The role of extracellular histones in systemic-onset juvenile idiopathic arthritis

Abstract

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=10752Electronic supplementary materialThe online version of this article (10.1186/s13052-019-0605-2) contains supplementary material, which is available to authorized users.

A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes’ interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19

“…Reactive HLH presents clinically as primary HLH (of genetic origin) and has been described in other pediatric rheumatologic diseases where NETs could also play key pathogenic roles such as in systemic juvenile idiopathic arthritis (sJIA) and lupus [ 51 , 52 ]. NETs have been proposed to be part of the pathogenesis of sJIA or MAS secondary to sJIA [ 53 ]. We did not have access to transcriptomic data form KD-derived neutrophils.…”

An Update on the Pathogenic Role of Neutrophils in Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease

“…Although various roles of NETs have been identified in AOSD, data on the role of NETs in SJIA are still limited. In one study, Hu et al demonstrated that active SJIA patients release a large amount of histones from NETs and that induced-serum histones promote the propagation of NETs, resulting in malignant feedback mechanisms, which may be the pathogenesis of SJIA [ 117 ]. A recent study showed that secondary neutrophil granule proteins, such as human neutrophil lipocalin and myeloperoxidase, were significantly increased in patients with SJIA [ 108 ].…”

“…Several recent studies showed elevated cell-free DNA and NET–related molecules in patients with active AOSD or SJIA, compared to those with inactive status or HC [ 27 , 28 , 63 , 109 , 117 ]. Furthermore, these levels, such as MPO–DNA and α –defensin, were correlated with the levels of disease activity markers of AOSD.…”

“…In a recent study, patients with active SJIA had more extracellular histones released by activated neutrophils than those with inactive SJIA and HC. They also correlated significantly with clinical disease activity [ 117 ]. However, these studies did not evaluate the associations between NET molecules and the prognosis of AOSD or SJIA.…”

A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes’ interactions points to Neutrophil Extracellular Traps as mediators of thrombosis in COVID-19

“…Reactive HLH presents clinically as primary HLH (of genetic origin) and has been described in other pediatric rheumatologic diseases where NETs could also play key pathogenic roles such as in systemic juvenile idiopathic arthritis (sJIA) and lupus 44,45 . NETs have been proposed to be part of the pathogenesis of sJIA or MAS secondary to sJIA 46 . We did not have access to transcriptomic data form KD-derived neutrophils.…”