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Lifestyle modifications, including increased physical activity and exercise, are recommended for non-alcoholic fatty liver disease (NAFLD). Inflamed adipose tissue (AT) contributes to the progression and development of NAFLD and oxylipins such as hydroxyeicosatetraenoic acids (HETE), hydroxydocosahexanenoic acids (HDHA), prostaglandins (PEG2), and isoprostanoids (IsoP), which all may play a role in AT homeostasis and inflammation. To investigate the role of exercise without weight loss on AT and plasma oxylipin concentrations in NAFLD subjects, we conducted a 12-week randomized controlled exercise intervention. Plasma samples from 39 subjects and abdominal subcutaneous AT biopsy samples from 19 subjects were collected both at the beginning and the end of the exercise intervention. In the AT of women, a significant reduction of gene expression of hemoglobin subunits (HBB, HBA1, HBA2) was observed within the intervention group during the 12-week intervention. Their expression levels were negatively associated with VO2max and maxW. In addition, pathways involved in adipocyte morphology alterations significantly increased, whereas pathways in fat metabolism, branched-chain amino acids degradation, and oxidative phosphorylation were suppressed in the intervention group (p < 0.05). Compared to the control group, in the intervention group, the ribosome pathway was activated, but lysosome, oxidative phosphorylation, and pathways of AT modification were suppressed (p < 0.05). Most of the oxylipins (HETE, HDHA, PEG2, and IsoP) in plasma did not change during the intervention compared to the control group. 15-F2t-IsoP significantly increased in the intervention group compared to the control group (p = 0.014). However, this oxylipin could not be detected in all samples. Exercise intervention without weight loss may influence the AT morphology and fat metabolism at the gene expression level in female NAFLD subjects.

Background: Work exposures play a significant role in adult-onset asthma, but the mechanisms of work-related asthma are not fully elucidated. Objective: We aimed to reveal the molecular mechanisms of work-related asthma associated with exposure to flour (flour asthma), isocyanate (isocyanate asthma), or welding fumes (welding asthma) and identify potential biomarkers that distinguish these groups from each other. Methods: We used a combination of clinical tests, transcriptomic analysis, and associated pathway analyses to investigate the underlying disease mechanisms of the blood immune cells and the airway epithelium of 61 men. Results: Compared with the healthy controls, the welding asthma patients had more differentially expressed genes than the flour asthma and isocyanate asthma patients, both in the airway epithelia and in the blood immune cells. In the airway epithelia, active inflammation was detected only in welding asthma patients. In contrast, many differentially expressed genes were detected in blood cells in all 3 asthma groups. Disease-related immune functions in blood cells, including leukocyte migration and inflammatory responses, and decreased expression of upstream cytokines such as TNF and IFN-gamma were suppressed in all the asthma groups. In transcriptomephenotype correlations, hyperresponsiveness (R similar to vertical bar 0.6 vertical bar) had the highest clinical relevance and was associated with a set of exposure group-specific genes. Finally, biomarker subsets of only 5 genes specifically distinguished each of the asthma exposure groups. Conclusions: This study provides novel data on the molecular mechanisms underlying work-related asthma. We identified a set of 5 promising biomarkers in asthma related to flour, isocyanate, and welding fume exposure to be tested and clinically validated in future studies.

Background: Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not. Objective: The aim was to define the differences in the milk allergen component-specific (casein, α-lactalbumin, ß-lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long-term outcomes of milk OIT. Methods: In this long-term, open-label follow-up study, 286 children started milk OIT between 2005 and 2015. Follow-up data were collected at two points: the post-buildup phase and long term (range 1–11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self-reported long-term milk consumption (high-milk dose, low-milk dose, and avoidance). Results: A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high-dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p

Background In allergic patients, clinical symptoms caused by pollen remind of symptoms triggered by viral respiratory infections, which are also the main cause of asthmatic exacerbations. In patients sensitized to birch pollen, Bet v 1 is the major symptom-causing allergen. Immune mechanisms driving Bet v 1-related responses of human blood cells have not been fully characterized. Objective To characterize the immune response to Bet v 1 in peripheral blood in patients allergic to birch pollen. Methods The peripheral blood mononuclear cells of birch-allergic (n = 24) and non-allergic (n = 47) adolescents were stimulated ex-vivo followed by transcriptomic profiling. Systems-biology approaches were employed to decipher disease-relevant gene networks and deconvolution of associated cell populations. Results Solely in birch-allergic patients, co-expression analysis revealed activation of networks of innate immunity and antiviral signalling as the immediate response to Bet v 1 stimulation. Toll-like receptors and signal transducer transcription were the main drivers of gene expression patterns. Macrophages and dendritic cells were the main cell subsets responding to Bet v 1. Conclusions and clinical relevance In birch-pollen-allergic patients, the activated innate immune networks seem to be, in part, the same as those activated during viral infections. This tendency of the immune system to read pollens as viruses may provide new insight to allergy prevention and treatment.

Silver (nAg) and titanium dioxide (nTiO

Consumers and manufacturers are exposed to nanosized zinc oxide (nZnO) and silver particles (nAg) via airways, but their biological effects are still not fully elucidated. To understand the immune effects, we exposed mice to 2, 10, or 50 μg of nZnO or nAg by oropharyngeal aspiration and analyzed the global gene expression profiles and immunopathological changes in the lungs after 1, 7, or 28 days. Our results show that the kinetics of responses varied in the lungs. Exposure to nZnO resulted in the highest accumulation of F4/80- and CD3-positive cells, and the largest number of differentially expressed genes (DEGs) were identified after day 1, while exposure to nAg caused peak responses at day 7. Additionally, nZnO mainly activated the innate immune responses leading to acute inflammation, whereas the nAg activated both innate and adaptive immune pathways, with long-lasting effects. This kinetic-profiling study provides an important data source to understand the cellular and molecular processes underlying nZnO- and nAg-induced transcriptomic changes, which lead to the characterization of the corresponding biological and toxicological effects of nZnO and nAg in the lungs. These findings could improve science-based hazard and risk assessment and the development of safe applications of engineered nanomaterials (ENMs), e.g., in biomedical applications.

Publisher Copyright: Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. BACKGROUND: Few studies have examined the interactions between individual socioeconomic position and neighbourhood deprivation and the findings so far are heterogeneous. Using a large sample of diverse cohorts, we investigated the interaction effect of neighbourhood socioeconomic deprivation and individual socioeconomic position, assessed using education, on mortality. METHODS: We did a longitudinal multicohort analysis that included six cohort studies participating in the European LIFEPATH consortium: the CoLaus (Lausanne, Switzerland), E3N (France), EPIC-Turin (Turin, Italy), EPIPorto (Porto, Portugal), Melbourne Collaborative Cohort Study (Melbourne, VIC, Australia), and Whitehall II (London, UK) cohorts. All participants with data on mortality, educational attainment, and neighbourhood deprivation were included in the present study. The data sources were the databases of each cohort study. Poisson regression was used to estimate the mortality rates and associations (relative risk, 95% CIs) with neighbourhood deprivation (Q1 being least deprived to Q5 being the most deprived). Baseline educational attainment was used as an indicator of individual socioeconomic position. Estimates were combined using pooled analysis and the relative excess risk due to the interaction was computed to identify additive interactions. FINDINGS: The cohorts comprised a total population of 168 801 individuals. The recruitment dates were 2003-06 for CoLaus, 1989-91 for E3N, 1992-98 for EPIC-Turin, 1999-2003 for EPIPorto, 1990-94 for MCCS, and 1991-94 for Whitehall II. We use baseline data only and mortality data obtained using record linkage. Age-adjusted mortality rates were higher among participants residing in more deprived neighbourhoods than those in the least deprived neighbourhoods (Q1 least deprived neighbourhoods, 369·7 per 100 000 person-years [95% CI 356·4-383·2] vs Q5-most deprived neighbourhoods 445·7 per 100 000 person-years [430·2-461·7]), but the magnitude of the association varied according to educational attainment (relative excess risk due to interaction=0·18, 95% CI 0·08-0·28). The relative risk for Q5 versus Q1 was 1·31 (1·23-1·40) among individuals with primary education or less, but less pronounced among those with secondary education (1·12; 1·04-1·21) and tertiary education (1·16; 1·07-1·27). Associations remained after adjustment for individual-level factors, such as smoking, physical activity, and alcohol intake, among others. INTERPRETATION: Our study suggests that the detrimental health effect of living in disadvantaged neighbourhoods is more pronounced among individuals with low education attainment, amplifying social inequalities in health. This finding is relevant to policies aimed at reducing health inequalities, suggesting that these issues should be addressed at both the individual level and the community level. FUNDING: The European Commission, European Regional Development Fund, the Portugese Foundation for Science and Technology.

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and moldy buildings can be identified, to unravel its corresponding pathomechanistic gene signatures, and to investigate potential molecular similarities with IEI. Fifty female adult-onset asthma patients were categorized based on exposure to building dampness and molds during disease initiation. IEI patients (n = 17) and healthy subjects (n = 21) were also included yielding 88 study subjects. IEI was scored with the Quick Environmental Exposure and Sensitivity Inventory (QEESI) questionnaire. Inflammation was evaluated by blood cell type profiling and cytokine measurements. Disease mechanisms were investigated via gene set variation analysis of RNA from nasal biopsies and peripheral blood mononuclear cells. Nasal biopsy gene expression and plasma cytokine profiles suggested airway and systemic inflammation in asthma without exposure to dampness (AND). Similar evidence of inflammation was absent in patients with dampness-and-mold-related asthma (AAD). Gene expression signatures revealed a greater degree of similarity between IEI and dampness-related asthma than between IEI patients and asthma not associated to dampness and mold. Blood cell transcriptome of IEI subjects showed strong suppression of immune cell activation, migration, and movement. QEESI scores correlated to blood cell gene expression of all study subjects. Transcriptomic analysis revealed clear pathomechanisms for AND but not AAD patients. Furthermore, we found a distinct molecular pathological profile in nasal and blood immune cells of IEI subjects, including several differentially expressed genes that were also identified in AAD samples, suggesting IEI-type mechanisms.

More than 5% of any population suffers from asthma, and there are indications that these individuals are more sensitive to nanoparticle aerosols than the healthy population. We used an air-liquid interface model of inhalation exposure to investigate global transcriptomic responses in reconstituted three-dimensional airway epithelia of healthy and asthmatic subjects exposed to pristine (nCuO) and carboxylated (nCuO(COOH)) copper oxide nanoparticle aerosols. A dose-dependent increase in cytotoxicity (highest in asthmatic donor cells) and pro-inflammatory signaling within 24 h confirmed the reliability and sensitivity of the system to detect acute inhalation toxicity. Gene expression changes between nanoparticle-exposed versus air-exposed cells were investigated. Hierarchical clustering based on the expression profiles of all differentially expressed genes (DEGs), cell-death-associated DEGs (567 genes), or a subset of 48 highly overlapping DEGs categorized all samples according to "exposure severity", wherein nanoparticle surface chemistry and asthma are incorporated into the dose-response axis. For example, asthmatics exposed to low and medium dose nCuO clustered with healthy donor cells exposed to medium and high dose nCuO, respectively. Of note, a set of genes with high relevance to mucociliary clearance were observed to distinctly differentiate asthmatic and healthy donor cells. These genes also responded differently to nCuO and nCuO(COOH) nanoparticles. Additionally, because response to transition-metal nanoparticles was a highly enriched Gene Ontology term (FDR 8 X 10(-13)) from the subset of 48 highly overlapping DEGs, these genes may represent biomarkers to a potentially large variety of metal/metal oxide nanoparticles.

Background Egg allergy is the second most common food allergy in children. Persistent food allergy increases the risk of anaphylaxis and reduces the quality of life. Objective To determine the efficacy of oral immunotherapy (OIT) with raw egg white powder and study its effects on humoral responses in children with persistent egg allergy. Methods Fifty children aged 6 to 17 years with egg allergy, diagnosed by double-blind, placebo-controlled food challenge, were randomized 3:2 to 8 months of OIT with a maintenance dose of 1 g of egg white protein or 6 months of avoidance after which the avoidance group crossed over to OIT. We examined changes in IgE, IgG4, and IgA concentrations to Gal d 1-4 during OIT compared with avoidance and assessed clinical reactivity at 8 and 18 months. Results After 8 months, 22 of 50 children (44%) on OIT and 1 of 21 (4.8%) on egg avoidance were desensitized to the target dose, 23 of 50 (46%) were partially desensitized (dose Conclusions OIT with raw egg enables liberation of egg products into the daily diet in most patients. Subjects with high egg white–specific IgE concentrations and sensitization to multiple egg allergen components at baseline benefit from prolonged treatment.

Toxicogenomics opens novel opportunities for hazard assessment by utilizing computational methods to map molecular events and biological processes. In this study, the transcriptomic and immunopathological changes associated with airway exposure to a total of 28 engineered nanomaterials (ENM) are investigated. The ENM are selected to have different core (Ag, Au, TiO2, CuO, nanodiamond, and multiwalled carbon nanotubes) and surface chemistries (COOH, NH2, or polyethylene glycosylation (PEG)). Additionally, ENM with variations in either size (Au) or shape (TiO2) are included. Mice are exposed to 10 µg of ENM by oropharyngeal aspiration for 4 consecutive days, followed by extensive histological/cytological analyses and transcriptomic characterization of lung tissue. The results demonstrate that transcriptomic alterations are correlated with the inflammatory cell infiltrate in the lungs. Surface modification has varying effects on the airways with amination rendering the strongest inflammatory response, while PEGylation suppresses toxicity. However, toxicological responses are also dependent on ENM core chemistry. In addition to ENM‐specific transcriptional changes, a subset of 50 shared differentially expressed genes is also highlighted that cluster these ENM according to their toxicity. This study provides the largest in vivo data set currently available and as such provides valuable information to be utilized in developing predictive models for ENM toxicity., C57BL/6 mice are exposed by oropharyngeal aspiration to 28 different engineered nanomaterials (ENM). Histological and cytological evaluation together with transcriptomics analyses reveals the important effect of surface functionalization (amination, carboxylation, or pegylation) as well as the significant role of the ENM core chemistry.

Titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles (NPs) have attracted a great deal of attention due to their excellent electrical, optical, whitening, UV-adsorbing and bactericidal properties. The extensive production and utilization of these NPs increases their chances of being released into the environment and conferring unintended biological effects upon exposure. With the increasingly prevalent use of the omics technique, new data are burgeoning which provide a global view on the overall changes induced by exposures to NPs. In this review, we provide an account of the biological effects of ZnO and TiO2 NPs arising from transcriptomics in in vivo and in vitro studies. In addition to studies on humans and mice, we also describe findings on ecotoxicology-related species, such as Danio rerio (zebrafish), Caenorhabditis elegans (nematode) or Arabidopsis thaliana (thale cress). Based on evidence from transcriptomics studies, we discuss particle-induced biological effects, including cytotoxicity, developmental alterations and immune responses, that are dependent on both material-intrinsic and acquired/transformed properties. This review seeks to provide a holistic insight into the global changes induced by ZnO and TiO2 NPs pertinent to human and ecotoxicology.

Background: After the Second World War, the population living in the Karelian region was strictly divided by the “iron curtain” between Finland and Russia. This resulted in different lifestyle, standard of living, and exposure to the environment. Allergic manifestations and sensitization to common allergens have been much more common on the Finnish compared to the Russian side. Objective: The remarkable allergy disparity in the Finnish and Russian Karelia calls for immunological explanations. Methods: Young people, aged 15-20 years, in the Finnish (n = 69) and Russian (n = 75) Karelia were studied. The impact of genetic variation on the phenotype was studied by a genome-wide association analysis. Differences in gene expression (transcriptome) were explored from the blood mononuclear cells (PBMC) and related to skin and nasal epithelium microbiota and sensitization. Results: The genotype differences between the Finnish and Russian populations did not explain the allergy gap. The network of gene expression and skin and nasal microbiota was richer and more diverse in the Russian subjects. When the function of 261 differentially expressed genes was explored, innate immunity pathways were suppressed among Russians compared to Finns. Differences in the gene expression paralleled the microbiota disparity. High Acinetobacter abundance in Russians correlated with suppression of innate immune response. High-total IgE was associated with enhanced anti-viral response in the Finnish but not in the Russian subjects. Conclusions and clinical relevance: Young populations living in the Finnish and Russian Karelia show marked differences in genome-wide gene expression and host contrasting skin and nasal epithelium microbiota. The rich gene-microbe network in Russians seems to result in a better-balanced innate immunity and associates with low allergy prevalence. publishedVersion

Bioactive, oxygenated metabolites of polyunsaturated fatty acids (PUFAs) are important indicators of inflammation and oxidative stress but almost nothing is known about their interactions with nanomaterials (NMs). To investigate the effects of nano-sized materials (n-TiO2, n-ZnO, n-Ag) and their bulk-sized or ionic (b-TiO2, b-ZnO, i-Ag) counterpart, we studied the status of oxidative stress and PUFA metabolism in THP-1 cells at low-toxic concentrations (

Allostatic load (AL) and epigenetic clocks both attempt to characterize the accelerated aging of biological systems, but at present it is unclear whether these measures are complementary or distinct. This study examines the cross-sectional association of AL with epigenetic age acceleration (EAA) in a subsample of 490 community-dwelling older adults participating in The Irish Longitudinal study on Aging (TILDA). A battery of 14 biomarkers representing the activity of four different physiological systems: immunological, cardiovascular, metabolic, renal, was used to construct the AL score. DNA methylation age was computed according to the algorithms described by Horvath, Hannum, and Levine allowing for estimation of whether an individual is experiencing accelerated or decelerated aging. Horvath, Hannum, and Levine EAA correlated 0.05, 0.03, and 0.21 with AL, respectively. Disaggregation by sex revealed that AL was more strongly associated with EAA in men compared with women as assessed using Horvath’s clock. Metabolic dysregulation was a strong driver of EAA in men as assessed using Horvath and Levine’s clock, while metabolic and cardiovascular dysregulation were associated with EAA in women using Levine’s clock. Results indicate that AL and the epigenetic clocks are measuring different age-related variance and implicate sex-specific drivers of biological aging.

The diversity and increasing prevalence of products derived from engineered nanomaterials (ENM), warrants implementation of non-animal approaches to health hazard assessment for ethical and practical reasons. Although non-animal approaches are becoming increasingly popular, there are almost no studies of side-by-side comparisons with traditional in vivo assays. Here, transcriptomics is used to investigate mechanistic similarities between healthy/asthmatic models of 3D air–liquid interface (ALI) cultures of donor-derived human bronchial epithelia cells, and mouse lung tissue, following exposure to copper oxide ENM. Only 19% of mouse lung genes with human orthologues are not expressed in the human 3D ALI model. Despite differences in taxonomy and cellular complexity between the systems, a core subset of matching genes cluster mouse and human samples strictly based on ENM dose (exposure severity). Overlapping gene orthologue pairs are highly enriched for innate immune functions, suggesting an important and maybe underestimated role of epithelial cells. In conclusion, 3D ALI models based on epithelial cells, are primed to bridge the gap between traditional 2D in vitro assays and animal models of airway exposure, and transcriptomics appears to be a unifying dose metric that links in vivo and in vitro test systems. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Background Recent findings suggest that circadian time regulates cellular functions in the skin and may affect protection against ultraviolet radiation (UVR). It is not known, however, whether UVR through skin directly affects the expression of circadian genes. We investigated the effect of ultraviolet B (UVB) exposure on cryptochrome circadian clock 1 (CRY1), cryptochrome circadian clock 2 (CRY2), and circadian associated repressor of transcription (CIART) genes. Methods Healthy volunteers (n = 12) were exposed to narrow-band UVB radiation of four standard erythemal dose (SED). Epidermal/dermal and subcutaneous adipose tissue samples were obtained by punch biopsies from irradiated and non-irradiated skin 10 cm away from the irradiated site 24 hours after UVB exposure. Gene expression of CRY1, CRY2, and CIART was measured using RT-PCR (TaqMan). Results Ultraviolet B radiation affected mRNA expression in the epidermal/dermal skin and in the subcutaneous adipose tissue. It down-regulated expression of CRY2 gene in the epidermal/dermal skin, whereas it up-regulated expression of CRY1 and CIART genes in the subcutaneous adipose tissue. Conclusion We showed for the first time that UVB radiation affects expression of circadian genes in the subcutaneous adipose tissue. Further studies are warranted to understand the mechanisms in detail.

Background: Seasonal allergic rhinitis (SAR) caused by intermittent exposure to seasonal pollen causes itching, nasal congestion, and repeated sneezing, with profound effects on quality of life, work productivity, and school performance. Although both the genotype and environmental factors can contribute to the immunologic basis of allergic reactions, the molecular underpinnings associated with the pathogenesis of allergic rhinitis are not entirely clear. Methods: To address these questions, nasal epithelial brushings were collected from 29 patients with SAR and 31 control subjects during and after the pollen season. We then implemented an orbitrap-based, bottom-up, label-free quantitative proteomics approach, followed by multivariate analyses to identify differentially abundant (DA) proteins among the 4 sample groups. Results: We identified a total of 133 DA proteins for which the most significantly overrepresented functional category was found to be interferon 1 signaling. Two proteins, cystatin 1 and myeloblastin, the former of which protects against protease activity of allergens and the latter with a role in epithelial barrier function, were DA in patients with SAR and control subjects, irrespective of season. Moreover, interferon-inducible protein with tetratricopeptide repeats 1, cystatin 1, and interferon-inducible protein with tetratricopeptide repeats 3 were found to be differentially regulated between patients with SAR and control subjects, with inverse abundance dynamics during the transition from fall to spring. Conclusion: We identified type 1 interferon-regulated proteins as biomarkers in patients with SAR, potentially playing an important role in its pathogenesis. Moreover, when compared with patients with SAR, healthy subjects exhibit an antagonistic proteomic response across seasons, which might prove to be a therapeutic target for disease prevention.

Carbon nanotubes (CNTs) have the potential to impact technological and industrial progress, but their production and use may, in some cases, cause serious health problems. Certain rod-shaped multiwalled CNTs (rCNTs) can, in fact, induce severe asbestos-like pathogenicity in mice, including granuloma formation, fibrosis, and even cancer. Evaluating the comparability between alternative hazard assessment methods is needed to ensure fast and reliable evaluation of the potentially adverse effects of these materials. To compare two alternative airway exposure methods, C57BL/6 mice were exposed to rCNTs by a state-of-the-art but laborious and expensive inhalation method (6.2–8.2 mg/m3, 4 h/day for 4 days) or by oropharyngeal aspiration (10 or 40 μg/day for 4 days), which is cheaper and easier to perform. In addition to histological and cytological studies, transcriptome analysis was also carried out on the lung tissue samples. Both inhalation and low-dose (10 μg/day) aspiration exposure to rCNTs promoted strong...

Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers. We find that atopic dermatitis and psoriasis can be classified by distinct microbes, which differ from healthy volunteers microbiome composition. Atopic dermatitis is dominated by a single microbe (Staphylococcus aureus), and associated with a disease relevant host transcriptomic signature enriched for skin barrier function, tryptophan metabolism and immune activation. In contrast, psoriasis is characterized by co-occurring communities of microbes with weak associations with disease related gene expression. Our work provides a basis for biomarker discovery and targeted therapies in skin dysbiosis., Atopic dermatitis (AD) and psoriasis (PSO) are associated with dysbiosis. Here, by analyses of skin microbiome and host transcriptome of AD and PSO patients, the authors find distinct microbial and disease-related gene transcriptomic signatures that differentiate both diseases.

After over a decade of nanosafety research, it is indisputable that the vast majority of nano-sized particles induce a plethora of adverse cellular responses - the severity of which is linked to the material's physicochemical properties. Differentiated THP-1 cells were previously exposed for 6 h and 24 h to silver, titanium dioxide, and zinc oxide nanoparticles at the maximum molar concentration at which no more than 15% cellular cytotoxicity was observed. All three nanoparticles differed in extent of induction of biological pathways corresponding to immune response signaling and metal ion homeostasis. In this study, we integrated gene and miRNA expression profiles from the same cells to propose miRNA biomarkers of adverse exposure to metal-based nanoparticles. We employed RNA sequencing together with a quantitative strategy that also enables analysis of the overlooked repertoire of length and sequence miRNA variants called isomiRs. Whilst only modest changes in expression were observed within the first 6 h of exposure, the miRNA/isomiR (miR) profiles of each nanoparticle were unique. Via canonical correlation and pathway enrichment analyses, we identified a co-regulated miR-mRNA cluster, predicted to be highly relevant for cellular response to metal ion homeostasis. These miRs were annotated to be canonical or variant isoforms of hsa-miR-142-5p, -342-3p, -5100, -6087, -6894-3p, and -7704. Hsa-miR-5100 was differentially expressed in response to each nanoparticle in both the 6 h and 24 h exposures. Taken together, this co-regulated miR-mRNA cluster could represent potential biomarkers of sub-toxic metal-based nanoparticle exposure.

Background Copper oxide (CuO) nanomaterials are used in a wide range of industrial and commercial applications. These materials can be hazardous, especially if they are inhaled. As a result, the pulmonary effects of CuO nanomaterials have been studied in healthy subjects but limited knowledge exists today about their effects on lungs with allergic airway inflammation (AAI). The objective of this study was to investigate how pristine CuO modulates allergic lung inflammation and whether surface modifications can influence its reactivity. CuO and its carboxylated (CuO COOH), methylaminated (CuO NH3) and PEGylated (CuO PEG) derivatives were administered here on four consecutive days via oropharyngeal aspiration in a mouse model of AAI. Standard genome-wide gene expression profiling as well as conventional histopathological and immunological methods were used to investigate the modulatory effects of the nanomaterials on both healthy and compromised immune system. Results Our data demonstrates that although CuO materials did not considerably influence hallmarks of allergic airway inflammation, the materials exacerbated the existing lung inflammation by eliciting dramatic pulmonary neutrophilia. Transcriptomic analysis showed that CuO, CuO COOH and CuO NH3 commonly enriched neutrophil-related biological processes, especially in healthy mice. In sharp contrast, CuO PEG had a significantly lower potential in triggering changes in lungs of healthy and allergic mice revealing that surface PEGylation suppresses the effects triggered by the pristine material. Conclusions CuO as well as its functionalized forms worsen allergic airway inflammation by causing neutrophilia in the lungs, however, our results also show that surface PEGylation can be a promising approach for inhibiting the effects of pristine CuO. Our study provides information for health and safety assessment of modified CuO materials, and it can be useful in the development of nanomedical applications. Electronic supplementary material The online version of this article (10.1186/s12989-019-0309-1) contains supplementary material, which is available to authorized users.

Individuals of lower socio-economic position (SEP) carry a heavier burden of disease and morbidity and live shorter lives on average compared with their more advantaged counterparts. This has sparked research interest in the processes and mechanisms via which social adversity gets biologically embedded. The present study directly compares the empirical worth of two candidate mechanisms: Allostatic Load (AL) and the Epigenetic Clock(s) for advancing our understanding of embodiment using a sub-sample of 490 individuals from the Irish Longitudinal Study (TILDA) who were explicitly selected for this purpose based on their inter-generational life course social class trajectory. A battery of 14 biomarkers representing the activity of 4 different physiological systems: Immunological, Cardiovascular, Metabolic, and Renal was used to construct the AL score. Biomarkers were dichotomised into high and low risk groups according to sex-specific quartiles of risk and summed to create a count ranging from 0-14. Three measures of epigenetic age acceleration were computed according to three sets of age-associated Cytosine-phosphate-Guanine (CpG) sites described by Horvath, Hannum and Levine. AL was strongly socially patterned across a number of measures of SEP, while the epigenetic clocks were not. AL partially mediated the association between measures of SEP and an objective measure of physiological functioning: performance on the Timed Up and Go (TUG test). We conclude that AL may represent the more promising candidate for understanding the pervasive link between SEP and health.

Background: Sufficient exposure to natural environments, in particular soil and its microbes, has been suggested to be protective against allergies. Objective: We aim at gaining more direct evidence of the environment-microbiota-health axis by studying the colonization of gut microbiota in mice after exposure to soil and by examining immune status in both a steady-state situation and during allergic inflammation. Methods: The gastrointestinal microbiota of mice housed on clean bedding or in contact with soil was analyzed by using 16S rRNA gene sequencing, and the data were combined with immune parameters measured in the gut mucosa, lung tissue, and serum samples. Results: We observed marked differences in the small intestinal and fecal microbiota composition between mice housed on clean bedding or in contact with soil, with a higher proportion of Bacteroidetes relative to Firmicutes in the soil group. The housing environment also influenced mouse intestinal gene expression, as shown by upregulated expression of the immunoregulatory markers IL-10, forkhead box P3, and cytotoxic T lymphocyte-associated protein 4 in the soil group. Importantly, using the murine asthma model, we found that exposure to soil polarizes the immune system toward T(H)1 and a higher level of anti-inflammatory signaling, alleviating T(H)2-ype allergic responses. The inflammatory status of the mice had a marked influence on the composition of the gut microbiota, suggesting bidirectional communication along the gut-lung axis. Conclusion: Our results provide evidence of the role of environmentally acquired microbes in alleviating against T(H)2-driven inflammation, which relates to allergic diseases.

Nano-sized metal oxides are currently the most manufactured nanomaterials (NMs), and are increasingly used in consumer products. Recent exposure data reveal a genuine potential for adverse health outcomes for a vast array of NMs, however the underlying mechanisms are not fully understood. To elucidate size-related molecular effects, differentiated THP-1 cells were exposed to nano-sized materials (n-TiO 2, n-ZnO and n-Ag), or their bulk-sized (b-ZnO and b-TiO 2 ) or ionic (i-Ag) counterparts, and genome-wide gene expression changes were studied at low-toxic concentrations ( 2 materials were nontoxic in MTT assay, inducing only minor transcriptional changes. ZnO and Ag elicited dose-dependent cytotoxicity, wherein ionic and particulate effects were synergistic with respect to n-ZnO-induced cytotoxicity. In gene expression analyzes, 6 h and 24 h samples formed two separate hierarchical clusters. N-ZnO and n-Ag shared only 3.1% and 24.6% differentially expressed genes (DEGs) when compared to corresponding control. All particles, except TiO 2 , activated various metallothioneins. At 6 h, n-Zn, b-Zn and n-Ag induced various immunity related genes associating to pattern recognition (including toll-like receptor), macrophage maturation, inflammatory response (TNF and IL-1beta), chemotaxis (CXCL8) and leucocyte migration (CXCL2-3 and CXCL14). After 24 h exposure, especially n-Ag induced the expression of genes related to virus recognition and type I interferon responses. These results strongly suggest that in addition to ionic effects mediated by metallothioneins, n-Zn and n-Ag induce expression of genes involved in several innate and adaptive immunity associated pathways, which are known to play crucial role in immuno-regulation. This raises the concern of safe use of metal oxide and metal nanoparticle products, and their biological effects.

Background/Aims: Chronic kidney disease (CKD) patients on dialysis are prone to vitamin D insufficiency despite oral vitamin D supplementation. Here, we studied whether narrow-band ultraviolet B (NB-UVB) exposures improve vitamin D balance. Methods: 14 haemodialysis patients and 15 healthy subjects receiving oral cholecalciferol 20 µg daily got nine NB-UVB exposures on the entire body. Serum 25-hydroxyvitamin D (25(OH)D) was measured by radioimmunoassay. Cutaneous mRNA expression levels of CYP27A1 and CYP27B1, two enzymes required for hydroxylation of vitamin D into its active metabolite, were also measured. Results: The baseline serum 25(OH)D concentration was 57.6 ± 18.2 nmol/l in the CKD patients and 74.3 ± 14.8 nmol/l in the healthy subjects. The NB-UVB course increased serum 25(OH)D by 14.0 nmol/l (95% CI 8.7-19.5) and 17.0 nmol/l (CI 13.7-20.2), respectively. At baseline the CKD patients showed significantly increased CYP27B1 levels compared to the healthy subjects. Conclusions: A short NB-UVB course is an efficient way to improve vitamin D balance in CKD patients on dialysis who are receiving oral vitamin D supplementation. The increased cutaneous CYP27B1 levels in the CKD patients suggest that the loss of renal activity of this enzyme is at least partially compensated for by the skin.

Rapidly declining biodiversity may be a contributing factor to another global megatrend—the rapidly increasing prevalence of allergies and other chronic inflammatory diseases among urban populations worldwide. According to the “biodiversity hypothesis,” reduced contact of people with natural environmental features and biodiversity may adversely affect the human commensal microbiota and its immunomodulatory capacity. Analyzing atopic sensitization (i.e., allergic disposition) in a random sample of adolescents living in a heterogeneous region of 100 × 150 km, we show that environmental biodiversity in the surroundings of the study subjects’ homes influenced the composition of the bacterial classes on their skin. Compared with healthy individuals, atopic individuals had lower environmental biodiversity in the surroundings of their homes and significantly lower generic diversity of gammaproteobacteria on their skin. The functional role of the Gram-negative gammaproteobacteria is supported by in vitro measurements of expression of IL-10, a key anti-inflammatory cytokine in immunologic tolerance, in peripheral blood mononuclear cells. In healthy, but not in atopic, individuals, IL-10 expression was positively correlated with the abundance of the gammaproteobacterial genus Acinetobacter on the skin. These results raise fundamental questions about the consequences of biodiversity loss for both allergic conditions and public health in general.

In the acute phase of atopic dermatitis (AD), T-helper type 2 (Th2) cytokines characterize the inflammatory response in the skin. IL-33 is a new tissue-derived cytokine, which is mainly expressed by cells of barrier tissues, and is known to activate Th2 lymphocytes, mast cells, and eosinophils. IL-33 signals through a receptor complex consisting of IL-33-specific receptor ST2 and a co-receptor IL-1RAcP. As IL-33 is known to promote Th2-type immunity, we examined expression profiles of IL-33 and its receptor components in human AD skin, in the murine model of AD, and in various cell models. We found increased expression of IL-33 and ST2 in AD skin after allergen or staphylococcal enterotoxin B (SEB) exposure, as well as in the skin of 22-week-old filaggrin-deficient mice. In addition, skin fibroblasts, HaCaT keratinocytes, primary macrophages, and HUVEC endothelial cells efficiently produced IL-33 in response to the combined stimulation of tumor necrosis factor-α and IFN-γ, which was further enhanced by a mimetic of double-stranded RNA. Finally, the increased expression of IL-33 and ST2 caused by irritant, allergen, or SEB challenge was suppressed by topical tacrolimus treatment. These results suggest an important role for IL-33-ST2 interaction in AD and highlight the fact that bacterial and viral infections may increase the production of IL-33.

Adaptive immunity is characterized by the expansion of an Ag-specific T cell population following Ag exposure. The precise mechanisms, however, that control the expansion and subsequent contraction in the number of Ag-specific T cells are not fully understood. We show that T cell/transmembrane, Ig, and mucin (TIM)-4, a receptor for phosphatidylserine, a marker of apoptotic cells, regulates adaptive immunity in part by mediating the removal of Ag-specific T cells during the contraction phase of the response. During Ag immunization or during infection with influenza A virus, blockade of TIM-4 on APCs increased the expansion of Ag-specific T cells, resulting in an increase in secondary immune responses. Conversely, overexpression of TIM-4 on APCs in transgenic mice reduced the number of Ag-specific T cells that remained after immunization, resulting in reduced secondary T cell responses. There was no change in the total number of cell divisions that T cells completed, no change in the per cell proliferative capacity of the remaining Ag-specific T cells, and no increase in the development of Ag-specific regulatory T cells in TIM-4 transgenic mice. Thus, TIM-4–expressing cells regulate adaptive immunity by mediating the removal of phosphatidylserine-expressing apoptotic, Ag-specific T cells, thereby controlling the number of Ag-specific T cells that remain after the clearance of Ag or infection.

Summary Background Narrowband ultraviolet B (NB-UVB) is a routine treatment for psoriasis and atopic dermatitis (AD) but its effect on vitamin D balance is not well studied. Objectives To examine whether NB-UVB treatment in winter improves vitamin D balance in psoriasis and AD, and to study the effects of NB-UVB on antimicrobial peptide and cytokine expression in the skin. Methods Eighteen adult patients with psoriasis, 18 with AD and 15 healthy subjects received a total of 15 NB-UVB exposures on the whole body, given three times a week. Serum calcidiol (25-hydroxyvitamin D) was measured by radioimmunoassay. Antimicrobial peptide and cytokine expression in skin lesions was examined by real-time quantitative polymerase chain reaction. Results At onset 16 (89%) patients with psoriasis, 17 (94%) patients with AD and eight (53%) healthy subjects had vitamin D insufficiency (calcidiol

Nanomaterials improve everyday products but their safety for human health is poorly known. In this study we explored immunological effects of five different nanomaterials on antigen presenting cells (APC) in vitro. Nanomaterials studied were rutile titanium dioxide (TiO2), amorphous silica-coated rutile titanium dioxide (TiO2-silica), zinc oxide (ZnO), single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT). APCs included mouse macrophages (RAW 264.7 cell line) and murine bone marrow-derived dendritic cells (bmDC). All studied particles were cytotoxic to bmDCs, and ZnO, TiO2 and TiO2-silica-induced dose-dependently cell death also in macrophages. ZnO had the most drastic immunological effects leading to high expression of proinflammatory cytokine, IL-1beta, and enhanced production of neutrophil chemoattractant CXCL-9 on both cell types. TiO2 and TiO2-silica stimulated the expression of IL-6, MIP-1alpha and TNF-alpha in macrophages, and increased their maturation, antigen presentation and co-stimulation activity. In contrast, SWCNT or MWCNT did not seem to have any significant immunological effects on the cell types studied suggesting that APCs might not be the target cells for carbon nanotubes. Due to diverse effects on different nanomaterials on immune cells we suggest that each new nanomaterial should be extensively studied in vitro and in vivo for risk assessment before their use in final products.

The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Both TIM-4, expressed on human and mouse macrophages and dendritic cells, and TIM-1 specifically bind to phosphatidylserine (PS) on the surface of apoptotic cells and do not bind to any other phospholipid tested. TIM-4+ peritoneal macrophages, TIM-1+ kidney cells, as well as TIM-4 or TIM-1 transfected cells efficiently phagocytose apoptotic cells and phagocytosis can be blocked by TIM-4 or TIM-1 mAbs. TIM proteins have a unique binding cavity made by an unusual conformation of the CC′ and FG loops of the TIM IgV domain and mutations in this cavity eliminated PS binding and phagocytosis. TIM-4 mAbs that block PS binding and phagocytosis map to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors that recognize PS, critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.

Palladium and nickel nanoparticles with variable but narrowly defined primary particle sizes in the range of 4-27 nm were investigated toward their catalytic activity and their ability to produce reactive oxygen species (ROS). The agglomerate size in the gas phase was between 50 and 150 nm, after transfer into solution probably larger. The catalytic activity was measured on the basis of CO oxidation to CO2. The formation of ROS was determined after transferring the particles into phosphate buffered saline (PBS), via the 2',7'-dichlorofluorescein method in a cell-free environment and with THP-1 cells. Activities were normalized with regard to catalyst surface area to enable a meaningful comparison of size effects. The solubility was measured for both materials and found to be 2 µg/ml for Ni and below the detection limit of 0.8 µg/ml for Pd. In the concentration range of about 4-250 µg/ml both materials induced a significant production of ROS in both acellular and cellular environments, with palladium being more active than nickel by several orders of magnitude. On an equal surface area concentration basis, both acellular and cellular ROS production showed a pronounced dependence on the primary particle size, with a maximum in the vicinity of 12 nm. The surface-specific catalytic activity also had a maximum at that size range. The correlation of these size effects is both surprising and - in combination with the poor solubility of palladium and nickel in PBS solution - a strong argument in favor of a particulate, catalytic mechanism for ROS production.