Dermatology Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
PLoS One. 2011;6(12):e28254. doi: 10.1371/journal.pone.0028254. Epub 2011 Dec 2.
Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes.
The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected.
Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression.
We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.
特应性皮炎（AD）的病理生理学背后存在几种常见的遗传和环境疾病机制。丝聚合蛋白（FLG）功能丧失对于 AD 和寻常型鱼鳞病（IV）的屏障损伤非常重要，而 IV 通常与 AD 相关。然而，其分子背景较为复杂，包括炎症和表皮分化基因在内的多个基因簇发生改变。
本研究旨在探讨 AD 和 IV 皮肤中的功能和分子改变是否直接取决于 FLG 功能丧失，以及 FLG 基因型是否决定了受影响下游分子途径的类型。
从瑞典的两家门诊诊所和一个具有已知 FLG 基因型的瑞典 AD 家族材料中招募了 AD/IV 患者（n = 43）和对照者（n = 15）。通过标准化问卷对他们进行临床检查并记录其病史。采集血样和打孔活检，使用标准技术评估经表皮水分流失（TEWL）和皮肤 pH 值。除了 FLG 基因分型外，还分析了 STS 基因以排除 X 连锁隐性鱼鳞病（XLI）。使用微阵列和实时定量 PCR 来比较不同 FLG 基因型之间的基因表达差异。在患有 AD 或 AD/IV 的患者中，几种不同的信号通路根据 FLG 基因型而改变。疾病严重程度、TEWL 和 pH 值在皮肤中跟随 FLG 缺乏；改变的基因和途径的数量与 FLG mRNA 表达相关。
我们进一步强调了 FLG 在皮肤屏障完整性和信号通路复杂补偿激活中的作用。这涉及到炎症、表皮分化、脂质代谢、细胞信号和黏附，以响应 FLG 依赖性皮肤屏障功能障碍。
