Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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: Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Ndate Fall, Alexei A Grom, Niklas Gruen, Dirk Foell
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 69 Issue 7 Pg. 1480-1494 (07 2017) ISSN: 2326-5205 [Electronic] United States
• PMID: 28296284 (Publication Type: Journal Article)
• Copyright: © 2017, American College of Rheumatology.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• CXCL10 protein, human
• CXCL9 protein, human
• Chemokine CXCL10
• Chemokine CXCL9
• Cytokines
• IL17A protein, human
• IL1B protein, human
• IL23A protein, human
• IL6 protein, human
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-17
• Interleukin-18
• Interleukin-1beta
• Interleukin-23 Subunit p19
• Interleukin-6
• Receptors, Antigen, T-Cell, gamma-delta
• S100A12 Protein
• canakinumab
• Interferon-gamma

Topics

• Adaptive Immunity (immunology)
• Adolescent
• Adult
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents (therapeutic use)
• Arthritis, Juvenile (drug therapy, immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Case-Control Studies
• Chemokine CXCL10 (immunology)
• Chemokine CXCL9 (immunology)
• Child
• Child, Preschool
• Cytokines (immunology)
• Female
• Humans
• Immunity, Innate (immunology)
• Interferon-gamma (immunology)
• Interleukin 1 Receptor Antagonist Protein (therapeutic use)
• Interleukin-17 (immunology)
• Interleukin-18 (immunology, pharmacology)
• Interleukin-1beta (immunology, pharmacology)
• Interleukin-23 Subunit p19 (immunology)
• Interleukin-6 (immunology)
• Male
• Receptors, Antigen, T-Cell, gamma-delta (metabolism)
• S100A12 Protein (immunology, pharmacology)
• T-Lymphocytes (immunology, metabolism)
• Young Adult