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The growing use of silver nanoparticles (Ag-NPs) in consumer products raises concerns about their toxicological potential. The purpose of the study was to investigate the size- and coating-dependent pulmonary toxicity of Ag-NPs in vitro and in vivo, using an ovalbumin (OVA)-mouse allergy model. Supernatants from (5.6-45 µg/mL) Ag50-PVP, Ag200-PVP or Ag50-citrate-treated NR8383 alveolar macrophages were tested for lactate dehydrogenase and glucuronidase activity, tumor necrosis factor (TNF)-α release and reactive oxygen species (ROS) production. For the in vivo study, NPs were intratracheally instilled in non-sensitized (NS) and OVA-sensitized (S) mice (1-50 µg/mouse) prior to OVA-challenge and bronchoalveolar lavage fluid (BALF) inflammatory infiltrate was evaluated five days after challenge. In vitro results showed a dose-dependent cytotoxicity of Ag-NPs, which was highest for Ag50-polyvinilpyrrolidone (PVP), followed by Ag50-citrate, and lowest for Ag200-PVP. In vivo 10-50 µg Ag50-PVP triggered a dose-dependent pulmonary inflammatory milieu in NS and S mice, which was significantly higher in S mice and was dampened upon instillation of Ag200-PVP. Surprisingly, instillation of 1 µg Ag50-PVP significantly reduced OVA-induced inflammatory infiltrate in S mice and had no adverse effect in NS mice. Ag50-citrate showed similar beneficial effects at low concentrations and attenuated pro-inflammatory effects at high concentrations. The lung microbiome was altered by NPs instillation dependent on coating and/or mouse batch, showing the most pronounced effects upon instillation of 50 µg Ag50-citrate, which caused an increased abundance of operational taxonomic units assigned to Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria. However, no correlation with the biphasic effect of low and high Ag-NPs dose was found. Altogether, both in vitro and in vivo data on the pulmonary effects of Ag-NPs suggest the critical role of the size, dose and surface functionalization of Ag-NPs, especially in susceptible allergic individuals. From the perspective of occupational health, care should be taken by the production of Ag-NPs-containing consumer products. [ABSTRACT FROM AUTHOR]

Background: IL-22 controls tissue homeostasis by both proinflammatory and anti-inflammatory effects. However, the anti-inflammatory mechanisms of IL-22 remain poorly investigated. Objective: We sought to investigate the anti-inflammatory role for IL-22 in human asthma. Methods: T-cell lines derived from lung biopsy specimens of asthmatic patients were characterized by means of flow cytometry. Human bronchial epithelial cells from healthy and asthmatic subjects were stimulated with IL-22, IFN-γ, or the combination of both cytokines. Effects of cytokine stimulation were investigated by using whole-genome analysis, ELISA, and flow cytometry. The functional consequence of cytokine stimulation was evaluated in an in vitro wound repair model and T cell–mediated cytotoxicity experiments. In vivo cytokine expression was measured by using immunohistochemistry and Luminex assays in bronchoalveolar lavage fluid of healthy and asthmatic patients. Results: The current study identifies a tissue-restricted antagonistic interplay of IL-22 and the proinflammatory cytokine IFN-γ. On the one hand, IFN-γ antagonized IL-22–mediated induction of the antimicrobial peptide S100A7 and epithelial cell migration in bronchial epithelial cells. On the other hand, IL-22 decreased epithelial susceptibility to T cell–mediated cytotoxicity by inhibiting the IFN-γ–induced expression of MHC-I, MHC-II, and CD54/intercellular adhesion molecule 1 molecules. Likewise, IL-22 inhibited IFN-γ–induced secretion of the proinflammatory chemokines CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vitro. Consistently, the IL-22 expression in bronchoalveolar lavage fluid of asthmatic patients inversely correlated with the expression of CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vivo. Conclusions: IL-22 might control the extent of IFN-γ–mediated lung inflammation and therefore play a tissue-restricted regulatory role. [Copyright &y& Elsevier]

Background: TH17 cells are of pathologic relevance in autoimmune disorders and presumably also in allergy and asthma. Regulatory T (Treg) cells, in contrast, suppress inflammatory and allergen-driven responses. Despite these disparate functions, both T-cell subsets have been shown to be dependent on TGF-β for their development. Objective: The aim of the study was to analyze the differentiation and function of human TH17 cells in comparison with other TH cell subsets. Methods: Naive human CD4+ T cells were differentiated in vitro, and gene expression was analyzed by means of quantitative real-time PCR, ELISA, and immunofluorescence. The function of TH cell subsets was assessed by monitoring the response of primary bronchial epithelial cells in coculture experiments. Results: In vitro differentiated TH17 cells differ from Treg and other TH cells in their potency to induce IL-6 and IL-1β expression in primary bronchial epithelial cells. TGF-β, IL-1β, IL-6, and IL-23 are necessary during TH17 cell differentiation to acquire these functions, including IL-17 production. In contrast, TGF-β alone is necessary and sufficient to induce the transcription factor RORC2. This transcription factor, previously thought to be specific for TH17 cells, is also expressed in Treg cells, CD25+ cells, cytotoxic T cells, and natural killer T cells. Conclusion: This study demonstrates mechanisms of differentiation to human TH17 cells, a subset that effectively and uniquely modulates the function of primary bronchial epithelial cells. [Copyright &y& Elsevier]

The pathogenesis of chronic inflammatory diseases is assumed to depend on activated T cells interacting with resident tissue cells or migratory inflammatory cells. The discovery of new T-cell subsets such as the IL-17–producing TH17 and T-regulatory cells innovated our understanding of T-cell biology. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. The understanding of IL-17 and TH17 differentiation pathways has also changed the perspective of immunologists regarding the basis of chronic tissue inflammation, particularly where TH1 cells were considered as driving force of the pathology. This review summarizes the recent developments on TH cell subsets and integrates these findings into existing concepts of immunopathologic mechanisms. [Copyright &y& Elsevier]

Sensitization to cross-reactive allergens complicates identifying the culprit insect in Hymenoptera venom allergy via diagnostic tests. This study evaluates sensitization to hyaluronidases (Api m 2 from honey bee (Apis mellifera) venom, HBV; Pol d 2 from European paper wasp (Polistes dominula) venom, PDV; and Ves v 2.0101 and Ves v 2.0201 from yellow jacket (Vespula vulgaris) venom, YJV) and their cross-reactivity in allergic patients from Italy, Spain, and Germany using ImmunoCAPs, ELISA, and basophil activation tests. Sensitization rates were 45% for Api m 2 in HBV-allergic subjects, 25% for Pol d 2 in PDV-allergic individuals, and 20% and 10% for Ves v 2.0201 and Ves v 2.0101 in YJV-allergic patients, respectively. Patients primarily sensitized to Api m 2 showed minimal cross-reactivity to vespid hyaluronidases, whereas those primarily sensitized to Pol d 2 or Ves v 2.0201 exhibited IgE reactivity to Api m 2. Neither Pol d 2 nor Ves v 2.0201 triggered basophil activation. Cross-reactivity of Api m 2, Pol d 2, and Ves v 2.0201 depends on the primary sensitizing venom. Sensitization to Pol d 2 and Ves v 2.0201 remains below 25%, yet these patients may exhibit cross-reactivity to Api m 2. Conversely, HBV-allergic patients sensitized to Api m 2 show minimal reactivity to Pol d 2 or Ves v 2.0201. [ABSTRACT FROM AUTHOR]

Extensive remodeling of the airways is a major characteristic of chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). To elucidate the importance of a deregulated immune response in the airways for remodeling processes, we established a matching Drosophila model. Here, triggering the Imd (immune deficiency) pathway in tracheal cells induced organ-wide remodeling. This structural remodeling comprises disorganization of epithelial structures and comprehensive epithelial thickening. We show that these structural changes do not depend on the Imd pathway's canonical branch terminating on nuclear factor κB (NF-κB) activation. Instead, activation of a different segment of the Imd pathway that branches off downstream of Tak1 and comprises activation of c-Jun N-terminal kinase (JNK) and forkhead transcription factor of the O subgroup (FoxO) signaling is necessary and sufficient to mediate the observed structural changes of the airways. Our findings imply that targeting JNK and FoxO signaling in the airways could be a promising strategy to interfere with disease-associated airway remodeling processes. [Display omitted] • Chronic epithelial immune activation leads to structural changes in the airways • Activation of JNK signaling via TAK1 mediates this airway remodeling • FoxO acts downstream of JNK signaling in inducing this airway remodeling • NF-κB factors are of minor relevance for this response Chronic activation of the immune system in the Drosophila airway epithelium induces massive structural changes of the organ. These structural changes are mediated by a bifurcation of the IMD pathway at the level of TAK1, involving the JNK pathway and subsequent activation of the transcription factor FoxO. [ABSTRACT FROM AUTHOR]

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation. [ABSTRACT FROM AUTHOR]

Purpose of Review: Stings of Hymenoptera of the superfamily Vespoidea such as yellow jackets, paper wasps or stinging ants are common triggers for severe and even fatal allergic reactions. Antigen 5 allergens are potent allergens in the majority of these venoms with major importance for diagnosis and therapy. Reviewed here are the characteristics of antigen 5 allergens, their role in component-resolved diagnostics as well as current limitations of the available diagnostics for proper therapeutic decisions. Recent Findings: Antigens 5 are proteins of unknown function in Hymenoptera venoms with high allergenic potency. They represent key elements in component-resolved diagnosis to discriminate between honeybee and vespid venom allergy. However, due to their pronounced cross-reactivity, there are remaining diagnostic and therapeutic challenges that have to be addressed. Summary: Antigens 5 are highly relevant venom allergens of the Vespoidea superfamily. Although their use in component-resolved diagnosis facilitates dissection of cross-reactivity and primary allergy in double sensitization to honeybee and vespid venom, new diagnostic concepts are needed to discriminate between allergies to different vespid species. [ABSTRACT FROM AUTHOR]

Background: The rise in asthma has been linked to different environmental and lifestyle factors including dietary habits. Whether dietary salt contributes to asthma incidence, remains controversial. We aimed to investigate the impact of higher salt intake on asthma incidence in humans and to evaluate underlying mechanisms using mouse models. Methods: Epidemiological research was conducted using the UK Biobank Resource. Data were obtained from 42,976 participants with a history of allergies. 24‐h sodium excretion was estimated from spot urine, and its association with asthma incidence was assessed by Cox regression, adjusting for relevant covariates. For mechanistic studies, a mouse model of mite‐induced allergic airway inflammation (AAI) fed with high‐salt diet (HSD) or normal‐salt chow was used to characterize disease development. The microbiome of lung and feces (as proxy for gut) was analyzed via 16S rRNA gene based metabarcoding approach. Results: In humans, urinary sodium excretion was directly associated with asthma incidence among females but not among males. HSD‐fed female mice displayed an aggravated AAI characterized by increased levels of total IgE, a TH2‐TH17‐biased inflammatory cell infiltration accompanied by upregulation of osmosensitive stress genes. HSD induced distinct changes in serum short chain fatty acids and in both gut and lung microbiome, with a lower Bacteroidetes to Firmicutes ratio and decreased Lactobacillus relative abundance in the gut, and enriched members of Gammaproteobacteria in the lung. Conclusions: High dietary salt consumption correlates with asthma incidence in female adults with a history of allergies. Female mice revealed HSD‐induced T‐cell lung profiles accompanied by alterations of gut and lung microbiome. [ABSTRACT FROM AUTHOR]