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Background: Epigenetic modifications are known to mediate both beneficial and unfavorable effects of environmental exposures on the development and clinical course of asthma. On the molecular level, epigenetic mechanisms participate in multiple aspects of the emerging and ongoing asthma pathology. Summary: Studies performed in the last several years expand our knowledge on the role of histone acetylation, a classical epigenetic mark, in the regulation of (patho)physiological processes of diverse cells playing a central role in asthma, including those belonging to the immune system (e.g., CD4+ T cells, macrophages) and lung structure (e.g., airway epithelial cells, pulmonary fibroblasts). Those studies demonstrate a number of specific histone acetylation-associated mechanisms and pathways underlying pathological processes characteristic for asthma, as well as report their modification modalities. Key Messages: Dietary modulation of histone acetylation levels in the immune system might protect against the development of asthma and other allergies. Interfering with the enzymes controlling the histone acetylation status of structural lung and (local) immune cells might provide future therapeutic options for asthmatics. Despite some methodological obstacles, analysis of the histone acetylation levels might improve asthma diagnostics. [ABSTRACT FROM AUTHOR]

Epithelial/immune interactions are characterized by the different properties of the various epithelial tissues, the mediators involved, and the varying immune cells that initiate, sustain, or abrogate allergic diseases on the surface. The intestinal mucosa, respiratory mucosa, and regular skin feature structural differences according to their primary function and surroundings. In the context of these specialized functions, the active role of the epithelium in shaping immune responses is increasingly recognizable. Crosstalk between epithelial and immune cells plays an important role in maintaining homeostatic conditions. While cells of the myeloid cell lineage, mainly macrophages, are the dominating immune cell population in the skin and the respiratory tract, lymphocytes comprise most intraepithelial immune cells in the intestine under healthy conditions. Common to all surface epithelia is the fact that innate immune cells represent the first line of immunosurveillance that either directly defeats invading pathogens or initiates and coordinates more effective successive immune responses involving adaptive immune cells and effector cells. Pharmacological approaches for the treatment of allergic and chronic inflammatory diseases involving epithelial barriers target immunological mediators downstream of the epithelium (such as IL‐4, IL‐5, IL‐13, and IgE). The next generation of therapeutics involves upstream events of the inflammatory cascade, such as epithelial‐derived alarmins and related mediators. [ABSTRACT FROM AUTHOR]

Rationale and Objective: Plasma extracellular vesicles (EVs) represent a vital source of molecular information about health and disease states. Due to their heterogenous cellular sources, EVs and their cargo may predict specific pathomechanisms behind disease phenotypes. Here we aimed to utilize EV microRNA (miRNA) signatures to gain new insights into underlying molecular mechanisms of obesity‐associated low type‐2 asthma. Methods: Obese low type‐2 asthma (OA) and non‐obese low type‐2 asthma (NOA) patients were selected from an asthma cohort conjointly with healthy controls. Plasma EVs were isolated and characterised by nanoparticle tracking analysis. EV‐associated small RNAs were extracted, sequenced and bioinformatically analysed. Results: Based on EV miRNA expression profiles, a clear distinction between the three study groups could be established using a principal component analysis. Integrative pathway analysis of potential target genes of the differentially expressed miRNAs revealed inflammatory cytokines (e.g., interleukin‐6, transforming growth factor‐beta, interferons) and metabolic factors (e.g., insulin, leptin) signalling pathways to be specifically associated with OA. The miR‐17–92 and miR‐106a–363 clusters were significantly enriched only in OA. These miRNA clusters exhibited discrete bivariate correlations with several key laboratory (e.g., C‐reactive protein) and lung function parameters. Plasma EV miRNA signatures mirrored blood‐derived CD4+ T‐cell transcriptome data, but achieved an even higher sensitivity in identifying specifically affected biological pathways. Conclusion: The identified plasma EV miRNA signatures and particularly the miR‐17–92 and ‐106a–363 clusters were capable to disentangle specific mechanisms of the obesity‐associated low type‐2 asthma phenotype, which may serve as basis for stratified treatment development. [ABSTRACT FROM AUTHOR]

Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs.

Background: Early‐life exposure to certain environmental bacteria including Acinetobacter lwoffii (AL) has been implicated in protection from chronic inflammatory diseases including asthma later in life. However, the underlying mechanisms at the immune‐microbe interface remain largely unknown. Methods: The effects of repeated intranasal AL exposure on local and systemic innate immune responses were investigated in wild‐type and Il6−/−, Il10−/−, and Il17−/− mice exposed to ovalbumin‐induced allergic airway inflammation. Those investigations were expanded by microbiome analyses. To assess for AL‐associated changes in gene expression, the picture arising from animal data was supplemented by in vitro experiments of macrophage and T‐cell responses, yielding expression and epigenetic data. Results: The asthma preventive effect of AL was confirmed in the lung. Repeated intranasal AL administration triggered a proinflammatory immune response particularly characterized by elevated levels of IL‐6, and consequently, IL‐6 induced IL‐10 production in CD4+ T‐cells. Both IL‐6 and IL‐10, but not IL‐17, were required for asthma protection. AL had a profound impact on the gene regulatory landscape of CD4+ T‐cells which could be largely recapitulated by recombinant IL‐6. AL administration also induced marked changes in the gastrointestinal microbiome but not in the lung microbiome. By comparing the effects on the microbiota according to mouse genotype and AL‐treatment status, we have identified microbial taxa that were associated with either disease protection or activity. Conclusion: These experiments provide a novel mechanism of Acinetobacter lwoffii‐induced asthma protection operating through IL‐6‐mediated epigenetic activation of IL‐10 production and with associated effects on the intestinal microbiome. [ABSTRACT FROM AUTHOR]

This document is a reply to a correspondence letter regarding a scientific study on obese asthmatics. The authors clarify that their primary aim was to gain insights into the underlying mechanisms of obesity-associated low type-2 asthma, rather than establish diagnostic biomarkers. They mention that further validation is needed for the identified microRNA markers. The authors also address questions about the cell types responsible for the release of extracellular vesicles with different microRNA cargo in obese asthmatics. The study was supported by various funding sources and the authors declare no conflicts of interest. [Extracted from the article]

Optimal pre-analytical conditions for blood sample processing and isolation of selected cell populations for subsequent transcriptomic and epigenomic studies are required to obtain robust and reproducible results. This pilot study was conducted to investigate the potential effects of timing of CD4+ T-cell processing from peripheral blood of atopic and non-atopic adults on their transcriptomic and epigenetic profiles. Two heparinized blood samples were drawn from each of three atopic and three healthy individuals. For each individual, CD4+ T-cells were isolated from the first blood sample within 2 h (immediate) or from the second blood sample after 24 h storage (delayed). RNA sequencing (RNA-Seq) and histone H3K27 acetylation chromatin immunoprecipitation sequencing (ChIP-Seq) analyses were performed. A multiplicity of genes was shown to be differentially expressed in immediately processed CD4+ T-cells from atopic versus healthy subjects. These differences disappeared when comparing delayed processed cells due to a drastic change in expression levels of atopy-related genes in delayed processed CD4+ T-cells from atopic donors. This finding was further validated on the epigenomic level by examining H3K27 acetylation profiles. In contrast, transcriptomic and epigenomic profiles of blood CD4+ T-cells of healthy donors remained rather unaffected. Taken together, for successful transcriptomics and epigenomics studies, detailed standard operation procedures developed on the basis of samples from both healthy and disease conditions are implicitly recommended. [ABSTRACT FROM AUTHOR]