Correlation of Professional Antigen-Presenting TbetCD11c B Cells With Bone Destruction in Untreated Rheumatoid Arthritis.

OBJECTIVE

Subsets of CD21 memory B cells (MBCs), including double-negative (DN, CD27IgD) and TbetCD11c cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21 MBCs correlate with joint destruction. However, whether this is due to the TbetCD11c subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21TbetCD11c MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA).

METHODS

Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating TbetCD11c MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of TbetCD11c B cells with T cells was used to assess costimulatory capacity.

RESULTS

CD21TbetCD11c MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The TbetCD11c MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, TbetCD11c B cells induced retinoic acid receptor-related orphan nuclear receptor γT expression in CD4 T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction.

CONCLUSION

This study suggests that TbetCD11c MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization.