title: Induction of interleukin-6 production by rituximab in human B cells.
abstract: OBJECTIVE
  Rituximab (RTX), an anti-CD20 monoclonal antibody, is highly effective in the treatment of several autoimmune diseases. The mechanism by which RTX treatment improves rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis is not easily related to B cell depletion alone. Prior studies have shown that RTX mediates a rapid stripping of CD20 and CD19 from the human B cell through a process known as trogocytosis. The aim of the present study was to investigate whether changes in B cell phenotype resulting from trogocytosis would diminish the ability of B cells to promote autoimmune disease.
  
  
  METHODS
  Human peripheral blood mononuclear cells were cultured with RTX under conditions that permitted trogocytosis. Changes in B cell phenotype and cytokine production were measured in the basal state and under conditions of activation with interleukin-4 (IL-4)/anti-CD40. The effects of RTX were characterized in terms of a requirement for interaction with the Fcγ receptor (FcγR) and other Fc-dependent interactions.
  
  
  RESULTS
  Trogocytosis induced a marked loss of surface CD19, IgD, CD40, and B cell-activating factor receptor, but did not alter induction of CD86 expression on purified B cells following IL-4/anti-CD40 treatment. Unexpectedly, RTX-dependent trogocytosis of normal human B cells in vitro led to a rapid up-regulation of IL-6 production, with no effect on the production of tumor necrosis factor α, IL-1β, interferon-γ, or IL-10. This effect was Fc-dependent and required the presence of an FcγR-bearing cell. Moreover, this effect involved the release of preformed intracellular IL-6 protein, as well as marked increases in IL-6 messenger RNA levels.
  
  
  CONCLUSIONS
  RTX-mediated trogocytosis of B cells in vitro results in acute production and release of IL-6. The nature of this effect and how it is related to the acute infusion reactions seen with RTX administration remain to be determined.
authors: Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Jonathan D
authors: JD
authors: Jones
authors: B JoNell
authors: BJ
authors: Hamilton
authors: Sladjana
authors: S
authors: Skopelja
authors: William F C
authors: WF
authors: Rigby
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007072:Immunoglobulin D / Q000378:metabolism; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D000069283:Rituximab; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D019013:CD40 Antigens; D007072:Immunoglobulin D; D053583:Interleukin-1beta; D015850:Interleukin-6; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D000069283:Rituximab