Tu108 - TNFR2 and Its Immune-regulatory Role in Shaping Pathogenic B Cell Fate in Rheumatoid Arthritis

Abstract Text: Background
Pathogenic B cells, such as age-associated B cells (ABCs), are enriched in rheumatoid arthritis (RA) and other autoimmune diseases, correlating with increased disease activity. Targeting these subsets offers a promising approach for precision B cell therapies. Previous studies demonstrated TNFR2 expression in B cells, but its role in B cell function remains unclear. We hypothesize that TNFR2 promotes the inflammatory role of pathogenic B cells, contributing to RA progression and severity.
Methods
CITE-seq data from paired blood and synovium samples of RA patients(n=9) ,and PBMCs from blood(n=10) and synovial fluid (n=5) of RA patients were analyzed to evaluate TNFR2 gene and protein expression respectively . Purified B cells were stimulated under ABC-polarizing conditions in the presence or absence of TNFR2 agonists or antagonists.TNFR2 expression, B cell differentiation into plasma cells was analyzed by flow cytometry, cytokine secretion was measured by ELISA. Analysis was done using seuratV5, Flowjo, and GraphPad prism.
Results
CITE-seq revealed the highest expression of TNFR2 in ABCs. TNFR2 high B cells in the synovium but not in blood expressed lower levels of plasma cell differentiation associated genes. There was a 4-fold increase of TNFR2 protein expression in synovial fluid B cells in RA patients compared blood B cells. TNFR2 agonist enhanced B cell TNF-α secretion (3-fold, p< 0.05) and inhibited B cell differentiation to plasmablasts (2-fold, p< 0.05).
Conclusions
TNFR2 promotes B cell antibody-independent inflammatory functions while inhibiting antibody-dependent functions. This novel finding underscores TNFR2 as a potential therapeutic target for precision B cell therapies.