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.

IL-6 in Inflammation, Immunity, and Disease

“…However, recent preliminary results indicate that tocilizumab treatment can correct the imbalance between Th17 and Treg in peripheral blood CD4 þ T cells (Samson et al 2012;Pesce et al 2013). Moreover, it was shown that the treatment caused a reduction in the level of serum IgG4-class anticyclic citrullinated peptide Ab in RA (Carbone et al 2013). Anti-aquaporin 4 (AQP4) Ab plays a pathological role in neuromyelitis optica, and tocilizumab treatment was found to improve clinical symptoms and reduce serum anti-AQP4 Ab titers, perhaps by inhibiting cell survival of the plasmablasts secreting this Ab (Chihara et al 2011;Araki et al 2013).…”

IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases

“…IL-21 promotes plasma cell differentiation and preferentially induces IgG4 production [ 9 ]. One study demonstrated that tocilizumab treatment causes a selective reduction in IL-21 production of memory/activated T cells, leading to a reduction in the serum levels of IgG4-specifi c anti-citrullinated peptide Ab in RA patients [ 69 ]. Several recent reports demonstrated that tocilizumab therapy led to an increase in the number of Treg cells in peripheral blood CD4 + T cell fractions in RA patients [ 70 -72 ] (Fig.…”

Multifocal Encephalopathy and Autoimmune-mediated Limbic Encephalitis Following Tocilizumab Therapy

“…Tocilizumab also inhibits IgG4 (not IgG1)-class anti-CCP antibodies by blocking the effects of IL-6 on IL-21 production induced by CD4-T-cells (6). IL-6 exhibits ambivalent effects with respect to inflammation and neurotrophic repair depending on the pathological context in the central nervous system (CNS) (7).…”