Identification of a systemic lupus erythematosus disease signature in resting naive B cells

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with alternating phases of heightened symptoms and periods of disease inactivity. Our investigation focuses on the distinct molecular profiles of resting naive B cells from both active and inactive SLE states in female adults, primarily of Black ancestry. We identified a distinct transcriptome and epigenome during inactive SLE. Transcriptional patterns indicated an increase in distinct cytokine signaling pathway expression in SLE B cells, encompassing both common and disease activity–specific components. Specifically, while both disease states exhibited interferon signatures, increased expression of IL-12, TNF-α/NF-κB, and CD40 signaling pathway genes was enriched in inactive disease. While some regions exhibited comparable epigenetic features in both disease states, such as TLR7 signaling genes, others were distinct. Chromatin accessibility in inactive disease indicated the involvement of MEF2 and bHLH family factors, such as E2A/E2-2, while active disease regions were defined by IRF family factors. This study illuminates both disease-associated programs and molecular changes to cell activation pathways capable of directing B cells toward diverse effector fates in active or inactive SLE. Our data also offer insights of particular importance for the design and monitoring of B cell–targeting treatments.