Novel insights in the pathogenesis of Juvenile Idiopathic Arthritis: an experimental in vitro and in vivo model for studying the role of different subsets of T helper lymphocytes.

Juvenile idiopathic arthritis (JIA) is the most frequent chronic inflammatory rheumatic condition in childhood, predisposing to a long-lasting morbidity and physical disability. JIA encompasses heterogeneous conditions that can be grouped in three major types: oligoarthritis, polyarthritis, and systemic arthritis. Although the pathogenesis of JIA is mostly unknown, the first two forms appear to be classical autoimmune conditions, induced by the breakdown of immunologic self-tolerance with a main involvement of the adaptive immunity, while the third is mainly mediated by the innate immunity. How T cell activation leads to joint damage is still a subject of many studies, that are also oriented to identify drugs able to prevent chronic inflammation by inhibiting biological key factors. Aims of our study were to analyze how different T lymphocytes influence synovial fibroblasts (SFbs) in driving the articular cartilage destruction, and to evaluate the effect of IL-17 inhibition in this experimental model. SFbs were obtained from healthy children and patients affected by JIA, and T helper lymphocytes subsets were isolated from blood of healthy controls, as well as from synovial fluid of active joints in patients with JIA. Cartilage invasion ability and degradation activity were studied in the presence of normal and JIA SFbs, in the presence of normal SFbs incubated with supernatants or corresponding cytokines from different T cell clones, and after the addition of the IL-17 blocker secukinumab. In vitro experiments were integrated with in vivo studies based on the inverse-wrap technique in SCID mice. We observed that JIA SFbs, compared to healthy SFbs, produced large amounts of matrix metalloproteinases (MMPs) and invaded cartilage with subsequent damage. Similar effects were detected by incubating healthy SFbs with the supernatants of different T helper subsets. T helper 17 cells promoted the release of MMP9 by SFbs, while non-classic Th1 mostly induced an over-activation of urokinase-plasminogen-activator. The invasive and destroying ability of healthy SFbs treated with stimulated T helper 17 conditioned media and with IL-17 resulted significantly reduced after the addition of secukinumab. In conclusion, a complex cross-talk between SFbs and different T cell clones predisposes to joint cartilage damage. Th17 lymphocytes through the release of IL-17 activate SFbs stimulating their invasive and destructive ability via MMPs, and this can be prevented by secukinumab.