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

McGrath, Sarah ; Grimstad, Kristoffer ; Thorarinsdottir, Katrin ; Forslind, Kristina LU ; Glinatsi, Daniel ; Leu Agelii, Monica ; Aranburu, Alaitz ; Sundell, Timothy ; Jonsson, Charlotte A. and Camponeschi, Alessandro , et al. (2024) In Arthritis and Rheumatology
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... (More)

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. (Figure presented.).

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publication status
in press
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Arthritis and Rheumatology
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85193702753
  • pmid:38570939
ISSN
2326-5191
DOI
10.1002/art.42857
language
English
LU publication?
yes
id
b06fe314-67a2-4f0b-8423-a0377664fac3
date added to LUP
2024-06-19 14:56:34
date last changed
2024-06-19 15:06:20
@article{b06fe314-67a2-4f0b-8423-a0377664fac3,
  abstract     = {{<p>Objective: Subsets of CD21<sup>−/low</sup> memory B cells (MBCs), including double-negative (DN, CD27<sup>−</sup>IgD<sup>−</sup>) and Tbet<sup>+</sup>CD11c<sup>+</sup> cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21<sup>−/low</sup> MBCs correlate with joint destruction. However, whether this is due to the Tbet<sup>+</sup>CD11c<sup>+</sup> subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21<sup>−/low</sup>Tbet<sup>+</sup>CD11c<sup>+</sup> 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<sup>+</sup>CD11c<sup>+</sup> MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet<sup>+</sup>CD11c<sup>+</sup> B cells with T cells was used to assess costimulatory capacity. Results: CD21<sup>−/low</sup>Tbet<sup>+</sup>CD11c<sup>+</sup> MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet<sup>+</sup>CD11c<sup>+</sup> 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<sup>+</sup>CD11c<sup>+</sup> B cells induced retinoic acid receptor–related orphan nuclear receptor γT expression in CD4<sup>+</sup> 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<sup>+</sup>CD11c<sup>+</sup> MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization. (Figure presented.).</p>}},
  author       = {{McGrath, Sarah and Grimstad, Kristoffer and Thorarinsdottir, Katrin and Forslind, Kristina and Glinatsi, Daniel and Leu Agelii, Monica and Aranburu, Alaitz and Sundell, Timothy and Jonsson, Charlotte A. and Camponeschi, Alessandro and Hultgård Ekwall, Anna Karin and Tilevik, Andreas and Gjertsson, Inger and Mårtensson, Inga Lill}},
  issn         = {{2326-5191}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis and Rheumatology}},
  title        = {{Correlation of Professional Antigen-Presenting Tbet<sup>+</sup>CD11c<sup>+</sup> B Cells With Bone Destruction in Untreated Rheumatoid Arthritis}},
  url          = {{http://dx.doi.org/10.1002/art.42857}},
  doi          = {{10.1002/art.42857}},
  year         = {{2024}},
}