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

Objective. Systemic-onset juvenile idiopathic arthritis (sJIA) is speculated to follow a biphasic course with an initial systemic disease phase driven by innate immune mechanisms and interleukin (IL)-1β as a key cytokine, while a second chronic arthritic phase 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 γδT cells in disease pathology, in human patients both the prevalence of IL-17 as well as the role of producing cells are still unclear. Methods. SJIA patients' and control serum samples were analyzed for IL-17A and related cytokine levels, while whole blood samples were studied for cellular IL-17 and IFNγ expression. Isolated sJIA and healthy control CD4+ and γδT cells were assayed for cytokine secretion in different culture systems. Results. IL-17A was prevalent in active sJIA serum while both ex vivo as well as in vitro experiments revealed γδT cells to over-express this cytokine. This was not seen with CD4+ T cells, which, on the contrary, expressed strikingly low levels of IFNγ. Therapeutic IL-1 blockade was associated with partial normalization of both cytokine expression phenotypes. Further, culturing healthy donor γδT cells in sJIA patients' serum or IL-1β, IL-18 and S100A12-spiked medium induced IL-17 over-expression similar to observations on patients' cells. Conclusions. A sJIA cytokine environment may prime particularly γδT cells for IL-17A over-expression. Thus, our observations in sJIA patients strongly support a pathophysiological role of these cells as proposed by the recent murine model. This article is protected by copyright. All rights reserved.