Andreas Böck

Childhood allergic asthma is associated with increased IL-13 and FOXP3 histone acetylation

reactivity in the BAL of Der p 2.1–vaccinated mice, confirming previous reports demonstrating the lack of IgE reactivity toward this recombinant hypoallergenic derivative (Fig 2, E). However, contrary to recent results, we did not observe an increase in the inhibitory Der p 2–specific IgG1 (Fig 2, E). 8 Furthermore, we observed no influence of Der p 2.1 vaccination on the production of Der p 2–specific IgG2a. This result could be explained by the fact that B cells require IL-4 to produce both IgG1 and IgE. Consequently, by decreasing IL-4–producing T cells, vaccination with Der p 2.1 also reduced the production of TH2-related immunoglobulins. Given their structural homology, Der p and Der f antigens demonstrate an important IgE cross-reactivity. On the basis of this cross-reactivity, we investigated whether vaccination with Der p 2.1 peptide could control the development of Der f–induced airway hyperresponsiveness. Vaccination with Der p 2.1 inhibited bronchial hyperresponsiveness in Der f–induced asthma to the same extent as in the Der p–induced asthma model (Fig 2, F). Collectively, these data demonstrate the protective effect of Der p 2.1 vaccinations given before and duringHDM sensitization. By inhibiting T-cell–mediated IL-4 production, Der p 2.1 vaccination is believed to dampen IgE production, leading to a global attenuation on airway inflammation and hyperresponsiveness. Lower levels of IgE lead to fewer allergen-IgE pathogenic complexes and therefore to less activation of innate cells such as eosinophils, mastocytes, and basophils. The fact that IgG1 was also decreased is intriguing. The decrease in IgG1 may be explained by the fact that IL-4 is also involved in the production of IgG1 in mice. Der p 2.1 vaccination could also promote the expansion of immunosuppressive cells, such as regulatory T cells or induced-regulatory B cells. Indeed, many reports demonstrate that specific immunotherapy promotes the emergence of IL-10–producing T and B cells in allergic patients. Another interesting finding is the fact that vaccination also dampens the frequencyofTH17 cells in lungs.Given thepotent role of these cells in severe asthma, this therapeutic strategy could represent an interesting alternative in some cases of severe allergic asthma.Most interestingly, we demonstrated that vaccination with Der p 2.1 could be effective inDer f asthmaticmice. Consequently, this vaccine may reduce IgE-mediated as well as T-cell–mediated allergic inflammation irrespective of the HDM species. Finally, the protective role provided by vaccination with a hypoallergenic peptide could be of interest clinically, especially in sensitized children in whom allergic processes are sequential from sensitization to asthma. For these individuals, peptide immunotherapy may offer an alternative to block the allergic process and prevent its progression to allergic asthma.

A switch in regulatory T cells through farm‐exposure during immune maturation in childhood

Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm‐milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the ‘asthma‐protective’ farm effect via Tregs during childhood immune maturation.

Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4

The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Here we show that, within this network, two interferon regulatory factors (IRF), IRF1 and IRF4, display opposing effects on Th9 differentiation. IRF4 dose-dependently promotes, whereas IRF1 inhibits, IL-9 production. Likewise, IRF1 inhibits IL-9 production by human Th9 cells. IRF1 counteracts IRF4-driven Il9 promoter activity, and IRF1 and IRF4 have opposing function on activating histone modifications, thus modulating RNA polymerase II recruitment. IRF1 occupancy correlates with decreased IRF4 abundance, suggesting an IRF1-IRF4-binding competition at the Il9 locus. Furthermore, IRF1 shapes Th9 cells with an interferon/Th1 gene signature. Consistently, IRF1 restricts the IL-9-dependent pathogenicity of Th9 cells in a mouse model of allergic asthma. Thus our study reveals that the molecular ratio between IRF4 and IRF1 balances Th9 fate, thus providing new possibilities for manipulation of Th9 differentiation.

Factors contributing to the occurrence and predictability of bronchial hyperresponsiveness to methacholine in children

Using a stepwise logistic regression analysis, we investigated clinical data, allergologic findings, spirometric data, and the cellular and humoral immune system in order to gain new insights into the role these parameters play in bronchial hyperresponsiveness to methacholine in children and to create a model for the prediction thereof. Bronchial hyperresponsiveness, which was found in 124 of 462 children (26.8%), was observed to have been influenced by an increased level of eosinophils, the positivity of the skin prick test for any of the allergens tested, a decreased baseline forced expiratory volume in 1 second (FEV1) (percent predicted), a decreased maximum expiratory flow at 50% expiration as a percent of forced vital capacity, and a decreased level of kappa-chain-assembled immunoglobulins. Logit analysis disclosed that the influence of all other parameters on the occurrence of bronchial hyperresponsiveness was of no further statistical significance. The degree of bronchial hyperresponsiveness (provocative dose causing a 20% fall in FEV1) showed a statistically significant correlation with the eosinophil count (Spearmans r = -0.198) and FEV1 (percent predicted) (Spearmans r= 0.203). Our findings suggest that allergic sensitization and eosinophilic reaction in children are major factors in contributing to the occurrence of bronchial hyperresponsiveness to methacholine.

IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort.

IL‐33 polymorphisms influence the susceptibility to asthma. IL‐33 indirectly induces Th2‐immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL‐33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL‐33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs.

Effect of Processing Intensity on Immunologically Active Bovine Milk Serum Proteins

Consumption of raw cow’s milk instead of industrially processed milk has been reported to protect children from developing asthma, allergies, and respiratory infections. Several heat-sensitive milk serum proteins have been implied in this effect though unbiased assessment of milk proteins in general is missing. The aim of this study was to compare the native milk serum proteome between raw cow’s milk and various industrially applied processing methods, i.e., homogenization, fat separation, pasteurization, ultra-heat treatment (UHT), treatment for extended shelf-life (ESL), and conventional boiling. Each processing method was applied to the same three pools of raw milk. Levels of detectable proteins were quantified by liquid chromatography/tandem mass spectrometry following filter aided sample preparation. In total, 364 milk serum proteins were identified. The 140 proteins detectable in 66% of all samples were entered in a hierarchical cluster analysis. The resulting proteomics pattern separated mainly as high (boiling, UHT, ESL) versus no/low heat treatment (raw, skimmed, pasteurized). Comparing these two groups revealed 23 individual proteins significantly reduced by heating, e.g., lactoferrin (log2-fold change = −0.37, p = 0.004), lactoperoxidase (log2-fold change = −0.33, p = 0.001), and lactadherin (log2-fold change = −0.22, p = 0.020). The abundance of these heat sensitive proteins found in higher quantity in native cow’s milk compared to heat treated milk, renders them potential candidates for protection from asthma, allergies, and respiratory infections.

Converging applications for active ageing policy

Purpose – This article attempts to match the future needs of older people with the possibilities arising from applications based on new technology.Design/methodology/approach – This article examines the implications of novel applications for active ageing policy. These applications are forecast to arise from the convergence of two or more previously separated science disciplines and technologies, including information and communication technologies, nanotechnologies, biotechnology and cognitive sciences.Findings – Research on converging applications (CA) is largely driven by health applications, and is likely to spill over into the older generations specific needs. Today, older peoples most urgent needs require little CA. In the future, however, the role of CA will become more important as technology develops and is more widely used.Originality/value – Owing to demographic change and its expected social and economic implications, there is a need to investigate how upcoming applications could contribute ...

Asthmatic farm children show increased CD3+ CD8low T-cells compared to non-asthmatic farm children

Several studies report an important role of CD8+ cytotoxic T-cells in atopy. Farm children show protection against atopy development, partly explained by CD4+ T-cell subtypes. Additional effects of CD8+ T-cells are unknown being investigated in this study within the PASTURE/EFRAIM birth cohort in PBMCs from farming and non-farming 6-year-old (N = 76) German children. CD3+ CD8+ CD25+ T-cells were analyzed by flow cytometry. Genotyping of 17q21 locus-SNPs associated with childhood asthma was performed. No differences in CD8+ T-cell subsets were seen between farmers and non-farmers regardless of asthma. Among farm children, asthmatics displayed increased CD3+ CD8low(CD25+) T-cells compared to non-asthmatics. Asthmatic farm children exhibited a lower PI-induced stimulatory capacity of CD3+ CD8low(CD25+) cells and a lower IFN-γ secretion than non-asthmatic farm children. Among farm children with GSDMB and ORMDL3 risk alleles, asthmatics displayed higher CD3+ CD8low cells than non-asthmatics. Our data indicates a specific role of CD8low T-cells in asthmatic farm children.