title: Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis.
abstract: OBJECTIVE
  Rheumatoid 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.
  
  
  METHODS
  RANKL 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.
  
  
  RESULTS
  Healthy 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.
  
  
  CONCLUSIONS
  These findings reveal the critical importance of B cells in bone homeostasis and their likely contribution to joint destruction in RA.
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Nida
authors.initials: N
authors.lastname: Meednu
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Hengwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Teresa
authors.initials: T
authors.lastname: Owen
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Victor
authors.initials: V
authors.lastname: Wang
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cistrone
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
authors.affiliation: University of Rochester Medical Center, Rochester, New York.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D009000:Monocytes; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism*; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013582:Synovial Fluid; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D053245:RANK Ligand; D012333:RNA, Messenger; C505688:TNFSF11 protein, human; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase