; and serum haptoglobin levels and clinical mastitis. Importantly these traits were not associated with reduced productivity and, in the case of cellular immune traits, were highly repeatable. Moreover these immune traits displayed significant between-animal variation suggesting that they may be altered by genetic selection. This study represents the largest simultaneous analysis of multiple immune traits in dairy cattle to-date and demonstrates that a number of immune traits are associated with health events. These traits represent useful selection markers for future programmes aimed at improving animal health and fitness. PMID:23776543

Effects of the space flight environment on the immune system

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald; Butel, Janet S.; Shearer, William T.

2003-01-01

Space flight conditions have a dramatic effect on a variety of physiologic functions of mammals, including muscle, bone, and neurovestibular function. Among the physiological functions that are affected when humans or animals are exposed to space flight conditions is the immune response. The focus of this review is on the function of the immune system in space flight conditions during actual space flights, as well as in models of space flight conditions on the earth. The experiments were carried out in tissue culture systems, in animal models, and in human subjects. The results indicate that space flight conditions alter cell-mediated immune responses, including lymphocyte proliferation and subset distribution, and cytokine production. The mechanism(s) of space flight-induced alterations in immune system function remain(s) to be established. It is likely, however, that multiple factors, including microgravity, stress, neuroendocrine factors, sleep disruption, and nutritional factors, are involved in altering certain functions of the immune system. Such alterations could lead to compromised defenses against infections and tumors.

Long-term alterations in neuroimmune responses after neonatal exposure to lipopolysaccharide.

PubMed

Boissé, Lysa; Mouihate, Abdeslam; Ellis, Shaun; Pittman, Quentin J

2004-05-26

Fever is an integral part of the host's defense to infection that is orchestrated by the brain. A reduced febrile response is associated with reduced survival. Consequently, we have asked if early life immune exposure will alter febrile and neurochemical responses to immune stress in adulthood. Fourteen-day-old neonatal male rats were given Escherichia coli lipopolysaccharide (LPS) that caused either fever or hypothermia depending on ambient temperature. Control rats were given pyrogen-free saline. Regardless of the presence of neonatal fever, adult animals that had been neonatally exposed to LPS displayed attenuated fevers in response to intraperitoneal LPS but unaltered responses to intraperitoneal interleukin 1beta or intracerebroventricular prostaglandin E(2). The characteristic reduction in activity that accompanies fever was unaltered, however, as a function of neonatal LPS exposure. Treatment of neonates with an antigenically dissimilar LPS (Salmonella enteritidis) was equally effective in reducing adult responses to E. coli LPS, indicating an alteration in the innate immune response. In adults treated as neonates with LPS, basal levels of hypothalamic cyclooxygenase 2 (COX-2), determined by semiquantitative Western blot analysis, were significantly elevated compared with controls. In addition, whereas adult controls responded to LPS with the expected induction of COX-2, adults pretreated neonatally with LPS responded to LPS with a reduction in COX-2. Thus, neonatal LPS can alter CNS-mediated inflammatory responses in adult rats.

Memory T cells in organ transplantation: progress and challenges

PubMed Central

Espinosa, Jaclyn R.; Samy, Kannan P.; Kirk, Allan D.

2017-01-01

Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses. PMID:26923209

Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts).

PubMed

Gattoni, A; Parlato, A; Vangieri, B; Bresciani, M; Derna, R

2006-01-01

This review is aimed at exhaustively presenting and discussing the interferon-gamma (IFN-gamma), a cytokine that plays an important role in inducing and modulating an array of immune responses. A review of the most significant and recent clinical trials was performed. Although IFN-gamma has some antiviral activity, it is much less active in this regard than type I IFNs. IFN-gamma is involved in the regulation of nearly all phases of the immune and inflammatory responses, including the activation and differentiation of T cells, B cells, NK cells, macrophages, and others. It is therefore best regarded as a distint immunoregulatory cytokine. IFN-gamma secretion is a hallmark of Th1 lymphocytes. It is also secreted by nearly all CD8 T cells, by some Th0 cells, and by NK cells. Each of these cell types secretes IFN-gamma only when activated, usually as part of immune response and especially in response to IL-2 and IL-12. IFN-gamma production is inhibited by IL-4, IL-10, TGFbeta, glucocorticoids, cyclosporin A and FK506. Nearly all cell types express the heterodimeric receptor for IFN-beta and respond to this cytokine by increasing the surface expression of class I MHC proteins. As a result, virtually any cell in the vicinity of an IFN-beta-secreting cell becomes more efficient at presenting endogenous antigens and hence a better target for cytotoxic killing if it harbors an intracellular pathogen. Unlike the type I IFNs, IFN-gamma also increases the expression of class II MHC proteins on professional APCs, and so promotes antigen presentation to helper T cells as well. It also induces de novo expression of class II MHC proteins on venular endothelial cells and on some other epithelial and connective tissue cells that do not otherwise express them, thus enabling these cell types to function as temporary APCs at sites of intense immune reactions. The effector functions of NK cells are to lyse virus-infected cells and to secrete IFN-gamma, which activates macrofages to destroy phagocytosed microbes. The mechanism of NK cell-mediates cytolysis is essentially the same as that of cytolysis by CTLS. NK cells lyse virally infected cells before antigen specific CTLS came become fully active, that is, during the first few days after viral infection. NK cells are expanded and activated by cytokines of innate immunity, such as IL-12 and IL-15, and they kill infected cells, especially those that display reduced levels of class I molecoles. Some tumors, especially those of hematopoietic origin, are targets of NK cells, perlevels or types of class I MHC molecules. Therefore, IFN-gamma serves critical functions in innate immunity and in specific cell-mediated immunity (in addition, IFN activates neutrophilis and stimulates the cytolitic activity of NK cells). Many IFNs-gamma induced effects result in heigtened immune surveillance. IFN-gamma is a remarkable cytokine that orchestrates many distinct cellular programs through transcriptional control over large numbers of genes. Many IFNs-gamma-induced effects resulting in heightend immune surveillance and immune system function during infection have been discussed in this review. As the pathogens (microorganism with the potential to cause tissue injury or disease) augment local IFN-gamma production, and IFN-gamma augments the immune system response, an important function of IFN-gamma during in vivo infection is suggested. IFN-gamma is primarily secreted by activated T cells and natural killer cells, and can promote macrophage activation, mediate antiviral e antibacterial immunity, enhance antigen presentation, orchestrate activation of the innate immune system, coordinate lymphocyte-endothelium interaction, regulate Th1/Th2 balance, and control cellular proliferation and apoptosis.

Vitamin E-coated dialyzer membranes downregulate expression of monocyte adhesion and co-stimulatory molecules.

PubMed

Betjes, Michiel G H; Hoekstra, Franciska M E; Klepper, M; Postma, Saskia M; Vaessen, Leonard M B

2004-01-01

In patients on chronic hemodialysis leukocyte activation has been related to the impaired function of the immune system. In this study we investigated if the vitamin E-coated dialyzer membrane could reduce monocyte activation thereby improving cellular immunity. This hypothesis was tested in a prospective crossover trial in which 14 stable hemodialysis patients were switched from the baseline hemophane dialyzer to a vitamin E-coated and thereafter a polysulphone dialyzer membrane or vice versa. Monocyte MHC class I, CD54 and ICAM-1 expression was significantly downregulated when a vitamin E-coated or polysulphone dialyzer was used. The use of a vitamin E membrane specifically decreased monocyte CD40 and CD86 expression. Lectin induced T cell proliferation increased with the use of the vitamin E-coated membrane as compared to polysulphone and hemophane dialyzers. Vitamin E-coated dialyzers induced a less-activated phenotype of monocytes and may improve cellular immunity.

Group B Streptococcal Maternal Colonization and Neonatal Disease: Molecular Mechanisms and Preventative Approaches

PubMed Central

Patras, Kathryn A.; Nizet, Victor

2018-01-01

Group B Streptococcus (GBS) colonizes the gastrointestinal and vaginal epithelium of a significant percentage of healthy women, with potential for ascending intrauterine infection or transmission during parturition, creating a risk of serious disease in the vulnerable newborn. This review highlights new insights on the bacterial virulence determinants, host immune responses, and microbiome interactions that underpin GBS vaginal colonization, the proximal step in newborn infectious disease pathogenesis. From the pathogen perspective, the function GBS adhesins and biofilms, β-hemolysin/cytolysin toxin, immune resistance factors, sialic acid mimicry, and two-component transcriptional regulatory systems are reviewed. From the host standpoint, pathogen recognition, cytokine responses, and the vaginal mucosal and placental immunity to the pathogen are detailed. Finally, the rationale, efficacy, and potential unintended consequences of current universal recommended intrapartum antibiotic prophylaxis are considered, with updates on new developments toward a GBS vaccine or alternative approaches to reducing vaginal colonization. PMID:29520354

Curcumin prevents human dendritic cell response to immune stimulants

PubMed Central

Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

2012-01-01

Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14+ monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing naïve CD4+ T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant. PMID:18639521

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

Curcumin prevents human dendritic cell response to immune stimulants

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

Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.

2008-09-26

Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14{sup +} monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays weremore » performed. Curcumin prevents DCs from responding to immunostimulants and inducing CD4{sup +} T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant.« less

Brain–immune interactions and the neural basis of disease-avoidant ingestive behaviour

PubMed Central

Pacheco-López, Gustavo; Bermúdez-Rattoni, Federico

2011-01-01

Neuro–immune interactions are widely manifested in animal physiology. Since immunity competes for energy with other physiological functions, it is subject to a circadian trade-off between other energy-demanding processes, such as neural activity, locomotion and thermoregulation. When immunity is challenged, this trade-off is tilted to an adaptive energy protecting and reallocation strategy that is identified as ‘sickness behaviour’. We review diverse disease-avoidant behaviours in the context of ingestion, indicating that several adaptive advantages have been acquired by animals (including humans) during phylogenetic evolution and by ontogenetic experiences: (i) preventing waste of energy by reducing appetite and consequently foraging/hunting (illness anorexia), (ii) avoiding unnecessary danger by promoting safe environments (preventing disease encounter by olfactory cues and illness potentiation neophobia), (iii) help fighting against pathogenic threats (hyperthermia/somnolence), and (iv) by associative learning evading specific foods or environments signalling danger (conditioned taste avoidance/aversion) and/or at the same time preparing the body to counteract by anticipatory immune responses (conditioning immunomodulation). The neurobiology behind disease-avoidant ingestive behaviours is reviewed with special emphasis on the body energy balance (intake versus expenditure) and an evolutionary psychology perspective. PMID:22042916

Effect of Punica granatum solvent extracts on immune system and disease resistance in Paralichthys olivaceus against lymphocystis disease virus (LDV).

PubMed

Harikrishnan, Ramasamy; Heo, Jaehyun; Balasundaram, Chellam; Kim, Man-Chul; Kim, Ju-Sang; Han, Yong-Jae; Heo, Moon-Soo

2010-10-01

We report the effect of aqueous, ethanol, and methanol solvent leaf extracts of Punica granatum on innate immune mechanisms, such as phagocytosis activity, respiratory burst activity, alternative complement activity, lysozyme activity and functional immunity in terms of percentage cumulative mortality and Relative Percent Survival (RPS) in olive flounder Paralichthys olivaceus naturally infected with lymphocystis disease virus (LDV) after 8 weeks. Infected fish were intraperitoneally administered with 0, 5, 50, and 100 mg kg(-1) body weight of solvent extracts. In groups treated with 50 and 100 mg kg(-1) body weight, the chosen innate immune parameters significantly increased after 8 weeks when compared to 0 mg kg(-1) dose, but not with 5 mg kg(-1). Administration of P. granatum solvent extracts for 8 weeks significantly reduced the percentage mortality with the consequent increase in RPS. The results suggest that intraperitoneal administration of the leaf extracts of P. granatum at 50 or 100 mg kg(-1) dose clearly enhance the innate immune responses and disease resistance after 8 weeks in P. olivaceus against natural LDV infection. Published by Elsevier Ltd.

Functional relevance of intestinal epithelial cells in inflammatory bowel disease.

PubMed

Okamoto, Ryuichi; Watanabe, Mamoru

2016-01-01

The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a "hub" which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually "depleted" in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.

Nuclear pore complex component MOS7/Nup88 is required for innate immunity and nuclear accumulation of defense regulators in Arabidopsis.

PubMed

Cheng, Yu Ti; Germain, Hugo; Wiermer, Marcel; Bi, Dongling; Xu, Fang; García, Ana V; Wirthmueller, Lennart; Després, Charles; Parker, Jane E; Zhang, Yuelin; Li, Xin

2009-08-01

Plant immune responses depend on dynamic signaling events across the nuclear envelope through nuclear pores. Nuclear accumulation of certain resistance (R) proteins and downstream signal transducers are critical for their functions, but it is not understood how these processes are controlled. Here, we report the identification, cloning, and analysis of Arabidopsis thaliana modifier of snc1,7 (mos7-1), a partial loss-of-function mutation that suppresses immune responses conditioned by the autoactivated R protein snc1 (for suppressor of npr1-1, constitutive 1). mos7-1 single mutant plants exhibit defects in basal and R protein-mediated immunity and in systemic acquired resistance but do not display obvious pleiotropic defects in development, salt tolerance, or plant hormone responses. MOS7 is homologous to human and Drosophila melanogaster nucleoporin Nup88 and resides at the nuclear envelope. In animals, Nup88 attenuates nuclear export of activated NF-kappaB transcription factors, resulting in nuclear accumulation of NF-kappaB. Our analysis shows that nuclear accumulation of snc1 and the defense signaling components Enhanced Disease Susceptibility 1 and Nonexpresser of PR genes 1 is significantly reduced in mos7-1 plants, while nuclear retention of other tested proteins is unaffected. The data suggest that specifically modulating the nuclear concentrations of certain defense proteins regulates defense outputs.

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.

T CELL REPLICATIVE SENESCENCE IN HUMAN AGING

PubMed Central

Chou, Jennifer P.; Effros, Rita B.

2013-01-01

The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of pro-inflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has far-reaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad. PMID:23061726

TmCactin plays an important role in Gram-negative and -positive bacterial infection by regulating expression of 7 AMP genes in Tenebrio molitor

PubMed Central

Jo, Yong Hun; Jung Kim, Yu; Beom Park, Ki; Hwan Seong, Jeong; Gon Kim, Soo; Park, Soyi; Young Noh, Mi; Seok Lee, Yong; Soo Han, Yeon

2017-01-01

Cactin was originally identified as an interactor of the Drosophila IκB factor Cactus and shown to play a role in controlling embryonic polarity and regulating the NF-κB signaling pathway. While subsequent studies have identified the roles for Cactin in the mammalian immune response, the immune function of Cactin in insects has not been described yet. Here, we identified a Cactin gene from the mealworm beetle, Tenebrio molitor (TmCactin) and characterized its functional role in innate immunity. TmCactin was highly expressed in prepupa to last instar stages, and its expression was high in the integument and Malpighian tubules of last instar larvae and adults. TmCactin was induced in larvae after infection with different pathogens and detectable within 3 hours of infection. The highest levels of TmCactin expression were detected at 9 hours post infection. TmCactin RNAi significantly decreased the survival rates of larvae after challenge with Escherichia coli and Staphylococcus aureus, but had no significant effect after challenge with Candida albicans. Furthermore, TmCactin RNAi significantly reduced the expression of seven antimicrobial peptide genes (AMPs) after bacterial challenge. Our results suggest that TmCactin may serve as an important regulator of innate immunity, mediating AMP responses against both Gram-positive and Gram-negative bacteria in T. molitor. PMID:28418029

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.

Gold kiwifruit ( Actinidia chinensis 'Hort16A') for immune support.

PubMed

Skinner, Margot A; Loh, Jacelyn M S; Hunter, Denise C; Zhang, Jingli

2011-05-01

Kiwifruit is a good source of several vitamins and minerals and dietary fibre, and contains a number of phytochemicals; so kiwifruit potentially provides health benefits beyond basic nutrition. Consumption of green kiwifruit can have positive effects on cardiovascular health through antioxidant activity, inhibition of platelet aggregation and lowered TAG levels, and gut health through improving laxation, aiding digestion and promoting a healthy gut microflora. The importance of nutrition on immune function is well recognised, with deficiencies in vitamins A, C, E, B6 and B12, folic acid, Zn, Cu, Fe and Se being associated with impaired immune function and increased susceptibility to diseases. Evidence is growing that kiwifruit enhances immunity, with several small murine studies showing enhancement of innate and adaptive immune function. Few studies have examined the effect of kiwifruit on immune function in human subjects, but a recent study has revealed that kiwifruit up-regulates several 'immune' and 'DNA and repair'-related gene sets, and down-regulates one gene set related to Ig secretion. Taken together, the evidence from the literature provides supporting data for designing a human intervention trial to validate the ability of kiwifruit to support immune function in healthy and immunocompromised populations.

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

Spector, June T., E-mail: spectj@uw.edu; Department of Medicine, School of Medicine, University of Washington, Seattle, WA; De Roos, Anneclaire J., E-mail: ajd335@drexel.edu

Background: Polychlorinated biphenyl (PCB) exposure has been associated with non-Hodgkin lymphoma in several studies, and the immune system is a potential mediator. Objectives: We analyzed associations of plasma PCBs with immune function measures. We hypothesized that higher plasma PCB concentrations are associated with lower immune function cross-sectionally, and that increases in PCB concentrations over a one year period are associated with decreases in immune function. Methods: Plasma PCB concentrations and immune function [natural killer (NK) cell cytotoxicity and PHA-induced T-lymphocyte proliferation (PHA-TLP)] were measured at baseline and one year in 109 postmenopausal overweight women participating in an exercise intervention studymore » in the Seattle, Washington (USA) area. Mixed models, with adjustment for body mass index and other potential confounders, were used to estimate associations of PCBs with immune function cross-sectionally and longitudinally. Results: Associations of PCBs with immune function measures differed across groups of PCBs (e.g., medium- and high-chlorinated and dioxin-like [mono-ortho-substituted]) and by the time frame for the comparison (cross-sectional vs. longitudinal). Higher concentrations of medium- and high-chlorinated PCBs were associated with higher PHA-TLP cross-sectionally but not longitudinally. The mean decrease in 0.5 µg/mL PHA-TLP/50.0 pmol/g-lipid increase in dioxin-like PCBs over one year was 51.6 (95% confidence interval 2.7, 100.5; P=0.039). There was no association between plasma PCBs and NK cytotoxicity. Conclusions: These results do not provide strong evidence of impaired cellular immunity from PCB exposure. Larger longitudinal studies with greater variability in PCB exposures are needed to further examine temporal associations of PCBs with immune function. - Highlights: • Plasma PCBs and immune function were measured in 109 women at baseline and one year. • Immune measures included T lymphocyte proliferation (TLP) and NK cell cytotoxicity. • Higher-chlorinated PCBs were positively associated with TLP in cross-section. • An increase in dioxin-like PCBs was associated with a decrease in TLP over one year. • We did not find strong evidence of impaired cellular immunity from PCB exposure.« less

Impaired intestinal immune barrier and physical barrier function by phosphorus deficiency: Regulation of TOR, NF-κB, MLCK, JNK and Nrf2 signalling in grass carp (Ctenopharyngodon idella) after infection with Aeromonas hydrophila.

PubMed

Chen, Kang; Zhou, Xiao-Qiu; Jiang, Wei-Dan; Wu, Pei; Liu, Yang; Jiang, Jun; Kuang, Sheng-Yao; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Feng, Lin

2018-03-01

In aquaculture, the occurrence of enteritis has increased and dietary nutrition is considered as one of the major strategies to solve this problem. In the present study, we assume that dietary phosphorus might enhance intestinal immune barrier and physical barrier function to reduce the occurrence of enteritis in fish. To test this assumption, a total of 540 grass carp (Ctenopharyngodon idella) were investigated by feeding graded levels of available phosphorus (0.95-8.75 g/kg diet) and then infection with Aeromonas hydrophila. The results firstly showed that phosphorus deficiency decreased the ability to combat enteritis, which might be related to the impairment of intestinal immune barrier and physical barrier function. Compared with optimal phosphorus level, phosphorus deficiency decreased fish intestinal antimicrobial substances activities or contents and down-regulated antimicrobial peptides mRNA levels leading to the impairment of intestinal immune response. Phosphorus deficiency down-regulated fish intestinal anti-inflammatory cytokines mRNA levels and up-regulated the mRNA levels of pro-inflammatory cytokines [except IL-1β and IL-12p35 in distal intestine (DI) and IL-12p40] causing aggravated of intestinal inflammatory responses, which might be related to the signalling molecules target of rapamycin and nuclear factor kappa B. In addition, phosphorus deficiency disturbed fish intestinal tight junction function and induced cell apoptosis as well as oxidative damage leading to impaired of fish intestinal physical barrier function, which might be partially associated with the signalling molecules myosin light chain kinase, c-Jun N-terminal protein kinase and NF-E2-related factor 2, respectively. Finally, based on the ability to combat enteritis, dietary available phosphorus requirement for grass carp (254.56-898.23 g) was estimated to be 4.68 g/kg diet. Copyright © 2017. Published by Elsevier Ltd.

Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer

PubMed Central

Gupta, Harshita B; Clark, Curtis A; Yuan, Bin; Sareddy, Gangadhara; Pandeswara, Srilakshmi; Padron, Alvaro S; Hurez, Vincent; Conejo-Garcia, José; Vadlamudi, Ratna; Li, Rong; Curiel, Tyler J

2016-01-01

As tumor PD-L1 provides signals to anti-tumor PD-1+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor-initiating cells (TICs) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TICs express more PD-L1 versus non-TICs. Silencing PD-L1 in B16 and ID8agg cells by shRNA (‘PD-L1lo’) reduced TIC numbers, the canonical TIC genes nanog and pou5f1 (oct4), and functions as assessed by tumorosphere development, immune-dependent and immune-independent tumorigenesis, and serial transplantability in vivo. Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, tumor-intrinsic PD-L1 signals promote TIC generation and virulence, possibly by promoting canonical TIC gene expression, suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses. PMID:28798885

Imagining 'reactivity': allergy within the history of immunology.

PubMed

Jamieson, Michelle

2010-12-01

An allergy is commonly understood to be an overreaction of the immune system to harmless substances that are misrecognised as foreign. This concept of allergy as an abnormal, misdirected immune response-a biological fault-stems from the idea that the immune system is an inherently defensive operation designed to protect the individual through an innate capacity to discriminate between the benign and toxic, or self and nonself. However, this definition of allergy represents a radical departure from its original formulation. Literally meaning 'altered reactivity', the term was coined in 1906 by Austrian paediatrician Clemens von Pirquet, to describe the fundamentally mutable nature of the immune response. This paper argues that the conventional interpretation of allergy-as-pathology derives from specific concepts of 'organism', 'response', and 'normal' immune function that have-for over a century-governed the perception and study of immune phenomena within immunology. Through an examination of Louis Pasteur's conceptualisation of the host body/microorganism relationship, I argue that immunology is founded on a view of the organism as a discrete, autonomous entity, and on a concomitant notion of the immune response as essentially reactive. Revisiting the concept of 'altered reactivity', this paper points to the fact that allergy was initially posited as a general theory of immune responsiveness and, importantly, one that poses a significant challenge to orthodox notions of immunopathology. It suggests that Pirquet's unique view of immune responsiveness presents an account of organismic or biological identity that encapsulates, rather than reduces, its ecological complexity. Copyright © 2010 Elsevier Ltd. All rights reserved.

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.

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

MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2.

PubMed

Zhou, Yu; Song, Yan; Shaikh, Zahir; Li, Hui; Zhang, Haiju; Caudle, Yi; Zheng, Shouhua; Yan, Hui; Hu, Dan; Stuart, Charles; Yin, Deling

2017-07-18

Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.

Effectiveness of aromatherapy with light thai massage for cellular immunity improvement in colorectal cancer patients receiving chemotherapy.

PubMed

Khiewkhern, Santisith; Promthet, Supannee; Sukprasert, Aemkhea; Eunhpinitpong, Wichai; Bradshaw, Peter

2013-01-01

Patients with colorectal cancer are usually treated with chemotherapy, which reduces the number of blood cells, especially white blood cells, and consequently increases the risk of infections. Some research studies have reported that aromatherapy massage affects the immune system and improves immune function by, for example, increasing the numbers of natural killer cells and peripheral blood lymphocytes. However, there has been no report of any study which provided good evidence as to whether aromatherapy with Thai massage could improve the immune system in patients with colorectal cancer. The objectives of this study were to determine whether the use of aromatherapy with light Thai massage in patients with colorectal cancer, who have received chemotherapy, can result in improvement of the cellular immunity and reduce the severity of the common symptoms of side effects. Sixty-six patients with colorectal cancer in Phichit Hospital, Thailand, were enrolled in a single-blind, randomised-controlled trial. The intervention consisted of three massage sessions with ginger and coconut oil over a 1-week period. The control group received standard supportive care only. Assessments were conducted at pre-assessment and at the end of one week of massage or standard care. Changes from pre-assessment to the end of treatment were measured in terms of white blood cells, neutrophils, lymphocytes, CD4 and CD8 cells and the CD4/CD8 ratio and also the severity of self-rated symptom scores. The main finding was that after adjusting for pre-assessment values the mean lymphocyte count at the post-assessment was significantly higher (P=0.04) in the treatment group than in the controls. The size of this difference suggested that aromatherapy with Thai massage could boost lymphocyte numbers by 11%. The secondary outcomes were that at the post assessment the symptom severity scores for fatigue, presenting symptom, pain and stress were significantly lower in the massage group than in the standard care controls. Aromatherapy with light Thai massage can be beneficial for the immune systems of cancer patients who are undergoing chemotherapy by increasing the number of lymphocytes and can help to reduce the severity of common symptoms.

Lymphocyte function following radioiodine therapy in patients with thyroid carcinoma.

PubMed

Barsegian, V; Müller, S P; Horn, P A; Bockisch, A; Lindemann, M

2011-01-01

Since the nuclear disaster in Fukushima has raised great concern about the danger of radioactivity, we here addressed the question if the therapeutic use of iodine 131, the most frequently applied radionuclide, was harmful to immune function in patients. It was our aim to define for the first time in a clinical setting how radioiodine therapy alters anti-microbial immune responses. In 21 patients with thyroid carcinoma anti-microbial lymphocyte responses were assessed by lymphocyte transformation test and ELISpot - measuring lymphocyte proliferation and on a single cell level production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) - prior to therapy, at day 1 and day 7 post therapy. Proliferative lymphocyte responses and interferon-γ production after in vitro stimulation with microbial antigens were significantly (p < 0.05) increased at day 1 vs. pre therapy, and returned to pre therapy levels at day 7. On the contrary, at day 1 interleukin-10 production was significantly (p < 0.05) reduced. Thus, we observed a short-term increase in pro-inflammatory immune responses. However, T lymphocyte responses were in the range of healthy controls at all three time points. Thyroid carcinoma patients receiving radioiodine therapy do not display any sign of immunosuppression.

Arginine methylation catalyzed by PRMT1 is required for B cell activation and differentiation.

PubMed

Infantino, Simona; Light, Amanda; O'Donnell, Kristy; Bryant, Vanessa; Avery, Danielle T; Elliott, Michael; Tangye, Stuart G; Belz, Gabrielle; Mackay, Fabienne; Richard, Stephane; Tarlinton, David

2017-10-12

Arginine methylation catalyzed by protein arginine methyltransferases (PRMT) is a common post-translational modification in mammalian cells, regulating many important functions including cell signalling, proliferation and differentiation. Here we show the role of PRMT1 in B-cell activation and differentiation. PRMT1 expression and activity in human and mouse peripheral B cells increases in response to in vitro or in vivo activation. Deletion of the Prmt1 gene in mature B cells establishes that although the frequency and phenotype of peripheral B cell subsets seem unaffected, immune responses to T-cell-dependent and -independent antigens are substantially reduced. In vitro activation of Prmt1-deficient B cells with a variety of mitogens results in diminished proliferation, differentiation and survival, effects that are correlated with altered signal transduction from the B cell receptor. Thus PRMT1 activity in B cells is required for correct execution of multiple processes that in turn are necessary for humoral immunity.PRMT1 is an arginine methyltransferase involved in a variety of cell functions. Here the authors delete PRMT1 specifically in mature B cells to show the importance of arginine methylation for B cell proliferation, differentiation and survival, and thereby for humoral immunity.

Immune function in Amazonian horticulturalists

PubMed Central

Blackwell, Aaron D.; Trumble, Benjamin C.; Suarez, Ivan Maldonado; Stieglitz, Jonathan; Beheim, Bret; Snodgrass, J. Josh; Kaplan, Hillard; Gurven, Michael

2016-01-01

Background Amazonian populations are exposed to diverse parasites and pathogens, including protozoal, bacterial, fungal, and helminthic infections. Yet much of our understanding of the immune system is based on industrialised populations where these infections are relatively rare. Aim We examine distributions and age-related differences in 22 measures of immune function for Bolivian forager-horticulturalists and US and European populations. Subjects and Methods Subjects were 6,338 Tsimane aged 0–90 years. Blood samples collected between 2004–2014 were analysed for 5-part blood differentials, C-reactive protein, erythrocyte sedimentation rate (ESR), and total immunoglobulins E, G, A, and M. Flow cytometry was used to quantify naive and non-naïve CD4 and CD8 T cells, natural killer cells, and B cells. Results Compared to reference populations, Tsimane have elevated levels of most immunological parameters, particularly immunoglobulins, eosinophils, ESR, B cells, and natural killer cells. However, monocytes and basophils are reduced and naïve CD4 cells depleted in older age groups. Conclusion Tsimane ecology leads to lymphocyte repertoires and immunoglobulin profiles that differ from those observed in industrialised populations. These differences have consequences for disease susceptibility and co-vary with patterns of other life history traits, such as growth and reproduction. PMID:27174705

Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells

PubMed Central

2012-01-01

Background We recently isolated and identified Zizimin2 as a functional factor that is highly expressed in murine splenic germinal center B cells after immunization with T-cell-dependent antigen. Zizimin2 was revealed to be a new family member of Dock (dedicator of cytokinesis), Dock11, which is the guanine nucleotide exchange factor for Cdc42, a low-molecular-weight GTPase. However, the molecular function of Zizimin2 in acquired immunity has not been elucidated. Results In this study, we show that the protein expression of Zizimin2, which is also restricted to lymphoid tissues and lymphocytes, is reduced in aged mice. Over-expression of full-length Zizimin2 induced filopodial formation in 293T cells, whereas expression of CZH2 domain inhibited it. Stimulation of Fcγ receptor and Toll-like receptor 4 triggered Zizimin2 up-regulation and Cdc42 activation in bone marrow-derived dendritic cells. Conclusions These data suggest that Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration. PMID:22494997

Serotonin modulates insect hemocyte phagocytosis via two different serotonin receptors

PubMed Central

Qi, Yi-xiang; Huang, Jia; Li, Meng-qi; Wu, Ya-su; Xia, Ren-ying; Ye, Gong-yin

2016-01-01

Serotonin (5-HT) modulates both neural and immune responses in vertebrates, but its role in insect immunity remains uncertain. We report that hemocytes in the caterpillar, Pieris rapae are able to synthesize 5-HT following activation by lipopolysaccharide. The inhibition of a serotonin-generating enzyme with either pharmacological blockade or RNAi knock-down impaired hemocyte phagocytosis. Biochemical and functional experiments showed that naive hemocytes primarily express 5-HT1B and 5-HT2B receptors. The blockade of 5-HT1B significantly reduced phagocytic ability; however, the blockade of 5-HT2B increased hemocyte phagocytosis. The 5-HT1B-null Drosophila melanogaster mutants showed higher mortality than controls when infected with bacteria, due to their decreased phagocytotic ability. Flies expressing 5-HT1B or 5-HT2B RNAi in hemocytes also showed similar sensitivity to infection. Combined, these data demonstrate that 5-HT mediates hemocyte phagocytosis through 5-HT1B and 5-HT2B receptors and serotonergic signaling performs critical modulatory functions in immune systems of animals separated by 500 million years of evolution. DOI: http://dx.doi.org/10.7554/eLife.12241.001 PMID:26974346

Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome.

PubMed

Matsubara, Ryuma; Aonuma, Hiroka; Kojima, Mikiko; Tahara, Michiru; Andrabi, Syed Bilal Ahmad; Sakakibara, Hitoshi; Nagamune, Kisaburo

2015-01-01

The apicomplexan parasite Toxoplasma gondii produces the plant hormone abscisic acid, but it is unclear if phytohormones are produced by the malaria parasite Plasmodium spp., the most important parasite of this phylum. Here, we report detection of salicylic acid, an immune-related phytohormone of land plants, in P. berghei ANKA and T. gondii cell lysates. However, addition of salicylic acid to P. falciparum and T. gondii culture had no effect. We transfected P. falciparum 3D7 with the nahG gene, which encodes a salicylic acid-degrading enzyme isolated from plant-infecting Pseudomonas sp., and established a salicylic acid-deficient mutant. The mutant had a significantly decreased concentration of parasite-synthesized prostaglandin E2, which potentially modulates host immunity as an adaptive evolution of Plasmodium spp. To investigate the function of salicylic acid and prostaglandin E2 on host immunity, we established P. berghei ANKA mutants expressing nahG. C57BL/6 mice infected with nahG transfectants developed enhanced cerebral malaria, as assessed by Evans blue leakage and brain histological observation. The nahG-transfectant also significantly increased the mortality rate of mice. Prostaglandin E2 reduced the brain symptoms by induction of T helper-2 cytokines. As expected, T helper-1 cytokines including interferon-γ and interleukin-2 were significantly elevated by infection with the nahG transfectant. Thus, salicylic acid of Plasmodium spp. may be a new pathogenic factor of this threatening parasite and may modulate immune function via parasite-produced prostaglandin E2.

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.

Regulatory role of Vγ1 γδ T cells in tumor immunity through IL-4 production.

PubMed

Hao, Jianlei; Dong, Siyuan; Xia, Siyuan; He, Weifeng; Jia, Hao; Zhang, Song; Wei, Jun; O'Brien, Rebecca L; Born, Willi K; Wu, Zhenzhou; Wang, Puyue; Han, Jihong; Hong, Zhangyong; Zhao, Liqing; Yin, Zhinan

2011-11-15

It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti-IL-4 Ab or IL-4(-/-) mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4-mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.

Plant Hormone Salicylic Acid Produced by a Malaria Parasite Controls Host Immunity and Cerebral Malaria Outcome

PubMed Central

Matsubara, Ryuma; Aonuma, Hiroka; Kojima, Mikiko; Tahara, Michiru; Andrabi, Syed Bilal Ahmad; Sakakibara, Hitoshi; Nagamune, Kisaburo

2015-01-01

The apicomplexan parasite Toxoplasma gondii produces the plant hormone abscisic acid, but it is unclear if phytohormones are produced by the malaria parasite Plasmodium spp., the most important parasite of this phylum. Here, we report detection of salicylic acid, an immune-related phytohormone of land plants, in P. berghei ANKA and T. gondii cell lysates. However, addition of salicylic acid to P. falciparum and T. gondii culture had no effect. We transfected P. falciparum 3D7 with the nahG gene, which encodes a salicylic acid-degrading enzyme isolated from plant-infecting Pseudomonas sp., and established a salicylic acid-deficient mutant. The mutant had a significantly decreased concentration of parasite-synthesized prostaglandin E2, which potentially modulates host immunity as an adaptive evolution of Plasmodium spp. To investigate the function of salicylic acid and prostaglandin E2 on host immunity, we established P. berghei ANKA mutants expressing nahG. C57BL/6 mice infected with nahG transfectants developed enhanced cerebral malaria, as assessed by Evans blue leakage and brain histological observation. The nahG-transfectant also significantly increased the mortality rate of mice. Prostaglandin E2 reduced the brain symptoms by induction of T helper-2 cytokines. As expected, T helper-1 cytokines including interferon-γ and interleukin-2 were significantly elevated by infection with the nahG transfectant. Thus, salicylic acid of Plasmodium spp. may be a new pathogenic factor of this threatening parasite and may modulate immune function via parasite-produced prostaglandin E2. PMID:26466097

Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment?

PubMed

Prins, Jelmer R; Eskandar, Sharon; Eggen, Bart J L; Scherjon, Sicco A

2018-04-01

Disturbances in fetal neurodevelopment have extensively been related to neurodevelopmental disorders in early and later life. Fetal neurodevelopment is dependent on adequate functioning of the fetal immune system. During pregnancy, the maternal immune system is challenged to both tolerate the semi-allogenic fetus and to protect the mother and fetus from microbes. The fetal immune system is influenced by maternal immune disturbances; therefore, perturbations in maternal immunity likely do not only alter pregnancy outcome but also alter fetal neurodevelopment. A possible common pathway could be modulating the functioning of tissue macrophages in the placenta and brain. Maternal immune tolerance towards the fetus involves several complex adaptations. In this active maternal immune state, the fetus develops its own immunity. As cytokines and other players of the immune system -which can pass the placenta- are involved in neurodevelopment, disruptions in immune balance influence fetal neurodevelopment. Several studies reported an association between maternal immune activation, complications of pregnancy as preeclampsia, and altered neonatal neurodevelopment. A possible pathway involves dysfunctioning of microglia cells, the immune cells of the brain. Functionality of microglia cells during normal pregnancy is, however, poorly understood. The recent outbreak of ZIKA virus (ZKV), but also the literature on virus infections in general and its consequences on microglial cell function and fetal neurodevelopment show the devastating effects a virus infection during pregnancy can have. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Microbiota regulate the development and function of the immune cells.

PubMed

Yu, Qing; Jia, Anna; Li, Yan; Bi, Yujing; Liu, Guangwei

2018-03-04

Microbiota is a group of microbes coexisting and co-evolving with the immune system in the host body for millions of years. There are mutual interaction between microbiota and the immune system. Immune cells can shape the populations of microbiota in the gut of animals and humans, and the presence of microbiota and the microbial products can regulate the development and function of the immune cells in the host. Although microbiota resides mainly at the mucosa, the effect of microbiota on the immune system can be both local at the mucosa and systemic through the whole body. At the mucosal sites, the presences of microbiota and microbial products have a direct effect on the immune cells. Microbiota induces production of effectors from immune cells, such as cytokines and inflammatory factors, influencing the further development and function of the immune cells. Experimental data have shown that microbial products can influence the activity of some key factors in signaling pathways. At the nonmucosal sites, such as the bone marrow, peripheral lymph nodes, and spleen, microbiota can also regulate the development and function of the immune cells via several mechanisms in mice, such as introduction of chromatin-level changes through histone acetylation and DNA methylation. Given the important effect of microbiota on the immune system, many immunotherapies that are mediated by immune system rely on gut microbiota. Thus, the study of how microbiota influences immune system bring a potential therapy prospect in preventing and treating diseases.

Immune System Dysregulation and Herpesvirus Reactivation Persist During Long-Duration Spaceflight

NASA Technical Reports Server (NTRS)

Crucian, B. E.; Stowe, R. P.; Mehta, S.; Uchakin, P.; Quiriarte, H.; Pierson, D.; Sams, C. F.

2010-01-01

Background: Immunity, latent herpesvirus reactivation, physiological stress and circadian rhythms were assessed during six month spaceflight onboard ISS. Blood and saliva samples were collected early, mid and late in-flight and returned for immediate analysis. Mid-point study data (10 of 17 planned subjects) will be presented. Results: Some shifts in leukocyte distribution occurred during flight, including alterations in CD8+ T cell maturation. General T cell function was consistently reduced early in-flight. Levels CD8+/IFNg+ producing T cells were depressed early in-flight, and immediately upon landing. Persistent mitogen-dependant reductions were observed in IFNg, IL-17a, IL-10, TNFa and IL-6 production. Monocyte production of IL-10 was reduced, whereas IL-8 levels were increased. Levels of mRNA for the TNFa, IL-6 and IFNg were transiently elevated early in-flight, and the dynamics of TNF and IL-6 gene expression were somewhat antagonistic to their corresponding receptors during flight. The number of virus-specific CD8+ T-cells was measured using MHC tetramers, while their function was measured using intracellular cytokine analysis following peptide stimulation. Both the number and function of EBV-specific cells decreased during flight as compared to preflight levels. The number of CMV-specific T-cells generally increased as the mission progressed while their function was variable. Viral (EBV) load in blood was elevated postflight. Anti-EBV VCA antibodies were significantly elevated by R+0; anti-EA antibodies were not significantly elevated at landing; and anti-CMV antibodies were somewhat elevated during flight. Higher levels of salivary EBV DNA were found during flight. VZV DNA reactivation occurred in 50 % of astronauts during flight, continuing for up to 30 days post-flight. CMV was shed in 35 % the in-flight and 30% of postflight urine samples of the crewmembers. There was generally a higher level of cortisol as measured in urine and saliva in the astronauts during flight, but plasma cortisol was relatively unchanged during flight. Circadian rhythm of salivary cortisol was altered during flight. Conclusion. Some alterations in immunity do not resolve during six month spaceflight, consequentially resulting in persistent herpesvirus reactivation. Ongoing immune dysregulation may represent specific clinical risks for exploration-class space missions.

An immunologic model for rapid vaccine assessment -- a clinical trial in a test tube.

PubMed

Higbee, Russell G; Byers, Anthony M; Dhir, Vipra; Drake, Donald; Fahlenkamp, Heather G; Gangur, Jyoti; Kachurin, Anatoly; Kachurina, Olga; Leistritz, Del; Ma, Yifan; Mehta, Riyaz; Mishkin, Eric; Moser, Janice; Mosquera, Luis; Nguyen, Mike; Parkhill, Robert; Pawar, Santosh; Poisson, Louis; Sanchez-Schmitz, Guzman; Schanen, Brian; Singh, Inderpal; Song, Haifeng; Tapia, Tenekua; Warren, William; Wittman, Vaughan

2009-09-01

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed "MIMIC" (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response. 2009 FRAME.

Dehydroepiandrosterone and multiple measures of functional immunity in young adults.

PubMed

Prall, Sean P; Muehlenbein, Michael P

2015-01-01

Human immune function is strongly influenced by variation in hormone concentrations. The adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S) are thought to be beneficial to immune function and disease resistance, but physiologically interact with testosterone and cortisol. We predict that DHEA and DHEA-S will interact with these other hormones in determining immunological outcomes. Understanding the interactive effects of these hormones will aid in understanding variability in immunocompetence and clarify discrepancies in human studies of androgen-immune interactions. Thirty-eight participants collected morning saliva over three days, from which concentrations of DHEA, DHEA-S, testosterone, and cortisol were measured, as well as salivary bacteria killing ability to measure innate immune function. From blood collection, serum was collected to measure innate immune function via a hemolytic complement assay, and whole blood collected and processed to measure proliferative responses of lymphocytes in the presence of mitogens. DHEA was negatively correlated with T cell proliferation, and positively correlated with salivary bacteria killing in male participants. Additionally, using regression models, DHEA-S was negatively associated with hemolytic complement activity, but interaction variables did not yield statistically significant relationships for any other outcome measure. While interactions with other hormones did not significantly relate with immune function measures in this sample, DHEA and DHEA-S did differentially impact multiple branches of the immune system. Generally characterized as immunosupportive in action, DHEA is shown to inhibit certain facets of innate and cell-mediated immunity, suggesting a more complex role in regulating immunocompetence. © 2015 Wiley Periodicals, Inc.

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity.

PubMed

Tauber, Svantje; Lauber, Beatrice A; Paulsen, Katrin; Layer, Liliana E; Lehmann, Martin; Hauschild, Swantje; Shepherd, Naomi R; Polzer, Jennifer; Segerer, Jürgen; Thiel, Cora S; Ullrich, Oliver

2017-01-01

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC-TOF-MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface-bound fucose. The reduced ICAM-1 expression and the loss of cell surface-bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable "steady state" after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions.

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

PubMed Central

Tauber, Svantje; Lauber, Beatrice A.; Paulsen, Katrin; Layer, Liliana E.; Lehmann, Martin; Hauschild, Swantje; Shepherd, Naomi R.; Polzer, Jennifer; Segerer, Jürgen; Thiel, Cora S.

2017-01-01

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC–TOF–MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface–bound fucose. The reduced ICAM-1 expression and the loss of cell surface–bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable “steady state” after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions. PMID:28419128

An Evolution-Based Screen for Genetic Differentiation between Anopheles Sister Taxa Enriches for Detection of Functional Immune Factors

PubMed Central

Takashima, Eizo; Williams, Marni; Eiglmeier, Karin; Pain, Adrien; Guelbeogo, Wamdaogo M.; Gneme, Awa; Brito-Fravallo, Emma; Holm, Inge; Lavazec, Catherine; Sagnon, N’Fale; Baxter, Richard H.; Riehle, Michelle M.; Vernick, Kenneth D.

2015-01-01

Nucleotide variation patterns across species are shaped by the processes of natural selection, including exposure to environmental pathogens. We examined patterns of genetic variation in two sister species, Anopheles gambiae and Anopheles coluzzii, both efficient natural vectors of human malaria in West Africa. We used the differentiation signature displayed by a known coordinate selective sweep of immune genes APL1 and TEP1 in A. coluzzii to design a population genetic screen trained on the sweep, classified a panel of 26 potential immune genes for concordance with the signature, and functionally tested their immune phenotypes. The screen results were strongly predictive for genes with protective immune phenotypes: genes meeting the screen criteria were significantly more likely to display a functional phenotype against malaria infection than genes not meeting the criteria (p = 0.0005). Thus, an evolution-based screen can efficiently prioritize candidate genes for labor-intensive downstream functional testing, and safely allow the elimination of genes not meeting the screen criteria. The suite of immune genes with characteristics similar to the APL1-TEP1 selective sweep appears to be more widespread in the A. coluzzii genome than previously recognized. The immune gene differentiation may be a consequence of adaptation of A. coluzzii to new pathogens encountered in its niche expansion during the separation from A. gambiae, although the role, if any of natural selection by Plasmodium is unknown. Application of the screen allowed identification of new functional immune factors, and assignment of new functions to known factors. We describe biochemical binding interactions between immune proteins that underlie functional activity for malaria infection, which highlights the interplay between pathogen specificity and the structure of immune complexes. We also find that most malaria-protective immune factors display phenotypes for either human or rodent malaria, with broad specificity a rarity. PMID:26633695

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

PubMed Central

Jones, Russell G.; Pearce, Edward J.

2017-01-01

Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts. PMID:28514674

Retinoic Acid as a Modulator of T Cell Immunity

PubMed Central

Bono, Maria Rosa; Tejon, Gabriela; Flores-Santibañez, Felipe; Fernandez, Dominique; Rosemblatt, Mario; Sauma, Daniela

2016-01-01

Vitamin A, a generic designation for an array of organic molecules that includes retinal, retinol and retinoic acid, is an essential nutrient needed in a wide array of aspects including the proper functioning of the visual system, maintenance of cell function and differentiation, epithelial surface integrity, erythrocyte production, reproduction, and normal immune function. Vitamin A deficiency is one of the most common micronutrient deficiencies worldwide and is associated with defects in adaptive immunity. Reports from epidemiological studies, clinical trials and experimental studies have clearly demonstrated that vitamin A plays a central role in immunity and that its deficiency is the cause of broad immune alterations including decreased humoral and cellular responses, inadequate immune regulation, weak response to vaccines and poor lymphoid organ development. In this review, we will examine the role of vitamin A in immunity and focus on several aspects of T cell biology such as T helper cell differentiation, function and homing, as well as lymphoid organ development. Further, we will provide an overview of the effects of vitamin A deficiency in the adaptive immune responses and how retinoic acid, through its effect on T cells can fine-tune the balance between tolerance and immunity. PMID:27304965

How Psychological States Affect the Immune System: Implications for Interventions in the Context of HIV.

ERIC Educational Resources Information Center

Littrell, Jill

1996-01-01

Discusses the psychological states associated with enhanced immune system functioning and those associated with suppressed immune functioning. Reviews studies of psychological and behavioral interventions to boost the immune systems of people who are HIV positive. Suggests that group interventions can enhance psychological states associated with…

Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain.

PubMed

Fantetti, Kristen N; Gray, Erica L; Ganesan, Priya; Kulkarni, Apurva; O'Donnell, Lauren A

2016-05-13

In the developing brain, self-renewing neural stem/progenitor cells (NSPC) give rise to neuronal and glial lineages. NSPC survival and differentiation can be altered by neurotropic viruses and by the anti-viral immune response. Several neurotropic viruses specifically target and infect NSPCs, in addition to inducing neuronal loss, which makes it difficult to distinguish between effects on NSPCs that are due to direct viral infection or due to the anti-viral immune response. We have investigated the impact of anti-viral immunity on NSPCs in measles virus (MV)-infected neonates. A neuron-restricted viral infection model was used, where NSPCs remain uninfected. Thus, an anti-viral immune response was induced without the confounding issue of NSPC infection. Two-transgenic mouse lines were used: CD46+ mice express the human isoform of CD46, the MV entry receptor, under the control of the neuron-specific enolase promoter; CD46+/IFNγ-KO mice lack the key anti-viral cytokine IFNγ. Multi-color flow cytometry and Western Blot analysis were used to quantify effects on NSPC, neuronal, and glial cell number, and quantify effects on IFNγ-mediated signaling and cell markers, respectively. Flow cytometric analysis revealed that NSPCs were reduced in CD46+/IFNγ-KO mice at 3, 7, and 10 days post-infection (dpi), but were unaffected in CD46+ mice. Early neurons showed the greatest cell loss at 7 dpi in both genotypes, with no effect on mature neurons and glial cells. Thus, IFNγ protected against NSPC loss, but did not protect young neurons. Western Blot analyses on hippocampal explants showed reduced nestin expression in the absence of IFNγ, and reduced doublecortin and βIII-tubulin in both genotypes. Phosphorylation of STAT1 and STAT2 occurred independently of IFNγ in the hippocampus, albeit with distinct regulation of activation. This is the first study to demonstrate bystander effects of anti-viral immunity on NSPC function. Our results show IFNγ protects the NSPC population during a neonatal viral CNS infection. Significant loss of NSPCs in CD46+/IFNγ-KO neonates suggests that the adaptive immune response is detrimental to NSPCs in the absence of IFNγ. These results reveal the importance and contribution of the anti-viral immune response to neuropathology and may be relevant to other neuroinflammatory conditions.

Loss of the LIM-only protein Fhl2 impairs inflammatory reaction and scar formation after cardiac ischemia leading to better hemodynamic performance.

PubMed

Goltz, Diane; Hittetiya, Kanishka; Gevensleben, Heidrun; Kirfel, Jutta; Diehl, Linda; Meyer, Rainer; Büttner, Reinhard

2016-04-15

The pathogenesis of myocardial ischemia-reperfusion injury (MI/R) involves an inflammatory response. Since the four-and-a-half LIM domain-containing protein 2 (Fhl2) has been observed to modulate immune cell migration, we aimed to study the consequences of Fhl2(-/-) under MI/R with respect to immune reaction, scar formation, and hemodynamic performance. In a closed chest model of 1h MI/R, immune cell invasion of phagocytic monocytes was characterized by flow cytometry and immunohistochemistry. In addition, infarct size was assessed by triphenyltetrazolium chloride/Masson trichrome staining 24h/21days after reperfusion and a set of hemodynamic parameters was recorded by catheterisation in Fhl2(-/-) mice and controls. While flow cytometry did not reveal differences in myocardial CD45(high) immune cell infiltrate, histological analysis showed that infiltrating immune cells in Fhl2(-/-) animals were preferentially located in the perivascular area, whereas in wild type, immune cells were well dispersed within the area at risk. After 24h and 21days of reperfusion, infarct size was significantly reduced in Fhl2(-/-) compared to WT animals. In addition, hemodynamic performance was better in Fhl2(-/-) mice, compared to WT mice up to day 21 of reperfusion. The loss of Fhl2 leads to an altered immune response to myocardial ischemia, which results in smaller infarcts and better hemodynamic performance up to 21days after myocardial ischemia reperfusion. Immune cell invasion plays a pivotal role in the context of MI/R. Fhl2 significantly influences immune cell function and immune cell interaction with injured cardiac tissue leading to altered scar composition. Copyright © 2016 Elsevier Inc. All rights reserved.

Vaccination prepartum enhances the beneficial effects of melatonin on the immune response and reduces platelet responsiveness in sheep

PubMed Central

2012-01-01

Background Melatonin regulates several physiological processes and its powerful action as antioxidant has been widely reported. Melatonin acts modulating the immune system, showing a protective effect on the cardiovascular system and improving vaccine administration as an adjuvant-like agent. Here, we have investigated the role of melatonin as an adjuvant of the Clostridium perfringens vaccine in prepartum sheep and whether melatonin modulates platelet physiology during peripartum. Results The experiments were carried out in peripartum sheep from a farm located in an area of Mediterranean-type ecosystem. Plasma melatonin levels were determined by ELISA and sheep platelet aggregation was monitored using an aggregometer. Here we demonstrated for the first time that plasma melatonin concentration were higher in pregnant (125 pg/mL) than in non-pregnant sheep (15 pg/mL; P < 0.05). Administration of melatonin prepartum did not significantly modify platelet function but significantly improved the immune response to vaccination against C. perfringens. Conclusion Administration of melatonin as an adjuvant provides a significant improvement in the immune response to vaccine administration prepartum against C. perfringens. PMID:22716226

Vaccines and immunization strategies for dengue prevention

PubMed Central

Liu, Yang; Liu, Jianying; Cheng, Gong

2016-01-01

Dengue is currently the most significant arboviral disease afflicting tropical and sub-tropical countries worldwide. Dengue vaccines, such as the multivalent attenuated, chimeric, DNA and inactivated vaccines, have been developed to prevent dengue infection in humans, and they function predominantly by stimulating immune responses against the dengue virus (DENV) envelope (E) and nonstructural-1 proteins (NS1). Of these vaccines, a live attenuated chimeric tetravalent DENV vaccine developed by Sanofi Pasteur has been licensed in several countries. However, this vaccine renders only partial protection against the DENV2 infection and is associated with an unexplained increased incidence of hospitalization for severe dengue disease among children younger than nine years old. In addition to the virus-based vaccines, several mosquito-based dengue immunization strategies have been developed to interrupt the vector competence and effectively reduce the number of infected mosquito vectors, thus controlling the transmission of DENV in nature. Here we summarize the recent progress in the development of dengue vaccines and novel immunization strategies and propose some prospective vaccine strategies for disease prevention in the future. PMID:27436365

Pangolin genomes and the evolution of mammalian scales and immunity

PubMed Central

Rayko, Mike; Tan, Tze King; Hari, Ranjeev; Komissarov, Aleksey; Wee, Wei Yee; Yurchenko, Andrey A.; Kliver, Sergey; Tamazian, Gaik; Antunes, Agostinho; Wilson, Richard K.; Warren, Wesley C.; Koepfli, Klaus-Peter; Minx, Patrick; Krasheninnikova, Ksenia; Kotze, Antoinette; Dalton, Desire L.; Vermaak, Elaine; Paterson, Ian C.; Dobrynin, Pavel; Sitam, Frankie Thomas; Rovie-Ryan, Jeffrine J.; Johnson, Warren E.; Yusoff, Aini Mohamed; Luo, Shu-Jin; Karuppannan, Kayal Vizi; Fang, Gang; Zheng, Deyou; Gerstein, Mark B.; Lipovich, Leonard; O'Brien, Stephen J.; Wong, Guat Jah

2016-01-01

Pangolins, unique mammals with scales over most of their body, no teeth, poor vision, and an acute olfactory system, comprise the only placental order (Pholidota) without a whole-genome map. To investigate pangolin biology and evolution, we developed genome assemblies of the Malayan (Manis javanica) and Chinese (M. pentadactyla) pangolins. Strikingly, we found that interferon epsilon (IFNE), exclusively expressed in epithelial cells and important in skin and mucosal immunity, is pseudogenized in all African and Asian pangolin species that we examined, perhaps impacting resistance to infection. We propose that scale development was an innovation that provided protection against injuries or stress and reduced pangolin vulnerability to infection. Further evidence of specialized adaptations was evident from positively selected genes involving immunity-related pathways, inflammation, energy storage and metabolism, muscular and nervous systems, and scale/hair development. Olfactory receptor gene families are significantly expanded in pangolins, reflecting their well-developed olfaction system. This study provides insights into mammalian adaptation and functional diversification, new research tools and questions, and perhaps a new natural IFNE-deficient animal model for studying mammalian immunity. PMID:27510566

Epstein-Barr Virus in Systemic Autoimmune Diseases

PubMed Central

Duus, Karen; Houen, Gunnar

2013-01-01

Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation. PMID:24062777

Epstein-Barr virus in systemic autoimmune diseases.

PubMed

Draborg, Anette Holck; Duus, Karen; Houen, Gunnar

2013-01-01

Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation.

Impacts of different expressions of PA-X protein on 2009 pandemic H1N1 virus replication, pathogenicity and host immune responses

PubMed Central

Lee, Jinhwa; Yu, Hai; Li, Yonghai; Ma, Jingjiao; Lang, Yuekun; Duff, Michael; Henningson, Jamie; Liu, Qinfang; Li, Yuhao; Nagy, Abdou; Bawa, Bhupinder; Li, Zejun; Tong, Guangzhi; Richt, Juergen A.; Ma, Wenjun

2017-01-01

Although several studies have investigated the functions of influenza PA-X, the impact of different expressions of PA-X protein including full-length, truncated or PA-X deficient forms on virus replication, pathogenicity and host response remains unclear. Herein, we generated two mutated viruses expressing a full-length or deficient PA-X protein based on the A/California/04/2009 (H1N1) virus that expresses a truncated PA-X to understand three different expressions of PA-X protein on virus replication, pathogenicity and host immune responses. The results showed that expression of either full-length or truncated PA-X protein enhanced viral replication and pathogenicity as well as reduced host innate immune response in mice by host shutoff activity when compared to the virus expressing the deficient PA-X form. Furthermore, the full-length PA-X expression exhibited a greater effect on virus pathogenicity than the truncated PA-X form. Our results provide novel insights of PA-X on viral replication, pathogenicity and host immune responses. PMID:28142079

T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences

PubMed Central

Madi, Asaf; Poran, Asaf; Shifrut, Eric; Reich-Zeliger, Shlomit; Greenstein, Erez; Zaretsky, Irena; Arnon, Tomer; Laethem, Francois Van; Singer, Alfred; Lu, Jinghua; Sun, Peter D; Cohen, Irun R; Friedman, Nir

2017-01-01

Diversity of T cell receptor (TCR) repertoires, generated by somatic DNA rearrangements, is central to immune system function. However, the level of sequence similarity of TCR repertoires within and between species has not been characterized. Using network analysis of high-throughput TCR sequencing data, we found that abundant CDR3-TCRβ sequences were clustered within networks generated by sequence similarity. We discovered a substantial number of public CDR3-TCRβ segments that were identical in mice and humans. These conserved public sequences were central within TCR sequence-similarity networks. Annotated TCR sequences, previously associated with self-specificities such as autoimmunity and cancer, were linked to network clusters. Mechanistically, CDR3 networks were promoted by MHC-mediated selection, and were reduced following immunization, immune checkpoint blockade or aging. Our findings provide a new view of T cell repertoire organization and physiology, and suggest that the immune system distributes its TCR sequences unevenly, attending to specific foci of reactivity. DOI: http://dx.doi.org/10.7554/eLife.22057.001 PMID:28731407

Extra virgin olive oil: a key functional food for prevention of immune-inflammatory diseases.

PubMed

Aparicio-Soto, Marina; Sánchez-Hidalgo, Marina; Rosillo, Ma Ángeles; Castejón, Ma Luisa; Alarcón-de-la-Lastra, Catalina

2016-11-09

Nowadays, it is clear that an unhealthy diet is one of the prime factors that contributes to the rise of inflammatory diseases and autoimmunity in the populations of both developed and developing countries. The Mediterranean diet has been associated with a reduced incidence of certain pathologies related to chronic inflammation and the immune system. Olive oil, the principal source of dietary lipids of the Mediterranean diet, possesses a high nutritional quality and a particular composition, which is especially relevant in the case of Extra Virgin Olive Oil (EVOO). EVOO is obtained from olives solely by mechanical or other physical preparation methods, under conditions that do not alter the natural composition. EVOO is described as a key bioactive food with multiple beneficial properties and it may be effective in the management of some immune-inflammatory diseases. In this review, the key research is summarised which provides evidence of the beneficial effects of EVOO and its minor components focusing on their mechanisms on immune-inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and sclerosis.

Modulation of Dendritic Cell Innate and Adaptive Immune Functions by Oral and Sublingual Immunotherapy

PubMed Central

Frischmeyer-Guerrerio, Pamela A.; Keet, Corinne A.; Guerrerio, Anthony L.; Chichester, Kristin L.; Bieneman, Anja P.; Hamilton, Robert G.; Wood, Robert A.; Schroeder, John T.

2014-01-01

Sublingual (SLIT) and oral immunotherapy (OIT) are promising treatments for food allergy, but underlying mechanisms are poorly understood. Dendritic cells (DC) induce and maintain Th2-type allergen-specific T cells, and also regulate innate immunity through their expression of Toll-like receptors (TLRs). We examined how SLIT and OIT influenced DC innate and adaptive immune responses in children with IgE-mediated cow's milk (CM) allergy. SLIT, but not OIT, decreased TLR-induced IL-6 secretion by myeloid DCs (mDCs). SLIT and OIT altered mDC IL-10 secretion, a potent inhibitor of FcεRI-dependent pro-inflammatory responses. OIT uniquely augmented IFN-α and decreased IL-6 secretion by plasmacytoid DCs (pDCs), which was associated with reduced TLR-induced IL-13 release in pDC-T cell co-cultures. Both SLIT and OIT decreased Th2 cytokine secretion to CM in pDC-T, but not mDC-T, co-cultures. Therefore, SLIT and OIT exert unique effects on DC-driven innate and adaptive immune responses, which may inhibit allergic inflammation and promote tolerance. PMID:25173802

EpiSweep: Computationally Driven Reengineering of Therapeutic Proteins to Reduce Immunogenicity While Maintaining Function.

PubMed

Choi, Yoonjoo; Verma, Deeptak; Griswold, Karl E; Bailey-Kellogg, Chris

2017-01-01

Therapeutic proteins are yielding ever more advanced and efficacious new drugs, but the biological origins of these highly effective therapeutics render them subject to immune surveillance within the patient's body. When recognized by the immune system as a foreign agent, protein drugs elicit a coordinated response that can manifest a range of clinical complications including rapid drug clearance, loss of functionality and efficacy, delayed infusion-like allergic reactions, more serious anaphylactic shock, and even induced auto-immunity. It is thus often necessary to deimmunize an exogenous protein in order to enable its clinical application; critically, the deimmunization process must also maintain the desired therapeutic activity.To meet the growing need for effective, efficient, and broadly applicable protein deimmunization technologies, we have developed the EpiSweep suite of protein design algorithms. EpiSweep seamlessly integrates computational prediction of immunogenic T cell epitopes with sequence- or structure-based assessment of the impacts of mutations on protein stability and function, in order to select combinations of mutations that make Pareto optimal trade-offs between the competing goals of low immunogenicity and high-level function. The methods are applicable both to the design of individual functionally deimmunized variants as well as the design of combinatorial libraries enriched in functionally deimmunized variants. After validating EpiSweep in a series of retrospective case studies providing comparisons to conventional approaches to T cell epitope deletion, we have experimentally demonstrated it to be highly effective in prospective application to deimmunization of a number of different therapeutic candidates. We conclude that our broadly applicable computational protein design algorithms guide the engineer towards the most promising deimmunized therapeutic candidates, and thereby have the potential to accelerate development of new protein drugs by shortening time frames and improving hit rates.