Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISG^hi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4⁺ and CD8⁺ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.

系统性红斑狼疮（SLE）患者表现出复杂的血液转录组，其细胞起源尚不清楚。使用单细胞 RNA 测序，我们分析了来自 33 名具有不同疾病活动程度的 SLE 儿童和 11 名匹配对照的约 276,000 个外周血单核细胞。干扰素刺激基因（ISG）表达的增加将系统性红斑狼疮儿童的细胞与健康对照细胞区分开来。高 ISG 表达特征 (ISG ^hi ) 源自主要细胞类型中少数转录定义的亚群，包括单核细胞、CD4 ⁺和 CD8 ⁺ T 细胞、自然杀伤细胞、常规和浆细胞样树突细胞、B 细胞，尤其是浆细胞。富含 ISG 和/或单基因狼疮相关基因的独特亚群的扩展将患者分类为疾病活动度最高的患者。对来自成人 SLE 的约 82,000 个单个外周血单核细胞进行分析，证实了疾病活动度最高的患者中类似亚群的扩张。这项研究为解决 SLE 转录特征的起源和疾病异质性以实现精准医学应用奠定了基础。