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One-week high-fat diet leads to reduced toll-like receptor 2 expression and function in young healthy men.
Wan, Z, Durrer, C, Mah, D, Simtchouk, S, Little, JP
Nutrition research (New York, N.Y.). 2014;(12):1045-51
Abstract
Toll-like receptor 2 (TLR2) is implicated in inflammatory responses to high-fat diet (HFD)-induced obesity in rodents, but human HFD studies examining TLR2-mediated immune responses are lacking. Our aim was to determine whether HFD affected TLR2 function in humans. We hypothesized that a short-term HFD in humans would impair TLR2-mediated immune function. Fasting blood samples were obtained from healthy young men (N = 9) before and after a 7-day HFD. Toll-like receptor 2 function was assessed in ex vivo whole blood cultures stimulated with the TLR2 agonist N-palmitoyl-S-[2,3-bis[palmitoyloxy]-[2RS]-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine (Pam3-Cys-SK4). Peripheral blood mononuclear cells (PBMCs) were isolated to examine TLR2, TLR4, and p47 subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47(phox)) protein expression via Western blotting. Pam3-Cys-SK4-stimulated secretion of interleukin-1β (-35%, P = .005), interleukin-6 (-32%, P = .01), and tumor necrosis factor-α (-33%, P = .06) was reduced following the HFD. High-fat diet resulted in decreased TLR2 (P = .049) and p47(phox) (P = .037) protein expression from PBMCs. To mimic lipid overload ex vivo, follow-up experiments were performed in whole blood cultures exposed to a mixture of free fatty acids for 24 hours; and surface protein expression of TLR2 and TLR4 on CD14+ monocytes was measured by flow cytometry. Free fatty acid exposure for 24 hours ex vivo reduced monocyte TLR2 levels by about 20% (P = .028). A 7-day HFD in young healthy men resulted in impaired TLR2 function. Decreased TLR2 and p47(phox) protein expression in PBMCs, possibly due to excess free fatty acids, may mediate this response. Our current findings indicate that impaired TLR2 response after HFD might be partially responsible for increased risk of infection in diet-induced obesity.
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Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.
Sassi, A, Lazaroski, S, Wu, G, Haslam, SM, Fliegauf, M, Mellouli, F, Patiroglu, T, Unal, E, Ozdemir, MA, Jouhadi, Z, et al
The Journal of allergy and clinical immunology. 2014;(5):1410-9, 1419.e1-13
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Abstract
BACKGROUND Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.
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Comprehensive biomarker monitoring in cytokine therapy: heterogeneous, time-dependent, and persisting immune effects of interleukin-10 application in psoriasis.
Döcke, WD, Asadullah, K, Belbe, G, Ebeling, M, Höflich, C, Friedrich, M, Sterry, W, Volk, HD
Journal of leukocyte biology. 2009;(3):582-93
Abstract
Cytokine and anticytokine treatments represent promising approaches for therapy of immune-mediated diseases. In humans, however, regulatory consequences of interference with the cytokine network are only partially understood. Biomarker analysis in clinical studies may help to overcome this complexity and provide novel information about the in vivo relevance of individual cytokines. We report systemic immunological effects of IL-10 therapy in 10 psoriasis patients during a 7-week treatment period followed by a 7-week observation period. IL-10 was given s.c. at 8 microg/kg/day or 20 microg/kg/3 x/week, and a broad range of immunological biomarkers was analyzed in an extended kinetics (17 time-points) before, during, and after IL-10 therapy. Besides the expected anti-inflammatory effects (e.g., inhibition of LPS-induced cytokine secretion), we found unexpected effects, such as activation of NK cells and an increase in parameters indicating proinflammatory activity (C-reactive protein and soluble IL-2R). Furthermore, cumulative effects (IgE and IgA), loss of effect (IL-1R antagonist and IFN-gamma secretion), or counter-regulation during and rebound after IL-10 therapy (TNF-alpha and IL-12/IL-23 p40) were found. Remarkably, some alterations were retained long after the 7-week treatment period (IL-4 secretion, monocytic CD86, and TGF-beta1). In summary, we found manifold effects of IL-10 far beyond the immediate anti-inflammatory activity considered initially. These findings may explain the rather disappointing clinical effects of IL-10 therapy in exacerbated inflammation but also hint to its role for sustained immunological reshaping. They further exemplify the importance of analyzing an extended kinetics of an entire panel of biomarkers for understanding the effects of therapeutic interference with the cytokine network.
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Effects of cyanocobalamin on immunity in patients with pernicious anemia.
Erkurt, MA, Aydogdu, I, Dikilitaş, M, Kuku, I, Kaya, E, Bayraktar, N, Ozhan, O, Ozkan, I, Sonmez, A
Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2008;(2):131-5
Abstract
OBJECTIVE The aim of the study was to evaluate the role of vitamin B(12) in patients with pernicious anemia. MATERIALS AND METHODS This study was conducted prospectively at the Turgut Ozal Medical Center, Department of Hematology, between April and November 2002. Absolute numbers and ratio of the surface antigens of T and B lymphocyte subgroups, CD4/CD8 ratio were calculated in order to evaluate changes in leukocyte and lymphocyte numbers; natural killer (NK) cell count, serum C3, C4, and levels of immunoglobulins G, A, and M were also measured to evaluate vitamin B(12) effect on immunity. Values obtained before treatment with cyanocobalamin were compared with those found during peak reticulocyte count. RESULTS In vitamin B(12)-deficient patients, absolute numbers of CD4+ and especially CD8+ lymphocytes were found to be decreased; CD4/CD8 ratio increased, and NK cell activity was depressed. After cyanocobalamin treatment, absolute numbers and percentage of lymphocyte subgroups were elevated. Increased CD4/CD8 ratio and depressed NK cell activity were restored and levels of C3, C4, and immunoglobulins were elevated. CONCLUSION These findings suggest that vitamin B(12) has important immunomodulatory effects on cellular immunity, and abnormalities in the immune system in pernicious anemia are restored by vitamin B(12) replacement therapy.
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Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.
Abdou, AM, Higashiguchi, S, Horie, K, Kim, M, Hatta, H, Yokogoshi, H
BioFactors (Oxford, England). 2006;(3):201-8
Abstract
The effect of orally administrated gamma-aminobutyric acid (GABA) on relaxation and immunity during stress has been investigated in humans. Two studies were conducted. The first evaluated the effect of GABA intake by 13 subjects on their brain waves. Electroencephalograms (EEG) were obtained after 3 tests on each volunteer as follows: intake only water, GABA, or L-theanine. After 60 minutes of administration, GABA significantly increases alpha waves and decreases beta waves compared to water or L-theanine. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the role of relaxant and anxiolytic effects of GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into 2 groups (placebo and GABA). All subjects were crossing a suspended bridge as a stressful stimulus. Immunoglobulin A (IgA) levels in their saliva were monitored during bridge crossing. Placebo group showed marked decrease of their IgA levels, while GABA group showed significantly higher levels. In conclusion, GABA could work effectively as a natural relaxant and its effects could be seen within 1 hour of its administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity under stress conditions.
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Effects of morphine and its metabolites on immune function in advanced cancer patients.
Hashiguchi, S, Morisaki, H, Kotake, Y, Takeda, J
Journal of clinical anesthesia. 2005;(8):575-80
Abstract
STUDY OBJECTIVE To determine whether morphine and its active metabolites such as morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) modulate immune function in patients with advanced cancer who required morphine for pain relief. DESIGN Prospective observational clinical study. SETTING Pain clinic of a university hospital. PATIENTS Fifteen patients who visited our clinic for control of advanced cancer pain. INTERVENTIONS During the initiation or changes of morphine therapy, venous blood samples were obtained at the enrollment of this study, 1 and 3 weeks after the change of morphine dose or route. MEASUREMENTS Lymphocyte subpopulation CD4+ and CD8+, activity of natural killer cell, phytohemagglutinin (PHA)-induced T-cell proliferation, and plasma immunoglobulin M and G concentrations were measured, as well as plasma concentrations of morphine, M-3-G, and M-6-G. MAIN RESULTS At the entry of the study, 6 patients did not receive any type of morphine medication (group 1), whereas 9 patients were treated with morphine for 1 month (group 2). Cancer pain, rated as 4 at the entry period, was reduced to 2 of 10 (visual analogue scale) during the study periods. Although the plasma concentrations of M-3-G and M-6-G in Group 1 were significantly less than those in Group 2, plasma concentrations of immunologic markers were similar between the groups. In Group 1, Spearman linear regression analysis showed negative correlation between morphine-derived metabolites and immunoglobulins or PHA-induced T-cell proliferation, whereas poor correlation was found with all immunologic parameters in Group 2. Stepwise linear regression analyses showed that the metabolites, rather than morphine per se, modulated immune function, reflected by PHA-induced T-cell proliferation and immunoglobulin G concentration in Group 1. CONCLUSIONS The present study suggests that some of humoral and cellular immunity are modulated by morphine-derived metabolites at the early phase of morphine therapy in patients with advanced cancer.
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Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention.
Jyonouchi, H, Geng, L, Ruby, A, Zimmerman-Bier, B
Neuropsychobiology. 2005;(2):77-85
Abstract
OBJECTIVE Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. METHODS This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. RESULTS ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. CONCLUSION Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities.
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Effects of a short-course of amoxicillin/clavulanic acid on systemic and mucosal immunity in healthy adult humans.
Dufour, V, Millon, L, Faucher, JF, Bard, E, Robinet, E, Piarroux, R, Vuitton, DA, Meillet, D
International immunopharmacology. 2005;(5):917-28
Abstract
Although amoxicillin/clavulanic acid (AMC) is the most frequently administered antibiotic in France, its in vivo effects on immunity in healthy adults have never, to our knowledge, been described. Eighteen healthy adult male volunteers, 25+/-6 years old, were treated for 5 days with oral amoxicillin (1 g) /clavulanate potassium (125 mg), two times daily. Systemic and local intestinal immunity parameters were sequentially explored before, during and after the antibiotic treatment. No significant differences were obtained for transudation markers (albumin and alpha1-antitrypsin) in sera, feces and saliva, showing that AMC did not induce inflammatory reaction. Phagocytosis, peripheral blood cell subsets, intracellular interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production by natural killer (NK) cells and cytotoxic T lymphocytes, intracellular TNF-alpha production by monocytes showed no significant differences throughout the trial. In fecal outputs, no significant differences were found in secretory immunoglobulin A (S-IgA), lactoferrin (Lf), lysozyme (Lz) and transforming growth factor (TGF)-beta1. In sera, concentrations of total IgA (T-IgA), S-IgA, IgM, Lf and Lz did not show any significant variations throughout the study, whereas concentrations of IgG were slightly but significantly reduced 15 days after AMC treatment. In saliva, concentrations of T-IgA were slightly but significantly higher, whereas S-IgA concentrations were unchanged. Our results showed that oral AMC intake did not induce any significant adverse effects on immunity in adult humans.
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Lysine-fortified wheat flour improves the nutritional and immunological status of wheat-eating families in northern China.
Zhao, W, Zhai, F, Zhang, D, An, Y, Liu, Y, He, Y, Ge, K, Scrimshaw, NS
Food and nutrition bulletin. 2004;(2):123-9
Abstract
The purpose of this study was to determine the impact of the fortification of wheat flour with lysine on selected health indicators among farm families obtaining 58% to 67% of their dietary protein from wheat. A man, a woman, and a child aged 5 to 12 years were studied from each of 88 families in a village near Huixian City, Henan Province, China. Half of the families received wheat flour fortified with 3 g of lysine per kilogram for three months, and the other half received wheat flour without fortification. The results showed a significantly greater gain in the height and weight of children receiving lysine-fortified wheat flour. Hemoglobin values were not affected. The mean prealbumin values of adult men and women were higher in those receiving lysine. The numbers of CD3 T cells increased significantly in women and children, as did the complement fraction C3 and IgG in men, IgA in women, and IgG, IgA, IgM, and C3 in children. These results indicate that lysine fortification of wheat flour can significantly improve some indicators of the nutritional status and immune function of family members consuming a wheat-based diet.
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Effects of deferiprone on immune status and cytokine pattern in thalassaemia major.
Del Vecchio, GC, Schettini, F, Piacente, L, De Santis, A, Giordano, P, De Mattia, D
Acta haematologica. 2002;(3):144-9
Abstract
OBJECTIVE The present study was undertaken to evaluate the possible occurrence of immunological abnormalities in thalassaemia major patients treated with deferiprone (L1). METHODS Longitudinal observational cohort study. RESULTS The absolute number of CD8+ lymphocytes was high and the CD4/CD8 ratio low before L1 treatment; these parameters returned to normal after 3 months of L1 treatment. TNF-alpha, IL-2 and IL-2sRalpha were elevated before L1 treatment (11.83 +/- 1.75, 11.75 +/- 3.91, 1,409 +/- 621 pg/ml, respectively), while IL-6 was normal (2.58 +/- 0.79 pg/ml). After 12 months of treatment, IL-10 was higher than in previous periods, although always within the normal range. TNF-alpha, IL-2 and IL-2sRalpha returned to normal after 12, 6, and 3 months of L1 treatment, respectively.