New insights into CD4+ T cell abnormalities in systemic sclerosis

Liu, Mengguo; Wu, Wenyu; Sun, Xinran; Yang, Ji; Xu, Jinhua; Fu, Wenwen; Li, Ming

doi:10.1016/j.cytogfr.2015.12.002

Cited by 49 publications

(34 citation statements)

References 64 publications

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“…Frequencies of Th17 cells and FoxP3+ cells were increased in skin biopsies of early SSc manifestation with the number of Th17 cells closely related to disease activity [16]. The recent literature suggests that Th17 and Treg activity is a hallmark of SSc, as Th17-type cytokines can induce both inflammation and fibrosis [17,18]. Tissue-selective trafficking of these inflammatory Th cells is mediated by chemokine receptor expression, such as CCR6 in Th17 cells [19].…”

Section: Introductionmentioning

confidence: 99%

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis

Almanzar

Klein²,

Schmalzing³

et al. 2016

Int Arch Allergy Immunol

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Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.

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Section: Introductionmentioning

confidence: 99%

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis

Almanzar

Klein²,

Schmalzing³

et al. 2016

Int Arch Allergy Immunol

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“…Currently, the main view is that there is a close and complex relationship between autoimmune abnormalities, increased collagen synthesis, and vascular injuries [14] . Our previous studies and other reports indicate the immune cells may be an important bridge linking the increased collagen synthesis with vascular injuries in SSc [15][16][17][18] . PIF is the most common internal organ brosis in SSc [5,8,19,20] .…”

Section: Discussionmentioning

confidence: 60%

Risk factors for pulmonary interstitial fibrosis in patients with systemic sclerosis

Yang

Cui

2020

Preprint

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Background Pulmonary interstitial fibrosis (PIF) is a frequent manifestation of systemic sclerosis (SSc). However, there is a lack of good clinical indicators for predicting PIF. Here, we evaluated autoantibodies and clinical phenotypes to predict the involvement of PIF in SSc. Methods Peripheral blood was collected from the 86 SSc patients enrolled in this study to detect autoantibodies. PIF, lung function, and heart function were analyzed by lung high-resolution computed tomography, pulmonary function test, and standard transthoracic echocardiography, respectively. The correlation between autoantibodies, clinical phenotype, and internal organ involvement were summarized. Results PIF occurred in 68.4% anti-SCL-70 antibody positive SSc patients (p = 0.0045), 59.8% anti-centromere antibody negative SSc patients (p = 0.0013), and 71.4% anti-SSA antibody positive SSc patients (p = 0.0107). PIF occurred in 94.1% anti-SCL-70 antibody and anti-SSA antibody double positive SSc patients, which was higher than in anti-SCL-70 antibody single positive patients, p = 0.0452. More SSc patients with digital ulcers had PIF (73.5%) than SSc patients without digital ulcers (p = 0.0008). Conclusion These data suggest that SSc patients with double positive for anti-SCL-70 and anti-SSA antibodies are more prone to develop PIF. In addition, digital ulcers are an important and convenient predictor for PIF in SSc patients.

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“…Subsequently, TGF-β signaling provokes typical pro-fibrotic modifications in SSc ( 13 ). Detection of autoantibodies directed against endothelial antigens and others, as well as T cell alterations in sera of SSc patients, supports the assumption that an impaired regulation of the immune system drives SSc pathogenesis ( 32 – 34 ).…”

Section: Introductionmentioning

confidence: 55%

Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study

et al. 2017

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Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.

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New insights into CD4+ T cell abnormalities in systemic sclerosis

Cited by 49 publications

References 64 publications

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis

Risk factors for pulmonary interstitial fibrosis in patients with systemic sclerosis

Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study

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