Multi-omics profiling of primary human B cells activated via distinct stimuli

B cells are central for immunity and immune-mediated diseases (IMD), but how distinct signaling pathways drive diverse activation responses over time is not comprehensively understood. Here, we obtain peripheral blood B cells from 27 female healthy donors for in vitro stimulation, profiling the response at multiple time points using RNA-seq, single-cell RNA-seq with surface protein markers (CITE-seq), and ATAC-seq. Using diverse stimuli including activation of the B cell receptor (BCR), Toll-like receptor 7 (TLR7), TLR9, CD40, and differentiation into double negative 2 (DN2) IgD – CD27 – CD11c + CD21 – B cells, our analyses uncover activation-dependent B cell states, stimulation-specific transcription factors and regulatory regions, the dynamic response of IMD-associated gene expression, and specific open chromatin regions associated with IMD genetic risk. Furthermore, we also identify a lupus risk variant in an enhancer regulating TNFSF4 expression. The analysis data can be accessed via an interactive browser: https://mgalab.shinyapps.io/bcellactivation . Our findings underscore how profiling the full breadth of B cell activation pathways may be important for understanding B cell biology in health and disease.