title: Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis.
abstract: OBJECTIVE
  Systemic-onset juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by arthritis and systemic features. Its pathogenesis is still largely unknown. It is characterized immunologically by natural killer (NK) cell dysfunction and cytokine signatures that predominantly feature interleukin-1 (IL-1), IL-6, and IL-18. Since IL-18 can drive NK cell function, we examined how the high plasma levels of this cytokine are related to the documented NK cell failure in these patients.
  
  
  METHODS
  The phenotype and function of NK cells from 10 healthy control subjects, 15 patients with polyarticular JIA, and 15 patients with systemic-onset JIA were characterized by staining and functional assays in vitro. IL-18 ligand binding was visualized by fluorescence microscopy. Phosphorylation of several MAP kinases and the IL-18 receptor beta (IL-18Rbeta) were visualized by Western blotting.
  
  
  RESULTS
  IL-18 from the plasma of systemic-onset JIA patients stimulated the activation of NK cells from healthy controls and bound its cognate receptor. However, NK cells from systemic-onset JIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-gamma, after IL-18 stimulation. Furthermore, treatment with IL-18 did not induce the phosphorylation of receptor-activated MAP kinases in NK cells. Alternate activation of NK cells by IL-12 induced NK cell cytotoxicity. We observed no additive effect of IL-18 in combination with IL-12 in systemic-onset JIA patients. Immunoprecipitation of IL-18Rbeta showed that NK cells from systemic-onset JIA could not phosphorylate this receptor after IL-18 stimulation.
  
  
  CONCLUSIONS
  The mechanism of the impaired NK cell function in systemic-onset JIA involves a defect in IL-18Rbeta phosphorylation. This observation has major implications for the understanding and, ultimately, the treatment of systemic-onset JIA.
authors.affiliation: Department of Pediatrics, Centre for Cellular and Molecular Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands. wjager@umcutrecht.nl
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Sebastiaan J
authors.initials: SJ
authors.lastname: Vastert
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
authors.forename: Nico M
authors.initials: NM
authors.lastname: Wulffraat
authors.forename: Wietse
authors.initials: W
authors.lastname: Kuis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Berent J
authors.initials: BJ
authors.lastname: Prakken
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000145:classification / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood / Q000494:pharmacology; D053728:Interleukin-18 Receptor beta Subunit / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
chemical_list: C115629:IL18RAP protein, human; D020382:Interleukin-18; D053728:Interleukin-18 Receptor beta Subunit; D054353:Perforin; D007371:Interferon-gamma; D020929:Mitogen-Activated Protein Kinase Kinases