Interleukin 23 is critical in the pathogenesis of spondyloarthropathy and acts on a novel population of interleukin 23R+ entheseal resident cells

Abstract

Spondyloarthropathy is characterised by inflammation, bone erosion, and new bone formation at the entheseal insertions of tendons and ligaments to bone. Lack of understanding of the underlying mechanisms that drive entheseal disease has seriously inhibited design of therapeutics. Although anti-tumour necrosis factor (TNF) therapy reduces signs and symptoms of inflammation, residual inflammation continues and bone growth is not inhibited. This suggests that TNF is not the optimum target to modify entheseal disease.We previously demonstrated that interleukin (IL) 23 is pivotal in autoimmune inflammation. Recently, genetic variants in the IL-23 receptor (IL23R) have been associated with development of spondyloarthropathy. Moreover, HLA-B27 (present in 90% of patients with ankylosing spondylitis) as well as associated bowel inflammation have been shown to induce IL-23 expression. However, the site and mechanism of action of IL23 are unknown and the reason why such dysregulation of IL23 is associated with inflammation specifically at the enthesis has been inexplicable. We now demonstrate that the entheses and aortic root contain a novel population of resident IL23R+ T cells, which allow the tissue to rapidly respond to IL23. Intravital microscopy reveals that these cells display an extremely restricted entheseal localisation and are absent from synovium and tendon proper. The cells express the molecule PLZF, which allows them to respond to cytokines extremely rapidly, and indeed entheses respond within hours to IL23 in vitro. Moreover, IL-23 expression in vivo in mice is sufficient by itself to rapidly induce the hallmark features of spondyloarthropathy with development of exceedingly specific enthesitis, aortitis, and typical bone erosion and new bone formation.The highly restricted distribution of IL23R+ cells provides the fundamental basis for the anatomical localisation of inflammation observed in spondyloarthropathy, as well as allowing a unified understanding of the genetic associations. These findings suggest that neutralisation of IL23 may be a truly disease modifying therapeutic approach. FundingMerck.