Refining atopic dermatitis pathogenesis: Early-life trajectories, noncanonical cytokines, and JAK-STAT signaling

Atopic dermatitis (AD) is increasingly understood as a biologically heterogeneous disease in which barrier dysfunction, type 2 inflammation, neuroimmune dysregulation, and intracellular signaling abnormalities interact in dynamic and context-dependent ways. This review highlights three concepts that have advanced the field in recent years. First, studies in early life suggest that AD harbors measurable preclinical abnormalities, developmental trajectories, and potential opportunities for targeted intervention. Second, recent work has refined the cytokine architecture of AD beyond interleukin (IL)-4 and IL-13 by identifying noncanonical cytokine circuits that shape distinct aspects of the disease phenotype, including upstream pathogenic T helper type 2 (TH2) cell activation, epidermal dysfunction, and itch. Third, rare gain-of-function (GOF) disorders involving signal transducer and activator of transcription 6 (STAT6) and Janus kinase 1 (JAK1) have consolidated the relevance of the IL-4/IL-13-JAK-STAT signaling axis in AD, providing insight into how specific alterations within this axis can drive severe allergic skin disease and associated systemic phenotypes. Considered together, these developments support a more differentiated view of AD pathophysiology, in which disease onset, tissue inflammation, barrier impairment, pruritus, and therapeutic response are governed by partially overlapping but nonidentical pathways.