Breaking old paradigms: Th17 cells in autoimmune arthritis

Abstract

Aberrant helper T cell activation has been implicated in the pathogenesis of an array of autoimmune diseases. In this review, we summarize evidence that suggests the involvement of a novel T cell subset, the Th17 lineage, in rheumatoid arthritis. In particular, we focus on the role of Th17 cells in inducing and perpetuating the chronic inflammation, cartilage damage, and bone erosion that are hallmark phases of joint destruction and consider current and emerging therapies that seek to disrupt the inflammatory Th17 network and shift the immune system back towards homeostasis.

Figure 1

Model of T cell subsets. Naïve CD4⁺ T cells commit to the Th1, Th2, Th17 or Treg lineages according to the composition of the local cytokine milieu. In the presence of TGF-b and IL-6 or IL-21 in mice and IL-1β, IL-6, IL-23, and TGF-β in humans, naïve precursors develop into Th17 cells characterized by the expression of various pro-inflammatory factors, including IL-17A, IL-17F, and IL-6. Recent evidence suggests a certain degree of plasticity in the Treg lineage; reports indicate that the presence of activated dendritic cells can induce the loss of Foxp3 expression and induce IL-17 production from Tregs.

Figure 2

Schematic of the involvement of Th17 cells in rheumatoid arthritis. Infiltrating Th17 cells produce IL-17, which synergizes with other pro-inflammatory cytokines present in the synovial fluid, leading to (a) the activation of synovial fibroblasts and dendritic cells, leading to a local milieu conducive to Th17 development and further upregulating inflammation, (b) phenotypical modification of chondrocytes, resulting in the production of aggrecanases and MMPs that participate in cartilage destruction and (c) the upregulation of RANKL on osteoclast-supporting cells and synovial fibroblasts, which promotes bone erosion.