Outside-in hypothesis revisited: the role of microbial, epithelial and immune interactions

Objective: Our understanding of the origin of allergic diseases has increased in recent years, highlighting the importance of microbial dysbiosis and epithelial barrier dysfunction in affected tissues. Exploring the microbial-epithelial-immune crosstalk underlying the mechanisms of allergic diseases will allow the development of novel prevention and treatment strategies of allergic diseases. Data sources: This review summarizes recent advances in microbial, epithelial, and immune interactions in atopic dermatitis, allergic rhinitis, chronic rhinosinusitis and asthma. Study selections: We performed a literature search, identifying relevant recent primary articles and review articles. Results: Dynamic crosstalk between the environmental factors and microbial, epithelial, and immune cells in the development of atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma underlies the pathogenesis of these disease. There is substantial evidence in the literature suggesting that environmental factors directly affect barrier function of epithelium. In addition, T helper 2 cells, type 2 innate lymphoid cells and their cytokine IL-13 damage skin and lung barriers. The effects of environmental factors may at least in part be mediated by epigenetic mechanisms.Histondeacetylase activation by type 2 immune response has a major effect on leaky barriers and blocking of histone deacetylase activity corrects the defective barrier in human air-liquid interface cultures and mouse models of allergic asthma with rhinitis. We also present and discuss a novel device to detect and monitor skin barrier dysfunction, which provides an opportunity to rapidly and robustly assess disease severity. Conclusion: A complex interplay between environmental factors, epithelium, and the immune system is involved in the development of systemic allergic diseases