Immune functions of the esophagus.

The esophagus has long been regarded as a simple conduit for food transport. A new paradigm now recognizes it as an immune organ actively involved in environmental sensing, antigen tolerance, and neuroimmune signaling to maintain mucosal homeostasis. The stratified squamous epithelium provides a vital physical barrier, supported by transmembrane mucins and regulated by posttranslational modifications, including citrullination mediated by esophagus-enriched peptidyl arginine deiminases. A unique esophageal microbiome, established early in life, shapes epithelial differentiation, gene expression, and immune development and response. Pattern recognition receptors and enriched IL-1 family cytokines, including the alarmins IL-33 and thymic stromal lymphopoietin, orchestrate rapid immune responses to diverse environmental stimuli, such as allergens. The protease-antiprotease balance, controlled by serine and cysteine proteases, notably kallikreins, and the inhibitors SERPINs and SPINKs, regulates cytokine activity and barrier integrity. Neuroimmune circuits link innate immune activation, sensory perception, and barrier regulation. Disruption of these pathways, including genetic variants in barrier components, proteases, and immune regulators, contributes to disease susceptibility and pathogenesis, most notably eosinophilic esophagitis. Thus, the esophagus is now understood to be an environmental sensing immune organ with functions in health and disease.