The role of interleukin-17 in the pathogenesis of rheumatoid arthritis

Abstract

Interleukin (IL)-17 (also known as IL-17A), the signature cytokine of the newly described T helper 17 (Th17) cell population, has been implicated in the pathogenesis of numerous autoimmune diseases including rheumatoid arthritis. IL-17 is the founding member of a new subclass of cytokines that have highly proinflammatory properties. Studies in rodents and mammalian cell culture systems, as well as clinical settings, support a role for IL-17 in promoting rheumatoid arthritis. This article discusses the history of the discovery of Th17 cells, the potential mechanisms of action of IL-17 in autoimmunity, and perspectives for IL-17-targeted cytokine therapy.

Figure 1. Old versus new models of Th cell development

In the original paradigm of CD4+ T cell differentiation, most CD4+ T helper cells could be classified into Th1 cells (typified by production of IFNγ) or Th2 cells (typified by production of IL-4, IL-5 and IL-13). Th1 cells were considered to promote host defense against most infectious microbes (both intracellular and extracellular), whereas Th2 cells were thought to act primarily against large Helminth worms. Th1 cells were also considered to be the major driver of autoimmune pathology in RA as well as other autoimmune diseases such as psoriasis, multiple sclerosis and Crohn's Disease. The heterodimeric cytokine IL-12, composed of the IL-12p40 and IL-12p35 subunits, was shown to be critical for development of Th1 cells, and hence efforts to block IL-12 with antibodies against the IL-12p40 subunit were pursued. In 2005, the discovery of the Th17 subset revised this model, which was partly revealed based on a new understanding of the shared role of the IL-12p40 subunit in the cytokine IL-23. Th17 cells are driven to differentiation by a combination of IL-1, IL-6 and TGFβ, and IL-23 (composed of the IL-12p40 and the IL-23p19 subunits) serves to expand and stabilize this lineage.