The dual nature of Ets-1: Focus to the pathogenesis of systemic lupus erythematosus

Leng, Rui‐Xue; Pan, Hai‐Feng; Chen, Gui-Mei; Feng, Chen-Chen; Fan, Yin‐Guang; Ye, Dong-Qing; Li, Xiang-Pei

doi:10.1016/j.autrev.2011.01.007

Cited by 33 publications

(27 citation statements)

References 44 publications

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“…Finally, we revealed that the expression of Ets-1 in PBMCs was significantly downregulated and correlated inversely with antidsDNA Ab production in SLE patients. Consistent with our results, a decreased Ets-1 mRNA level in PBMCs of SLE patients was also reported (54). Collectively, our findings in vivo were consistent with previous data, as well as our findings in vitro, which demonstrated that Ets-1 was a functional target of miR-155, which was vital for HMGB1 to confer anti-dsDNA Ab induction.…”

Section: Discussionsupporting

confidence: 83%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed “circulating DNA-containing ICs”), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.

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Section: Discussionsupporting

confidence: 83%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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“…28 ETS1 encodes a transcription factor that regulates the differentiation of Th1 cells, regulatory T cells and B cells by affecting the function of other key regulators like T-bet, Foxp3 and Blimp-1. 29 UBASH3A encodes a T-cell ubiquitin ligand that acts as a negative regulator of T-cell receptor (TCR)-mediated signaling. 30 …”

Section: Discussionmentioning

confidence: 99%

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

et al. 2014

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Objective A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples. Results We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusion This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

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“…The transcription factor Ets-1, originally discovered as an oncogene (v-ets) within the genome of the avian leukemia virus [33], shows a dual nature in autoimmune diseases [34]. It was reported to be overexpressed in rheumatoid arthritis (RA) synovial membrane and to be involved in the destructive pathway of RA [35].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-146a and Ets-1 Gene Polymorphisms Are Associated with Pediatric Uveitis

et al. 2014

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BackgroundMicroRNA-146a (miR-146a) was a key negative regulator of autoimmunity. V-Ets oncogene homolog 1 (Ets-1) was demonstrated to bind to the miR-146a promoter region and markedly affects miR-146a promoter activity. This study aimed to investigate the association of miR-146a and Ets-1 gene polymorphisms with pediatric uveitis in a Han Chinese population.Methodology/Principal FindingsA total of 520 patients and 1204 healthy controls were included in the present study. Five single-nucleotide polymorphisms (SNPs), miR-146a/rs2910164, miR-146a/rs57095329, miR-146a/rs6864584, ets-1/rs1128334 and ets-1/rs10893872 were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. The expression of Ets-1 in peripheral blood mononuclear cells from genotyped healthy controls was tested by real-time PCR. Two SNPs (rs2910164 and rs10893872) were associated with pediatric uveitis in this study. The frequencies of the rs2910164 GG genotype and G allele were significantly increased (Pc = 3.11×10−4; Pc = 2.75×10−6) while the CC genotype and C allele were significantly decreased (Pc = 0.001; Pc = 2.75×10−6) in patients compared with normal controls. The frequencies of the rs10893872 CC genotype and C allele were significantly increased (Pc = 3.89×10−4; Pc = 0.01) while the CT genotype and T allele were significantly decreased (Pc = 0.004; Pc = 0.01) in patients compared with normal controls. The SNP rs2910164 GG genotype and G/C allele were also associated with the presence of microvascular leakage as detected by fundus fluorescein angiography in pediatric uveitis (Pc = 0.01; Pc = 0.005, respectively). Ets-1 expression in rs10893872 CC carriers was significantly higher than in CT and TT individuals (Pc = 0.013). There was no association of the other three SNPs with pediatric uveitis.ConclusionsThis study shows that miR-146a and Ets-1 are both associated with pediatric uveitis in Han Chinese. SNP rs10893872 may affect the genetic predisposition to pediatric uveitis by modulating expression of Ets-1.

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The dual nature of Ets-1: Focus to the pathogenesis of systemic lupus erythematosus

Cited by 33 publications

References 44 publications

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

MicroRNA-146a and Ets-1 Gene Polymorphisms Are Associated with Pediatric Uveitis

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