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Comprehending cutaneous lupus Cutaneous lupus erythematosus (CLE) is a disfiguring skin condition that affects most patients with systemic lupus erythematosus (SLE) and can be resistant to treatment even when systemic disease is responsive. Billi et al. analyzed CLE lesions and paired normal-appearing skin biopsies, as well as circulating immune cell subsets, to better understand changes in the skin that drive CLE pathogenesis. Using single-cell RNA sequencing and spatial RNA sequencing, they identified a type I IFN–rich signature in prelesional, normal-looking skin that influenced transcription and cell-cell communication for all major skin cell types. CD16 + dendritic cells, which are associated with SLE, were also shaped by the type I IFN environment, and cells in these sites shifted toward a proinflammatory phenotype. Together, these data provide insights into transcriptional changes in the skin that contribute to CLE pathogenesis.