Deoxynivalenol (DON), a highly prevalent mycotoxin food contaminant, is known to have immunotoxic effects. In the current study, the potential of dietary interventions with specific mixtures of trans-galactosyl-oligosaccharides (TOS) to alleviate these effects were assessed in a murine influenza vaccination model. Vaccine-specific immune responses were measured in C57Bl/6JOlaHsd mice fed diets containing DON, TOS or a combination, starting 2 weeks before the first vaccination. The direct effects of TOS and its main oligosaccharide, 3′-galactosyl-lactose (3′-GL), on DON-induced damage were studied in Caco-2 cells, as an in vitro model of the intestinal epithelial barrier. Exposure to DON significantly reduced vaccine-specific immune responses and the percentages of Tbet+ Th1 cells and B cells in the spleen. DON significantly altered epithelial structure and integrity in the ileum and reduced the SCFA levels in the cecum. Adding TOS into DON-containing diets significantly improved vaccine-specific immune responses, restored the immune cell balance in the spleen and increased SCFA concentrations in the cecum. Incubating Caco-2 cells with TOS and 3′-GL in vitro further confirmed their protective effects against DON-induced barrier disruption, supporting immune modulation. Overall, dietary intervention with TOS can attenuate the adverse effects of DON on Th1-mediated immune responses and gut homeostasis. These beneficial properties might be linked to the high levels of 3′-GL in TOS.
The maternal polyinosinic:polycytidylic acid (poly(I:C)) animal model is frequently used to study how maternal immune activation may impact neuro development in the offspring. Here, we present the first systematic review and meta-analysis on the effects of maternal poly(I:C) injection on immune mediators in the offspring and provide an openly accessible systematic map of the data including methodological characteristics. Pubmed and EMBASE were searched for relevant publications, yielding 45 unique papers that met inclusion criteria. We extracted data on immune outcomes and methodological characteristics, and assessed the risk of bias. The descriptive summary showed that most studies reported an absence of effect, with an equal number of studies reporting an increase or decrease in the immune mediator being studied. Meta-analysis showed increased IL-6 concentrations in the offspring of poly(I:C) exposed mothers. This effect appeared larger prenatally than post-weaning. Furthermore, poly(I:C) administration during mid-gestation was associated with higher IL-6 concentrations in the offspring. Maternal poly(I:C) induced changes in IL-1β, Il-10 and TNF-α concentrations were small and could not be associated with age of offspring, gestational period or sampling location. Finally, quality of reporting of potential measures to minimize bias was low, which stresses the importance of adherence to publication guidelines. Since neurodevelopmental disorders in humans tend to be associated with lifelong changes in cytokine concentrations, the absence of these effects as identified in this systematic review may suggest that combining the model with other etiological factors in future studies may provide further insight in the mechanisms through which maternal immune activation affects neurodevelopment.
Selenium (Se)-enriched proteins are an important dietary source of Se for humans; however, only a few Se-enriched proteins have been identified. In the present study, we tested for potential antioxidant activity by Se-enriched soy protein, both in vitro and in vivo. Se-enriched soy protein isolate (S-SPI) was shown to have a higher free radical scavenging ability compared to ordinary soy protein isolate (O-SPI). Furthermore, Caco-2 cell viability was improved by S-SPI at low doses, whereas O-SPI did not. In addition, S-SPI was shown to inhibit oxidative stress via modulation of the NRF2-HO1 signaling pathway, upregulating the expression of downstream antioxidant enzymes (GPx, SOD). To further study the antioxidant capacity of S-SPI, BALB/c female mice were given oral gavages with 0.8 mL of S-SPI or O-SPI (5 g/kg/d, 20 g/kg/d and 40 g/kg/d) or saline as control. Hepatic GPx and SOD activity increased with increasing S-SPI dosage, but not with O-SPI. Taken together, our results suggest that Se-enriched soy protein has a high antioxidant ability and may be used as a dietary supplement for people with oxidative dam-age-mediated diseases.
To the Editor, Selenium is an essential micronutrient that plays a crucial role in immune responses.1 Selenomethionine (SeMet), an organic form of selenium, is the main nutritional source of selenium for animals and humans. We previously demonstrated that dietary SeMet supplementation reduced mast cell activation in a murine food allergy model.2 In vitro studies in the murine and rat mast cell lines demonstrated that pretreatment with selenium attenuates IgE-induced mediator release3, 4 and indicated a suppressive effect on signal transduction. In this study, we investigated the effects of SeMet on human mast cell (HMC) responses. To this end, primary human mast cells were cultured from CD34-positive peripheral blood cells. In order to investigate whether SeMet could affect immunoglobulin (Ig)E-mediated mast cell activation by interfering with the binding of IgE to the IgE receptor or through attenuation of events distal to IgE sensitization, HMC were either (1) preincubated with SeMet, sensitized with human IgE (huIgE) and then challenged with anti-huIgE (ahuIgE), or (2) sensitized using huIgE, incubated with SeMet and then challenged with aHuIgE. To assess HMC activation, degranulation by the release of β-hexosaminidase (β-hex) and interleukin (IL) 8 production was measured.5 Compared to the negative control, preincubating HMC overnight with SeMet reduced the release of β-hex and production of IL-8 (Figure 1A). This effect was not observed if the cells were incubated with SeMet after sensitization with HuIgE (Figure 1B). In addition, preincubation with SeMet prior to sensitization with huIgE and challenge with ahuIgE was observed to significantly reduce calcium flux (Figure 1C), a crucial process for mast cell degranulation.6 To assess whether preincubation with SeMet would also lead to reduction of mast cell activation in a more biologically relevant context, we investigated HMC responses after sensitization with sera obtained from soy-allergic patients and challenge with soy proteins. For this purpose, soy protein isolate (SPI), β-conglycinin (7S), and glycinin (11S) were isolated from soybean flour, of which SPI was found to have the biggest effect size in IgE-mediated mast cell activation (Figure S1A). HMC were preincubated with SeMet, sensitized with sera from either healthy donors or from soy-allergic patients and subsequently challenged with SPI. Within 15 soy-allergic sera tested, sensitization of HMC with 2 sera induced high levels of degranulation after challenge with SPI (Figure S1B). In line with these findings, soy-specific serum IgE levels higher than 100 IU were detected in these two sera (Table S1), which were therefore selected for use in subsequent experiments. No response was detected when HMC sensitized with sera from healthy donors were challenged with SPI (Figure S1C). Next, the effect of SeMet on the soy-specific mast cell activation was assessed. In addition to β-hex release, the expression of the high-affinity IgE receptor (FcεRI) and IgE binding was measured. Indeed, soy protein-specific IgE crosslinking with SPI led to a reduced mast cell activation in HMC preincubated with SeMet prior to sensitization with serum from soy-allergic patients (Figure 2A,B). Also, activation of serum-sensitized HMC with anti-huIgE gave parallel results. In addition, SeMet preincubation reduced the expression of FcεRI in a dose-dependent manner in HMC sensitized with sera from soy-allergic patients (Figure 2C). IgE binding was significantly lower only when the cells had been preincubated with 20 µg SeMet/ml (Figure 2C). In HMC sensitized with sera from healthy controls, no soy protein-specific degranulation was observed (Figure S2). Since serum from healthy controls contains low levels of IgE (with no specificity for soy protein), IgE crosslinking with ahuIgE induced mast cell activation. In parallel to the other experiments, SeMet induced a decrease in FcεRI expression and IgE binding on healthy sera sensitized HMC, which induced decrease in degranulation (Figure S2). In conclusion, this is the first report showing attenuation of mast cell activation by SeMet in primary HMC. We demonstrate an attenuation of the allergic effector response by SeMet following allergen-specific sensitization. In addition, we showed that SeMet potentially affects mast cell activation by reducing FcεRI expression and FcεRI downstream signaling events. Further studies are needed to elucidate the molecular mechanisms involved, but these results indicate that SeMet-induced reduction of FcεRI expression and IgE binding could potentially serve as an interesting mechanism to prevent mast cell activation and degranulation. Altogether, our data suggest that use of SeMet as a supplementary nutrient may be considered as a potential strategy to reduce allergic responses. Leon Knippels is current Danone Nutricia employee, and Johan Garssen is a part time employee of Danone Nutricia Research and Utrecht University. Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE); stock options from IgGenix, Seed Health, ClostraBio, and ImmuneID; is Director of the World Allergy Organization Center of Excellence for Stanford, Advisor at Cour Pharma, Consultant for Excellergy, Red tree ventures, Eli Lilly, and Phylaxis, Co-founder of Before Brands, Alladapt, Latitude, and IgGenix; and National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers, outside the submitted work; patents include, "Mixed allergen composition and methods for using the same," "Granulocyte-based methods for detecting and monitoring immune system disorders," and "Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders." All remaining authors declare no conflict of interest. A.H. and L.K. involved in conceptualization. B.H. and X.Z. involved in methodology. X.Z. involved in formal analysis. K.N., J.G., and H.C. involved in investigation. X.Z. and B.H. involved in data curation. A.H. and L.K. involved in project administration. X.Z. involved in writing original draft preparation. X.Z., A.H., and L.K. involved in writing review and editing. I.C., D,D., and J.G. involved in visualization. J.G., H.C., and F.R. involved in supervision. All authors have read and agreed to the published version of the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Cow's milk allergy is a common food allergy in infants, and is associated with an increased risk of developing other allergic diseases. Dietary selenium (Se), one of the essential micronutrients for humans and animals, is an important bioelement which can influence both innate and adaptive immune responses. However, the effects of Se on food allergy are still largely unknown. In the current study it was investigated whether dietary Se supplementation can inhibit whey-induced food allergy in an animal research model. Three-week-old female C3H/HeOuJ mice were intragastrically sensitized with whey protein and cholera toxin and randomly assigned to receive a control, low, medium or high Se diet. Acute allergic symptoms, allergen specific immunoglobulin (Ig) E levels and mast cell degranulation were determined upon whey challenge. Body temperature was significantly higher in mice that received the medium Se diet 60 min after the oral challenge with whey compared to the positive control group, which is indicative of impaired anaphylaxis. This was accompanied by reductions in antigen-specific immunoglobulins and reduced levels of mouse mast cell protease-1 (mMCP-1). This study demonstrates that oral Se supplementation may modulate allergic responses to whey by decreasing specific antibody responses and mMCP-1 release.
The hygiene hypothesis states that improved hygiene and the resulting disappearance of once endemic diseases is at the origin of the enormous increase in immune related disorders such as autoimmune diseases seen in the industrialized world. Helminths, such as Schistosoma mansoni, are thought to provide protection against the development of autoimmune diseases by regulating the host's immune response. This modulation primarily involves induction of regulatory immune responses, such as generation of tolerogenic dendritic cells and alternatively activated macrophages. This points towards the potential of employing helminths or their products/metabolites as therapeutics for autoimmune diseases that are characterized by an excessive inflammatory state, such as multiple sclerosis (MS), type I diabetes (T1D) and inflammatory bowel disease (IBD). In this review, we examine the known mechanisms of immune modulation by S. mansoni, explore preclinical and clinical studies that investigated the use of an array helminthic products in these diseases, and propose that helminthic therapy opens opportunities in the treatment of chronic inflammatory disorders.
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