Spatial characterization of skin lesions in discoid and systemic lupus erythematosus

Lupus erythematosus (LE) skin lesions are associated with significant dysregulation of the local immune microenvironment. However, the spatial distribution and interactions between stromal and immune cells within affected tissues remain poorly characterized. In this study, we employed Stereo-seq to construct a single-cell resolution spatial transcriptomic atlas of lesional skin from patients with discoid lupus erythematosus (DLE) and systemic lupus erythematosus (SLE). Our analysis revealed that keratinocyte subpopulations in distinct differentiation states presented cell type-specific profiles of inflammatory mediator expression. Notably, a subset of stress keratinocytes located predominantly at the epidermis-dermis interface mediated the recruitment of T cells and plasma cells, potentially through an IFN-γ-JAK-STAT axis driving CXCL9/10/11-CXCR3 signaling, and these effects were more pronounced in active SLE lesions compared to chronic DLE lesions. Spatial profiling revealed immune cell niches resembling tertiary lymphoid structures (TLS), which were particularly prominent in chronic DLE and SLE lesions. These lupus-associated TLS structures were characterized by the coordinated infiltration of multiple cell subsets, including age-associated B cells, precursors of germinal center B cells, naïve B cells, regulatory T cells, T peripheral helper and/or T follicular helper cells, memory T cells, and CCL14⁺ vascular endothelial cells, which presented the spatial characteristics of the lymphoid follicle-like structures in chronic LE skin lesions. Collectively, our findings provide a comprehensive spatial characterization of the cellular components and molecular features within LE skin lesions.