Elevated plasma level of HMGB1 is associated with disease activity and combined alterations with IFN-alpha and TNF-alpha in systemic lupus erythematosus

Ma, Chao; Jiao, Yang; Zhang, Jie; Yang, Qingrui; Zhang, Zhifen; Shen, Yajuan; Chen, Zi‐Jiang; Zhao, Yong

doi:10.1007/s00296-010-1636-6

Cited by 98 publications

(79 citation statements)

References 38 publications

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“…[16] Some studies have reported a relationship between the high serum level of HMGB1 and flare-ups of lupus disease activity. [17,18] All of these observations support the notion that the HMBG1-RAGE pathway plays a part in the pathogenesis of SLE.…”

supporting

confidence: 75%

“…[37] Studies have shown that the HMGB1 plasma level, one of the main RAGE ligands, is increased in the circulation of SLE, leading to the binding and consumption of sRAGE during the inflammatory process. [18,38] Another possible regulatory route of the sRAGE level is through alternative splicing and proteinases. Zong et al [39] recently proposed that sRAGE might not only function as a 'decoy' to exert its inhibitory effects on RAGE but also act in a more direct way by binding to the cell surface of RAGE to block the formation of homodimers.…”

Section: Discussionmentioning

confidence: 99%

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A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

2013

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Amaç: Bu çalışmada sistemik lupus eritematöz (SLE) olan hastalarda ileri glikasyon son ürünlerinin çözünür reseptörünün (sRAGE) plazma düzeyleri değerlendirildi ve bu düzeylerin farklı klinik, laboratuvar ve tedavi parametreleri ile olan ilişkisi araştırıldı. Hastalar ve yöntemler:Çalışmaya toplam 120 SLE hastası (111 kadın, 9 erkek) ve yaş ve cinsiyet eşleştirmeli 40 sağlıklı kontrol alındı. Plazma sRAGE düzeyleri, ticari olarak satılan enzim bağlı immünosorbent test (ELISA) kiti kullanılarak ölçüldü. Plazma sRAGE düzeyleri ve SLE'nin klinik ve laboratuvar özellikleri arasındaki muhtemel ilişki de değerlendirildi. Farklı tedavi yöntemlerinin sRAGE plazma düzeyleri üzerindeki etkinliği incelendi. Bulgular: Sağlıklı kontrollere kıyasla, SLE hastalarının plazma sRAGE düzeyleri anlamlı düzeyde daha düşüktü (p=0.003). Cilt döküntüsü veya serozit olan hastaların sRAGE düzeyleri, olmayanlara kıyasla anlamlı düzeyde daha yüksekti (sırasıyla p=0.036 ve p=0.017). Daha uzun süre tedavi edilen SLE hastalarının sRAGE düzeyleri, daha kısa süreli tedavi edilenlerden daha yüksekti (p=0.000). Kortikosteroid ile tedavi edilen ve kombine tedavi edilen hastalar arasında düzey açısından anlamlı bir fark yoktu (p=0.89). sRAGE düzeyleri ve total beyaz kan hücre (WBC) sayımı (r=-0.356; p=0.003), lenfosit (r=0.341; p<0.001) ve nötrofil (r=0.289; p=0.006) arasında anlamlı negatif bir ilişki vardı.Sonuç: Çalışmamızda SLE hastalarında sRAGE plazma düzeylerinin anlamlı derecede azaldığı bulundu. Bu da, sRAGE düzeylerinin hastalığın patogenezinde muhtemel bir rol oynadığını göstermektedir.Anahtar sözcükler: İleri glikasyon son ürünü; reseptör; sistemik lupus eritematöz. Objectives:In this study, we aimed to evaluate the plasma levels of a soluble receptor for advanced glycation end products (sRAGE) in patients with systemic lupus erythematosus (SLE) and to investigate their relationship with different clinical, laboratory, and therapeutic parameters. Patients and methods:A total of 120 patients with SLE (111 females, 9 males) and 40 age-and gender-matched healthy controls were included. The plasma sRAGE levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA). The possible relationship between plasma sRAGE levels with SLE clinical and laboratory characteristics were also assessed. The effectiveness of different therapeutic modalities on plasma sRAGE levels was analyzed. Results:The SLE patients had significantly lower plasma levels of sRAGE than the healthy controls (p=0.003). The patients with a skin rash or serositis had significantly higher sRAGE levels than those without (p=0.036 and p=0.017, respectively). The SLE patients who were treated over a longer period of time showed higher levels of sRAGE than those treated for shorter periods (p=0.000). No significant difference in levels was found among the patients treated with corticosteroids and those treated with combined therapy (p=0.89). There was a significant negative correlation between the sRAGE level and the total white blood cell (WBC) count (...

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supporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

2013

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“…Furthermore, in experimental systems, depletion of neutrophils can protect against antibody-mediated glomerulonephritis (56) and lupus serum from human patients can induce neutrophil-mediated organ damage (57). The presence of neutrophilic infiltrates has been recognized as an early feature of glomerulonephritis (58, 59), while proteins released from neutrophilic granules are toxic to glomerular structures (59-61) and circulate at elevated levels in the blood (62)(63)(64). To these previous observations, a role has recently been hypothesized for NET formation in the pathogenesis of -and organ damage associated with -SLE (16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus

Knight¹,

Zhao²,

Luo³

et al. 2013

J. Clin. Invest.

343

365

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Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoantigens in SLE. We propose that aberrant NET formation is also linked to organ damage and to the premature vascular disease characteristic of human SLE. Here, we demonstrate enhanced NET formation in the New Zealand mixed 2328 (NZM) model of murine lupus. NZM mice also developed autoantibodies to NETs as well as the ortholog of human cathelicidin/LL37 (CRAMP), a molecule externalized in the NETs. NZM mice were treated with Cl-amidine, an inhibitor of peptidylarginine deiminases (PAD), to block NET formation and were evaluated for lupus-like disease activity, endothelial function, and prothrombotic phenotype. Cl-amidine treatment inhibited NZM NET formation in vivo and significantly altered circulating autoantibody profiles and complement levels while reducing glomerular IgG deposition. Further, Cl-amidine increased the differentiation capacity of bone marrow endothelial progenitor cells, improved endothelium-dependent vasorelaxation, and markedly delayed time to arterial thrombosis induced by photochemical injury. Overall, these findings suggest that PAD inhibition can modulate phenotypes crucial for lupus pathogenesis and disease activity and may represent an important strategy for mitigating cardiovascular risk in lupus patients.

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“…10 In SLE patients, HMGB1-nucleic acids complexes are released from secondary necrotic cells and forms ICs with the corresponding autoantibodies, which are significantly elevated in the sera. 1,3,10,11 Depositon of HMGB1-containing ICs are also found in target tissues, such as the skin 12 and kidney, 13 where they contribute to both chronic inflammation and tissue injury. The proinflammatory activity of HMGB1 is mostly attributed to its ligation with RAGE, 14 which is a member of the immunoglobulin superfamily of cell surface molecules.…”

mentioning

confidence: 99%

Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis

Sun

Jiao

Cui

et al. 2013

Laboratory Investigation

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of immune complexes (ICs), which contain a complex mixture of autoantigens nucleic acids, nucleic acids-associated proteins and corresponding autoantibodies. In SLE, ICs are deposited in multiple organs. Vasculopathy and vasculitis in SLE are typical complications and are associated with deposition of ICs on endothelium, endothelial activation and inflammatory cell infiltration. However, the effects of ICs on endothelial cells and the mechanisms involved remain unclear. In this study, we have demonstrated for the first time that ICs upregulated cell surface expression of the receptor for advanced glycation end products (RAGE), the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), increased the secretion of the chemokines interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), the proinflammatoy cytokines interleukin 6 (IL-6), tumor necrosis factor-a (TNF-a) and promoted the activation of the transcription factor NF-kB p65 in human endothelial cells (Po0.05). ICs also increased transendothelial migration of monocytes (Po0.05). One of the mechanisms underlying these activating effects of ICs on human endothelial cells involves cell signaling by high-mobility group box 1 protein (HMGB1)-RAGE axis, as these effects can be partially blocked by HMGB1 A-box, soluble RAGE (sRAGE), SB203580, PD98059, Bay 117082 (Po0.05) and co-treatment with these agents (Po0.05). In conclusion, ICs elicit proinflammatory responses in human endothelial cells and alter their function involving cellular signaling via the HMGB1-RAGE axis in the pathogenesis of SLE vasculitis.

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Elevated plasma level of HMGB1 is associated with disease activity and combined alterations with IFN-alpha and TNF-alpha in systemic lupus erythematosus

Cited by 98 publications

References 38 publications

A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus

Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis

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