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The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation, drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review focuses on the importance of examining other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be beneficial in the development of common therapeutics for current clinical management and disease prevention in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Watkinson, Looi, Laing, Cianferoni and Kicic.)

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F + eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-β, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-β-mediated oesophageal and lung fibrosis is also reduced in Aspergillus-challenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5- and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients., (© 2021 John Wiley & Sons Ltd.)

Background: Eosinophilic esophagitis (EoE) is a chronic disease characterized histologically by > 15 eosinophils per high-power field (eos/hpf). Esophageal mucosal mast cells have been implicated in EoE pathogenesis. The association of atopy with EoE has been established but has not been correlated with levels of serum tryptase. The lack of concurrent atopy in some patients suggests the possibility that atopy may either be the related subtype of EoE or may be a sign of comorbidities. No study has looked at whether patients present with different phenotypes/comorbid disease when they have evidence of elevated serum tryptase. We hypothesized that these patients differ with respect to presentation and comorbidities with more refractory GI disease.Aims: To examine whether elevations of serum tryptase associate with different, more severe clinical presentations in EoE patients which may be explained via mast cell activation.Materials and Methods: Retrospective chart review identified 72 patients with EoE with results for serum tryptase between 2015 and 2016. Patients were classified as TryptaseHI (tryptase > 10.9 µg/l) and TryptaseLO (< 10.9 µg/l). Clinical characteristics and treatment response were compared using univariate analysis and multivariate regression between the groups.Results: Out of 72 patients, 12 were tested as TryptaseHI (16.7%, 95% CI 8.1-25.3%). TryptaseHI was associated frequently with asthma (P = 0.0003), urticaria (P = 0.002), arthralgia (P = 0.005), sinusitis (P = 0.03), nausea/vomiting (P = 0.046), and eosinophilic gastrointestinal disease (P = 0.001). Asthma and arthralgia were found to be significantly associated with TryptaseHI (P = 0.0013, P = 0.0098, respectively). Mucosal eosinophil counts and tryptase levels were not correlated (R2 0.095, P = 0.77). Tryptase did not resolve with resolution of esophageal eosinophilia.Conclusions: We found that EoE patients with elevated tryptase levels more commonly presented with asthma, urticaria, arthralgia, nausea/vomiting, sinusitis, and more distal eosinophilia. This indicates that atopy in EoE patients warrants further exploration. The lack of correlation between histologic remission and reduction of serum tryptase levels post-treatment suggests that mast cell activation may be an independent, yet associated disease. More study into this unique association is warranted. [ABSTRACT FROM AUTHOR]

Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP). VIP mediates immunological function through interaction with specific receptors namely VPAC-1, VPAC-2, CRTH2 and PAC1 that are expressed on several immune cells such as eosinophils, mast cells, neutrophils, and lymphocytes; therefore, provide the basis for the action of VIP on the immune system. Additionally, VIP mediated action varies according to target organ depending upon the presence of specific VIP associated receptor, involved immune cells and the microenvironment of the organ. Herein, we present an integrative review of the current understanding on the role of VIP and associated receptors in allergic diseases, the presence of VIP receptors on various immune cells with particular emphasis on the role of VIP in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Being crucial signal molecule of the neuroendocrine-immune network, the development of stable VIP analogue and/or antagonist may provide the future therapeutic drug alternative for the better treatment of these allergic diseases. Taken together, our current review summarizes the current understandings of VIP biology and further explore the significance of neuroendocrine cells derived VIP in the recruitment of inflammatory cells in allergic diseases that may be helpful to the investigators for planning the experiments and accordingly predicting new therapeutic strategies for combating allergic diseases. Summarized graphical abstract will help the readers to understand the significance of VIP in allergic diseases. [ABSTRACT FROM AUTHOR]