Combining computational target prioritization and a B cell maturation assay for target evaluation studies in systemic lupus erythematosus
Bibliographic record
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".