The fundamental defect(s) that drives atopic dermatitis (AD) remains controversial. “Outside in” proponents point to the important association of filaggrin gene mutations and other skin barrier defects with AD. The “inside out” proponents derive support from evidence that AD occurs in genetic animal models with overexpression of type 2 immune pathways in their skin, and humans with gain-of-function mutations in their type 2 response develop severe AD. The observation that therapeutic biologics, targeting type 2 immune responses, can reverse AD provides compelling support for the importance of “inside out” mechanisms of AD. In this review, we propose a central role for epithelial cell dysfunction that accounts for the dual role of skin barrier defects and immune pathway activation in AD. The complexity of AD has its roots in the dysfunction of the epithelial barrier that allows the penetration of allergens, irritants, and microbes into a cutaneous milieu that facilitates the induction of type 2 immune responses. The AD phenotypes and endotypes that result in chronic skin inflammation and barrier dysfunction are modified by genes, innate/adaptive immune responses, and different environmental factors that cause skin barrier dysfunction. There is also compelling evidence that skin barrier dysfunction can alter the course of childhood asthma, food allergy, and allergic rhinosinusitis. Effective management of AD requires a multipronged approach, not only restoring cutaneous barrier function, microbial flora, and immune homeostasis but also enhancing skin epithelial differentiation.

导致特应性皮炎 (AD) 的基本缺陷仍然存在争议。“由外而内”的支持者指出丝聚蛋白基因突变和其他皮肤屏障缺陷与 AD 的重要关联。“由内而外”的支持者从以下证据中获得支持：AD 发生在皮肤中 2 型免疫通路过度表达的遗传动物模型中，而在 2 型反应中具有功能获得性突变的人类会发展为严重的 AD。针对 2 型免疫反应的治疗性生物制剂可以逆转 AD 的观察结果为 AD 的“由内而外”机制的重要性提供了有力的支持。在这篇综述中，我们提出了上皮细胞功能障碍的核心作用，它解释了皮肤屏障缺陷和免疫通路激活在 AD 中的双重作用。AD 的复杂性源于上皮屏障的功能障碍，它允许过敏原、刺激物和微生物渗透到皮肤环境中，从而促进 2 型免疫反应的诱导。导致慢性皮肤炎症和屏障功能障碍的 AD 表型和内型受到基因、先天/适应性免疫反应和导致皮肤屏障功能障碍的不同环境因素的影响。还有令人信服的证据表明，皮肤屏障功能障碍可以改变儿童哮喘、食物过敏和过敏性鼻窦炎的病程。AD 的有效管理需要多管齐下，不仅要恢复皮肤屏障功能、微生物菌群和免疫稳态，还要增强皮肤上皮分化。