A multi-omics resource of B cell activation reveals genetic mechanisms for immune-mediated diseases

Vitor R. C. Aguiar; Marcella E. Franco; Nada Abdel Aziz; Daniela Fernandez‐Salinas; Marcos Chiñas; Mariasilvia Colantuoni; Qian Xiao; Nicolaj S. Hackert; Yifei Liao; Rodrigo Cervantes‐Díaz; Marc Todd; Brian Wauford; Alex Wactor; Vaishali Prahalad; Raquel Laza Briviesca; Roxane Darbousset; Qiang Wang; Scott A. Jenks; Kevin S. Cashman; Esther Zumaquero; Zhu Zhu; Junning Case; Paloma Cejas; Miguel Gomez; Hannah C. Ainsworth; Miranda C. Marion; Mehdi Benamar; Pui Y. Lee; Lauren A. Henderson; Margaret H. Chang

doi:10.1038/s41467-026-78656-w

Genetic & Genomic MedicineNature CommunicationsOct 23, 2026

Peer-reviewed journal article

A multi-omics resource of B cell activation reveals genetic mechanisms for immune-mediated diseases

Vitor R. C. Aguiar iD, Marcella E. Franco iD, Nada Abdel Aziz iD, Daniela Fernandez‐Salinas, Marcos Chiñas iD, Mariasilvia Colantuoni iD, Qian Xiao iD, Nicolaj S. Hackert iD, Yifei Liao iD, Rodrigo Cervantes‐Díaz iD, Marc Todd iD, Brian Wauford, Alex Wactor, Vaishali Prahalad, Raquel Laza Briviesca iD, Roxane Darbousset iD, Qiang Wang, Scott A. Jenks iD, Kevin S. Cashman iD, Esther Zumaquero iD, Zhu Zhu iD, Junning Case, Paloma Cejas iD, Miguel Gomez, Hannah C. Ainsworth iD, , María Gutiérrez‐Arcelus iD

Abstract

Most genetic variants that confer risk of complex immune-mediated diseases (IMDs) affect gene regulation in specific cell types. Their target genes and focus cell types are often unknown, partially because some effects are hidden in untested cell states. B cells play central roles in IMDs, including autoimmune, allergic, infectious, and cancer-related diseases. Despite this established importance, B cell activation states are underrepresented in functional genomics studies. In this study, we obtained B cells from 26 healthy female donors and stimulated them in vitro with six activation conditions targeting key pathways: the B cell receptor (BCR), Toll-like receptor 7 (TLR7), TLR9, CD40, and a cocktail that promotes differentiation into double negative 2 (DN2) IgD- CD27- CD11c+ CD21- B cells, a likely pathogenic subset implicated in autoimmunity and infection. We profiled up to 24 B cell activation states and up to 5 control conditions using RNA-seq, single-cell RNA-seq with surface protein markers (CITE-seq), and ATAC-seq. We characterize how IMD-associated genes respond to stimuli and group into distinct functional programs. High-depth RNA-seq data reveals widespread splicing effects during B cell activation. Using single-cell data, we describe stimulus-dependent B cell fates. Chromatin data reveal transcription factors likely involved in B cell activation, and activation-dependent open chromatin regions that are enriched in IMD genetic risk. We experimentally validate a lupus risk variant in a stimulus-specific open chromatin region that regulates TNFSF4 expression, highlighting the relevance of studying B cell activation to elucidate disease association. These data are shared via an interactive browser that can be used to query the dynamics of gene regulation and B cell differentiation during activation by different stimuli, enhancing further investigation of B cells and their role in IMDs: https://mgalab.shinyapps.io/bcellactivation.

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