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

Author:

McGrath Sarah1,Grimstad Kristoffer2,Thorarinsdottir Katrin1,Forslind Kristina3,Glinatsi Daniel4,Leu Agelii Monica1ORCID,Aranburu Alaitz1,Sundell Timothy1,Jonsson Charlotte A.1,Camponeschi Alessandro1,Hultgård Ekwall Anna‐Karin5,Tilevik Andreas6,Gjertsson Inger5ORCID,Mårtensson Inga‐Lill1ORCID

Affiliation:

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

Abstract

ObjectiveSubsets of CD21−/low memory B cells (MBCs), including double‐negative (DN, CD27IgD) 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).MethodsClinical 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.ResultsCD21−/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.ConclusionThis 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.image

Funder

Swedish Research Council

Tornspiran Foundation

Publisher

Wiley

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