Purpose of review Immediate hypersensitivity disorders, such as asthma, food intolerance, and anaphylaxis, have risen dramatically since the 20th century, marking a shift in the global disease burden. While mast cells have been associated with IgE-mediated disorders, they also play important roles in homeostasis. To prevent chronic inflammation and aberrant tissue remodeling, tight regulation of mast cells is essential in response to microorganisms, autoantigens, and environmental changes. Recent findings The surge in mast cell-mediated disorders and evidence of mast cell interactions with epithelial and neural networks have led to the epithelial barrier hypothesis. This hypothesis extends the protective role of the epithelium by highlighting its integrated communication with both the nervous and immune systems, proposing that dysregulated nerve–mast cell signaling at epithelial barriers contributes to the development of immediate hypersensitivity disorders – both allergic and nonallergic phenotypes. In turn, it offers new strategies for prevention and treatment, focusing on restoring barrier integrity and modulating neuroimmune pathways. Summary Clinical populations including hypermobility syndromes, such as certain Ehlers–Danlos syndrome variants and Job syndrome, exemplify the systemic consequences of disrupted epithelial barriers and chronic nerve–mast cell dysregulation. Accordingly, this review discusses the co-emergence of hypersensitivity and hypermobility syndromes as manifestations of immune–neuro–epithelial dysfunction in the context of modern environmental change.
Fenner et al. (2025) studied this question.