Background/Purpose: B cells contribute to rheumatoid arthritis (RA) pathogenesis through antibody-dependent and -independent mechanisms. Thus, identifying regulators of B cell fate in RA is essential for developing targeted therapies. SLAMF7, a transmembrane protein in the SLAM family, is known for promoting monocyte pro-inflammatory responses. Although plasma cells and some B cells express SLAMF7, its influence on B cell function and differentiation in RA remains unclear. We hypothesized that SLAMF7 regulates B cell differentiation into plasma cells (PCs) and contributes to RA progression via modulation of autoantibody-dependent and independent functions.

Methods: We analyzed single-cell transcriptomic and surface protein expression (CITE-seq) data from paired blood and synovia of RA patients (n = 61) from the Accelerating Medicines Partnership RA/SLE cohort. SLAMF7 surface protein expression was validated by flow cytometry in peripheral blood mononuclear cells (PBMCs, n = 12) and synovial fluid mononuclear cells (SFMCs, n = 7). Immunohistochemistry was performed on RA synovial tissue to localize SLAMF7 expression in CD20+B cells and CD138+PCs. Purified total B cells were differentiated into age-associated B cells (ABCs) using ABC polarizing conditions, then further differentiated into PCs in the presence or absence of recombinant human SLAMF7 protein (n = 3). The effect of SLAMF7 on B cell proliferation was assessed using CFSE dye dilution assays (n = 3). Data analysis was conducted using Seurat v5, Flowjo, and GraphPad Prism.

Results: SLAMF7 gene expression was significantly increased in synovial compared to blood B cells (p < 0.05) and greater than 80% of PCs expressed SLAMF7. Age-associated B cells (ABC) and activated B cell clusters upregulated SLAMF7 in RA synovium. SLAMF7⁺ B cells exhibit higher plasma cell gene score compared to SLAMF7- B cells, indicating a positive correlation between SLAMF7 expression and plasma cell differentiation. Flow cytometry confirmed higher SLAMF7 surface expression in synovial B cells versus blood B cells (17.25% vs. 4.67%, p < 0.05). SLAMF7+B cells in synovial fluid were significantly enriched in double negative (DN, 46.9% vs. 1.91%) and memory B cell populations (30.4% vs. 8.27%, p < 0.05). Among DN subsets, DN2 (IgD-CD27-CD11c+CXCR5-, 54.25%) and DN3 (IgD-CD27-CD11c-CXCR5-, 41.7%) B cells were the predominant SLAMF7+ DN populations. SLAMF7 expression in DN2 cells was significantly higher in synovium compared to blood (54.25% vs. 16.7%, p < 0.05). Immunohistochemistry confirmed SLAMF7+expression by synovial CD20+B cells and CD138+PCs. Functionally, in vitro stimulation with recombinant SLAMF7 significantly suppressed B cell proliferation (p < 0.05), while enhancing plasma cell differentiation, as determined by increased expression of CD38 and CD27.

Conclusion: Our results demonstrate significant SLAMF7 upregulation in RA synovial B cells and implicate SLAMF7 as a functional regulator of B cell functions. SLAMF7 promotes plasma cell differentiation but also inhibits B cell proliferation, suggesting dual roles in modulating B cells within inflamed joints.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/slamf7-drives-plasma-cell-differentiation-in-rheumatoid-arthritis-synovium/