Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
Sci Transl Med. 2022 Apr 27;14(642):eabn2263. doi: 10.1126/scitranslmed.abn2263.
Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Previous studies suggest that nonlesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA sequencing and spatial RNA sequencing. We demonstrate that normal-appearing skin of patients with lupus represents a type I interferon-rich, prelesional environment that skews gene transcription in all major skin cell types and markedly distorts predicted cell-cell communication networks. We also show that lupus-enriched CD16 dendritic cells undergo robust interferon education in the skin, thereby gaining proinflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and nonlesional skin in lupus and suggest a role for skin education of CD16 dendritic cells in CLE pathogenesis.
皮肤狼疮红斑（CLE）是一种影响外貌且发病机制尚未完全阐明的疾病，常与系统性红斑狼疮相关。既往研究提示非皮损处的角质形成细胞可能在疾病易感性中发挥作用，但目前尚未对此进行全面研究，也未在其他细胞群中进行研究。为了研究 CLE 的免疫发病机制，我们通过整合的单细胞 RNA 测序和空间 RNA 测序分析了狼疮患者的正常皮肤、皮损皮肤和循环免疫细胞。我们证明狼疮患者的正常皮肤代表了一种 I 型干扰素丰富的、皮损前环境，使所有主要皮肤细胞类型的基因转录发生倾斜，并显著扭曲预测的细胞间通讯网络。我们还表明，狼疮富集的 CD16 树突状细胞在皮肤中经历强烈的干扰素教育，从而获得促炎表型。总之，我们的数据全面描述了狼疮皮损和非皮损皮肤，并提示 CD16 树突状细胞在 CLE 发病机制中的皮肤教育作用。
