Journal
ARTHRITIS & RHEUMATOLOGY
Volume 68, Issue 4, Pages 805-816Publisher
WILEY
DOI: 10.1002/art.39489
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Funding
- NIH Rochester Autoimmunity Center of Excellence [U19-AI-563262]
- NIH [P01-AI-078907]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases Accelerated Medicines Partnership [1-UH2-AR-067690]
- Bertha and Louis Weinstein research fund
- NIH USPHS [AR-48697, AR-63650]
- New York State Stem Cell Science [N13G-084]
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ObjectiveRheumatoid arthritis (RA) is a systemic autoimmune disease that often leads to joint damage. The mechanisms of bone damage in RA are complex, involving activation of bone-resorbing osteoclasts (OCs) by synoviocytes and Th17 cells. This study was undertaken to investigate whether B cells play a direct role in osteoclastogenesis through the production of RANKL, the essential cytokine for OC development. MethodsRANKL production by total B cells or sorted B cell subpopulations in the peripheral blood and synovial tissue from healthy donors or anti-cyclic citrullinated peptide-positive patients with RA was examined by flow cytometry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. To define direct effects on osteoclastogenesis, B cells were cocultured with CD14+ monocytes, and OCs were enumerated by tartrate-resistant acid phosphatase staining. ResultsHealthy donor peripheral blood B cells were capable of expressing RANKL upon stimulation, with switched memory B cells (CD27+IgD-) having the highest propensity for RANKL production. Notably, switched memory B cells in the peripheral blood from RA patients expressed significantly more RANKL compared to healthy controls. In RA synovial fluid and tissue, memory B cells were enriched and spontaneously expressed RANKL, with some of these cells visualized adjacent to RANK+ OC precursors. Critically, B cells supported OC differentiation in vitro in a RANKL-dependent manner, and the number of OCs was higher in cultures with RA B cells than in those derived from healthy controls. ConclusionThese findings reveal the critical importance of B cells in bone homeostasis and their likely contribution to joint destruction in RA.
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