Background

Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as “improvement” under therapy. These observations were mainly made in trials and based on microarray data.

Objectives

Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry.

Methods

Biopsy specimens from 59 patients with moderate-to-severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab [n = 22] or cyclosporine [n = 8]) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted.

Results

Both lesional and nonlesional skin showed a stable “core” signature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, T_H17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized T_H17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab.

Conclusion

The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of T_H17 and natural killer cell signaling.

中文翻译：

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特应性皮炎显示稳定和动态的皮肤转录组特征。

背景

特应性皮炎（AD）的皮肤转录组研究显示，广泛的失调以及治疗中的“改善”。这些观察结果主要是在试验中并基于微阵列数据。

目标

我们的目的是探讨皮肤转录组以及全身治疗对TREATgermany注册中心患者的影响。

方法

对59例全身治疗前至中度AD患者和30例全身治疗开始后12周（dupilumab [n = 22]或环孢霉素[n = 8]）和31例健康对照的活检标本进行mRNA测序。进行差异表达，途径富集，相关性和共表达网络分析。

结果

病变和非病变皮肤均显示出稳定的“核心”特征，其特征在于表皮分化受到干扰和IL-31 / IL-1信号传导受到激活。第二动态签名表现出对2型炎症，T逐渐富集_ħ 17信令，和自然杀伤细胞的功能。与疾病活动相关的标记物具有表皮屏障特性和免疫调节功能。IL4RA是排名前三位的中央失调基因之一。环孢菌素导致更明显的整体转录组回复和标准化的T _H17细胞/ IL23信号转导，而dupilumab导致表皮分化标记物水平的升高。两种治疗均大大降低了2型标记物的水平，但总体而言，残留轮廓与健康皮肤仍存在很大差异。IL4RA和IL13的较低水平以及IL36A的高表达与对dupilumab的更强临床反应有关。

结论

AD核心标志的特征在于与角质形成细胞分化和痒信号相关的基因失调。动态特征反映了由2型细胞因子主导的进行性免疫反应，并具有T _H 17和自然杀伤细胞信号转导的额外作用。