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Combining computational target prioritization and a B cell maturation assay for target evaluation studies in systemic lupus erythematosus.

Ming-Mei Shang,Zhuang Liu,B. Knezevic,C. Westerberg,S. Panda,Hai Fang,N. Landén,Michael Sundström,Julian C. Knight,L. Berg

Published 2025 in Translational research : the journal of laboratory and clinical medicine

ABSTRACT

BACKGROUND AND PURPOSE Systemic lupus erythematosus (SLE) is a systemic autoimmune disease involving production of autoantibodies by B cells. This study aimed at identifying novel drug targets using a computational algorithm to select targets and thereafter validate the top ranked 11 targets by siRNA knockdown in a primary B cell maturation assay. EXPERIMENTAL APPROACH The top 1% genes (∼150 genes) from SLE genome-wide association studies were ranked by Priority index (Pi), a computational tool integrating genomic and network information to prioritize disease-relevant genes. These were further filtered by network connectivity, drugability, for ranking highly in autoimmune diseases and for not directly interfering with the B cell stimulation cocktail used. From this, 11 genes were selected for validation by siRNA knockdown: IFNGR1, IL-2, IRF4, IL-12A, IL-12B, VCAM-1, ATF6B, RELA, IKBKG, CHUK and MAPK14. Effects on induced maturation and viability of primary blood B cells were analyzed by flow cytometry, and effects on IgG secretion were investigated by ELISA. RNA-sequencing of B cells treated with siRNA was performed to investigate molecular mechanisms underlying the functional alterations. KEY RESULTS Experimental results show that several of the targets (IFNGR1, IL-2, IL-12A, MAPK14, IRF4, CHUK, ATF6B, IKBKG, and RELA) are involved in B cell maturation, as knockdown caused reduced IgG production and/or decreased maturation of B cells. The observed variability of effects on IgG secretion and B cell maturation suggests differences in the mechanistic roles of the proteins encoded by these genes. RNA-seq analysis of cells where expression of the targeted genes had been modulated showed effects on the expression level of hundreds of genes involved in cellular processes important for B cell functions. CONCLUSION AND IMPLICATIONS Combining the target prioritization algorithm with experimental functional validation studies by gene knockdown and whole transcriptomics profiling constitutes a promising approach to identify potential novel drug targets in immune disorders.

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