Spondyloarthropathies (SpA) are a family of rheumatic diseases affecting 1-3% of the population. They comprise several conditions including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease, undifferentiated spondyloarthritis and juvenile spondyloarthritis. Chronic peripheral and axial joint inflammation with characteristic features of enthesitis, together with extra articular manifestations including psoriasis, intestinal inflammation and uveitis distinguish SpA from other forms of inflammatory arthritis. Genetic studies have identified susceptibility genes common to the subgroups of SpA, which implicate the interleukin-23 (IL-23) signalling pathway in the pathogenesis of SpA. Whilst human studies suggest production and sensitivity to IL-23 are likely increased, and IL-23-responsive cells are expanded in many forms of SpA it is still not clear where IL-23 is produced, the relative and differential contributions of IL-23-mediated effector cytokines IL-17 and IL-22 at particular tissue sites and how IL-23 drives SpA in genetically-prone individuals. This thesis sought to examine IL-23 mediated effects and interactions at typical SpA inflammatory tissue sites including the joint, intestine and skin, utilising both human experimental work and a new mouse model of SpA.
I firstly analysed human tissue to further characterize IL-23-responsive cells influencing progression of psoriasis (Ps) to psoriatic arthritis (PsA). Results showed elevated frequencies of both IL-17 and IL-22 producing CD4+ T cells, with high co-expression of IL-23-receptor (IL-23R), to be a feature of both Ps and PsA. However distribution of these cells differed considerably at the disease tissue sites including lower frequencies of IL-22+ CD4+ T cells in synovial fluid compared to skin and peripheral blood, and concomitant lack of IL-22 expression in synovial tissue. This data suggests that IL-23 mediated Th17 and Th22 cells may have common, as well as divergent roles in the pathogenesis of SpA.
Secondly I investigated the role of IL-23 and examined the relative contributions of IL-17 and IL-22 in the development and progression of spondyloarthritis and Crohn’s-like ileitis in β-1,3-glucan (curdlan) treated BALB/c ZAP70W163C-mutant (SKG) mice. SKG mice triggered with intraperitoneal (i.p.) curdlan were found to develop arthritis, enthesitis and ileitis that was IL-23-dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified endoplasmic reticulum stress, goblet cell dysfunction and pro-inflammatory cytokine production. IL-17A was pathogenic while IL-22 was protective of ileitis in SKG mice, and the usually resistant BALB/c strain developed curdlan-induced ileitis with anti-IL-22. Thus we showed in this SpA model that in response to systemic β-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/22-dependent enthesitis.
In the final component of this thesis I characterised β-1,3-glucan (curdlan) induced psoriasis-like inflammation in SKG mice and further investigated the role of IL-23, IL-22/IL-17, T regulatory cells (Tregs) and microbiota, in disease development and progression. Following i.p. curdlan, SKG mice were found to develop skin inflammation that histologically shares several key characteristic features with human psoriasis. The psoriasis-like inflammation was shown to be IL-23 dependent and IL-22 mediated. Germ Free SKG mice did not develop skin inflammation in response to curdlan, however colonisation with a limited microbiota resulted in the induction of psoriasis-like skin inflammation. Tregs modulated the severity of skin inflammation through the suppression of IL-23 secretion. Intradermal injection of IL-23 induced IL-22 mediated, microbiota dependent psoriasis-like inflammation in naïve SKG mice. These data suggests that IL-23 driven psoriasis in this SpA model, is dependent on the relative contributions of IL-17 and IL-22, microbiota and the balance of T effector and T regulatory cells.
Collectively the work presented in this thesis highlights the pivotal role that IL-23 signalling plays in the pathogenesis of SpA. It identifies differing distribution of IL-23-mediated Th17 and Th22 cells in the peripheral blood, joint and skin of patients with SpA; demonstrates that intestinal IL-23 provokes mucosal dysregulation which drives intestinal inflammation and spondyloarthritis; and characterises IL-23 dependent psoriasis-like inflammation in the SKG mouse model of SpA demonstrating the influence of downstream mediators IL-17 and IL-22, microbiota and Tregs on disease pathogenesis. These aspects of IL-23 signalling in SpA are previously unreported and may assist further research into the development of therapeutic agents for patients suffering with SpA.