W174 - Multiomics Atlas of Human B Cell Activation Helps Decipher Lupus Pathogenesis

Marcella Franco; Mehdi Benamar; Raquel Laza-Briviesca; Margaret Chang; Emily Banasiak; Alex Wactor; Qiang Wang; Marc Todd; Brian Wauford; Roxane Darbousset; Scott Jenks; Kevin Cashman; Esther Zumaquero; Zhu Zhu; Junning Case; Paloma Cejas; Miguel Gomez; Pui Lee; Lauren Henderson; Kevin Wei; Henry Long; Ignacio Sanz; Jeffrey Sparks; Esra Meidan; Peter Nigrovic; Maria Gutierrez-Arcelus, Phd – Boston Children's Hospital

Abstract Text: Systemic lupus erythematosus (SLE) is an autoimmune disease that is highly heterogeneous and remains among the most difficult to control. Its heritability is high (up to 66%), and more than 100 genetic susceptibility loci have been identified. Most of these loci implicate common non-coding variants that likely affect gene regulation, especially in activated B cells. However, for most risk loci the regulatory effects and target genes remain unknown. Despite B cells being a main driver of SLE, there is a lack of functional genomics data in human B cells during activation. In this study, we first transcriptomically characterized B cell activation by targeting the B cell receptor (BCR), Toll-like receptor (TLR) 7, TLR9, and CD40 activation pathways at multiple time points, totalling 29 in vitro conditions in five healthy subjects. We then focused on B cells activated via BCR, TLR7, and a condition to differentiate B cells into a subset (IgD- CD27- CXCR5- CD21- CD11c+, DN2) expanded in SLE patients. Utilizing bulk RNA-seq on our cohort of 23 healthy individuals with enriched heterozygosity for SLE risk variants, we identify pathway-specific allele-specific expression of SLE genes. In order to pinpoint the specific regulatory elements likely affected by risk variants, we performed ATAC-seq. Finally, we single-cell profiled mRNA and 137 surface proteins (CITE-seq) to evaluate SLE gene regulation in specific B cell states. In this work, we generated a unique resource of human B cell activation and provide an in-depth analysis of the contributions of SLE risk loci to specific activation pathways.