Frontiers in Immunology (Aug 2023)

Double-negative-2 B cells are the major synovial plasma cell precursor in rheumatoid arthritis

  • Elinor Wing,
  • Catherine Sutherland,
  • Katherine Miles,
  • David Gray,
  • Carl S. Goodyear,
  • Thomas D. Otto,
  • Stefan Breusch,
  • Graeme Cowan,
  • Mohini Gray

DOI
https://doi.org/10.3389/fimmu.2023.1241474
Journal volume & issue
Vol. 14

Abstract

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B cells are key pathogenic drivers of chronic inflammation in rheumatoid arthritis (RA). There is limited understanding of the relationship between synovial B cell subsets and pathogenic antibody secreting cells (ASCs). This knowledge is crucial for the development of more targeted B-cell depleting therapies. While CD11c+ double-negative 2 (DN2) B cells have been suggested as an ASC precursor in lupus, to date there is no proven link between the two subsets in RA. We have used both single-cell gene expression and BCR sequencing to study synovial B cells from patients with established RA, in addition to flow cytometry of circulating B cells. To better understand the differentiation patterns within the diseased tissue, a combination of RNA-based trajectory inference and clonal lineage analysis of BCR relationships were used. Both forms of analysis indicated that DN2 B cells serve as a major precursors to synovial ASCs. This study advances our understanding of B cells in RA and reveals the origin of pathogenic ASCs in the RA synovium. Given the significant role of DN2 B cells as a progenitor to pathogenic B cells in RA, it is important to conduct additional research to investigate the origins of DN2 B cells in RA and explore their potential as therapeutic targets in place of the less specific pan-B cells depletion therapies currently in use.

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