Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
Clin Exp Allergy. 2010 Jul;40(7):965-72. doi: 10.1111/j.1365-2222.2010.03522.x.
Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions, immunodysregulation, disrupted epidermal barrier function and IgE-mediated sensitization to food and environmental allergens. Identification of the aetiology of AD has become increasingly a priority, as it is clear that the disease burden exceeds AD alone, with many children suffering severe, multi-system and occasionally life-threatening allergic disease. Previous approaches to understanding AD have centred on mechanisms in the adaptive immune system, often with an emphasis on the Th1-Th2 paradigm. Recently, the conceptual focus has increasingly shifted to include a primary defect in the epithelial barrier as a threshold event in moderate-to-severe AD. Familial aggregation of the disease is well established through many family studies of AD, asthma and allergic rhinitis, suggesting a significant heritable component. The identification of loss-of-function mutations in the filaggrin (FLG) gene, whose product is a key structural protein in the outermost layer of the epidermis in up to 50% of patients with AD, provides a significant insight into explaining disease initiation and points to a complex secondary interplay of environmental and immunological sequelae once barrier disruption is established. The elucidation of the environmental, genetic and immunobiological modifiers of this structural molecule may also direct our understanding of the pathomechanisms and endotypes central to the atopic diathesis. The recent identification of a murine model for FLG-AD, with the detection of a homozygous frame-shift mutation in the Flg gene in flaky-tail (ft/ft) mice, stands to rapidly accelerate our understanding of mechanisms and therapeutic intervention points in AD. Refining the molecular understanding of AD and its subtypes will allow for specific diagnostic, treatment and ultimately, preventative algorithms, and has opened an exciting new world of investigative challenges and collaborations.
特应性皮炎（AD）是一种炎症性疾病，其特征为瘙痒性皮损、免疫失调、表皮屏障功能障碍以及 IgE 介导的对食物和环境变应原的致敏。明确 AD 的病因已变得越来越重要，因为显然疾病负担不仅仅是 AD，许多儿童患有严重的、多系统的、偶尔危及生命的过敏性疾病。以前对 AD 的理解方法主要集中在适应性免疫系统的机制上，通常强调 Th1-Th2 范式。最近，概念重点越来越多地转向将上皮屏障的主要缺陷作为中重度 AD 的一个阈值事件。通过对 AD、哮喘和过敏性鼻炎的许多家族研究，该疾病的家族聚集得到了很好的证实，这表明存在明显的遗传成分。在多达 50%的 AD 患者中，丝聚合蛋白（FLG）基因的功能丧失性突变的鉴定为解释疾病的发生提供了重要的见解，并指出一旦屏障破坏确立，就会出现复杂的环境和免疫后果的二次相互作用。阐明这种结构分子的环境、遗传和免疫生物学调节剂也可能有助于我们理解特应性素质的中心病理机制和内型。最近在具有 Flg 基因纯合移码突变的鳞屑尾（ft/ft）小鼠中鉴定出 FLG-AD 的小鼠模型，有望迅速加速我们对 AD 机制和治疗干预点的理解。对 AD 及其亚型的分子理解的细化将允许特定的诊断、治疗，最终是预防算法，并开辟了一个令人兴奋的新的调查挑战和合作的世界。
