Induction of Interleukin-6 Production by Rituximab in Human B Cells




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.


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.


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.


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.