Correlation of Professional Antigen‐Presenting Tbet⁺CD11c⁺ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis

Abstract

ObjectiveSubsets 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).MethodsClinical 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.ResultsCD21–/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.ConclusionThis 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.image