B cell Isoform Usage Alterations in Systemic Lupus Erythematosus 4059

Description Systemic lupus erythematosus (SLE) is a life-threatening inflammatory disease with varying clinical manifestations. Despite evidence of alternative splicing disruption playing a role in disease pathogenesis, our current understanding remains limited. In this study, we investigated B cell isoform usage in SLE. Analysis of publicly available RNA-seq of B cells in SLE patients and healthy controls identified differential expression of 17 splicing factors in SLE compared to healthy controls. We further found hundreds of genes with differential isoform usage in SLE B cells. Notably, IRF5, a transcription factor that resides in SLE risk locus, demonstrated aberrant isoform usage. Leveraging GWAS, quantitative trait loci catalogues (QTL), and fine-mapping strategies we identified the candidate causal SLE-isoform QTL variants that seemed to modulate IRF5 alternative promoter usage. In primary naïve B cells activated with a cocktail that induces the CD11c+ DN2 B cell subset, we observed IRF5 upregulation at 24 hours. In addition, specific isoforms were enriched at different time points after activation. Primary B cell manipulation with CRISPR indicated a particular role of IRF5 in the cell cycle, cell division and the hallmark pathways of interferon-alpha. Overall, our findings highlight the importance of isoform usage disruption in SLE and suggest that a risk variant for SLE affects alternative promoter usage for IRF5, which may play important roles in B cell activation. Funding Sources Lupus Research Alliance (LRA)