The interleukin-23/interleukin-17 axis in spondyloarthritis

Abstract

Purpose of review: To inform readers of recent advances in our understanding of the development and function of Th17 T cells and emerging data suggesting that the interleukin-23/interleukin-17 axis may be involved in the pathogenesis of spondyloarthritis.

Recent findings: The discovery of CD4+ Th17 T cells and the interleukin-23/interleukin-17 axis has challenged existing paradigms and the role of Th1 T cells in many autoimmune diseases. The development and cytokine profile of Th17 T cells differs in mice and humans. In humans, interleukin-23 synergizes with interleukin-6 and interleukin-1 to promote Th17 development. In mice, transforming growth factor-beta and interleukin-6 are critical, whereas interleukin-23 is more important at later stages promoting interleukin-17 production. In mice, CD4+ cells producing interferon-gamma appear to be distinct from interleukin-17-producing cells, while in humans cells secreting both cytokines have been observed. Growing evidence from animal models, cytokine analyses of patient fluids, and whole-genome association studies suggest that the interleukin-23/interleukin-17 axis plays an important role in spondyloarthritis pathogenesis. Possible links between an HLA-B27-induced unfolded protein response and activation of the interleukin-23/interleukin-17 axis have been observed in animal models and may contribute to the development of the spondyloarthritis phenotype.

Summary: Activation of the interleukin-23/interleukin-17 axis in spondyloarthritis has important therapeutic implications.

Figure 1

Proposed mechanism linking HLA-B27 misfolding to activation of the IL-23/IL-17 axis in spondyloarthritis. Cytokines that upregulate class I (HLA-B27) expression may trigger UPR activation under conditions where HLA-B27 misfolding reaches a critical threshold. This in turn would polarize cells such as macrophages to produce more IL-23 relative to IL-12. In susceptible individuals with permissive (non-protective) IL-23 receptor genotypes (Θ) this may promote Th17 activation over Th1, thus promoting IL-17 production and inflammation. Other UPR-modulated cytokines such as IFN-β (not shown) could create a positive feedback loop exacerbating HLA-B27 upregulation, misfolding, and UPR activation. (Modified from Colbert RA et al., HLA-B27 Misfolding and Spondyloarthropathies. In: Lopez-Larrea, C. ed. Molecular Mechanisms of Spondyloarthropathies. Austin, TX. Landes Bioscience/Eurekah 2008:(in press).)