title: Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis.
abstract: Systemic-onset juvenile idiopathic arthritis (JIA) is speculated to follow a biphasic course, with an initial systemic disease phase driven by innate immune mechanisms and interleukin-1β (IL-1β) as a key cytokine and a second chronic arthritic phase that may be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mouse model points to a critical role of IL-17-expressing γ/δ T cells in disease pathology, in humans, both the prevalence of IL-17 and the role of IL-17-producing cells are still unclear.
  
  
  
  Serum samples from systemic JIA patients and healthy pediatric controls were analyzed for the levels of IL-17A and related cytokines. Whole blood samples were studied for cellular expression of IL-17 and interferon-γ (IFNγ). CD4+ and γ/δ T cells isolated from the patients and controls were assayed for cytokine secretion in different culture systems.
  
  
  
  IL-17A was prevalent in sera from patients with active systemic JIA, while both ex vivo and in vitro experiments revealed that γ/δ T cells overexpressed this cytokine. This was not seen with CD4+ T cells, which expressed strikingly low levels of IFNγ. Therapeutic IL-1 blockade was associated with partial normalization of both cytokine expression phenotypes. Furthermore, culturing healthy donor γ/δ T cells in serum from systemic JIA patients or in medium spiked with IL-1β, IL-18, and S100A12 induced IL-17 overexpression at levels similar to those observed in the patients' cells.
  
  
  
  A systemic JIA cytokine environment may prime γ/δ T cells in particular for IL-17A overexpression. Thus, our observations in systemic JIA patients strongly support a pathophysiologic role of these cells, as proposed by the recent murine model.
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kessel
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lippitz
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Toni
authors.identifier: 0000-0003-4337-9260
authors.initials: T
authors.lastname: Weinhage
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Claas
authors.identifier: 0000-0001-9247-4729
authors.initials: C
authors.lastname: Hinze
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Wittkowski
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ndate
authors.initials: N
authors.lastname: Fall
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Gruen
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D020381:Interleukin-17 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology / Q000494:pharmacology; D053583:Interleukin-1beta / Q000276:immunology / Q000494:pharmacology; D053760:Interleukin-23 Subunit p19 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D000067616:S100A12 Protein / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D016207:Cytokines; C508717:IL17A protein, human; C508585:IL1B protein, human; C508840:IL23A protein, human; C508600:IL6 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D020381:Interleukin-17; D020382:Interleukin-18; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000067616:S100A12 Protein; C541220:canakinumab; D007371:Interferon-gamma