Professional antigen-presenting Tbet+CD11c+ B cells correlate with bone destruction in untreated rheumatoid arthritis.

OBJECTIVE:Subsets of CD21-/low memory B cells (MBCs), including double-negative (DN, CD27-IgD-) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21-/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21-/low Tbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in untreated RA patients (uRA). METHODS:Clinical observations were combined with flow cytometry (n=36) and single cell (sc)RNA and V(D)J sequencing (n=4) of peripheral blood MBCs from uRA patients. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA-sequencing data of synovial B cells. In vitro co-culture of Tbet+CD11c+ B cells with T cells was used to assess co-stimulatory capacity. RESULTS:CD21-/low Tbet+CD11c+ MBCs in peripheral blood correlated with bone destruction but no other clinical parameters analysed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V-genes. Gene expression analysis of these cells identified a unique signature of over 150 upregulated genes associated with antigen presentation functions including: BCR activation and clathrin-mediated antigen internalisation, regulation of actin filaments, endosomes and lysosomes, antigen processing, loading, presentation and co-stimulation, a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced RORγT expression in CD4+ T cells, thereby polarising to Th17 cells, a T-cell subset critical for osteoclastogenesis and associated with bone destruction. CONCLUSION:This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T-cell activation and Th17 polarisation.