Revisiting Atopy: The IgE-Dependent Amplification Loop as a Forgotten Driver of Atopic Dermatitis

The role of IgE‑mediated allergy in atopic dermatitis (AD) has been progressively downplayed as contemporary models emphasize barrier dysfunction, type‑2 cytokine–driven inflammation, pruritus pathways, immune dysregulation, and microbial imbalance. This shift, however, has obscured a defining feature of extrinsic AD: a functional IgE‑dependent amplification loop operating across the epidermal and dermal immune network and extending into the draining lymph node. Emerging evidence shows that Langerhans cells, inflammatory dermal dendritic cells, inflammatory dendritic epidermal cells (IDECs), mast cells, and basophils can acquire environmental allergens through FcεRI‑bound IgE, enabling efficient antigen capture, processing, and T‑cell activation. Among these, IDECs appear central to IgE‑mediated delayed‑type hypersensitivity and the development of spongiosis following epicutaneous allergen exposure. Integrating these findings, we propose a mechanistic model in which IgE‑bearing antigen‑presenting cells initiate and sustain a positive feedback circuit that reinforces type‑2 inflammation and contributes to the chronicity of extrinsic AD. Re‑positioning this IgE‑dependent circuit within the broader pathophysiology of AD provides a revised framework that reconciles classical atopy with modern immunologic insights and highlights new therapeutic opportunities targeting IgE–FcεRI signaling, IDEC biology, and allergen‑driven epidermal immune activation.