Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (T(H)2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T(H)17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.

The immunology of asthma

Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.

/pdf/gut-brain-axis-and-the-microbiota-3ksluuopxy.pdf

Gut/brain axis and the microbiota

https://www.rs.tus.ac.jp/iwakuralab/pdf/review_il17family.pdf

Functional Specialization of Interleukin-17 Family Members

The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease.

Asthma is a T lymphocyte-controlled disease of the airway wall caused by inflammation, overproduction of mucus and airway wall remodeling leading to bronchial hyperreactivity and airway obstruction. The airway epithelium is considered an essential controller of inflammatory, immune and regenerative responses to allergens, viruses and environmental pollutants that contribute to asthma pathogenesis. Epithelial cells express pattern recognition receptors that detect environmental stimuli and secrete endogenous danger signals, thereby activating dendritic cells and bridging innate and adaptive immunity. Improved understanding of the epithelium's function in maintaining the integrity of the airways and its dysfunction in asthma has provided important mechanistic insight into how asthma is initiated and perpetuated and could provide a framework by which to select new therapeutic strategies that prevent exacerbations and alter the natural course of the disease.

The airway epithelium in asthma

The inflammatory cytokine interleukin (IL)-17 is involved in the pathogenesis of allergic diseases. However, the identity and functions of IL-17–producing T cells during the pathogenesis of allergic diseases remain unclear. Here, we report a novel subset of TH2 memory/effector cells that coexpress the transcription factors GATA3 and RORγt and coproduce TH17 and TH2 cytokines. Classical TH2 memory/effector cells had the potential to produce IL-17 after stimulation with proinflammatory cytokines IL-1β, IL-6, and IL-21. The number of IL-17-TH2 cells was significantly increased in blood of patients with atopic asthma. In a mouse model of allergic lung diseases, IL-17–producing CD4+ TH2 cells were induced in the inflamed lung and persisted as the dominant IL-17–producing T cell population during the chronic stage of asthma. Treating cultured bronchial epithelial cells with IL-17 plus TH2 cytokines induced strong up-regulation of chemokine eotaxin-3, Il8, Mip1b, and Groa gene expression. Compared with classical TH17 and TH2 cells, antigen-specific IL-17–producing TH2 cells induced a profound influx of heterogeneous inflammatory leukocytes and exacerbated asthma. Our findings highlight the plasticity of TH2 memory cells and suggest that IL-17–producing TH2 cells may represent the key pathogenic TH2 cells promoting the exacerbation of allergic asthma.

/pdf/a-novel-subset-of-cd4-th2-memory-effector-cells-that-produce-1xp3wt7pe6.pdf

A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma

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A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma