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Roles of Interactions Between Toll-Like Receptors and Their Endogenous Ligands in the Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease.

ABSTRACT: Systemic juvenile idiopathic arthritis (JIA) and adult-onset Still's disease (AOSD) are systemic inflammatory disorders that manifest as high-spiking fever, joint pain, evanescent skin rash, and organomegaly. Their pathogenesis is unclear, but inflammation is triggered by activation of the innate immune system with aberrant production of proinflammatory cytokines. Along with extrinsic factors, intrinsic pathways can trigger an unexpected immune response. Damage-associated molecular patterns (DAMPs) induce the activation of innate immune cells, leading to sterile inflammation in systemic JIA and AOSD. These endogenous proteins interact with Toll-like receptors (TLRs), which are pattern recognition receptors, and mediate immune signaling following stimulation by pathogen-associated molecular patterns and DAMPs. Several DAMPs, such as S100 proteins, play a role in the development or severity of systemic JIA and AOSD, in which their interactions with TLRs are altered. Also, the expression levels of genes encoding DAMPs contribute to the susceptibility to systemic JIA and AOSD. Herein, we review reports that TLR and DAMP signaling initiates and/or maintains the inflammatory response in systemic JIA and AOSD, and their correlations with the clinical characteristics of those diseases. In addition, we assess their utility as biomarkers or therapeutics for systemic JIA and AOSD.

SUBMITTER: Jung JY

PROVIDER: S-EPMC7674197 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Roles of Interactions Between Toll-Like Receptors and Their Endogenous Ligands in the Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease.

Jung Ju-Yang JY Kim Ji-Won JW Suh Chang-Hee CH Kim Hyoun-Ah HA

Frontiers in immunology 20201105

Systemic juvenile idiopathic arthritis (JIA) and adult-onset Still's disease (AOSD) are systemic inflammatory disorders that manifest as high-spiking fever, joint pain, evanescent skin rash, and organomegaly. Their pathogenesis is unclear, but inflammation is triggered by activation of the innate immune system with aberrant production of proinflammatory cytokines. Along with extrinsic factors, intrinsic pathways can trigger an unexpected immune response. Damage-associated molecular patterns (DAM ...[more]

PMID: 33224145

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Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Project description:BackgroundTo explore the effects of extracellular histones released by activated neutrophils on systemic-onset juvenile idiopathic arthritis (SoJIA), and to study the change of serum histone level between the active and remissive stage of SoJIA, then to clarify the role of serum histone in the pathogenesis of SoJIA.MethodsTwenty-six patients with SoJIA were recruited, and clinical informations were collected, and the serum histone was detected by ELISA. While neutrophils from normal children were incubated with the serum from the patients with SoJIA, also including incubated with FeCL3 and histone, the extracellular histone was detected, respectively; heparin was added to the above-mentioned groups to observe the changes of extracellular histone levels. The proportions of neutrophils, which released NETs, were calculated by confocal microscope.ResultsThe levels of serum histones in active SoJIA group (0.90 ± 0.90) were significantly higher than in remissive SoJIA group (0.17 ± 0.10) (P = 0.0009), and also higher than in control group (0.14 ± 0.09) (P = 0.246). Histone affects on clinical manifestations (including fever, rash, joint pain, liver and spleen enlargement, and serositis), except for joint pain. The proportions of neutrophils releasing NETs, that neutrophils were incubated with the serum from active SoJIA group, were 31.93% significantly higher than 12.32% from remissive SoJIA group (P < 0.0001). The proportions of neutrophils releasing NETs, that neutrophils were incubated with different concentration FeCl3 or with different concentration histones respectively, were positively correlated with the concentration of incubation; while heparins were added, NETs from neutrophils could be reduced effectively.ConclusionsThe level of serum histone is positively correlated with the activity of SoJIA. Serum histone may be from NETs, which were released by activated neutrophils. Free iron can activate neutrophils to produce NETs, which may release histones, and histones can further promote NETs to be released, that results in a positive feedback loop of histones, and that may be one of the pathogenesis of acute SoJIA or MAS secondary to SoJIA. Histones maybe play one of important roles in the pathogenesis of SoJIA. Heparin can act on histones to prevent histone-induced inflammation.Trial registrationChiCTR-OOC-15006228. Registered 9 April 2015, http://www.chictr.org.cn/showproj.aspx?proj=10752.

Dataset Information

Roles of Interactions Between Toll-Like Receptors and Their Endogenous Ligands in the Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease.

Publications

Roles of Interactions Between Toll-Like Receptors and Their Endogenous Ligands in the Pathogenesis of Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease.

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