Department of Clinical and Experimental Sciences (Sir Henry Wellcome Laboratories, Faculty of Medicine), University of Southampton, Southampton, Hants, UK.
Department of Primary Care and Population Sciences (Faculty of Medicine), University of Southampton, Southampton, Hants, UK.
Br J Dermatol. 2021 May;184(5):913-922. doi: 10.1111/bjd.19431. Epub 2020 Sep 20.
Atopic dermatitis (AD) arises from a complex interaction between an impaired epidermal barrier, environmental exposures, and the infiltration of T helper (Th)1/Th2/Th17/Th22 T cells. Transcriptomic analysis has advanced our understanding of gene expression in cells and tissues. However, molecular quantitation of cytokine transcripts does not predict the importance of a specific pathway in AD or cellular responses to different inflammatory stimuli.
To understand changes in keratinocyte transcriptomic programmes in human cutaneous disease during development of inflammation and in response to treatment.
We performed in silico deconvolution of the whole-skin transcriptome. Using co-expression clustering and machine-learning tools, we resolved the gene expression of bulk skin (seven datasets, n = 406 samples), firstly, into keratinocyte phenotypes identified by unsupervised clustering and, secondly, into 19 cutaneous cell signatures of purified populations from publicly available datasets.
We identify three unique transcriptomic programmes in keratinocytes - KC1, KC2 and KC17 - characteristic of immune signalling from disease-associated Th cells. We cross-validate those signatures across different skin inflammatory conditions and disease stages and demonstrate that the keratinocyte response during treatment is therapy dependent. Broad-spectrum treatment with ciclosporin ameliorated the KC17 response in AD lesions to a nonlesional immunophenotype, without altering KC2. Conversely, the specific anti-Th2 therapy, dupilumab, reversed the KC2 immunophenotype.
Our analysis of transcriptomic signatures in cutaneous disease biopsies reveals the effect of keratinocyte programming in skin inflammation and suggests that the perturbation of a single axis of immune signal alone may be insufficient to resolve keratinocyte immunophenotype abnormalities.
特应性皮炎（AD）是由表皮屏障受损、环境暴露和辅助性 T 细胞（Th）1/Th2/Th17/Th22 浸润的复杂相互作用引起的。转录组分析提高了我们对细胞和组织中基因表达的理解。然而，细胞因子转录本的分子定量并不能预测特定途径在 AD 中的重要性或细胞对不同炎症刺激的反应。
了解人类皮肤疾病中角质形成细胞转录组程序在炎症发展过程中的变化，以及对治疗的反应。
我们进行了全皮肤转录组的计算机去卷积。使用共表达聚类和机器学习工具，我们首先将批量皮肤（七个数据集，n=406 个样本）的基因表达解析为通过无监督聚类鉴定的角质形成细胞表型，其次解析为从公开可用数据集纯化的 19 个皮肤细胞特征。
我们在角质形成细胞中鉴定出三种独特的转录组程序-KC1、KC2 和 KC17-它们是与疾病相关的 Th 细胞的免疫信号特征。我们在不同的皮肤炎症条件和疾病阶段对这些特征进行了交叉验证，并证明了治疗期间角质形成细胞的反应是依赖于治疗的。环孢素的广谱治疗改善了 AD 病变中 KC17 的反应，使其向非病变免疫表型转变，而不改变 KC2。相反，特异性抗 Th2 治疗药物度普利尤单抗逆转了 KC2 免疫表型。
我们对皮肤疾病活检转录组特征的分析揭示了角质形成细胞编程在皮肤炎症中的作用，并表明单独干扰单一免疫信号轴可能不足以解决角质形成细胞免疫表型异常。
