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Surface expression and genotypes of Toll-like receptors 2 and 4 in patients with juvenile idiopathic arthritis and systemic lupus erythematosus.

ABSTRACT: BACKGROUND: Chronic arthritis is a common feature of juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE). It was subsequently discovered that Toll-like receptors (TLRs) are able to upregulate cytokine production in response to endogenous ligands released after tissue damage, suggesting that TLRs can maintain an inflammatory response even in absence of pathogen. Thus, TLRs may contribute to increased inflammation in JIA and SLE patients. The aim of this study was to investigate the role of TLRs in JIA and SLE. We examined the in vivo expression and polymorphisms of TLR2 and TLR4 in peripheral monocytes of patients with JIA and SLE during active and inactive disease phases. METHODS: This single center cohort study consisted of JIA and SLE affected children and control subjects. TLR2 and TLR4 protein expression on CD14+ monocytes was examined by flow cytometry. TLR2 and TLR4 genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism method (RFLP-PCR). RESULTS: A significant reduction in the level of TLR4 expression (p???0.001) was observed on monocytes of patients with JIA and SLE compared with that of healthy control subjects. There was no correlation between the TLR2 or TLR4 genotypes and the observed differential TLR protein expression on monocytes. CONCLUSIONS: To conclude, our observations suggest involvement of investigated TLRs in the pathogenesis of JIA and SLE. It still remains to be elucidated whether reduced TLR4 expression is cause of chronic arthritis or a result of some feedback loop.

SUBMITTER: Kirchner M

PROVIDER: S-EPMC3626865 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Surface expression and genotypes of Toll-like receptors 2 and 4 in patients with juvenile idiopathic arthritis and systemic lupus erythematosus.

Kirchner Martina M Sonnenschein Anja A Schoofs Simon S Schmidtke Peter P Umlauf Volker N VN Mannhardt-Laakmann Wilma W

Pediatric rheumatology online journal 20130305 1

<h4>Background</h4>Chronic arthritis is a common feature of juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE). It was subsequently discovered that Toll-like receptors (TLRs) are able to upregulate cytokine production in response to endogenous ligands released after tissue damage, suggesting that TLRs can maintain an inflammatory response even in absence of pathogen. Thus, TLRs may contribute to increased inflammation in JIA and SLE patients. The aim of this study was to ...[more]

PMID: 23497095

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Project description:BackgroundThis study evaluated the association between peptidyl arginine deiminase type IV (PADI4) and interleukin 33 (IL-33) with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA).MethodWe searched the PubMed, Web of Science, Embase and Cochrane Library databases to retrieve articles published up to January 20, 2023. Stata/SE 17.0 (College Station, TX) software was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). The cohort study, case-control study focusing on the PADI4, IL-33 polymorphism, and SLE, JIA were retrieved. The data included basic information of each study and the genotypes and allele frequencies.ResultsStudies in PADI4 rs2240340 = 2 and 3 IL-33(rs1891385 = 3, rs10975498 = 2, rs1929992 = 4) were found in 6 articles. Overall, only the IL-33 rs1891385 show significant association between SLE in all 5 models. The results were OR (95% CI) = 1.528 (1.312, 1.778), P = .000 in Allele model (C vs A), OR (95% CI) =1.473 (1.092, 1.988), P = .000 in Dominant model (CC + CA vs AA), 2.302 (1.583, 3.349), P = .000 in Recessive model (CC vs CA + AA), 2.711 (1.845, 3.983), P = .000 in Homozygote model (CC vs AA), 5.568 (3.943, 7.863), P = .000 in Heterozygote model (CA vs AA). PADI4 rs2240340, IL-33 rs10975498, IL-33 rs1929992 were not found to be association with the risk of SLE and JIA. In gene model, statistically significant association was found between IL-33 rs1891385 and SLE in sensitivity analysis. Egger's publication bias plot showed there was no publication bias (P = .165). Only in recessive model the heterogeneity test was significant (I2 = 57.9%, P ≤ .093) of IL-33 rs1891385.ConclusionThe current study suggests that in all 5 model, IL-33 rs1891385 polymorphism may be associated with genetic susceptibility to SLE. There was unclear association found between PADI4 rs2240340, IL-33 rs10975498, and IL-33 rs1929992 polymorphisms and SLE and JIA. Due to the limitations of included studies and the risk of heterogeneity, additional research is required to confirm our findings.Prospero registration numberCRD42023391268.

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)

Dataset Information

Surface expression and genotypes of Toll-like receptors 2 and 4 in patients with juvenile idiopathic arthritis and systemic lupus erythematosus.

Publications

Surface expression and genotypes of Toll-like receptors 2 and 4 in patients with juvenile idiopathic arthritis and systemic lupus erythematosus.

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