Article Text

PDF
FRI0452 Are Gm-Csf-Producing Th17 Cells Important in The Pathogenesis of Psoriatic Arthritis?
  1. C. Stober,
  2. J. Goodall,
  3. H. Gaston
  1. Medicine, University of Camridge, Cambridge, United Kingdom

Abstract

Background Psoriasis [Ps] is a common chronic inflammatory skin condition affecting about 1–2% of the world population; approximately 20–30% of patients have psoriatic arthritis [PsA]. PsA can affect peripheral and axial joints, eyes, ileum, colon and skin. Genetic studies reveal common candidate genes including IL23R, IL12B, STAT3, and CARD9, all associated with IL-23 signalling. We demonstrated increased frequencies of Th17 cells in patients with Ps and PsA and the clinical importance of IL-23/Th17 is revealed by the efficacy of biologics targeting this pathway. Whilst IL-17 was thought to be pathogenic in inflammatory conditions such as experimental autoimmune encephalomyelitis, the redundancy of IL-17 but essential requirement for GM-CSF release by Th17 cells was shown. GM-CSF+ T cells were identified in cerebrospinal fluid from patients with multiple sclerosis but a role in the aetio-pathogenesis of PsA has not been established.

Objectives 1) Are GM-CSF+ T cells enriched in peripheral blood and synovial fluid obtained from patients with PsA?

2) Is GM-CSF co-produced with IFN-g?

3) Do CD4+GM-CSF+ T cells express surface markers characteristic of Th17?

4) Is GM-CSF release augmented by exogenous IL-23 and/or IL-12?

Methods PBMC or synovial fluid derived from patients with PsA, or healthy donor (HD) PBMC, were stimulated with anti-CD3/anti-CD28 +/− recombinant IL-23 or IL-12. Supernatants were harvested and analysed by ELISA for IL-17, IFN-γ or GM-CSF. Alternatively, cells were activated with phorbol myristate acetate (PMA) and ionomycin, and evaluated for the expression of the Th17-associated cell surface markers CCR6, CD161 & IL-23R plus IL-17A, IFN-g and GM-CSF by flow cytometry.

Results GM-CSF release from PsA PBMC was higher than that of HD, whereas IFN-g levels were higher in HD. This was most significant on comparing the ratio of IFN-g to GM-CSF. On examining the co-expression of GM-CSF and IFN-g in CD4+ T cells, PsA patients had higher proportions of GM-CSF+ single positive and fewer GM-CSF+IFN-g+ relative to HD. There was also marked enrichment of CD4+GM-CSF+ cells in synovial fluid. On evaluating the expression of the Th17-associated markers CCR6, CD161 and IL-23R, we demonstrated that whereas almost all CD4+IL-17+ cells expressed CCR6, approximately 50% of CD4+GM-CSF+ cells expressed this chemokine receptor. Surprisingly, there were fewer PsA patient CD4+GM-CSF+ peripheral blood T cells co-expressing CCR6, CD161 and IL-23R relative to HD. Finally, IL-23 has been shown to render Th17 cells more pathogenic, hence we examined the effect of this cytokine on GM-CSF release. We showed that whilst IL-17 release was enhanced by exogenous IL-23, GM-CSF release was significantly downregulated with little effect on IFN-g. In contrast, IL-12 increased IFN-g and GM-CSF, and reduced IL-17.

Conclusions IL-23 and Th17 cells are therapeutic targets in PsA, and mouse models of inflammation suggest that pathogenic Th17 cells release GM-CSF. We reveal that GM-CSF release is elevated in patients with PsA, and GM-CSF+ cells are enriched in diseased joints. However, only a proportion of GM-CSF+ cells exhibited features of Th17. Furthermore, IL-23 downmodulated GM-CSF whilst enhancing IL-17. Given that GM-CSF was mainly produced by cells not co-expressing IFN-g in PsA patients [in contrast to healthy donors], this subset may be pathogenic in PsA and warrants further investigation.

Disclosure of Interest None declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.