The skin is the largest immunological organ in the body, containing immune cells that play a role in both food allergen sensitization and desensitization. The "dual allergen exposure hypothesis" posits that sensitization to food allergens may occur with cutaneous exposure on inflamed skin, eg, atopic dermatitis (AD), but early oral consumption generally leads to tolerance. However, only one-third of children with AD develop food allergy, suggesting a more complex mechanism for allergen sensitization. Emerging evidence suggests that the outcome of cutaneous allergen exposure is context-dependent and largely influenced by the state of the skin barrier, with healthy skin promoting natural tolerance. Current research supports the ability to induce desensitization through repeated application of allergen to the skin, known as epicutaneous immunotherapy (EPIT). Preclinical research with an occlusive patch has demonstrated a significantly reduced Th2-driven immunological response when applied to intact, uninflamed skin, and induction of a unique population of regulatory T cells that express a broader range of homing receptors, which may be able to maintain sustained protection. In clinical studies of children aged 1 through 11 years with peanut allergy, EPIT with an occlusive patch resulted in significant desensitization with no major differences in efficacy or safety between children with and without AD. These data begin to answer the conundrum of how allergen applied to the skin can lead to both sensitization and desensitization, and future studies should enable us to optimize the power of the skin as a complex immunological organ to treat allergic, autoimmune, and autoinflammatory disorders.
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