Defining Patient-Level Molecular Heterogeneity in Psoriasis Vulgaris Based on Single-Cell Transcriptomics.
Defining Patient-Level Molecular Heterogeneity in Psoriasis Vulgaris Based on Single-Cell Transcriptomics.
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基于单细胞转录组学定义寻常型银屑病患者水平的分子异质性。
DOI：
10.3389/fimmu.2022.842651
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
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识别人类疾病的遗传变异为治疗开发建立了目标，并有助于为个体患者量身定制治疗。大规模的转录组学分析已经将患者之间的这种分子异质性的研究扩展到体细胞组织。然而，批量RNA分析的较低分辨率，特别是在复杂的复合组织如皮肤中，限制了其成功。在这里，我们展示了询问慢性皮肤炎性疾病寻常型银屑病患者水平分子差异的方法，利用从活动性病变中分离的CD45+细胞的单细胞RNA测序。高度银屑病特异性转录异常显示大于平均个体间方差，提名他们作为临床异质性的潜在来源。我们发现，这些趋化因子之一，CXCL13，表现出显着的相关性与病变的严重程度在我们的患者系列。我们的分析还建立了银屑病皮肤驻留记忆T细胞中升高的基因富集了协调染色质和CDC 42依赖性细胞骨架重塑的程序，其特定组分在单细胞水平上与Th17身份明显相关。总的来说，这些分析描述了系统的手段，解剖细胞类型和患者水平的差异，皮肤银屑病使用高分辨率的人类炎症性疾病的转录谱。
Identifying genetic variation underlying human diseases establishes targets for therapeutic development and helps tailor treatments to individual patients. Large-scale transcriptomic profiling has extended the study of such molecular heterogeneity between patients to somatic tissues. However, the lower resolution of bulk RNA profiling, especially in a complex, composite tissue such as the skin, has limited its success. Here we demonstrate approaches to interrogate patient-level molecular variance in a chronic skin inflammatory disease, psoriasis vulgaris, leveraging single-cell RNA-sequencing of CD45+ cells isolated from active lesions. Highly psoriasis-specific transcriptional abnormalities display greater than average inter-individual variance, nominating them as potential sources of clinical heterogeneity. We find that one of these chemokines, CXCL13, demonstrates significant correlation with severity of lesions within our patient series. Our analyses also establish that genes elevated in psoriatic skin-resident memory T cells are enriched for programs orchestrating chromatin and CDC42-dependent cytoskeleton remodeling, specific components of which are distinctly correlated with and against Th17 identity on a single-cell level. Collectively, these analyses describe systematic means to dissect cell type- and patient-level differences in cutaneous psoriasis using high-resolution transcriptional profiles of human inflammatory disease.