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In de westerse wereld is de dieetinname van meervoudig onverzadigde langeketen-n-3-vetzuren relatief laag, terwijl deze vetzuren bijdragen aan de neurologische en visuele ontwikkeling, het functioneren van het immuunsysteem en bescherming bieden tegen hart- en vaatziekten. Uit recent onderzoek is gebleken dat deze n-3-vetzuren mogelijk ook de kans op het ontwikkelen van een allergie verminderen. Zo toonden kleinschalige, placebogecontroleerde interventiestudies aan dat de suppletie van langeketen-n-3-vetzuren -in de vorm van visolie- tijdens de zwangerschap en lactatie bescherming kan bieden tegen het ontstaan van atopisch eczeem van het kind en op latere leeftijd de kans op het ontwikkelen van astma kan verminderen. De effecten zijn echter niet eenduidig en de timing en dosering van de n-3-vetzuurinterventie en de genetische predispositie kunnen van cruciaal belang zijn voor het beschermende effect. Dit moet in grootschalige interventiestudies verder worden onderzocht. Onderzoek naar de effecten van n-3-vetzuren bij allergie richt zich met name op preventie. Er zijn echter aanwijzingen dat allergie gepaard kan gaan met verminderde n-3-vetzuur-plasmaniveaus, wat mogelijk kan bijdragen aan de mate van ernst van de symptomen. Meer onderzoek naar de toepassing van langeketen-n-3-vetzuren is niet alleen nodig voor preventie, maar ook ter ondersteuning van de behandeling van allergieën, zoals atopisch eczeem en astma, mogelijk in combinatie met medicijnen.

Background: Screening for specific IgE against 2S albumin proteins Ara h 2 and 6 has good positive predictive value in diagnosing peanut allergy. From the third 2S member Ara h 7, 3 isoforms have been identified. Their allergenicity has not been elucidated. Objective: This study investigated the allergenicity of Ara h 7 isoforms compared to Ara h 2 and 6. Methods: Sensitization of 15 DBPCFC-confirmed peanut-allergic patients to recombinant Ara h 2.0201, Ara h 6.01 and isoforms of recombinant Ara h 7 was determined by IgE immunoblotting strips. A basophil activation test (BAT) was performed in 9 patients to determine IgE-cross-linking capacities of the allergens. Sensitivity to the allergens was tested in 5 patients who were sensitized to at least 1 Ara h 7 isoform, by a concentration range in the BAT. 3D prediction models and sequence alignments were used to visualize differences between isoforms and to predict allergenic epitope regions. Results: Sensitization to Ara h 7.0201 was most frequent (80%) and showed to be equally potent as Ara h 2.0201 and 6.01 in inducing basophil degranulation. Sensitization to Ara h 7.0201 together with Ara h 2.0201 and/or 6.01 was observed, indicating the presence of unique epitopes compared to the other 2 isoforms. Differences between the 3 Ara h 7 isoforms were observed in C-terminal cysteine residues, pepsin and trypsin cleavage sites and 3 single amino acid substitutions. Conclusion & clinical relevance: The majority of peanut-allergic patients are sensitized to isoform Ara h 7.0201, which is functionally as active as Ara h 2.0201 and 6.01. Unique epitopes are most likely located in the C-terminus or an allergenic loop region which is a known allergenic epitope region for Ara h 2.0201 and 6.01. Due to its unique epitopes and allergenicity, it is an interesting candidate to improve the diagnostic accuracy for peanut allergy.

Background: The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). Main body: The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell-cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. Conclusion: The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs. © 2017 The Author(s).

Background: At-risk infants can be prevented from developing food allergy symptoms by feeding them hypoallergenic formulas containing cow's milk protein hydrolysates. This preventive effect might be a result of oral tolerance induction by immunogenic peptide fractions in the hydrolysates. Early exposure to toleranceinducing peptides could prevent the development of allergic symptoms. It is hypothesised that synbiotics (pre- and probiotics) can further enhance tolerance induction. Method: Three-week-old female C3H/ HeOuJ mice (N = 6-8) were exposed orally to (1) PBS (positive control for allergy), to (2) whey protein (positive control for tolerance induction), or (3) a low dose mixture of beta-lactoglobulin-derived peptides (18 amino acids) with a synbiotics-enriched diet prior to sensitization. Thereafter, the mice were fed a control cow's milk protein-free diet and sensitized to whey protein using cholera toxin as an adjuvant. Mice were intradermally challenged with whey protein, and clinical symptoms, such as acute allergic skin response and anaphylactic shock, were measured. Results: The combination of the peptide intervention with a synbiotics-enriched diet resulted in a significant reduction in the acute allergic skin response compared to the allergic positive control. Furthermore, the combined peptides-synbiotics exposure prevented from developing significantly higher anaphylactic shock symptoms when compared to the sham-sensitized controls. Conclusion: Oral exposure to specific betalactoglobulin- derived peptides with synbiotics leads to protection against acute allergic responses. The beta-lactoglobulinderived peptides were administered at a dosage 100-fold lower than previously described by Meulenbroek et al. [1], therefore a combined approach like this might reduce the peptide dose needed to prevent allergy. Future research is needed for unravelling the underlying mechanisms of the preventive effect of this combined exposure.

Background: Although never evaluated for efficacy, n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS). Objective: This study was designed to investigate, in a mast cell dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment,via peroxisome proliferator-activated receptor gamma (PPARG) activation. Methods: Maternally separated rats were subjected to hypersensitivity-inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil supplemented diets [4% soy oil (SO) and 3% tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg . kg(-1) . d(-1)). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor alpha (TNF-alpha) and beta-hexosaminidase release. Results: Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 +/- 4 vs. 128 +/- 12 (P < 0.05) vs. 115 +/- 14 and 82 +/- 5 vs. 127 +/- 16 (P< 0.01) vs. 113 +/- 19, respectively]. Comparison of SO-T7 with its control showed similar results [74 +/- 6 vs. 103 +/- 13 (P < 0.05) vs. 115 +/- 17 and 66 +/- 3 vs. 103 +/- 10 (P < 0.05) vs. 117 +/- 11, respectively]. Erythrocytes showed significant LCPUFA uptake in the absence of colonic PPARG activation. Rosiglitazone induced increased PPARG target gene expression, but did not prevent hypersensitivity. Mast cell degranulation never differed between groups. Rosiglitazone and LCPUFAs significantly reduced PMA/calcium ionophore induced TNF-alpha release but not degranulation of HMC-1 cells.. Conclusion: Dietary LCPUFAs did not reverse stress-induced visceral hypersensitivity in maternally separated rats. Although further research is needed, claims concerning LCPUFAs as a treatment option in IBS cannot be confirmed at this point and should be regarded with caution.

Human milk is very rich in nondigestible oligosaccharides, which support colonization of Bifidobacteria and Lactobacilli and immune maturation. Manufactured nondigestible oligosaccharides are added to infant formula in order to mimic functional aspects of human milk oligosaccharides. They support the growth of beneficial microbes and reduce gastrointestinal and respiratory infections. Furthermore they reduce the risk of developing allergic disease when provided early in life. Oral tolerance induction is key in the prevention of allergies. Environmental factors such as dietary constituents and the colonization with commensal microorganisms at the mucosal surface are crucial for the generation of mucosal tolerance. Evidence is building that nondigestible galacto- and fructo-oligosaccharides can either directly or indirectly modulate the GALT and systemic immune system in health and disease. Besides increasing IL-10 and IgA in mice and human, they were found to induce functional regulatory T-cells in spleens of mice affected with cow’s milk allergy. In addition, they induce galectin-9 capable of IgE neutralization. The immunologic basis by which nondigestible oligosaccharides may affect the mucosal and systemic immune system is discussed in this book chapter.

To provide insight in the molecular basis for intestinal host-microbe interactions, we determined the genome-wide transcriptional response of human intestinal epithelial cells following exposure to cells of Bifidobacterium breve. To select an appropriate test system reflecting inflammatory conditions, the responsiveness to TNF-a was compared in T84, Caco-2 and HT-29 cells. The highest TNF-a response was observed in HT-29 cells and this cell line was selected for exposure to the B. breve strains M-16V, NR246 and UCC2003. After one hour of bacterial pre-incubation followed by two hours of additional TNF-a stimulation, B. breve M-16V (86%), but to a much lesser extent strains NR246 (50%) or UCC2003 (32%), showed a strain-specific reduction of the HT-29 transcriptional response to the inflammatory treatment. The most important functional groups of genes that were transcriptionally suppressed by the presence of B. breve M-16V, were found to be involved in immune regulation and apoptotic processes. About 54% of the TNF-a induced genes were solely suppressed by the presence of B. breve M-16V. These included apoptosis-related cysteine protease caspase 7 (CASP7), interferon regulatory factor 3 (IRF3), amyloid beta (A4) precursor protein-binding family A member 1 (APBA1), NADPH oxidase (NOX5), and leukemia inhibitory factor receptor (LIFR). The extracellular IL-8 concentration was determined by an immunological assay but did not change significantly, indicating that B. breve M-16V only partially modulates the TNF-a pathway. In conclusion, this study shows that B. breve strains modulate gene expression in HT-29 cells under inflammatory conditions in a strain-specific way. © 2011 Wageningen Academic Publishers.

The prevalence of food allergies is increasing worldwide, particularly but not only in developed countries and has an impact on the quality of life of affected children and adults. Food allergies can develop when immunological tolerance against harmless food allergens is hampered. Currently, no lasting treatment options are available to restore long-lasting tolerance in peanut-allergic patients. Immunotherapeutic approaches aiming to restore tolerance are still under development. Major issues are efficacy and the frequent occurrence of sometimes severe allergic reactions. To further optimize these immunotherapeutic approaches, more interest is gained towards the use of specific adjuvants during immunotherapy, such as anti-IgE antibody omalizumab or even dietary components. The rationale behind the use of dietary adjunct therapy is that these components have immunomodulatory capacities, and may already skew the immune response away from the allergenic phenotype towards a more regulatory or T helper 1 (Th1) phenotype. Hereby they support the immunotherapeutic approaches, rendering them more safe and efficacious. The most important focus of this thesis was the investigation of the immunomodulatory effects of dietary non-digestible oligosaccharide (NDO) mixtures consisting of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) and short-and long-chain fructo-oligosaccharides (scFOS/lcFOS). Based on previous studies, it was hypothesized that they might be able to contribute to the safety and efficacy of developing approaches for allergen-specific immunotherapy. These immunomodulatory effects were investigated in in vitro models using blood of peanut-allergic patients. The results of this thesis provide valuable insights into the immunomodulatory effects of non-digestible oligosaccharides, as they, for example, can skew the immune function towards a more regulatory and Th1-like phenotype in an in vitro environment. In addition, NDOs were able to reduce basophil degranulation and modify antigen presentation by DCs in the presence of peanut-extract. The development of peanut allergy and food allergy in general is a complex phenomenon, which requires more research to understand, but we hypothesize that adjunct therapy with NDOs in combination with immunotherapy might be the next step in safely inducing long-lasting tolerance in peanut-allergic patients.