Role of polymorphonucleates in the pathogenesis of systemic juvenile idiopathic arthritis and Still's disease: a proof of concept study

Abstract

Background Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still9s disease (AOSD) are autoinflammatory disorders characterized by neutrophilia and abnormal innate immunity response [1]. It has been hypothesized a pathogenic role of neutrophils, because of patients neutrophilia, maybe related to the typical higher production of pro-inflammatory cytokines, like IL-1β, whose role in these disorders should explain the efficacy of IL-1 blockers [2, 3]. IL-1β is synthesized as inactive form and its activation is mediated by the NLRP3 inflammasome [4]. Increased release of this cytokine in the extracellular environment lead to a positive feedback loop that perpetuates and amplifies itself stimulation [5]. This mechanism as well as neutrophils9 activation state could be modified in sJIA and AOSD. Objectives Our aim was to verify possible differences between sJIA and Still9s patients compared to healthy donors, in term of PMNs responsiveness to the extracellular environment and activation state. Methods PMNs were obtained from heparinised venous blood of sJIA patients (n=6), AOSD patients (n=4) and healthy controls (HC, n=8). All patients9 samples were collected during stages of active or non-active disease, according to international disease activity criteria used for the assessment of each disease. After lipopolysaccharide (LPS) treatment, IL-1β content in PMNs supernatants was measured by ELISA assay. CD11b expression levels were measured by flow cytometry, together with intracellular ROS levels through the H 2 DCFDA ROS-indicator. Results In comparison with HC, sJIA PMNs showed an increased IL-1β secretion after LPS stimulation (p Conclusions Data from our proof of concepts study suggest a possible involvement of PMNs in the pathogenesis of sJIA and AOSD, since they seem more active respect healthy ones and more sensitive to pro-inflammatory stimuli. Although further studies are necessary to confirm and validate this hypothesis, the trend observed may have a potential role in the direction of future therapeutic studies. References Pay, S., et al., A multicenter study of patients with adult-onset Still9s disease compared with systemic juvenile idiopathic arthritis. Clin Rheumatol, 2006. 25(5): p. 639-44. Mellins, E.D., et al., Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol, 2011. 7(7): p. 416-26. Mavragani, C.P., et al., Adult-Onset Still9s Disease: From Pathophysiology to Targeted Therapies. Int J Inflam, 2012. 2012: p. 879020. Martinon, F., et al., The inflammasomes: guardians of the body. Annu Rev Immunol, 2009. 27: p. 229-65. Frosch, M., et al., The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum, 2009. 60(3): p. 883-91. Disclosure of Interest None declared