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Abstract: This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing (SPT), or elevated allergen‐specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random‐effects models. Early‐life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13‐1.34; I2: 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15‐1.37; I2: 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08‐1.87; I2: 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen‐specific serum/plasma IgE levels. [ABSTRACT FROM AUTHOR]

Background: Although total IgE levels have been proposed as a biomarker for disease severity in atopic dermatitis (AD) and are increased in the majority of AD patients, they do not correlate with disease severity during short-term follow-up. During the synthesis of immunoglobulins, free light chains (Ig-FLCs) are produced in excess over heavy chains. In comparison with IgE molecules, Ig-FLCs have a very short serum half-life. Therefore, Ig-FLCs might be more suitable as a biomarker for disease severity during follow-up. Recent studies showed increased serum levels of kappa Ig-FLCs in infants with AD, correlating with disease severity. The aim of this study was to investigate serum kappa Ig- FLC levels in adults with AD, and their correlation to disease severity. Methods: Serum kappa If-FLC and total IgE levels were measured in 82 moderate to severe AD patients and 49 nonatopic controls. Blood was collected from patients before start of treatment with potent topical steroids (European classification: III-IV). 32 patients were treated during a clinical admission, and in this subpopulation a second blood sample was taken after 2 weeks of treatment. Clinical severity was determined by the Six Area Six Sign Atopic Dermatitis (SASSAD) severity score and a panel of serum biomarkers, including thymus and activation-regulated chemokine (TARC). Results: Serum kappa Ig-FLCs levels in adult AD patients were not increased compared to non-atopic controls. Moreover, we observed no correlation between kappa Ig-FLC serum levels and disease severity determined by SASSAD and a panel of serum biomarkers, including TARC. Serum kappa Ig-FLC levels did also not decrease during treatment. Conclusion: There are no differences in serum kappa Ig-FLC levels between adult patients suffering from moderate to severe AD compared to non-atopic controls. Moreover, serum levels of kappa Ig-FLCs cannot be used as a biomarker for disease severity in adult AD. [ABSTRACT FROM AUTHOR]

Background Prevention guidelines for infants at high risk of allergic disease recommend hydrolysed formula if formula is introduced before 6 months, but evidence is mixed. Adding specific oligosaccharides may improve outcomes. Objective To evaluate whether partially hydrolysed whey formula containing oligosaccharides (0.8 g/100 ml) (pHF-OS) can prevent eczema in high-risk infants [ISRCTN65195597]. Methods We conducted a parallel-group, multicentre, randomized double-blind controlled trial of pHF-OS vs standard cow's milk formula. Infants with a family history of allergic disease were randomized (stratified by centre/maternal allergy) to active ( n = 432) or control ( n = 431) formula until 6 months of age if formula was introduced before 18 weeks. Primary outcome was cumulative incidence of eczema by 12 months in infants randomized at 0-4 weeks (375 pHF-OS, 383 control). Secondary outcomes were cumulative incidence of eczema by 12 or 18 months in all infants randomized, immune markers at 6 months and adverse events. Results Eczema occurred by 12 months in 84/293 (28.7%) infants allocated to pHF-OS at 0-4 weeks of age, vs 93/324 (28.7%) control (OR 0.98 95% CI 0.68, 1.40; P = 0.90), and 107/347 (30.8%) pHF-OS vs 112/370 (30.3%) control in all infants randomized (OR 0.99 95% CI 0.71, 1.37; P = 0.94). pHF-OS did not change most immune markers including total/specific IgE; however, pHF-OS reduced cow's milk-specific IgG1 ( P < 0.0001) and increased regulatory T-cell and plasmacytoid dendritic cell percentages. There was no group difference in adverse events. Conclusion pHF-OS does not prevent eczema in the first year in high-risk infants. The immunological changes found require confirmation in a separate cohort. [ABSTRACT FROM AUTHOR]

Background Cow's milk allergy is a common food allergy in childhood and no effective preventive or curative treatment is available. This study aimed at comparing single short-chain galacto- (sc GOS), long-chain fructo- (lc FOS) or pectin-derived acidic oligosaccharides (p AOS) and/or mixtures of sc GOS/lc FOS (GF) or sc GOS/lc FOS/p AOS ( GFA) to prevent or treat food allergy. Methods In the preventive protocol, C3H/HeOuJ mice were fed diets containing single oligosaccharides or mixtures GF or GFA throughout the study protocol. In the treatment protocol, GF or GFA was provided for 4 wk starting after the last sensitization. The allergic skin response and anaphylaxis scores were determined, after oral challenge whey-specific immunoglobulins were measured, and q PCR for T-cell markers and Foxp3 counts using immunohistochemistry were performed on the small intestine and colon. Results Only in the preventive setting, the GF or GFA mixture, but not the single oligosaccharides, reduced the allergic skin response and whey-IgG1 levels in whey-sensitized mice, compared to the control diet. Both GF and GFA increased the number of Foxp3+ cells in the proximal small intestine of whey - compared to sham-sensitized mice. Expression of Th2 and Th17 m RNA markers increased in the middle part of the small intestine of whey-sensitized mice, which was prevented by GF. By contrast, GFA enhanced Tbet (Th1), IL-10 and TGF-β m RNA expression compared to GF which was maintained in the distal small intestine and/or colon. Conclusions Dietary supplementation with sc GOS/lc FOS or sc GOS/lc FOS/p AOS during sensitization, both effectively reduce allergic symptoms but differentially affect mucosal immune activation in whey-sensitized mice. [ABSTRACT FROM AUTHOR]

Background Several studies investigated whether hydrolysed proteins can induce tolerance to cow's milk ( CM) in children at risk of developing CM allergy. Due to methodological problems and inconsistent findings, the evidence for a tolerogenic effect is limited. A major problem is that different hydrolysates may give different outcomes due to variations in their production and composition. Objective The aim of the study was to investigate the effect of the degree of hydrolysis on the allergenicity and immunogenicity of whey hydrolysates. Methods The hydrolysis of whey was stopped at different time-points between 1 and 60 min. In 18 CM allergic patients, the allergenicity of the hydrolysates was determined by immunoblot and the basophil activation test. To test immunogenicity, CM-specific T cell lines were generated. Results In most patients, increasing time of hydrolysis decreased Ig E recognition and basophil activation. However, in five patients, hydrolysed proteins induced more basophil activation than non-hydrolysed proteins. The immunoblot data indicated that these patients recognized either a 25- to 30-kDa degradation product of casein or a 10-kDa degradation product of whey. Although T cell activation was decreased in all patients over time, half of them still showed a positive response to the proteins after 60 min of hydrolysis. Conclusion Increasing the time of hydrolysis reduces both allergenicity and immunogenicity of whey hydrolysates in most but not all patients. This indicates that not the degree of hydrolysis is decisive but the presence and stability of Ig E and T cell epitopes in the hydrolysate recognized by individual patients. [ABSTRACT FROM AUTHOR]

Background Recently, we have shown that dietary long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) largely prevent allergic sensitization in a murine model for cow's milk allergy. The aim of this study was to assess the contribution of regulatory T cells (Treg) in the prevention of food allergy by n-3 LCPUFA. Methods C3H/HeOuJ female donor mice were fed a control or fish oil diet before and during oral sensitization with cow's milk protein whey. Acute allergic skin response ( ASR), anaphylaxis, body temperature, serum immunoglobulins, and mouse mast cell protease-1 (mmcp-1) were assessed. Splenocytes of sham- or whey-sensitized donor mice fed either control or fish oil diet were adoptively transferred to naïve recipient mice. Recipient mice received a whole splenocyte suspension, splenocytes ex vivo depleted of CD25+ cells, or MACS-isolated CD4+ CD25+ Treg. Recipient mice were sham- or whey-sensitized and fed control diet. Results The ASR as well as whey-specific Ig E and whey-specific Ig G1 levels were reduced in whey-sensitized donor mice fed the fish oil diet as compared to the control diet. Splenocytes of control-diet-fed whey-sensitized donors transferred immunologic memory. By contrast, splenocytes of fish-oil-fed whey-sensitized - but not sham-sensitized - donors transferred tolerance to recipients as shown by a reduction in ASR and serum mmcp-1, and depletion of CD25+ Treg abrogated this. Transfer of CD25+ Treg confirmed the involvement of Treg in the suppression of allergic sensitization. Conclusions CD25+ Treg are crucial in whey allergy prevention by n-3 LCPUFA. [ABSTRACT FROM AUTHOR]

Background Cow's milk allergy is one of the most common food allergies in children and no treatment is available. Dietary lipid composition may affect the susceptibility to develop allergic disease. Objective Assess whether dietary supplementation with long chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) prevents the establishment of food allergy. Methods Mice were fed a control or fish oil diet before and during oral sensitization with whey. Acute allergic skin response, serum immunoglobulins as well as dendritic cell ( DC) and T cell subsets in mesenteric lymph nodes ( MLN), spleen and/or small intestine were assessed. Results The acute allergic skin response was reduced by more than 50% in sensitized mice fed the fish oil diet compared to the control diet. In addition, anti-whey-IgE and anti-whey-IgG1 levels were decreased in the fish oil group. Serum transfer confirmed that the Th2-type humoral response was suppressed since sera of fish oil fed sensitized mice had a diminished capacity to induce an allergic effector response in naïve recipient mice compared to control sera. Furthermore, the acute skin response was diminished upon passive sensitization in fish oil fed naïve recipient mice. In addition, the percentage of activated Th1 cells was reduced by fish oil in spleen and MLN of sham mice. The percentage of activated Th2 cells was reduced in both sham- and whey-sensitized mice. In contrast, whey-sensitized mice showed an increased percentage of CD11b+ CD103+ CD8α- DC in MLN in association with enhanced FoxP3+ regulatory T cells (Treg) in spleen and intestine of fish oil fed whey-sensitized mice compared to sham mice. Conclusions and Clinical Relevance Dietary n-3 LCPUFA largely prevented allergic sensitization in a murine model for cow's milk allergy by suppressing the humoral response, enhancing local intestinal and systemic Treg and reducing acute allergic symptoms, suggesting future applications for the primary prevention of food allergy. [ABSTRACT FROM AUTHOR]

Summary Background In a murine model of allergic inflammation, B ifidobacterium breve M-16 V has been shown to reduce IL-4 and IgE by inducing IL-10 and IFN-γ. However, it remains unknown whether this strain has the same effect in humans with allergic disease. Objective To determine the effects of B ifidobacterium breve M-16 V combined with a prebiotic oligosaccharide mixture (synbiotic) on atopic markers, ex vivo cytokine production by peripheral blood mononuclear cells ( PBMCs) and circulating regulatory T cell percentage in infants with atopic dermatitis. Methods In a double-blind, placebo-controlled multi-centre trial, 90 infants with atopic dermatitis, age <7 months, were randomized to receive an infant formula with B ifidobacterium breve M-16 V and a mixture of short chain galactooligosaccharides and long chain fructooligosaccharides ( Immunofortis®), or the same formula without synbiotics during 12 weeks. At week 0 and 12, plasma levels of IL-5, IgG1, IgG4, CTACK and TARC, ex vivo cytokine responses by PBMCs and percentage of regulatory T cells, were determined. Results There were no significant differences between the synbiotic and the placebo group in IL-5, IgG1, IgG4, CTACK and TARC levels and ex vivo cytokine production by anti- CD3/anti- CD28-stimulated PBMCs. With allergen-specific stimuli, we found a decreased IL-12p40/70 and IL-12p70 production in response to egg allergen ( P = 0.04 and P = 0.01, respectively) and decreased IL-12p70 production in response to peanut allergen ( P = 0.003) in the synbiotic compared with the placebo group. Circulating regulatory T cell percentage did not significantly differ between the groups. Conclusions and Clinical Relevance This synbiotic mixture has no detectable effect on plasma levels of the analysed atopic disease markers, ex vivo cytokine production and circulating regulatory T cell percentage in infants with atopic dermatitis, besides down-regulation of IL-12 production in egg- and peanut-stimulated PBMCs. These results do not support the use of this synbiotic in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Prebiotic galacto- and fructo-oligosaccharides (sc GOS/lc FOS) resembling non-digestible oligosaccharides in human milk reduce the development of atopic disorders. However, the underlying mechanisms are still unclear. Galectins are soluble-type lectins recognizing β-galactoside containing glycans. Galectin-9 has been shown to regulate mast cell degranulation and T-cell differentiation. In this study, the involvement of galectin-9 as a mechanism by which sc GOS/lc FOS in combination with Bifidobacterium breve M-16 V protects against acute allergic symptoms was investigated. Methods: Mice were sensitized orally to whey, while being fed with a diet containing sc GOS/lc FOS and Bifidobacterium breve M-16 V ( GF/ Bb) or a control diet. Galectin-9 expression was determined by immunohistochemistry in the intestine and measured in the serum by ELISA. T-cell differentiation was investigated in the mesenteric lymph nodes ( MLN) as well as in galectin-9-exposed peripheral blood mononuclear cells ( PBMC) cultures. Sera of the mice were evaluated for the capacity to suppress mast cell degranulation using a RBL-2 H3 degranulation assay. In addition, in a double-blind, placebo-controlled multicenter trial, galectin-9 levels were measured in the sera of 90 infants with atopic dermatitis who received hydrolyzed formulae with or without GF/ Bb. Results: Galectin-9 expression by intestinal epithelial cells and serum galectin-9 levels were increased in mice and humans following dietary intervention with GF/ Bb and correlated with reduced acute allergic skin reaction and mast cell degranulation. In addition, GF/ Bb enhanced Th1- and Treg-cell differentiation in MLN and in PBMC cultures exposed to galectin-9. Conclusions: Dietary supplementation with GF/ Bb enhances serum galectin-9 levels, which associates with the prevention of allergic symptoms. [ABSTRACT FROM AUTHOR]

Background Symptoms of allergy are largely attributed to an IgE-mediated hypersensitivity response. However, a considerable number of patients also exhibit clinical features of allergy without detectable systemic IgE. Previous work showed that Ig-free light chains (IgLC) may act as an alternate mechanism to induce allergic responses. CD4+CD25+ T cells are crucial in the initiation and regulation of allergic responses and compromised function might affect the response to allergens. Objective To examine the contribution of CD4+CD25+ T cells and IgLC towards the whey-allergic response. Methods Mice were sensitized orally with whey using cholera toxin as an adjuvant. CD25+ T cells were depleted in vivo using a CD25 mAb. The acute allergic skin response to whey and ex vivo colon reactivity was measured in the presence or absence of F991, a specific inhibitor of IgLC. Serum whey-specific antibodies and IgLC in serum and mesenteric lymph node (MLN) supernatants were measured. Depletion of CD4+CD25+ T cells was confirmed in the spleen. Results Anti-CD25 treatment strongly reduced whey-specific antibody levels and resulted in a partial depletion of effector T cells and a major depletion of Foxp3+ regulatory T cells. Surprisingly, despite the abolished specific IgE response, the acute allergic skin response to whey was not affected. IgLC levels were enhanced in the serum and MLN supernatants of CD25-depleted sensitized mice. F991 inhibited the acute skin response and colon hyperreactivity in anti-CD25-treated mice, indicating that these responses were mainly IgLC dependent. Conclusions Depletion of CD4+CD25+ T cells resulted in a switch from an IgE- to an IgLC-dependent acute skin response and functional hyperresponsiveness of the colon. Our data suggest that CD25+ T cells play a crucial role in balancing cow's milk allergy between IgE and IgE-independent responses and both mechanisms might play a role in allergic responses to the same allergen. Cite this as: B. C. A. M. van Esch, B. Schouten, B. R. J. Blokhuis, G. A. Hofman, L. Boon, J. Garssen L. M. J. Knippels, L. E. M. Willemsen and F. A. Redegeld, Clinical & Experimental Allergy, 2010 (40) 1414–1421. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that human breast milk oligosaccharides play a role in the development of the immune system in infants, and may consequently inhibit the onset of allergy. A specific prebiotic mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (GOS/FOS) has been shown to reduce the incidence of atopic dermatitis (AD) at 6 months of age in infants at risk for allergy. Aim of the study: This study was aimed to analyze the effect of GOS/FOS on the immune response in these infants. Methods: In a double-blind randomized placebo-controlled study, infants received a hypoallergenic whey formula with either 8 g/l GOS/FOS in a 9 : 1 ratio (IMMUNOFORTISTM) or 8 g/l maltodextrine (placebo) for 6 months. At 3 months of age, children were vaccinated with Hexavac against a.o. diphteria, tetanus, polio (DTP). At 6 months of age, plasma samples were collected from 84 infants (verum group n = 41, placebo group n = 43). Levels of total immunoglobulins (Ig) and of cow’s milk protein (CMP-) and DTP-specific Ig were measured. Results: GOS/FOS supplementation led to a significant reduction in the plasma level of total IgE, IgG1, IgG2 and IgG3, whereas no effect on IgG4 was observed. CMP-specific IgG1 was significantly decreased. DTP-specific Ig levels were not affected. Conclusions: This study shows that GOS/FOS supplementation induces a beneficial antibody profile. GOS/FOS reduces the total Ig response and modulates the immune response towards CMP, while leaving the response to vaccination intact. This suggests that oral GOS/FOS supplementation is a safe method to restrain the atopic march. [ABSTRACT FROM AUTHOR]

Background The central role of specific IgE in cow's milk allergy (CMA) is well documented. However, less is known about the function of other immunoglobulin isotypes in allergy and tolerance to cow's milk proteins (CMPs). Objective To determine differences in the antibody responses that are associated with allergy and tolerance to cow's milk in allergic, atopic and non-atopic individuals of different age groups. Methods Nineteen infants (<1 year), 18 children (6–14 years) and 41 adults (21–68 years) were included. Each age group was comprised of subjects with CMA, atopic individuals without a history of CMA and non-atopic subjects. Levels of specific IgE, IgG4, IgG1 and IgA to whole cow's milk and the six most abundant individual CMPs were determined in plasma by ELISA. For comparison, specific IgE and IgG4 were measured to ovomucoid and house dust mite (HDM) in individuals allergic for the respective allergens, and in atopic and non-atopic subjects without allergy. Results In infants and children with CMA, αs1-casein and β-lactoglobulin induced the highest specific IgE response, whereas αs1-casein was the most allergenic CMP in adult patients. Specific IgG4 and IgG1 responses were the highest to αs1-casein and β-lactoglobulin in all age groups, while κ-casein and α-lactalbumin induced the highest levels of IgA. CMP-specific IgG4 was higher in atopic children and adults without CMA, as compared with non-atopic individuals. A similar difference between tolerant atopic and non-atopic subjects was observed for IgG4 specific to ovomucoid, whereas HDM-specific IgG4 was not detectable in these subjects. Conclusion Maintenance of tolerance to cow's milk in atopic children and adults without CMA is associated with elevated levels of specific IgG4, in combination with low specific IgE. The up-regulation of specific IgG4 in tolerant atopic individuals may be related to the type of allergen and its regular dose of exposure. [ABSTRACT FROM AUTHOR]

Background One to two percent of infants suffer from IgE-mediated allergic reactions against cow's milk proteins. Most children develop clinical tolerance, but approximately 15% are still allergic by the age of 10 years. Little is known about the T cell epitopes in individual cow's milk protein in relation to allergy and tolerance. Objective To identify T cell epitopes in αs1-casein, the most abundant milk protein, and to investigate T cell responses toward these epitopes in allergic, atopic and non-atopic children. Methods Allergen-specific T cell lines (TCLs) were derived from peripheral blood mononuclear cells of 11 cow's milk allergic, nine atopic and nine non-atopic children. T cell responses were measured to αs1-casein and to overlapping peptides (18-mers), spanning the αs1-casein molecule. Proliferation was determined by incorporation of 3H-thymidine, and cytokine production (IL-10, IL-13 and IFN-γ) was measured by ELISA. Results Four main regions (amino acid (AA) residues 43–66, 73–96, 91–114 and 127–180) in the αs1-casein molecule were immunogenic to T cells, among which the AA residues 133–156 spanned the immunodominant part. Only subtle differences were found in peptide recognition between the subject groups. Some of the peptides induced slightly Th1- or Th2-skewed cytokine responses. The increased levels of IL-10 in response to αs1-casein observed in TCLs from atopic children appeared not to be linked to recognition of specific IL-10-inducing epitopes. Conclusions The immunodominant sequence in αs1-casein is spanned by AA residues 133–156. Tolerance towards αs1-casein in atopic children may be mediated by an overall induction of IL-10 and not by recognition of certain T cell epitopes. The identified T cell epitopes in children with cow's milk allergy may be useful targets in developing peptide immunotherapy. [ABSTRACT FROM AUTHOR]

Although as pretreatment oral tolerance is a potent means to achieve systemic suppression, its application in ongoing disease is controversial. Here we propose that availability of naive T cells may critically determine whether immunological tolerance is achieved during ongoing antigenic reactivity. Infusion of naive antigen-specific T cells into mice directly prior to eliciting a secondary Th2 response induces these naive cells to actively engage in the antigenic response despite presence of established memory. Naive antigen-specific T-cells divided faster, produced more interleukin (IL)-2, IL-4 and IL-5 and enhanced immunoglobulin E (IgE) release during a secondary Th2 response, compared with naive T cells that were infused prior to a primary response. Despite such contribution by new cohorts of naive T cells co-infusion of mucosal Tr together with naive T cells could suppress enhanced IgE release during a secondary Th2 response. We conclude that naive T cells contribute to a secondary Th2 response and although they can still be suppressed in the presence of sufficient numbers of mucosal Tr, they may interfere with potential therapeutic application of mucosal tolerance. [ABSTRACT FROM AUTHOR]

We have studied delayed-type hypersensitivity (DTH) responses to picryl chloride (PCl) in the lungs of mice. Intranasal challenge with 0.6% picryl sulphonic acid (PSA), a water soluble form of PCl, of BALB/c mice, sensitized with PCl epicutaneously 1 week earlier, induced an accumulation of mononuclear inflammatory cells around bronchioli and blood vessels. Maximal inflammatory responses were seen 48 hr after challenge. These responses were antigen-specific, and also T-cell dependent, since athymic nude mice failed to show this reaction. A role for mast cells in the responses was studied using two strains of mast cell-deficient mice. In one of these (W/Wv) lung DTH responses to PCl were reduced severely. In the other strain (S1/S1d) the responses around vessels were decreased slightly, whereas the responses in the interstitial tissue and around bronchioli were similar to those in +/+ littermate controls. Involvement of serotonin was investigated using two serotonin receptor antagonists, i.e. methysergide and ketanserin. Treatment of mice with either of the antagonists prevented occurrence of the DTH-like reaction in the lung after intranasal antigen challenge. In the lungs of sensitized mice, significantly increased permeability was established 2 hr after antigen challenge. It was concluded that release of serotonin in the lung may provide an environment that comprises local vascular permeability and that facilitates the local recruitment and possibly the activation of DTH effector T cells, leading to subsequent attraction of mononuclear leucocytes into the lung. Immunological regulation of the DTH-like reactions in the lung was similar to that of contact sensitivity in the skin, since intravenous injection of an antigen-specific T-cell suppressor inducer factor prior to sensitization or pretreatment with a high dose of picryl sulphonic acid intravenously both resulted in reduction of the DTH-like lung histological response to picryl sulphonic acid. From these findings it was concluded that DTH-like lung responses are similar to DTH responses in the skin. [ABSTRACT FROM AUTHOR]

Inadequate reactions of the immune system, i.e. allergic or hypersensitivity reactions, can lead to lung tissue injury. We investigated the relationship of type IV hypersensitivity, as an example of IgE independent hypersensitivity, with the induction of airway hyperreactivity. After antigen challenge (picrylsulphonic acid (PSA] in picrylchloride (PCl) sensitized mice, peribronchial and perivascular accumulation of mononuclear cells was found that was maximal 48 h after challenge. At several time points after challenge, changes in smooth muscle tone of mouse isolated tracheas were measured isometrically. In sensitized mice the response to carbachol was increased, reaching a maximum 48 h after challenge. This hyperreactivity was not found in athymic (nude) mice. We concluded from these data that airway hyperreactivity can be immunologically induced other than by IgE. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is a food allergen driven disease that is accompanied by interleukin (IL) 13 overexpression and esophageal barrier dysfunction allowing transepithelial food allergen permeation. Nutraceuticals, such as short-chain fatty acids (SCFAs) that restore barrier function and increase immune fitness may be a promising tool in the management of EoE. Here, we investigated the effects of the SCFAs acetate, propionate, and butyrate on an IL-13-compromised human esophageal epithelial barrier, including the mechanisms involved., Methods: An air-liquid interface culture model of differentiated human EPC2-hTERT (EPC2) was used to study whether SCFAs could restore barrier function after IL-13-induced impairment. Esophageal epithelial barrier function was monitored by transepithelial electrical resistance (TEER) and FITC-dextran paracellular flux, and was further examined by qPCR and immunohistochemical analysis. G protein-coupled receptor (GPR) GPR41, GPR43, GPR109a, or histone deacetylase (HDAC) (ant)agonists were used to assess mechanisms of action of SCFAs., Results: IL-13 stimulation decreased TEER and increased FITC flux, which was counteracted by butyrate and propionate, but not acetate treatment. Barrier proteins FLG and DSG1 mRNA expression was upregulated following butyrate and propionate treatment, whereas expression of eosinophil chemoattractant CCL26 and protease CAPN14 was downregulated. Similarly, butyrate and propionate restored FLG and DSG1 protein expression. Similar effects were observed with an HDAC antagonist but not with GPR agonists., Conclusion: Nutraceuticals butyrate and propionate restore the barrier function of esophageal epithelial cells after an inflammatory insult and may be of therapeutic benefit in the management of EoE., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Hundreds of plant species release their pollen into the air every year during early spring. During that period, pollen allergic as well as non-allergic patients frequently present to doctors with severe respiratory tract infections. Our objective was therefore to assess whether pollen may interfere with antiviral immunity., Methods: We combined data from real-life human exposure cohorts, a mouse model and human cell culture to test our hypothesis., Results: Pollen significantly diminished interferon-λ and pro-inflammatory chemokine responses of airway epithelia to rhinovirus and viral mimics and decreased nuclear translocation of interferon regulatory factors. In mice infected with respiratory syncytial virus, co-exposure to pollen caused attenuated antiviral gene expression and increased pulmonary viral titers. In non-allergic human volunteers, nasal symptoms were positively correlated with airborne birch pollen abundance, and nasal birch pollen challenge led to downregulation of type I and -III interferons in nasal mucosa. In a large patient cohort, numbers of rhinoviruspositive cases were correlated with airborne birch pollen concentrations., Conclusion: The ability of pollen to suppress innate antiviral immunity, independent of allergy, suggests that high-risk population groups should avoid extensive outdoor activities when pollen and respiratory virus seasons coincide., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: At a group level, hangover severity during the day has been described to follow an inverted U-shaped curve, with gradually increasing severity scores that, after reaching a peak, gradually decrease toward zero. The aim of this study was to examine if and how individual drinkers' hangover severity scores vary during the day., Methods: Data from a survey (Penning et al., ) in which 727 drinkers reported on their latest alcohol hangover were reanalyzed. The temporal pattern of each individual's hangover was first categorized as belonging to 1 of 6 types based on predefined temporal characteristics., Results: Three dominant hangover patterns emerged as comprising more than 95% of the sample: (i) a continuous decline hangover (Severity Type 1 hangover, 54.5%), (ii) a steady state hangover (Severity Type 2 hangover, 19.1%), and (iii) an inverted U-shaped curve hangover (Severity Type 3 hangover, 21.8%). Of these 3 patterns, Severity Type 2 hangovers are associated with significantly less alcohol consumption and with having the lowest severity scores of individual hangover symptoms. Severity Type 1 hangovers are associated with having the highest severity of individual hangover symptoms. In line with significantly lower levels of alcohol consumption, Severity Type 2 hangovers were significantly more often observed in women when compared to men. Severity Type 1 hangovers were significantly more common in men than in women. Severity Type 3 hangovers, characterized by the increased presence of gastrointestinal complaints, were equally commonly experienced in men and women., Conclusions: This study revealed that the temporal pattern of hangover severity can follow marked interindividual variability. Three common temporal patterns were identified, which are uniquely related to the amount of alcohol consumed and the presence and severity of different individual hangover symptoms. Better understanding of individual differences in hangover typology may help to delineate mechanisms underlying alcohol hangover., (Copyright © 2018 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism.)

Aim: Eosinophilic oesophagitis (EO) is an emerging worldwide disease, closely associated with male gender and allergic disorders. This study investigated the distribution of allergy markers in a cohort of children with EO., Methods: We analysed allergy markers in 91 children (62 males and 29 females) with EO and a control group of 45 age-matched children who had non-EO gastrointestinal allergic symptoms. The markers analysed were serum cow's milk-specific and hen's egg-specific IgE, thymic stromal lymphopoietin (TSLP), thymus-regulated and activation-regulated chemokine (TARC/CCL17) and immunoglobulin free light chain (Ig-fLC)., Results: In the EO group, cow's milk-specific IgE levels were detectable in 41.9% of males and 62.1% of females and hen's egg-specific levels in 25% of males and 26.9% of females. There was no gender difference in increased TSLP or TARC levels. Kappa Ig-fLC were increased in 5.6% of males and 20.8% of females (p = 0.058) and lambda Ig-fLC in 1.9% of males and 33.3% of females (p = 0.000). No gender differences were found in the control group., Conclusion: Our findings suggest that serum TSLP might be a potential marker of EO and TARC of non-EO gastrointestinal food allergies. In EO, serum Ig-fLC appeared higher in females, adding another gender difference to the biology of EO., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Recently, we have shown that dietary long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFA) largely prevent allergic sensitization in a murine model for cow's milk allergy. The aim of this study was to assess the contribution of regulatory T cells (Treg) in the prevention of food allergy by n-3 LCPUFA., Methods: C3H/HeOuJ female donor mice were fed a control or fish oil diet before and during oral sensitization with cow's milk protein whey. Acute allergic skin response (ASR), anaphylaxis, body temperature, serum immunoglobulins, and mouse mast cell protease-1 (mmcp-1) were assessed. Splenocytes of sham- or whey-sensitized donor mice fed either control or fish oil diet were adoptively transferred to naïve recipient mice. Recipient mice received a whole splenocyte suspension, splenocytes ex vivo depleted of CD25+ cells, or MACS-isolated CD4+ CD25+ Treg. Recipient mice were sham- or whey-sensitized and fed control diet., Results: The ASR as well as whey-specific IgE and whey-specific IgG1 levels were reduced in whey-sensitized donor mice fed the fish oil diet as compared to the control diet. Splenocytes of control-diet-fed whey-sensitized donors transferred immunologic memory. By contrast, splenocytes of fish-oil-fed whey-sensitized - but not sham-sensitized - donors transferred tolerance to recipients as shown by a reduction in ASR and serum mmcp-1, and depletion of CD25+ Treg abrogated this. Transfer of CD25+ Treg confirmed the involvement of Treg in the suppression of allergic sensitization., Conclusions: CD25+ Treg are crucial in whey allergy prevention by n-3 LCPUFA., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Prebiotic galacto- and fructo-oligosaccharides (scGOS/lcFOS) resembling non-digestible oligosaccharides in human milk reduce the development of atopic disorders. However, the underlying mechanisms are still unclear. Galectins are soluble-type lectins recognizing β-galactoside containing glycans. Galectin-9 has been shown to regulate mast cell degranulation and T-cell differentiation. In this study, the involvement of galectin-9 as a mechanism by which scGOS/lcFOS in combination with Bifidobacterium breve M-16V protects against acute allergic symptoms was investigated., Methods: Mice were sensitized orally to whey, while being fed with a diet containing scGOS/lcFOS and Bifidobacterium breve M-16V (GF/Bb) or a control diet. Galectin-9 expression was determined by immunohistochemistry in the intestine and measured in the serum by ELISA. T-cell differentiation was investigated in the mesenteric lymph nodes (MLN) as well as in galectin-9-exposed peripheral blood mononuclear cells (PBMC) cultures. Sera of the mice were evaluated for the capacity to suppress mast cell degranulation using a RBL-2H3 degranulation assay. In addition, in a double-blind, placebo-controlled multicenter trial, galectin-9 levels were measured in the sera of 90 infants with atopic dermatitis who received hydrolyzed formulae with or without GF/Bb., Results: Galectin-9 expression by intestinal epithelial cells and serum galectin-9 levels were increased in mice and humans following dietary intervention with GF/Bb and correlated with reduced acute allergic skin reaction and mast cell degranulation. In addition, GF/Bb enhanced T(h)1- and T(reg)-cell differentiation in MLN and in PBMC cultures exposed to galectin-9., Conclusions: Dietary supplementation with GF/Bb enhances serum galectin-9 levels, which associates with the prevention of allergic symptoms., (© 2012 John Wiley & Sons A/S.)

To determine familial risk of early suicide, data on cause of death of all Dutch residents aged 20-55 years who died between 1995 and 2001 were linked to data of their parents. Men whose father died by suicide had a higher odds of suicide themselves, relative to men whose father died of other causes (Odds Ratio (OR): 2.5; 95% confidence interval: 1.8-3.6). This effect was slightly stronger in the case of mother's suicide (OR: 3.4; 2.3-5.0). The same effect was observed for women, for suicide by father (OR: 2.2; 1.3-3.7) and mother (OR: 4.6; 2.6-8.0). The odds of suicide increased with decreasing age at death of parent. Parental suicide is predictive for offspring suicide. Our data suggest that the predictive value is higher in case the mother died by suicide, particularly if the mother died by suicide at a young age., (© 2011 The American Association of Suicidology.)