Beyond T helper 2 cells: Integrating immune, barrier, microbial, and neuroimmune pathways in atopic dermatitis pathogenesis.

Atopic dermatitis is a heterogeneous inflammatory skin disease long-defined by skin barrier dysfunction and type 2 (T helper cell [Th]2) immune dysregulation. Dupilumab established interleukin (IL)-4 and IL-13 as key therapeutic targets, yet partial response rates underscore contributions from Th1, Th17, Th22, and other pathways that vary by age, ethnicity, and disease stage. Cytokine signaling convergence through the Janus kinase/signal transducers and activators of transcription axis underlies the broad efficacy of oral Janus kinase inhibitors, while persistence of tissue-resident memory T cells in clinically resolved skin highlights the role of immune memory and supports therapeutic strategies targeting OX40/OX40L. The neuroimmune axis, exemplified by IL-31 signaling and keratinocyte-neuron crosstalk, drives pruritus and perpetuates local inflammation. Additionally, keratinocyte dysregulation and lipid abnormalities perpetuate barrier defects, while impaired antimicrobial defenses permit Staphylococcus aureus overgrowth and further skew immunity. Emerging therapies, including IL-22, IL-31, IL-18, OX40 pathway inhibitors, and AhR agonists, continue to expand opportunities for individualized treatment of atopic dermatitis. Together, these advances emphasize atopic dermatitis as a systemic, relapsing disease caused and sustained by simultaneous immunologic, barrier, microbial, and neural dysregulation. A deeper mechanistic understanding will lead to long-term disease modification and relief.