Epigenetic programming underpins B cell dysfunction in human SLE

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naïve cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remains poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset from SLE and healthy subjects. Our data define a differentiation hierarchy between the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naïve cells and was dominated by accessible chromatin enriched in AP-1 and EGR transcription factor motifs. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.