title: Absence of interleukin-17 receptor a signaling prevents autoimmune inflammation of the joint and leads to a Th2-like phenotype in collagen-induced arthritis.
abstract: OBJECTIVE
  Interleukin-17A (IL-17A) signals through the IL-17 receptor (IL-17R) A/C heterodimer. IL-17RA serves as a common receptor subunit for several IL-17 cytokine family members. Lack of IL-17RA signaling may therefore have additional effects beyond those of lack of IL-17A alone. The present study was undertaken to determine the role of IL-17RA signaling in autoimmune arthritis.
  
  
  METHODS
  Disease incidence and severity were scored in type II collagen-treated wild-type, IL-17RA-deficient, and IL-23p19-deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL-17RA signaling was blocked in vivo in mice with antigen-induced arthritis (AIA).
  
  
  RESULTS
  Comparable to the findings in IL-23p19-deficient mice, IL-17RA-deficient mice were completely protected against the development of collagen-induced arthritis (CIA). However, IL-17RA-deficient mice exhibited an increased number of IL-4-producing CD4+ T cells, distinct from IL-17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL-17RA-deficient mice had a reduced ability to induce IL-6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL-17RA signaling in AIA reduced synovial inflammation.
  
  
  CONCLUSIONS
  These results demonstrate that absence of IL-17RA leads to a Th2-like phenotype characterized by IL-4 production and suggest that IL-17RA signaling plays a critical role in the regulation of IL-4 in CIA and the development of autoimmune inflammation of the joint.
authors: Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors: Odilia B J
authors: OB
authors: Corneth
authors: Adriana M C
authors: AM
authors: Mus
authors: Patrick S
authors: PS
authors: Asmawidjaja
authors: Roel G J
authors: RG
authors: Klein Wolterink
authors: Menno
authors: M
authors: van Nimwegen
authors: Maarten D
authors: MD
authors: Brem
authors: Yara
authors: Y
authors: Hofman
authors: Rudi W
authors: RW
authors: Hendriks
authors: Erik
authors: E
authors: Lubberts
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology* / Q000503:physiopathology; D001327:Autoimmune Diseases / Q000503:physiopathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D020381:Interleukin-17 / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000378:metabolism; D007596:Joints / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010950:Plasma Cells / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*; D018418:Th2 Cells / Q000473:pathology*
chemical_list: C491673:Il17ra protein, mouse; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D053722:Receptors, Interleukin-17; D015847:Interleukin-4