A comprehensive analysis of rheumatoid arthritis B cells reveals the importance of CD11c<sup>+ve</sup>double-negative-2 B cells as the major synovial plasma cell precursor

Wing, Elinor; Sutherland, Catherine; Miles, Katherine; Gray, David; Goodyear, Carl S.; Otto, Thomas D.; Breusch, S. J.; Cowan, Gillian; Gray, Mohini

doi:10.1101/2023.02.15.526468

Cited by 3 publications

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References 68 publications

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“…This work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) ( http://www.ecdf.ed.ac.uk/ ). This article was submitted as a preprint to BioRxiv as Wing et al 2023 ( 53 ).…”

Section: Acknowledgmentsmentioning

confidence: 99%

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

et al. 2023

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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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confidence: 99%

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

et al. 2023

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“…These include (pre-)antibody-secreting cells, based on the presence of secretory immunoglobulin transcripts and the overlap in B cell receptor sequences between atypical B cells and plasma cells, and antigen-presenting cells, based on the upregulation of surface proteins that promote interactions between B cells and T cells. 9 , 11 , 15 , 16 , 17 , 18 , 19 The multiple and conflicting effector functions previously assigned to atypical B cells may suggest functional heterogeneity among this population.…”

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confidence: 99%

Atypical B cells consist of subsets with distinct functional profiles

Reyes,

Batugedara,

Dutta

et al. 2023

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Atypical B cells consist of subsets with distinct effector functions

Reyes

Batugedara

Dutta

et al. 2022

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Atypical B cells are a population of activated B cells that are commonly enriched in individuals with chronic immune activation. Prior studies to determine the function of these cells have yielded conflicting results, possibly due to functional heterogeneity among this B cell population. To better define the role(s) of atypical B cells in the host adaptive immune response, we performed single-cell sequencing of transcriptomes, cell surface markers, and B cell receptors in individuals with chronic Plasmodium falciparum exposure, a condition known to lead to accumulation of circulating atypical B cells. Our studies identified previously uncharacterized populations of atypical B cells with distinct transcriptional and functional profiles: i) anergy or tolerance, ii) increased ability to interact with T cells, and iii) preparation for high translational activity as seen in pre-antibody secreting cells. We identified a set of cell surface markers to distinguish these distinct atypical B cell subsets and confirmed their presence in malaria-experienced children and adults using flow cytometry. P. falciparum-specific cells were present in equal proportions within each of these populations, indicating that all three subsets develop in response to antigen stimulation. Collectively, our findings help explain the conflicting observations in prior studies involving the functions of atypical B cells and indicate the need for reclassification of these cells into multiple distinct subsets to better understand their role in the adaptive immune response in chronic inflammatory conditions.

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A comprehensive analysis of rheumatoid arthritis B cells reveals the importance of CD11c^+vedouble-negative-2 B cells as the major synovial plasma cell precursor

Cited by 3 publications

References 68 publications

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

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

Atypical B cells consist of subsets with distinct functional profiles

Atypical B cells consist of subsets with distinct effector functions

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A comprehensive analysis of rheumatoid arthritis B cells reveals the importance of CD11c+vedouble-negative-2 B cells as the major synovial plasma cell precursor

Cited by 3 publications

References 68 publications

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

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

Atypical B cells consist of subsets with distinct functional profiles

Atypical B cells consist of subsets with distinct effector functions

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A comprehensive analysis of rheumatoid arthritis B cells reveals the importance of CD11c^+vedouble-negative-2 B cells as the major synovial plasma cell precursor