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

Sarah McGrath; Kristoffer Grimstad; Katrin Thorarinsdottir; Kristina Forslind; Daniel Glinatsi; Monica Leu Agelii; Alaitz Aranburu; Timothy Sundell; Charlotte A Jonsson; Alessandro Camponeschi; Anna-Karin Hultgård Ekwall; Andreas Tilevik; Inger Gjertsson; Inga-Lill Mårtensson

doi:10.1002/art.42857

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

Arthritis Rheumatol. 2024 Apr 3. doi: 10.1002/art.42857. Online ahead of print.

Authors

Affiliations

¹ Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and School of Bioscience, University of Skövde, Skövde, Sweden.
³ Lund University, Lund, Sweden, and Spenshult Research and Development Centre, Halmstad, Sweden.
⁴ Skaraborg Hospital, Skövde, Sweden.
⁵ Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and Sahlgrenska University Hospital, Gothenburg, Sweden.
⁶ School of Bioscience, University of Skövde, Skövde, Sweden.

PMID: 38570939
DOI: 10.1002/art.42857

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.

Abstract

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