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

Arthritis Rheumatol. 2024 Aug;76(8):1263-1277. doi: 10.1002/art.42857. Epub 2024 May 21.

Abstract

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-/lowTbet+CD11c+ 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 Tbet+CD11c+ MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity.

Results: CD21-/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. 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 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, Tbet+CD11c+ 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 Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization.

MeSH terms

  • Adult
  • Aged
  • Antigen Presentation / immunology
  • Arthritis, Rheumatoid* / immunology
  • B-Lymphocytes / immunology
  • CD11c Antigen* / immunology
  • CD11c Antigen* / metabolism
  • Female
  • Humans
  • Male
  • Memory B Cells / immunology
  • Middle Aged
  • Synovial Membrane / immunology

Substances

  • CD11c Antigen