Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor III

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions, multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1-/- skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17-skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of two Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth and treatment with a targeted therapy significantly improved skin lesions in patients. Overall design: Examination of whole transcriptome in patients with Severe Dermatitis, Multiple Allergies, and Metabolic Wasting (SAM) Syndrome

桥粒芯糖蛋白1（Desmoglein 1，Dsg1）是一类仅表达于陆生脊椎动物复层组织的钙粘蛋白，这类组织作为机体重要的物理与免疫屏障。人类体内Dsg1功能丧失突变可引发皮肤病变、多种过敏症，分离得到的患者角质形成细胞会表现出促变应性细胞因子表达上调。然而，Dsg1遗传缺失导致慢性炎症的具体机制仍不明晰。为明确Dsg1缺失引发的系统性应答，我们在小鼠体内敲除了3个串联排列的Dsg1基因。对胚胎期Dsg1基因敲除（Dsg1-/-）小鼠皮肤的全转录组分析显示，在胚胎发育第17.5天（E17.5）时，黏附、分化与角化相关基因的表达出现延迟，其中部分基因在E18.5时表达恢复或上调。对比Dsg1缺陷小鼠与人类的表皮转录组，二者呈现出共有的IL-17偏倚炎症特征。尽管Dsg1-/-小鼠中观察到的细胞间黏附受损与抗Dsg1落叶型天疱疮抗体引发的损伤相似，但天疱疮皮肤病变的IL-17特征较弱。与上述发现的临床意义相符，针对2例Dsg1缺陷患者采用原本用于治疗银屑病的IL-12/IL-23拮抗剂进行治疗后，患者的皮肤病变得到改善。综上，除破坏物理屏障外，基因突变导致的Dsg1功能缺失会在出生前引发类银屑病样炎症特征，且靶向治疗可显著改善患者的皮肤病变。整体实验设计：对重症皮炎、多重过敏与代谢消耗（Severe Dermatitis, Multiple Allergies, and Metabolic Wasting, SAM）综合征患者的全转录组进行检测。