Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis.
Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis.
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DOI：
10.1136/annrheumdis-2021-220209
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发表时间：
2021-11
影响因子：
27.4
通讯作者：
Fuschiotti P
中科院分区：
文献类型：
--
作者：
Gaydosik AM;Tabib T;Domsic R;Khanna D;Lafyatis R;Fuschiotti P
虽然T细胞参与了系统性硬化症（SSc）的发病机制，但缺乏对进行性SSc患者受影响皮肤中T细胞介导的免疫应答的全面研究。SSc皮肤活检的基于液滴的单细胞转录组分析为解剖患者特异性T细胞异质性开辟了途径，为鉴定与SSc皮肤病严重程度相关的功能途径相关的新基因表达提供了基础。通过基于液滴的测序（10X Genomics）进行单细胞RNA测序，重点关注来自27名活动性SSc患者和10名健康供体的皮肤活检的3，729个CD3+淋巴细胞（867个细胞来自正常，2，862个细胞来自SSc皮肤样本）。进行性SSc皮肤样本的共聚焦免疫荧光显微镜验证了转录结果，并可视化了T细胞亚群的空间定位。我们确定了健康和SSc皮肤中与不同信号通路相关的再循环和组织驻留T细胞的几个子集。虽然大多数簇在患者和对照之间共享共同的基因表达特征，但我们在SSc皮肤中鉴定了一个独特的再循环CXCL13+ T细胞簇，其表达T辅助滤泡样基因表达特征，并且似乎准备促进患者发炎皮肤内的B细胞反应。目前可用的逆转甚至减缓SSc进展的疗法导致免疫细胞的广泛杀伤和随后的毒性，包括死亡。确定驱动SSc发病机制的精确免疫机制可能导致选择性靶向异常免疫应答的创新疗法，从而产生更好的疗效和更低的毒性。
Although T cells have been implicated in the pathogenesis of systemic sclerosis (SSc), a comprehensive study of T-cell mediated immune responses in the affected skin of patients with progressive SSc is lacking. Droplet-based single-cell transcriptome analysis of SSc skin biopsies opens avenues for dissecting patient-specific T-cell heterogeneity, providing a basis for identifying novel gene expression related to functional pathways associated with severity of SSc skin disease. Single-cell RNA-sequencing was performed by Droplet-based sequencing (10X Genomics), focusing on 3,729 CD3+ lymphocytes (867 cells from normal and 2,862 cells from SSc skin samples) from skin biopsies of 27 patients with active SSc and 10 healthy donors. Confocal immunofluorescence microscopy of progressive SSc skin samples validated transcriptional results and visualized spatial localizations of T-cell subsets. We identified several subsets of recirculating and tissue-resident T cells in healthy and SSc skin that were associated with distinct signaling pathways. While most clusters shared a common gene expression signature between patients and controls, we identified a unique cluster of recirculating CXCL13+ T cells in SSc skin which expressed a T helper follicular-like gene expression signature and that appears to be poised to promote B-cell responses within the inflamed skin of patients. Current available therapies to reverse or even slow progression of SSc lead to broad killing of immune cells and consequent toxicities, including death. Identifying the precise immune mechanism(s) driving SSc pathogenesis could lead to innovative therapies that selectively target the aberrant immune response, resulting in better efficacy and less toxicity.