Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Here, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aeroallergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed coincident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine tumor necrosis factor–α. These observations provide important insights into a potential mechanism underlying the development of allergic comorbidity in early life in children with AD, which involves altered NK cell functional responses, and define an endotype of severe AD.

中文翻译：

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儿童早期严重特应性皮炎中过度炎症性 NKG2D 低 NK 细胞的进行性积累

特应性皮炎 (AD) 是一种慢性炎症性皮肤病，通常先于食物过敏、哮喘和过敏性鼻炎发生。流行的范式认为，自然杀伤 (NK) 细胞频率和功能的降低导致 AD 发病机制，但 NK 细胞对过敏性合并症的潜在机制和贡献仍然不明确。在此，对 AD 儿童早期生命纵向队列中的循环 NK 细胞进行分析，结果显示 NK 细胞逐渐积累，且激活受体 NKG2D 表达较低，这与更严重的 AD 和对过敏原的敏感性有关。这在对食物和空气过敏原（哮喘发展的危险因素）共同敏感的儿童中最为显着。对一组儿童进行的个体水平纵向分析显示，获得性或持续性致敏的 NK 细胞上 NKG2D 会同时减少，这与通过表皮失水评估的皮肤屏障功能受损有关。 NK 细胞上 NKG2D 的低表达与溶细胞功能的抑制相关，但与促炎细胞因子肿瘤坏死因子-α 的过度释放相关。这些观察结果为了解 AD 儿童早期过敏性合并症的潜在机制提供了重要见解，其中涉及 NK 细胞功能反应的改变，并定义了严重 AD 的内型。