Year: 2025
Type: article
Abstract: Description Most genetic variants that confer risk of complex immune-mediated diseases (IMD) 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 are drivers of IMDs such as lupus and multiple sclerosis. Yet, B cell activation states are underrepresented in functional genomics studies. In this study, we obtained B cells from a total of 23 healthy female donors. We stimulated B cells in vitro by targeting key pathways in six activation conditions such as the CD40, B cell receptor, TLR7, TLR9, and a cocktail that promotes differentiation into double negative 2 (DN2) B cells. We profiled B cell activation at different time points using RNA-seq, single-cell RNA-seq coupled with surface protein markers (CITE-seq), and ATAC-seq. We provide an in-depth characterization of how IMD-associated genes respond to stimuli and group into modules with distinct functions. Using single-cell data, we describe pathway-dependent B cell fates. Chromatin data reveal the transcription factors involved in pathway-dependent B cell activation. These open chromatin regions capture a significant proportion of the heritability of IMDs and elucidate IMD-associated variants with previously unknow function. 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. Funding Sources Supported by Lupus Research Alliance (LRA); Arthritis National Research Foundation (ANRF); Gilead; Join Biology Consortium (JBC) Topic Categories Computational and Systems Immunology (COMP)
Source: The Journal of Immunology
Authors: Vitor R.C. Aguiar, Marcella E. Franco, Daniela Fernandez-Salinas, Marcos Chinas, Qian Xiao, Nicolaj Hackert, Mariasilvia Colantuoni, Nada Abdel Aziz, Marc Todd, Brian Wauford, Alexandra Wactor, Vaishali Prahalad, Raquel Laza Briviesca, Roxane Darbousset, Qiang Wang, Emily Banasiak, Scott Jenks, Kevin Cashman, Esther C. Zumaquero-Martinez, Zhu Zhu, Junning Case, Paloma Cejas, Miguel Gomez, Mehdi Benamar, Pui Lee, Lauren Henderson, Margaret H. Chang, Kevin Wei, Henry Long, Carl Langefeld, Ignacio Sanz, Jeffrey Sparks, Esra Meidan, Peter Nigrovic, Maria Gutierrez-Arcelus
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416446827
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