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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. 

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease characterized by a diverse cadre of clinical presentations. CLE commonly occurs in patients with systemic lupus erythematosus (SLE), and CLE can also develop in the absence of systemic disease. Although CLE is a complex and heterogeneous disease, several studies have identified common signaling pathways, including those of type I interferons (IFNs), that play a key role in driving cutaneous inflammation across all CLE subsets. However, discriminating factors that drive different phenotypes of skin lesions remain to be determined. Thus, we sought to understand the skin-associated cellular and transcriptional differences in CLE subsets and how the different types of cutaneous inflammation relate to the presence of systemic lupus disease. In this study, we utilized two distinct cohorts comprising a total of 150 CLE lesional biopsies to compare discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE) in patients with and without associated SLE. Using an unbiased approach, we demonstrated a CLE subtype-dependent gradient of B cell enrichment in the skin, with DLE lesions harboring a more dominant skin B cell transcriptional signature and enrichment of B cells on immunostaining compared to ACLE and SCLE. Additionally, we observed a significant increase in B cell signatures in the lesional skin from patients with isolated CLE compared with similar lesions from patients with systemic lupus. This trend was driven primarily by differences in the DLE subgroup. Our work thus shows that skin-associated B cell responses distinguish CLE subtypes in patients with and without associated SLE, suggesting that B cell function in skin may be an important link between cutaneous lupus and systemic disease activity.