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

Abstract

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.

Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

“…We further extend the observation from previous studies 34 , 36 that synovial plasma cells are generated from locally activated B cells, including activated B cells, ABCs, and memory B cells. The finding that the ABCs are a precursor of plasma cells in the synovium is consistent with a recent report 80 . Further, our work highlights the likely important signals promoting synovial B cell activation and selection, including antigen (reflected in upregulation of BCR signaling), cytokines (most notably IFNG ), and direct cell–cell interactions, mainly involving Tph/Tfh cells.…”

Single-cell profiling of CD11c+ B cells in atherosclerosis

“…To further investigate CD11c+ B cells in human atherosclerosis, CITESeq of 60 CAD patients with low and high CAD severity was used to further subtype and characterize CD11c+ B cells. Our study was the first to demonstrate that DN2 B cells, which were known to expand in autoimmune diseases such as RA and SLE ( 10 , 11 ), also increase with aging and with high CAD severity. These DN2 cells could potentially contribute to an increase in atherosclerotic burden through the production of atherogenic IgG to MDA, as the frequency of DN2 cells was significantly correlated with plasma IgG to MDA ( Figure 6 ).…”

“…CD11c+ B cells have been described as proinflammatory B cells through the production of IgG to autoantigens as well as inflammatory cytokines, e.g., IFNg ( 8 , 9 ). Increases in CD11c+ B cells have been shown to be associated with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), as well as aging ( 10 , 11 ). Yet, subsets of CD11c+ B cells are poorly defined, and their roles in atherosclerosis are incompletely explored.…”

From neglect to spotlight: the underappreciated role of B cells in cutaneous inflammatory diseases

“…This process constructs a potential pathogenesis axis that spans from transitional B cells to ASCs ( 60 ). Recently, CD27 and IgD double-negative-2 B cells (DN2 B cells), akin to atMBCs, have been also implicated as the major precursor of ASCs and associated with the pathogenesis in patients with rheumatoid arthritis (RA) ( 62 ). Collectively, these parallels between the two prevalent autoimmune diseases potentially converge upon the pathogenic role of atMBCs or DN2 B cells differentiating into autoreactive ASCs.…”