TNF‐α promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic‐onset juvenile idiopathic arthritis

Modesto, Consuelo; Patiño‐García, Ana; Sotillo, Elena; Merino, José Luís; García-Consuegra, Julia; Merino, Rosa; Rúa, Ma J.; Sierrasesúmaga, Luis; Arnal, C

doi:10.1080/03009740510026652

Cited by 31 publications

(29 citation statements)

References 12 publications

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“…In addition, the −308G genotype has been associated with better response to anti-TNF-α treatment in JIA patients, confirming adult data [17]. In some studies oligoarticular arthritis is significantly associated to the −238 SNP [10] [16] [18] [19].…”

Section: Introductionsupporting

confidence: 63%

“…Furthermore, associations between TNF-α SNPs and subtypes of JIA have been found [12] [13]. The most frequently studied TNF-α SNP is located at −308 position, where the presence of the rare A allele was associated with a major gene expression, high level of TNF-α expression, and more aggressive JIA phenotypes [14]- [16]. The presence of the allele −308A is associated to JIA and to a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after in Vitro Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

Kirchner¹,

Strothmann²,

Sonnenschein³

et al. 2014

WJV

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Oligoarticular juvenile idiopathic arthritis (oJIA) is an antigen-driven and lymphocyte-mediated autoimmune disorder with irregularity in the adaptive immune system. Auto reactive T cells, activated by cartilage-derived auto antigens, produce pro-inflammatory cytokines as IFN-γ and IL-17. Failure of regulatory T cells leads to decreased anti-inflammatory cytokine IL-10 production and results in the loss of immune tolerance. This activation of innate and adaptive immunity stimulates the release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α. Thus, inhibition of these cytokines is considered as an appropriate therapeutic strategy for oJIA. The aim of this study was to investigate whether the blockade of a single cytokine pathway in the present cytokine setting causes an unfavourable imbalance in the cytokine system or whether the blockade is sufficient to suppress the inflammatory condition. We examined the cytokine secretion after in vitro inhibition of IL-1 and TNF-α of patients with oJIA and healthy subjects. This single center cohort study consisted of oJIA affected children and control subjects. Cytokine profiles from cell culture supernatants were examined with multiplex fluorescent bead immunoassay by flow cytometry. Adalimumab prevents highly effective and very selective effect of the cytokine TNF-α. Due to its structure, the mode of action of etanercept is difficult to display. In addition, adalimumab and etanercept appear in vitro suppressive to IFN-γ. The efficiency of both substances is particularly supported by the increased secretion of anti-inflammatory cytokine IL-4. In contrast, anakinra unselectively inhibits the pro-inflammatory macrophage cytokines. To conclude, our observations suggest that inhibition of IL-1 or TNF-α may contribute to the unselective decline of other pro-inflammatory cytokines in oJIA patients. The selective anti-inflammatory effect of cytokine inhibitors is most * Corresponding author. M. Kirchner et al. 111likely supported by an increase of IL-4 or IL-10. It still remains to be elucidated whether the reduced IFN-γ secretion is maybe causative for the increased susceptibility to infections with opportunistic pathogens.

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Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after in Vitro Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

Kirchner¹,

Strothmann²,

Sonnenschein³

et al. 2014

WJV

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“…The role of −308A/G polymorphism in JIA was investigated in many studies. Some authors found that the A allele was significantly more frequent in JIA subjects with respect to controls and was related to a higher disease activity [36] and a poor prognosis [43, 74]. Zeggini et al showed that the TNF −308A allele is more frequently found in rheumatoid factor positive juvenile polyarthritis and is associated with a more severe disease, while the more common TNF −308G allele may be protective [13].…”

Section: Resultsmentioning

confidence: 99%

TNF-αPolymorphisms in Juvenile Idiopathic Arthritis: Which Potential Clinical Implications?

Sereno

Breda

Laganà

et al. 2012

International Journal of Rheumatology

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Whether tumor necrosis factor alpha (TNF-α) gene polymorphisms (SNPs) influence disease susceptibility and treatment of patients with juvenile idiopathic arthritis (JIA) is presently uncertain. TNF-α is one of the most important cytokine involved in JIA pathogenesis. Several single nucleotide polymorphisms (SNPs) have been identified within the region of the TNF-α gene but only a very small minority have proven functional consequences and have been associated with susceptibility to JIA. An association between some TNF-α SNPs and adult rheumatoid arthritis (RA) susceptibility, severity and clinical response to anti-TNF-α treatment has been reported. The most frenquetly studied TNF-α SNP is located at −308 position, where a substitution of the G allele with the rare A allele has been found. The presence of the allele −308A is associated to JIA and to a poor prognosis. Besides, the −308G genotype has been associated with a better response to anti-TNF-α therapy in JIA patients, confirming adult data. Psoriatic and oligoarticular arthritis are significantly associated to the −238 SNP only in some works. Studies considering other SNPs are conflicting and inconclusive. Large scale studies are required to define the contribution of TNF-α gene products to disease pathogenesis and anti-TNF-α therapeutic efficacy in JIA.

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“…Subjects with both TNFA- 857T allele and the DRB1:04:05 allele had an increased OR of 3.84 for systemic JIA. In 2005 a Spanish group reported on the association between the TNFA -308 allele and systemic onset JIA [84]. In 2001 Donn et al identified a 5′ flanking region polymorphism of the MIF gene which encodes the macrophage migration inhibitory factor in patients with systemic onset JIA vs controls (MIF-173*C) [85].…”

Section: Genetics Of Systemic Onset Jiamentioning

confidence: 99%

Immunogenetics of juvenile idiopathic arthritis: A comprehensive review

Hersh

Prahalad

2015

Journal of Autoimmunity

118

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Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthropathy of childhood. Juvenile idiopathic arthritis is believed to be a complex genetic trait influenced by both genetic and environmental factors. Twin and family studies suggest a substantial role for genetic factors in the predisposition to JIA. Describing the genetics is complicated by the heterogeneity of JIA; the International League of Associations for Rheumatology (ILAR) has defined seven categories of JIA based on distinct clinical and laboratory features. Utilizing a variety of techniques including candidate gene studies, the use of genotyping arrays such as Immunochip, and genome wide association studies (GWAS), both human leukocyte antigen (HLA) and non-HLA susceptibility loci associated with JIA have been described. Several of these polymorphisms (e.g. HLA class II, PTPN22, STAT4) are shared with other common autoimmune conditions; other novel polymorphisms that have been identified may be unique to JIA. Associations with oligoarticular and RF-negative polyarticular JIA are the best characterized. A strong association between HLA DRB1:11:03/04 and DRB1:08:01, and a protective effect of DRB1:15:01 have been described. HLA DPB1:02:01 has also been associated with oligoarticular and RF-negative polyarticular JIA. Besides PTPN22, STAT4 and PTPN2 variants, IL2, IL2RA, IL2RB, as well as IL6 and IL6R loci also harbor variants associated with oligoarticular and RF-negative polyarticular JIA. RF-positive polyarticular JIA is associated with many of the shared epitope encoding HLA DRB1 alleles, as well as PTPN22, STAT4 and TNFAIP3 variants. ERA is associated with HLA B27. Most other associations between JIA categories and HLA or non-HLA variants need confirmation. The formation of International Consortia to ascertain and analyze large cohorts of JIA categories, validation of reported findings in independent cohorts, and functional studies will enhance our understanding of the genetic underpinnings of JIA.

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TNF‐α promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic‐onset juvenile idiopathic arthritis

Cited by 31 publications

References 12 publications

Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after <i>in</i> <i>Vitro</i> Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after <i>in</i> <i>Vitro</i> Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

TNF-αPolymorphisms in Juvenile Idiopathic Arthritis: Which Potential Clinical Implications?

Immunogenetics of juvenile idiopathic arthritis: A comprehensive review

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TNF‐α promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic‐onset juvenile idiopathic arthritis

Cited by 31 publications

References 12 publications

Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after &lt;i&gt;in&lt;/i&gt; &lt;i&gt;Vitro&lt;/i&gt; Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after &lt;i&gt;in&lt;/i&gt; &lt;i&gt;Vitro&lt;/i&gt; Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

TNF-αPolymorphisms in Juvenile Idiopathic Arthritis: Which Potential Clinical Implications?

Immunogenetics of juvenile idiopathic arthritis: A comprehensive review

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Product

Resources

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Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after <i>in</i> <i>Vitro</i> Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α

Distinct Cytokine Profiles in Patients with Oligoarticular Juvenile Idiopathic Arthritis after <i>in</i> <i>Vitro</i> Blockade of Interleukin (IL)-1 and Tumor Necrosis Factor (TNF)-α