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Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis.

ABSTRACT: OBJECTIVE:To investigate whether single-nucleotide polymorphisms (SNPs) within the genes PRF1, GZMB, UNC13D, and Rab27a, which are involved in natural killer cell dysfunction and known to contribute to the risk of hemophagocytic lymphohistiocytosis (HLH), confer an increased risk of susceptibility to systemic-onset juvenile idiopathic arthritis (JIA). METHODS:Four SNPs across the PRF1 gene locus, 5 for GZMB, 7 for UNC13D, and 11 for Rab27a were investigated using MassArray genotyping in 133 UK Caucasian patients with systemic-onset JIA and 384 ethnically matched unrelated control subjects. Additional control genotypes were accessed from the data generated by the Wellcome Trust Case Control Consortium. RESULTS:No significant association was found between any SNP within the 4 selected loci and systemic-onset JIA, by either single-point or haplotype analysis. CONCLUSION:The results of this study demonstrate that genes involved in HLH do not confer a significant risk of association with systemic-onset JIA.

SUBMITTER: Donn R

PROVIDER: S-EPMC2675009 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis.

Donn Rachelle R Ellison Stuart S Lamb Rebecca R Day Thomas T Baildam Eileen E Ramanan Athimalaipet V AV

Arthritis and rheumatism 20080301 3

<h4>Objective</h4>To investigate whether single-nucleotide polymorphisms (SNPs) within the genes PRF1, GZMB, UNC13D, and Rab27a, which are involved in natural killer cell dysfunction and known to contribute to the risk of hemophagocytic lymphohistiocytosis (HLH), confer an increased risk of susceptibility to systemic-onset juvenile idiopathic arthritis (JIA).<h4>Methods</h4>Four SNPs across the PRF1 gene locus, 5 for GZMB, 7 for UNC13D, and 11 for Rab27a were investigated using MassArray genotyp ...[more]

PMID: 18311812

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Project description:ObjectivesIndoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-?. We previously reported highly increased levels of IFN-? and corresponding IDO activity in patients with hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory syndrome. On the other hand, IFN-? and IDO were low in patients with systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory syndrome. As HLH can occur as a complication of sJIA, the opposing levels of both IFN-? and IDO are remarkable. In animal models for sJIA and HLH, the role of IFN-? differs from being protective to pathogenic. In this study, we aimed to unravel the role of IDO1 in the pathogenesis of sJIA and HLH.MethodsWild-type and IDO1-knockout (IDO1-KO) mice were used in 3 models of sJIA or HLH: complete Freund's adjuvant (CFA)-injected mice developed an sJIA-like syndrome and secondary HLH (sHLH) was evoked by either repeated injection of unmethylated CpG oligonucleotide or by primary infection with mouse cytomegalovirus (MCMV). An anti-CD3-induced cytokine release syndrome was used as a non-sJIA/HLH control model.ResultsNo differences were found in clinical, laboratory and hematological features of sJIA/HLH between wild-type and IDO1-KO mice. As IDO modulates the immune response via induction of regulatory T cells and inhibition of T cell proliferation, we investigated both features in a T cell-triggered cytokine release syndrome. Again, no differences were observed in serum cytokine levels, percentages of regulatory T cells, nor of proliferating or apoptotic thymocytes and lymph node cells.ConclusionsOur data demonstrate that IDO1 deficiency does not affect inflammation in sJIA, sHLH and a T cell-triggered cytokine release model. We hypothesize that other tryptophan-catabolizing enzymes like IDO2 and tryptophan 2,3-dioxygenase (TDO) might compensate for the lack of IDO1.

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

Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis.

Publications

Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis.

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