title: Interleukin-6 receptor blockade selectively reduces IL-21 production by CD4 T cells and IgG4 autoantibodies in rheumatoid arthritis.
abstract: Interleukin-6 (IL-6) levels are known to be increased in patients with rheumatoid arthritis (RA). Tocilizumab, a monoclonal antibody to the IL-6 receptor (IL-6R), reduces disease activity in RA, although its mechanisms of action remain unclear. Since IL-6 regulates cytokine production by CD4 T cells during activation, we investigated whether treatment with tocilizumab altered the phenotype and cytokine production by CD4 T cells in patients with rheumatoid arthritis. We show here that tocilizumab treatment does not change the production of cytokines by naïve CD4 T cells. However, tocilizumab treatment causes a selective decrease of IL-21 production by memory/activated CD4 T cells. Since IL-21 is known to promote plasma cell differentiation, we examined the effect of tocilizumab on the production of autoantibodies. We show that there is a decrease in the levels of IgG4 anti-CCP antibodies, but there is no effect on IgG1 anti-CCP antibodies. In addition, we show that IL-21 is a powerful inducer of IgG4 production by B cells. Thus, IL-6 contributes to the presence of IgG4-specific anti-CCP autoantibodies in RA patients, likely through its effect on IL-21 production by CD4 T cells, and IL-6R blockade down-regulates this pathway.
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Carbone
authors.forename: Augusta
authors.initials: A
authors.lastname: Wilson
authors.forename: Sean A
authors.initials: SA
authors.lastname: Diehl
authors.forename: Janice
authors.initials: J
authors.lastname: Bunn
authors.forename: Sheldon M
authors.initials: SM
authors.lastname: Cooper
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincon
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D017326:Clinical Trials, Phase III as Topic; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D018448:Models, Immunological; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D000098546:Interleukin-21
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D007378:Interleukins; D019947:Receptors, Interleukin-6; C502936:tocilizumab; D000098546:Interleukin-21
keywords: CD4 T; IL-21; IL-6; IgG4; Interleukin-6; auti-CCP; rheumatoid arthritis; tocilizumab