RESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Linfocitos T CD4-Positivos/metabolismo , Inmunoglobulina G/inmunología , Interleucinas/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Adulto , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Autoanticuerpos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Ensayos Clínicos Fase III como Asunto , Citocinas/metabolismo , Femenino , Humanos , Masculino , Modelos InmunológicosRESUMEN
C-reactive protein (CRP), an acute phase protein in humans and rabbits, is part of the innate immune system. The role of CRP in host defense has been thought to be largely due to its ability to bind phosphocholine, activate complement, and interact with IgGRs (FcgammaRs). We have shown previously that transgenic rabbit CRP (rbCRP) protects mice from lethal challenges with platelet-activating factor (PAF). To investigate the mechanism of this protection, we created additional lines of transgenic mice that express either wild-type rbCRP, a variant of rbCRP with altered complement activation activity (Y175A), or a variant of rbCRP unable to bind phosphocholine (F66Y/E81K). In the current study, these lines were challenged with a single injection of PAF and their survival monitored. Mice expressing wild-type and Y175A rbCRP were protected against challenge by PAF whereas mice expressing F66Y/E81K rbCRP were not. Treatment with cobra venom factor did not affect survival, confirming the results with the Y175A rbCRP variant and indicating that complement activation was not required to mediate protection. Both wild-type rbCRP and Y175A rbCRP were capable of binding PAF in vitro whereas F66Y/E81K rbCRP was not. Although other interpretations are possible, our results suggest that the protective effect of rbCRP against PAF is due to sequestration of PAF.