Publications by authors named "Huub F J Savelkoul"

159 Publications

Differences in growth of Trypanoplasma borreli in carp serum is dependent on transferrin genotype.

Fish Shellfish Immunol 2021 Apr 14. Epub 2021 Apr 14.

Polish Academy of Sciences, Institute of Ichthyobiology and Aquaculture in Gołysz, Zaborze, 43-520, Chybie, Poland. Electronic address:

Kinetoplastid parasites require transferrin (Tf), being the main source of iron, for growth and multiplication. This group of parasites developed a unique receptor-mediated system for acquiring host Tf which bears no structural homology with the host transferrin receptor. Trypanoplasma borreli, a blood parasite of common carp, probably uses a similar mechanism to sequester iron from host transferrin. In this study, we demonstrate a critical role of Tf for parasite growth. For in vitro studies we isolated and purified Tf from carp homozygous for the D or G allele of Tf. We obtained Tf-depleted serum using specific antibodies to carp Tf and studied gene expression in vivo during T. borreli infection with Real Time-quantitative PCR. We demonstrate that T. borreli cannot survive in medium supplemented with Tf-depleted serum while reconstitution with Tf restores normal growth. The critical role of Tf for parasite survival was shown in incomplete medium (medium without serum): addition of purified Tf significantly increased parasite survival. We also demonstrate that Tf polymorphism has a significant impact on T. borreli multiplication. Cultured parasites die more quickly in an environment containing D-typed Tf, as compared to medium with G-typed Tf. Gene expression during T. borreli infection in carp did not show an acute phase response. We could, however, observe an increased transcription of Tf in the head kidney, which may be associated with an immunological function of the Tf protein.
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http://dx.doi.org/10.1016/j.fsi.2021.04.011DOI Listing
April 2021

Asthma-Associated Long TSLP Inhibits the Production of IgA.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Center for Immunology of Infectious Diseases and Vaccination, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands.

Thymic stromal lymphopoietin (TSLP) contributes to asthmatic disease. The concentrations of protective IgA may be reduced in the respiratory tract of asthma patients. We investigated how homeostatic short TSLP (shTSLP) and asthma-associated long TSLP (loTSLP) regulate IgA production. B cells from healthy donors were stimulated in the presence or absence of shTSLP or loTSLP; the concentrations of IgA, IgM, IgE, and IgG antibodies were determined in cell culture supernatants; and B cells were analyzed by flow cytometry. LoTSLP, but not shTSLP, suppressed the secretion of IgA but not of IgE. The type 2 cytokine IL-4, which in addition to loTSLP contributes to asthmatic disease, did not affect the production of IgA or the frequency of IgA+ B cells. Instead, IL-4 increased IgG production, especially of the subclasses IgG2 and IgG4. LoTSLP inhibited IgA secretion by sorted memory B cells but not by naïve B cells. Although loTSLP inhibited IgA production, the vitamin A metabolite retinoic acid promoted the secretion of IgA, also in the presence of loTSLP, suggesting that vitamin A may promote IgA production in asthma. Our data demonstrate that asthma-associated loTSLP negatively regulates the secretion of IgA, which may negatively impact the surveillance of mucosal surfaces in asthma.
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http://dx.doi.org/10.3390/ijms22073592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036615PMC
March 2021

Vitamin D and Allergy Susceptibility during Gestation and Early Life.

Nutrients 2021 Mar 21;13(3). Epub 2021 Mar 21.

Cell Biology and Immunology Group, Wageningen University & Research, 6708 WD Wageningen, The Netherlands.

Worldwide, the prevalence of allergies in young children, but also vitamin D deficiency during pregnancy and in newborns is rising. Vitamin D modulates the development and activity of the immune system and a low vitamin D status during pregnancy and in early life might be associated with an increased risk to develop an allergy during early childhood. This review studies the effects of vitamin D during gestation and early life, on allergy susceptibility in infants. The bioactive form of vitamin D, 1,25(OH)2D, inhibits maturation and results in immature dendritic cells that cause a decreased differentiation of naive T cells into effector T cells. Nevertheless, the development of regulatory T cells and the production of interleukin-10 was increased. Consequently, a more tolerogenic immune response developed against antigens. Secondly, binding of 1,25(OH)2D to epithelial cells induces the expression of tight junction proteins resulting in enhanced epithelial barrier function. Thirdly, 1,25(OH)2D increased the expression of anti-microbial peptides by epithelial cells that also promoted the defense mechanism against pathogens, by preventing an invasive penetration of pathogens. Immune intervention by vitamin D supplementation can mitigate the disease burden from asthma and allergy. In conclusion, our review indicates that a sufficient vitamin D status during gestation and early life can lower the susceptibility to develop an allergy in infants although there remains a need for more causal evidence.
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http://dx.doi.org/10.3390/nu13031015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003945PMC
March 2021

Early immune responses in skin and lymph node after skin delivery of Toll-like receptor agonists in neonatal and adult pigs.

Vaccine 2021 Mar 5;39(13):1857-1869. Epub 2021 Mar 5.

Wageningen Bioveterinary Research, Wageningen University & Research, P.O. Box 29703, 2502 LS The Hague, the Netherlands.

The skin is potentially an important vaccine delivery route facilitated by a high number of resident antigen presenting cells (APCs), which are known to be stimulated by different Toll-like receptor agonists (TLRa). In this study, neonatal and adult pigs were vaccinated in the skin using dissolving microneedle patches to investigate the immuno-stimulatory potential of different TLRa and possible age-dependent differences early after vaccination. These patches contained TLR1/2a (Pam3Cys), TLR7/8a (R848) or TLR9a (CpG ODN) combined with inactivated porcine reproductive and respiratory syndrome virus (PRRSV) or with an oil-in-water stable emulsion. Vaccinated skin and draining lymph nodes were analysed for immune response genes using microfluidic high-throughput qPCR to evaluate the early immune response and activation of APCs. Skin pathology and immunohistochemistry were used to evaluate the local immune responses and APCs in the vaccinated skin, respectively. In both neonatal and adult pigs, skin vaccination with TLR7/8a induced the most prominent early inflammatory and immune cell responses, particularly in the skin. Skin histopathology and immunohistochemistry of APCs showed comparable results for neonatal and adult pigs after vaccination with the different TLRa vaccines. However, in vaccinated neonatal pigs in the skin and draining lymph node more immune response related genes were upregulated compared to adult pigs. We showed that both neonatal and adult skin could be stimulated to develop an immune response, particularly after TLR7/8a vaccination, with age-dependent differences in regulation of immune genes. Therefore, age-dependent differences in local early immune responses should be considered when developing skin vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.028DOI Listing
March 2021

Enhanced Uptake of Processed Bovine β-Lactoglobulin by Antigen Presenting Cells: Identification of Receptors and Implications for Allergenicity.

Mol Nutr Food Res 2021 Apr 10;65(8):e2000834. Epub 2021 Mar 10.

Cell Biology & Immunology, Wageningen University & Research Centre, Wageningen, the Netherlands.

Scope: β-lactoglobulin (BLG) is a major cow milk allergen encountered by the immune system of infants fed with milk-based formulas. To determine the effect of processing on immunogenicity of BLG, this article characterized how heated and glycated BLG are recognized and internalized by APCs. Also, the effect of heat-induced structural changes as well as gastrointestinal digestion on immunogenicity of BLG is evaluated.

Methods And Results: The binding and uptake of BLG from raw cow milk and heated either alone (BLG-H) or with lactose/glucose (BLG-Lac and BLG-Glu) to the receptors present on APCs are analyzed by ELISA and cell-binding assays. Heated and glycated BLG is internalized via galectin-3 (Gal-3)and scavenger receptors (CD36 and SR-AI) while binding to the receptor for advanced glycation end products (R AGE) does not cause internalization. Receptor affinity of BLG is dependent on increased hydrophobicity, β-sheet exposure and aggregation. Digested glycated BLG maintained binding to sRAGE and Gal-3 but not to CD36 and SR-AI, and is detected on the surface of APCs. This suggests a mechanism via which digested glycated BLG may trigger innate (via RAGE) and adaptive immunity (via Gal-3).

Conclusions: This study defines structural characteristics of heated and glycated BLG determining its interaction with APCs via specific receptors thus revealing enhanced immunogenicity of glycated versus heated BLG.
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http://dx.doi.org/10.1002/mnfr.202000834DOI Listing
April 2021

Novel standardized method for extracellular flux analysis of oxidative and glycolytic metabolism in peripheral blood mononuclear cells.

Sci Rep 2021 Jan 18;11(1):1662. Epub 2021 Jan 18.

Human and Animal Physiology, Department of Animal Sciences, Wageningen University and Research, De Elst 1 6708 WD, P.O. Box 338, 6700 AH, Wageningen, The Netherlands.

Analyzing metabolism of peripheral blood mononuclear cells (PBMCs) provides key opportunities to study the pathophysiology of several diseases, such as type 2 diabetes, obesity and cancer. Extracellular flux (XF) assays provide dynamic metabolic analysis of living cells that can capture ex vivo cellular metabolic responses to biological stressors. To obtain reliable data from PBMCs from individuals, novel methods are needed that allow for standardization and take into account the non-adherent and highly dynamic nature of PBMCs. We developed a novel method for extracellular flux analysis of PBMCs, where we combined brightfield imaging with metabolic flux analysis and data integration in R. Multiple buffy coat donors were used to demonstrate assay linearity with low levels of variation. Our method allowed for accurate and precise estimation of XF assay parameters by reducing the standard score and standard score interquartile range of PBMC basal oxygen consumption rate and glycolytic rate. We applied our method to freshly isolated PBMCs from sixteen healthy subjects and demonstrated that our method reduced the coefficient of variation in group mean basal oxygen consumption rate and basal glycolytic rate, thereby decreasing the variation between PBMC donors. Our novel brightfield image procedure is a robust, sensitive and practical normalization method to reliably measure, compare and extrapolate XF assay data using PBMCs, thereby increasing the relevance for PBMCs as marker tissue in future clinical and biological studies, and enabling the use of primary blood cells instead of immortalized cell lines for immunometabolic experiments.
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http://dx.doi.org/10.1038/s41598-021-81217-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814123PMC
January 2021

A 2 Week Cross-over Intervention with a Low Carbohydrate, High Fat Diet Compared to a High Carbohydrate Diet Attenuates Exercise-Induced Cortisol Response, but Not the Reduction of Exercise Capacity, in Recreational Athletes.

Nutrients 2021 Jan 6;13(1). Epub 2021 Jan 6.

Division of Human Nutrition and Health, Wageningen University & Research (WUR), 6700 AH Wageningen, The Netherlands.

Low carbohydrate, high fat (LCHF) diets are followed by athletes, but questions remain regarding effects of LCHF on metabolic adaptation, exercise-induced stress, immune function and their time-course. In this cross-over study, 14 recreational male athletes (32.9 ± 8.2 years, VO2max 57.3 ± 5.8 mL/kg/min) followed a two week LCHF diet (<10 En% carbohydrates (CHO), ~75En% Fat) and a two week HC diet (>50 En% CHO), in random order, with a wash-out period of >2 weeks in between. After 2 days and 2 weeks on either diet, participants performed cycle ergometry for 90 min at 60%W. Blood samples for analysis of cortisol, free fatty acids (FFA), glucose and ketones, and saliva samples for immunoglobin A (s-IgA) were collected at different time points before and after exercise. The LCHF diet resulted in higher FFA, higher ketones and lower glucose levels compared to the HC diet ( < 0.05). Exercise-induced cortisol response was higher after 2 days on the LCHF diet (822 ± 215 nmol/L) compared to 2 weeks on the LCHF diet (669 ± 243 nmol/L, = 0.004) and compared to both test days following the HC diet (609 ± 208 and 555 ± 173 nmol/L, both < 0.001). Workload was lower, and perceived exertion higher, on the LCHF diet compared to the HC diet on both occasions. A drop in s-IgA following exercise was not seen after 2 days on the LCHF diet, in contrast to the HC diet. In conclusion, the LCHF diet resulted in reduced workload with metabolic effects and a pronounced exercise-induced cortisol response after 2 days. Although indications of adaptation were seen after 2 weeks on the LCHF diet, work output was still lower.
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http://dx.doi.org/10.3390/nu13010157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825040PMC
January 2021

Modulatory Effects of Osthole on Lipopolysaccharides-Induced Inflammation in Caco-2 Cell Monolayer and Co-Cultures with THP-1 and THP-1-Derived Macrophages.

Nutrients 2020 Dec 31;13(1). Epub 2020 Dec 31.

Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland.

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150-450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied ( < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 ( < 0.01) and 300 ng/μL for NF-κB ( < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.
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http://dx.doi.org/10.3390/nu13010123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824174PMC
December 2020

Immune responses induced by inactivated porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in neonatal pigs using different adjuvants.

Vet Immunol Immunopathol 2021 Feb 15;232:110170. Epub 2020 Dec 15.

Wageningen Livestock Research, Wageningen University & Research, the Netherlands.

Vaccination of neonatal pigs could be supportive to prevent porcine reproductive and respiratory syndrome virus (PRRSV), which is an important porcine pathogen causing worldwide welfare and health problems in pigs of different age classes. However, neonatal immunity substantially differs to adults, thus different vaccines may be required in neonateal pigs. We examined if the immunogenicity and efficacy of inactivated PRRSV (iPRRSV) vaccines in neonatal pigs could be improved with adjuvants containing oil-in water (O/W) emulsions with or without Toll-like receptor (TLR) agonists and by altering the delivery route from intramuscular (i.m.) to the skin. Three-day-old PRRSV-naïve piglets (n = 54, divided in 6 groups) received a prime vaccination and a booster vaccination four weeks later. The vaccine formulations consisted of different O/W emulsions (Montanide™ ISA28RVG (ISA28)), a squalene in water emulsion (SWE) for i.m. or a Stable Emulsion (SE) with squalene for skin vaccination) and/or a mixture of TLR1/2, 7/8 and 9 agonists (TLRa) combined with iPRRSV strain 07V063. These vaccines were delivered either i.m. (ISA28, SWE, TLRa or SWE + TLRa) or into the skin (skiSE + TLRa) with dissolving microneedle (DMN)-patches. All animals received a challenge with homologous PRRSV three weeks after booster vaccination. Specific antibodies, IFN-γ production and viremia were measured at several time-points after vaccination and/or challenge, while lung pathology was studied at necropsy. After booster vaccination, only ISA28 induced a specific antibody response while a specific T-cell IFN-γ response was generated in the SWE group, that was lower for ISA28, and absent in the other groups. This suggests that prime vaccination in neonates induced a specific immune response after booster vaccination, dependent on the emulsion formulation, but not dependent on the presence of the TLRa or delivery route. Despite the measured immune responses none of the vaccines showed any efficacy. Further research focused on the early immune response in draining lymph nodes is needed to elucidate the potential of TLR agonists in vaccines for neonatal pigs.
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http://dx.doi.org/10.1016/j.vetimm.2020.110170DOI Listing
February 2021

The Impact of Milk and Its Components on Epigenetic Programming of Immune Function in Early Life and Beyond: Implications for Allergy and Asthma.

Front Immunol 2020 21;11:2141. Epub 2020 Oct 21.

Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands.

Specific and adequate nutrition during pregnancy and early life is an important factor in avoiding non-communicable diseases such as obesity, type 2 diabetes, cardiovascular disease, cancers, and chronic allergic diseases. Although epidemiologic and experimental studies have shown that nutrition is important at all stages of life, it is especially important in prenatal and the first few years of life. During the last decade, there has been a growing interest in the potential role of epigenetic mechanisms in the increasing health problems associated with allergic disease. Epigenetics involves several mechanisms including DNA methylation, histone modifications, and microRNAs which can modify the expression of genes. In this study, we focus on the effects of maternal nutrition during pregnancy, the effects of the bioactive components in human and bovine milk, and the environmental factors that can affect early life (i.e., farming, milk processing, and bacterial exposure), and which contribute to the epigenetic mechanisms underlying the persistent programming of immune functions and allergic diseases. This knowledge will help to improve approaches to nutrition in early life and help prevent allergies in the future.
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http://dx.doi.org/10.3389/fimmu.2020.02141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641638PMC
October 2020

The Effect of Atopic Dermatitis and Diet on the Skin Transcriptome in Staffordshire Bull Terriers.

Front Vet Sci 2020 16;7:552251. Epub 2020 Oct 16.

Faculty of Veterinary Medicine, Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.

Canine atopic dermatitis (CAD) has a hereditary basis that is modified by interactions with the environment, including diet. Differentially expressed genes in non-lesional skin, determined by RNA sequencing before and after a dietary intervention, were compared between dogs with naturally occurring CAD ( = 4) and healthy dogs ( = 4). The dogs were fed either a common commercial heat-processed high carbohydrate food (kibble diet) ( = 4), or a non-processed high fat food (raw meat-based diet) ( = 4). At the end of the diet intervention, 149 differentially expressed transcripts were found between the atopic and healthy dogs. The main canonical pathways altered by the dysregulation of these genes were angiopoietin signaling, epidermal growth factor signaling, activation of angiogenesis, and alterations in keratinocyte proliferation and lipid metabolism. On the other hand, 33 differently expressed transcripts were found between the two diet groups, of which 8 encode genes that are annotated in the current version of the dog genome: immunoglobulin heavy constant mu (), immunoglobulin lambda-like polypeptide 5 (), B-cell antigen receptor complex-associated protein beta chain (), polymeric immunoglobulin receptor (), cystathionine β-synthase (), argininosuccinate synthase 1 (), secretory leukocyte peptidase inhibitor (), and mitochondrial ribosome recycling factor (). All genes were upregulated in the raw diet group. In conclusion the findings of this study suggest alterations in lipid and keratinocyte metabolism as well as angiogenesis in the skin of atopic dogs. Additionally, a possible enhancement of innate immunity and decrease in oxidative stress was seen in raw food fed dogs, which could have an important role in preventing hypersensitivities and disturbed immunity at young age.
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http://dx.doi.org/10.3389/fvets.2020.552251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596200PMC
October 2020

Impact of Yeast-Derived β-Glucans on the Porcine Gut Microbiota and Immune System in Early Life.

Microorganisms 2020 Oct 13;8(10). Epub 2020 Oct 13.

Laboratory of Microbiology, Wageningen University, 6700 EH Wageningen, The Netherlands.

Piglets are susceptible to infections in early life and around weaning due to rapid environmental and dietary changes. A compelling target to improve pig health in early life is diet, as it constitutes a pivotal determinant of gut microbial colonization and maturation of the host's immune system. In the present study, we investigated how supplementation of yeast-derived β-glucans affects the gut microbiota and immune function pre- and post-weaning, and how these complex systems develop over time. From day two after birth until two weeks after weaning, piglets received yeast-derived β-glucans or a control treatment orally and were subsequently vaccinated against Typhimurium. Faeces, digesta, blood, and tissue samples were collected to study gut microbiota composition and immune function. Overall, yeast-derived β-glucans did not affect the vaccination response, and only modest effects on faecal microbiota composition and immune parameters were observed, primarily before weaning. This study demonstrates that the pre-weaning period offers a 'window of opportunity' to alter the gut microbiota and immune system through diet. However, the observed changes were modest, and any long-lasting effects of yeast-derived β-glucans remain to be elucidated.
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http://dx.doi.org/10.3390/microorganisms8101573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601942PMC
October 2020

Current Understanding of Natural Antibodies and Exploring the Possibilities of Modulation Using Veterinary Models. A Review.

Front Immunol 2020 10;11:2139. Epub 2020 Sep 10.

Adaptation Physiology Group, Department of Animal Sciences, Wageningen University, Wageningen, Netherlands.

Natural antibodies (NAb) are defined as germline encoded immunoglobulins found in individuals without (known) prior antigenic experience. NAb bind exogenous (e.g., bacterial) and self-components and have been found in every vertebrate species tested. NAb likely act as a first-line immune defense against infections. A large part of NAb, so called natural autoantibodies (NAAb) bind to and clear (self) neo-epitopes, apoptotic, and necrotic cells. Such self-binding antibodies cannot, however, be considered as pathogenic autoantibodies in the classical sense. IgM and IgG NAb and NAAb and their implications in health and disease are relatively well-described in humans and mice. NAb are present in veterinary (and wildlife) species, but their relation with diseases and disorders in veterinary species are much less known. Also, there is little known of IgA NAb. IgA is the most abundant immunoglobulin with essential pro-inflammatory and homeostatic properties urging for more research on the importance of IgA NAb. Since NAb in humans were indicated to fulfill important functions in health and disease, their role in health of veterinary species should be investigated more often. Furthermore, it is unknown whether levels of NAb-isotypes and/or idiotypes can and should be modulated. Veterinary species as models of choice fill in a niche between mice and (non-human) primates, and the study of NAb in veterinary species may provide valuable new insights that will likely improve health management. Below, examples of the involvement of NAb in several diseases in mostly humans are shown. Possibilities of intravenous immunoglobulin administration, targeted immunotherapy, immunization, diet, and genetic modulation are discussed, all of which could be well-studied using animal models. Arguments are given why veterinary immunology should obtain inspiration from human studies and why human immunology would benefit from veterinary models. Within the One concept, findings from veterinary (and wildlife) studies can be related to human studies and so that both fields will mutually benefit. This will lead to a better understanding of NAb: their origin, activation mechanisms, and their implications in health and disease, and will lead to novel health management strategies for both human and veterinary species.
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http://dx.doi.org/10.3389/fimmu.2020.02139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511776PMC
September 2020

Binding of CML-Modified as Well as Heat-Glycated β-lactoglobulin to Receptors for AGEs Is Determined by Charge and Hydrophobicity.

Int J Mol Sci 2020 Jun 26;21(12). Epub 2020 Jun 26.

Food Quality & Design Group, Wageningen University & Research Centre, 6708 WG Wageningen, The Netherlands.

Intake of dietary advanced glycation end products (AGEs) is associated with inflammation-related health problems. Nε-carboxymethyl lysine (CML) is one of the best characterised AGEs in processed food. AGEs have been described as ligands for receptors present on antigen presenting cells. However, changes in protein secondary and tertiary structure also induce binding to AGE receptors. We aimed to discriminate the role of different protein modifications in binding to AGE receptors. Therefore, β-lactoglobulin was chemically modified with glyoxylic acid to produce CML and compared to β-lactoglobulin glycated with lactose. Secondary structure was monitored with circular dichroism, while hydrophobicity and formation of β-sheet structures was measured with ANS-assay and ThT-assay, respectively. Aggregation was monitored using native-PAGE. Binding to sRAGE, CD36, and galectin-3 was measured using inhibition ELISA. Even though no changes in secondary structure were observed in all tested samples, binding to AGE receptors increased with CML concentration of CML-modified β-lactoglobulin. The negative charge of CML was a crucial determinant for the binding of protein bound CML, while binding of glycated BLG was determined by increasing hydrophobicity. This shows that sRAGE, galectin-3, and CD36 bind to protein bound CML and points out the role of negatively charged AGEs in binding to AGE receptors.
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http://dx.doi.org/10.3390/ijms21124567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348724PMC
June 2020

Differential immunomodulation of porcine bone marrow derived dendritic cells by E. coli Nissle 1917 and β-glucans.

PLoS One 2020 19;15(6):e0233773. Epub 2020 Jun 19.

Cell Biology and Immunology group, Department of Animal Sciences, Wageningen University, Wageningen, The Netherlands.

In early life and around weaning, pigs are at risk of developing infectious diseases which compromise animal welfare and have major economic consequences for the pig industry. A promising strategy to enhance resistance against infectious diseases is immunomodulation by feed additives. To assess the immune stimulating potential of feed additives in vitro, bone marrow-derived dendritic cells were used. These cells play a central role in the innate and adaptive immune system and are the first cells encountered by antigens that pass the epithelial barrier. Two different feed additives were tested on dendritic cells cultured from fresh and cryopreserved bone marrow cells; a widely used commercial feed additive based on yeast-derived β-glucans and the gram-negative probiotic strain E. coli Nissle 1917. E. coli Nissle 1917, but not β-glucans, induced a dose-dependent upregulation of the cell maturation marker CD80/86, whereas both feed additives induced a dose-dependent production of pro- and anti-inflammatory cytokines, including TNFα, IL-1β, IL-6 and IL-10. Furthermore, E. coli Nissle 1917 consistently induced higher levels of cytokine production than β-glucans. These immunomodulatory responses could be assessed by fresh as well as cryopreserved in vitro cultured porcine bone marrow-derived dendritic cells. Taken together, these results demonstrate that both β-glucans and E. coli Nissle 1917 are able to enhance dendritic cell maturation, but in a differential manner. A more mature dendritic cell phenotype could contribute to a more efficient response to infections. Moreover, both fresh and cryopreserved bone marrow-derived dendritic cells can be used as in vitro pre-screening tools which enable an evidence based prediction of the potential immune stimulating effects of different feed additives.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233773PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304589PMC
August 2020

IgE cross-reactivity measurement of cashew nut, hazelnut and peanut using a novel IMMULITE inhibition method.

Clin Chem Lab Med 2020 Oct;58(11):1875-1883

Department of Internal Medicine, Section of Allergy and Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.

Background Tree nut-allergic individuals are often sensitised towards multiple nuts and seeds. The underlying cause behind a multi-sensitisation for cashew nut, hazelnut, peanut and birch pollen is not always clear. We investigated whether immunoglobulin E antibody (IgE) cross-reactivity between cashew nut, hazelnut and peanut proteins exists in children who are multi-allergic to these foods using a novel IMMULITE®-based inhibition methodology, and investigated which allergens might be responsible. In addition, we explored if an allergy to birch pollen might play a role in this co-sensitisation for cashew nut, hazelnut and peanut. Methods Serum of five children with a confirmed cashew nut allergy and suffering from allergic symptoms after eating peanut and hazelnut were subjected to inhibition immunoassays using the IMMULITE® 2000 XPi. Serum-specific IgE (sIgE) to seed storage allergens and pathogenesis-related protein 10 (PR10) allergens were determined and used for molecular multicomponent allergen correlation analyses with observed clinical symptoms and obtained inhibition data. Results IgE cross-reactivity was observed in all patients. Hazelnut extract was a strong inhibitor of cashew nut sIgE (46.8%), while cashew nut extract was less able to inhibit hazelnut extract (22.8%). Peanut extract showed the least inhibition potency. Moreover, there are strong indications that a birch pollen sensitisation to Bet v 1 might play a role in the observed symptoms provoked upon ingestion of cashew nut and hazelnut. Conclusions By applying an adjusted working protocol, the IMMULITE® technology can be used to perform inhibition assays to determine the risk of sIgE cross-reactivity between very different food components.
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http://dx.doi.org/10.1515/cclm-2019-1083DOI Listing
October 2020

Plasmacytoid dendritic cell and myeloid dendritic cell function in ageing: A comparison between elderly and young adult women.

PLoS One 2019 12;14(12):e0225825. Epub 2019 Dec 12.

Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands.

Ageing is associated with a changing immune system, leading to inflammageing (increased levels of inflammation markers in serum) and immunosenescence (reduced immune cells and reduced responses towards pathogens). This results in reduced vaccination responses and increased infections in elderly. Much is known about the adaptive immune system upon ageing, but less is known about the innate immune system. Therefore, the aim of this study was to compare innate immune function of Toll like receptor (TLR)-mediated responses between elderly and young adult women. To this end, elderly and young adult women were compared to study the effect of ageing on the relative prevalence and reactivity to TLR-mediated responses of myeloid- and plasmacytoid dendritic cells (mDC, pDC). In addition, TLR expression and inflammatory markers in serum were investigated. Elderly women had reduced numbers of circulating pDCs. In addition, pDCs and mDCs of elderly women responded differently towards TLR stimulation, especially TLR7/8 mediated stimulation was reduced, compared to young adults. In serum, markers involved in inflammation were generally increased in elderly. In conclusion, this study confirms and extends the knowledge about immunosenescence and inflammageing on innate immunity in elderly women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225825PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907850PMC
March 2020

The Two Faces of Cow's Milk and Allergy: Induction of Cow's Milk Allergy vs. Prevention of Asthma.

Nutrients 2019 Aug 19;11(8). Epub 2019 Aug 19.

Cell Biology and Immunology Group, Wageningen University & Research, 6708 WD, Wageningen, The Netherlands.

Cow's milk has been consumed by humans for over 5000 years and contributed to a drastic change in lifestyle form nomadic to settled communities. As the composition of cow's milk is relatively comparable to breast milk, it has for a very long time been used as an alternative to breastfeeding. Today, cow's milk is typically introduced into the diet of infants around 6 months, except when breastfeeding is not an option. In that case, most often cow's milk based infant formulas are given. Some children will develop cow's milk allergy (CMA) during the first year of life. However, epidemiological evidence also suggests that consumption of unprocessed, "raw" cow's milk is associated with a lowered prevalence of other allergies. This Special Issue of on "Cow's Milk and Allergy" (https://www.mdpi.com/journal/nutrients/special_issues/milk_allergy) is dedicated to these two different sides of cow's milk and allergy, ranging from epidemiology of CMA, clinical presentation and sensitization patterns, treatment and prevention, effects of milk processing, and current management guidelines for CMA, but also the epidemiological evidence linking cow's milk to lower asthma prevalence as well as the tolerance-inducing effect of raw cow's milk in food allergy models. In this editorial, we discuss these issues by highlighting the contributions in this Special Issue.
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http://dx.doi.org/10.3390/nu11081945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722535PMC
August 2019

Genomic Regions Associated with IgE Levels against spp. Antigens in Three Horse Breeds.

Genes (Basel) 2019 08 8;10(8). Epub 2019 Aug 8.

Animal Breeding and Genomics, Wageningen University & Research, 6700 AH Wageningen, The Netherlands.

Insect bite hypersensitivity (IBH), which is a cutaneous allergic reaction to antigens from spp., is the most prevalent skin disorder in horses. Misdiagnosis is possible, as IBH is usually diagnosed based on clinical signs. Our study is the first to employ IgE levels against several recombinant spp. allergens as an objective, independent, and quantitative phenotype to improve the power to detect genetic variants that underlie IBH. Genotypes of 200 Shetland ponies, 127 Icelandic horses, and 223 Belgian Warmblood horses were analyzed while using a mixed model approach. No single-nucleotide polymorphism (SNP) passed the Bonferroni corrected significance threshold, but several regions were identified within and across breeds, which confirmed previously identified regions of interest and, in addition, identifying new regions of interest. Allergen-specific IgE levels are a continuous and objective phenotype that allow for more powerful analyses when compared to a case-control set-up, as more significant associations were obtained. However, the use of a higher density array seems necessary to fully employ the use of IgE levels as a phenotype. While these results still require validation in a large independent dataset, the use of allergen-specific IgE levels showed value as an objective and continuous phenotype that can deepen our understanding of the biology underlying IBH.
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http://dx.doi.org/10.3390/genes10080597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723964PMC
August 2019

The Impact of Pectin Supplementation on Intestinal Barrier Function in Healthy Young Adults and Healthy Elderly.

Nutrients 2019 Jul 9;11(7). Epub 2019 Jul 9.

Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands.

Intestinal barrier function is suggested to decrease with aging and may be improved by pectin intake. The aim of this study was to investigate the effects of four weeks pectin supplementation on gastrointestinal barrier function in vivo and ex vivo in different age groups. In a randomized, double-blind, placebo-controlled, parallel study, 52 healthy young adults (18-40 years) and 48 healthy elderly (65-75 years) received 15 g/day pectin or placebo for four weeks. Pre- and post-intervention, in vivo gastrointestinal permeability by a multisugar test, and defense capacity in mucosal samples were assessed. Sigmoid biopsies were collected post-intervention from subgroups for Ussing chamber experiments and gene transcription of barrier-related genes. Pectin intervention did not affect in vivo gastroduodenal, small intestinal, colonic, and whole gut permeability in young adults nor in elderly ( ≥ 0.130). Salivary and fecal sIgA and serum IgA were not significantly different between pectin versus placebo in both age groups ( ≥ 0.128). In both young adults and elderly, no differences in transepithelial electrical resistance and fluorescein flux ( ≥ 0.164) and relative expression of genes analyzed ( ≥ 0.222) were found between pectin versus placebo. In conclusion, intestinal barrier function was not affected by four weeks pectin supplementation neither in healthy young adults nor in healthy elderly.
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http://dx.doi.org/10.3390/nu11071554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683049PMC
July 2019

Differential Effects of Dry vs. Wet Heating of β-Lactoglobulin on Formation of sRAGE Binding Ligands and sIgE Epitope Recognition.

Nutrients 2019 Jun 25;11(6). Epub 2019 Jun 25.

Cell Biology & Immunology, Wageningen University & Research Centre, 6700 AA Wageningen, The Netherlands.

The effect of glycation and aggregation of thermally processed β-lactoglobulin (BLG) on binding to sRAGE and specific immunoglobulin E (sIgE) from cow milk allergic (CMA) patients were investigated. BLG was heated under dry conditions (water activity < 0.7) and wet conditions (in phosphate buffer at pH 7.4) at low temperature (<73 °C) and high temperatures (>90 °C) in the presence or absence of the milk sugar lactose. Nε-(carboxymethyl)-l-lysine (CML) western blot and glycation staining were used to directly identify glycation structures on the protein fractions on SDS-PAGE. Western blot was used to specify sRAGE and sIgE binding fractions. sRAGE binding was highest under wet-heated BLG independent of the presence of the milk sugar lactose. Under wet heating, high-molecular-weight aggregates were most potent and did not require the presence of CML to generate sRAGE binding ligands. In the dry system, sRAGE binding was observed only in the presence of lactose. sIgE binding affinity showed large individual differences and revealed four binding profiles. Dependent on the individual, sIgE binding decreased or increased by wet heating independent of the presence of lactose. Dry heating required the presence of lactose to show increased binding to aggregates in most individuals. This study highlights an important role of heating condition-dependent protein aggregation and glycation in changing the immunogenicity and antigenicity of cow's milk BLG.
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http://dx.doi.org/10.3390/nu11061432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627217PMC
June 2019

Toll-like receptor agonists as adjuvants for inactivated porcine reproductive and respiratory syndrome virus (PRRSV) vaccine.

Vet Immunol Immunopathol 2019 Jun 30;212:27-37. Epub 2019 Apr 30.

Wageningen Bioveterinary Research, Wageningen University & Research, the Netherlands.

Toll-like receptor (TLR) agonists can effectively stimulate antigen-presenting cells (APCs) and are anticipated to be promising adjuvants in combination with inactivated vaccines. In this study, the adjuvant potential of three different TLR-agonists were compared with an oil-in-water (O/W) adjuvant in combination with inactivated porcine reproductive and respiratory syndrome virus (iPRRSV) applied by different administration routes: intramuscular (i.m.) or into the skin using dissolving microneedle (DMN) patches. Pigs received a prime vaccination followed by a booster vaccination four weeks later. TLR1/2 (Pam3Cys), TLR7/8 (R848) or TLR9 (CpG ODN) agonists were used as adjuvant in combination with iPRRSV strain 07V063. O/W adjuvant (Montanide™) was used as reference control adjuvant and one group received a placebo vaccination containing diluent only. All animals received a homologous challenge with PRRSV three weeks after the booster vaccination. Antibody and IFN-γ production, serum cytokines and viremia were measured at several time-points after vaccination and/or challenge, and lung pathology at necropsy. Our results indicate that a TLR 1/2, 7/8 or 9 agonist as adjuvant with iPRRSV does not induce a detectable PRRSV-specific immune response, independent of the administration route. However, the i.m. TLR9 agonist group showed reduction of viremia upon challenge compared to the non-vaccinated animals, supported by a non-antigen-specific IFN-γ level after booster vaccination and an anamnestic antibody response after challenge. Montanide™-adjuvanted iPRRSV induced antigen-specific immunity after booster combined with reduction of vireamia. Skin application of TLR7/8 agonist, but not the other agonists, induced a local skin reaction. Further research is needed to explore the potential of TLR agonists as adjuvants for inactivated porcine vaccines with a preference for TLR9 agonists.
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http://dx.doi.org/10.1016/j.vetimm.2019.04.008DOI Listing
June 2019

ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging mice.

Immun Ageing 2019 8;16. Epub 2019 Mar 8.

4Laboratory of Microbiology, Wageningen University and Research, Wageningen, The Netherlands.

Background: The use of as potential therapeutic intervention is receiving increasing attention. Health benefits attributed to this bacterium include an improvement of metabolic disorders and exerting anti-inflammatory effects. The abundance of is associated with a healthy gut in early mid- and later life. However, the effects of on a decline in intestinal health during the aging process are not investigated yet. We supplemented accelerated aging mice with for 10 weeks and investigated histological, transcriptional and immunological aspects of intestinal health.

Results: The thickness of the colonic mucus layer increased about 3-fold after long-term supplementation and was even significantly thicker compared to mice supplemented with WCFS1. Colonic gene expression profiles pointed towards a decreased expression of genes and pathways related to inflammation and immune function, and suggested a decreased presence of B cells in colon. Total B cell frequencies in spleen and mesenteric lymph nodes were not altered after supplementation. Mature and immature B cell frequencies in bone marrow were increased, whereas B cell precursors were unaffected. These findings implicate that B cell migration rather than production was affected by supplementation. Gene expression profiles in ileum pointed toward a decrease in metabolic- and immune-related processes and antimicrobial peptide production after supplementation. Besides, decreased the frequency of activated CD80CD273 B cells in Peyer's patches. Additionally, the increased numbers of peritoneal resident macrophages and a decrease in Ly6C monocyte frequencies in spleen and mesenteric lymph nodes add evidence for the potentially anti-inflammatory properties of .

Conclusions: Altogether, we show that supplementation with prevented the age-related decline in thickness of the colonic mucus layer and attenuated inflammation and immune-related processes at old age. This study implies that supplementation can contribute to a promotion of healthy aging.
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http://dx.doi.org/10.1186/s12979-019-0145-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408808PMC
March 2019

Sialyllactose and Galactooligosaccharides Promote Epithelial Barrier Functioning and Distinctly Modulate Microbiota Composition and Short Chain Fatty Acid Production .

Front Immunol 2019 12;10:94. Epub 2019 Feb 12.

Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands.

Human milk oligosaccharides (HMO) and prebiotic oligosaccharides are proposed to confer several health benefits to the infant. They shape the microbiota, have anti-inflammatory properties, and support epithelial barrier functioning. However, in order to select the best oligosaccharides for inclusion in infant formulas, there is a need to increase our understanding of the specific effects of HMO and prebiotics on the host immune system. Therefore, we investigated the effects of the HMO sialyllactose (SL), and galactooligosaccharides (GOS) on epithelial barrier functioning, microbiota composition, and SCFA production. The effect of GOS and SL on epithelial barrier functioning and microbiota composition was investigated using models. Epithelial barrier function was investigated by transcriptome analysis of fully polarized Caco-2 cells exposed for 6 h to SL or GOS. In addition, epithelial cell growth, alkaline phosphatase production, and re-epithelization was studied. Further, we investigated the effect of SL and GOS on microbiota composition and SCFA production using fecal batch cultures. Transcriptome analysis showed that SL and GOS both induced pathways that regulate cell cycle control. This gene-expression profile translated to a phenotype of halted proliferation and included the induction of alkaline phosphatase activity, a marker of epithelial cell differentiation. SL and GOS also promoted re-epithelialization in an epithelial wound repair assay. SL and GOS did show distinct modulation of microbiota composition, promoting the outgrowth of and bifidobacteria, respectively, which resulted in distinct changes in SCFA production profiles. Our results show that SL and GOS can both modulate epithelial barrier function by inducing differentiation and epithelial wound repair, but differentially promote the growth of specific genera in the microbiota, which is associated with differential changes in SCFA profiles.
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http://dx.doi.org/10.3389/fimmu.2019.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380229PMC
December 2019

Age-associated Impairment of the Mucus Barrier Function is Associated with Profound Changes in Microbiota and Immunity.

Sci Rep 2019 02 5;9(1):1437. Epub 2019 Feb 5.

Top Institute Food and Nutrition, Wageningen, The Netherlands.

Aging significantly increases the vulnerability to gastrointestinal (GI) disorders but there are few studies investigating the key factors in aging that affect the GI tract. To address this knowledge gap, we used 10-week- and 19-month-old litter-mate mice to investigate microbiota and host gene expression changes in association with ageing. In aged mice the thickness of the colonic mucus layer was reduced about 6-fold relative to young mice, and more easily penetrable by luminal bacteria. This was linked to increased apoptosis of goblet cells in the upper part of the crypts. The barrier function of the small intestinal mucus was also compromised and the microbiota were frequently observed in contact with the villus epithelium. Antimicrobial Paneth cell factors Ang4 and lysozyme were expressed in significantly reduced amounts. These barrier defects were accompanied by major changes in the faecal microbiota and significantly decreased abundance of Akkermansia muciniphila which is strongly and negatively affected by old age in humans. Transcriptomics revealed age-associated decreases in the expression of immunity and other genes in intestinal mucosal tissue, including decreased T cell-specific transcripts and T cell signalling pathways. The physiological and immunological changes we observed in the intestine in old age, could have major consequences beyond the gut.
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http://dx.doi.org/10.1038/s41598-018-35228-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363726PMC
February 2019

Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol.

Nutrients 2019 Jan 22;11(2). Epub 2019 Jan 22.

Department of Cell Biology and Immunology, Wageningen University & Research, 6708 WD Wageningen, The Netherlands.

Background: Pycnogenol (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far.

Aim: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated.

Findings: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion.

Conclusions: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).
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http://dx.doi.org/10.3390/nu11020214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412808PMC
January 2019

Aged mice display altered numbers and phenotype of basophils, and bone marrow-derived basophil activation, with a limited role for aging-associated microbiota.

Immun Ageing 2018 29;15:32. Epub 2018 Nov 29.

1Cell Biology and Immunology Group, Wageningen University, Wageningen, the Netherlands.

Background: The influence of age on basophils is poorly understood, as well as the effect of aging-associated microbiota on basophils. Therefore, we studied the influence of aging and aging-associated microbiota on basophil frequency and phenotype, and differentiation from basophil precursors.

Results: Basophils became more abundant in bone marrow (BM) and spleens of 19-month-old mice compared with 4-month-old mice. Aged basophils tended to express less CD200R3 and more CD123, both in BM and spleen. Differences in microbiota composition with aging were confirmed by 16S sequencing. Microbiota transfers from young and old mice to germ-free recipients revealed that CD11b tended to be lowered on splenic basophils by aging-associated microbiota. Furthermore, abundance of , , , and family positively correlated and CD123 expression, whereas abundance negatively correlated with basophils numbers.Subsequently, we purified FcεRIαCD11cCD117 BM-derived basophils and found that those from aged mice expressed lower levels of CD11b upon stimulation. Higher frequencies of IL-4 basophils were generated from basophil precursors of aged mice, which could be reproduced in basophils derived from germ-free recipients of aging-associated microbiota.

Conclusions: Collectively, these results show the influence of aging on basophils. Furthermore, this study shows that aging-associated microbiota altered activation of BM-derived basophils in a similar fashion as observed in BM-derived basophils from aged mice.
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http://dx.doi.org/10.1186/s12979-018-0135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263040PMC
November 2018

Bovine Lactoferrin Enhances TLR7-Mediated Responses in Plasmacytoid Dendritic Cells in Elderly Women: Results From a Nutritional Intervention Study With Bovine Lactoferrin, GOS and Vitamin D.

Front Immunol 2018 20;9:2677. Epub 2018 Nov 20.

Cell Biology and Immunology, Wageningen University, Wageningen, Netherlands.

During aging the immune system is dysregulated. Especially plasmacytoid dendritic cells (pDCs) and myeloid DCs (mDCs) have reduced Toll like receptor (TLR)-mediated responses resulting in increased susceptibility to infections. Consumption of bovine lactoferrin (bLF) has been shown to reduce infections with viruses. Galacto-oligosacharides (GOS) and vitamin D are associated with reduced pro-inflammatory cytokine levels in serum, and increased TLR7/8 responses, respectively. A double-blind placebo-controlled nutritional intervention study in elderly women was performed, to investigate the potential of bLF, GOS, and vitamin D to restore TLR responsiveness of pDCs and mDCs and to reduce inflammatory markers in serum. The nutritional intervention group ( = 15) received bLF for 3 weeks, followed by 3 weeks of bLF + GOS, and subsequently 3 weeks of bLF + GOS + vitamin D. The placebo group ( = 15) received maltodextrin for 9 weeks. Every 3 weeks, blood was collected and TLR responses of pDCs and mDCs, and inflammation-related markers in serum were measured. After 3 weeks of bLF supplementation, increased TLR7/8 and TLR1/2 responses were observed in pDCs of the nutritional intervention group compared to the placebo group. When the effects of the entire nutritional intervention were investigated, increased TLR1/2 mediated responses in mDCs were observed, and in serum sVCAM tended to decrease. Finally, based on the RAND-36 questionnaire physical function tended to improve in the intervention group. Since especially TLR7-mediated responses in pDCs were enhanced after bLF supplementation compared to placebo, this suggests that bLF may contribute to antiviral responses mediated by pDC in elderly women.Clinical trial registry number: NCT03026244, clinicaltrials.gov.
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http://dx.doi.org/10.3389/fimmu.2018.02677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255898PMC
October 2019

The Basophil Activation Test reduces the need for a food challenge test in children suspected of IgE-mediated cow's milk allergy.

Clin Exp Allergy 2019 03 18;49(3):350-356. Epub 2018 Dec 18.

Department of Paediatrics, Rijnstate Hospital, Arnhem, The Netherlands.

Background: The gold standard for the diagnosis of cow's milk allergy is the Double-Blind Placebo-Controlled Food Challenge (DBPCFC) test. However, disadvantages of the DBPCFC are the potential risk of anaphylactic reactions, the time-consuming procedure and high costs.

Objective: The aim of this study was to determine the reliability of the Basophil Activation Test (BAT) both for the initial diagnosis of cow's milk allergy in children and for the determination of tolerance in children with cow's milk allergy.

Methods: Ninety-seven BATs and cow's milk-specific IgE (sIgE) tests were performed in 86 infants/young children, suspected of (persistent) cow's milk allergy, who were qualified for an in-hospital DBPCFC. The BAT was performed with cow's milk extract and the purified major allergens casein, α-lactalbumin, β-lactoglubulin. Basophil activation was determined by CD63 upregulation measured by flow cytometry. The BAT results were compared to the DBPCFC outcomes.

Results: Based on unequivocal DBPCFC and BAT result combinations (80%), the BAT had a sensitivity and specificity of 100% (CI: 86%-100% and 68%-100%, respectively) in IgE-sensitized children (41% of the tested children). All non-IgE-sensitized children (59%) had a negative DBPCFC and BAT, except for five patients. These latter showed delayed and relatively mild symptoms in the DBPCFC with a negative BAT, supporting a non-IgE-mediated allergy in these children.

Conclusions And Clinical Relevance: The BAT seems reliable and cost-effective to diagnose patients with an IgE-mediated cow's milk allergy. In IgE-sensitized patients, a BAT might replace a DBPCFC. For non-IgE-sensitized patients presenting with mild symptoms, we propose to consider a (double-blind) extended (time) challenge test at home.
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http://dx.doi.org/10.1111/cea.13307DOI Listing
March 2019