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A3.9 IL-17RA Signalling is Essential for Collagen Induced Arthritis Development
  1. Odilia BJ Corneth1,2,
  2. Adriana MC Mus1,2,
  3. Patrick S Asmawidjaja1,2,
  4. Maarten D Brem1,2,
  5. Franka Luk1,2,
  6. Wendy Dankers1,2,
  7. Rudi W Hendriks3,
  8. Erik Lubberts1,2
  1. 1Department of Rheumatology
  2. 2Department of Immunology
  3. 3Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Abstract

Introduction IL-17A plays an important role in collagen-induced arthritis (CIA). It signals through the IL-17 receptor (IL-17R) A and C heterodimer. The IL-17RA appears to be a common receptor subunit for several IL-17 cytokine family members, including IL-17A, IL-17C and IL-17F. Lack of IL-17RA signalling may therefore have a broader effect than lack of IL-17A alone. We therefore aim to determine the role of IL-17RA signalling in arthritis.

Methods Disease incidence and severity were scored in wild type (positive control), IL-17RA deficient and IL-23p19 deficient (negative control) mice in CIA. T helper cell profiles and humoral immune responses were analysed by flow cytometry and immuno-histo-chemistry. Serum auto-reactive IgG antibodies were measured by ELISA. Pathogenicity of T cells and total splenocytes was determined in a functional assay in vitro.

Results As expected, wild type mice developed CIA from day 21 after the first immunisation. IL-23p19 deficient mice did not develop arthritis. Interestingly, IL-17RA deficient mice were completely protected against CIA, even after a third immunisation. This is in contrast to IL-17A deficient mice, of which 20% is still susceptible to CIA. T cells in IL-17RA deficient mice display a Th2-like phenotype in CIA with higher proportions of IL-4 producing CD4 T cells. This population is distinct from IL-17A producing T cells. The shift in T cell phenotype induces a less inflammatory B cell response with fewer plasma cells in the spleen and lower pathogenic IgG2a antibody production in favour of IgG1 production. In a functional assay, both isolated CD4+ T cells and total splenocytes of IL-17RA deficient mice were less capable of inducing pro-inflammatory IL-6 production by normal, IL-17RA expressing synovial fibroblasts in CIA in vitro.

Conclusions Here we show that lack of IL-17RA signalling prevents auto-immune inflammation of the joint. In addition, T helper cells shift to a Th2 like phenotype characterised by IL-4 production. T cells and splenocytes of these mice are less pathogenic, leading to lower pathogenic IgG2a antibody levels in serum. This is in contrast with IL-17A deficient mice and suggests that other factors involved in CD4+ T cell differentiation and pathogenicity can signal through the IL-17RA.

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