Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells

Yoshizaki, Ayumi; Taniguchi, Takashi; Saigusa, Ryosuke; Fukasawa, Takemichi; Ebata, Satoshi; Numajiri, Hiroko; Nakamura, Kouki; Yamashita, Takashi; Takahashi, Takehiro; Toyama, Tetsuo; Asano, Yoshihide; Tedder, Thomas F.; Sato, Shinichi

doi:10.1136/annrheumdis-2015-207405

Cited by 14 publications

(7 citation statements)

References 45 publications

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“…Next, to assess if the pDC response to HSV-1 is TLR9 mediated, we exposed sorted splenic GFP + pDCs ( Figure S1R ) to CpG-ODN or UV-inactivated HSV-1 in the presence of either TLR9 antagonist (ODN 2088) or ODN 2088 negative control (ODN 2088 control) ( Yoshizaki et al, 2016 ). In line with our in vivo experiments, in vitro pDC exposure to either CpG-ODN or HSV-1 induced robust expression of IFN-α, which was effectively blocked by the TLR9 antagonist ( Figure 5G ), indicating that the pDCs response to HSV-1 requires direct TLR9 stimulation.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis

Jamali

Sendra

et al. 2020

Cell Reports

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SUMMARY The presence and potential functions of resident plasmacytoid dendritic cells (pDCs) in peripheral tissues is unclear. We report that pDCs constitutively populate naïve corneas and are increased during sterile injuries or acute herpes simplex virus 1 (HSV-1) keratitis. Their local depletion leads to severe clinical disease, nerve loss, viral dissemination to the trigeminal ganglion and draining lymph nodes, and mortality, while their local adoptive transfer limits disease. pDCs are the main source of HSV-1-induced IFN-α in the corneal stroma through TLR9, and they prevent re-programming of regulatory T cells (Tregs) to effector ex-Tregs. Clinical signs of infection are observed in pDC-depleted corneas, but not in pDC-sufficient corneas, following low-dose HSV-1 inoculation, suggesting their critical role in corneal antiviral immunity. Our findings demonstrate a vital role for corneal pDCs in the control of local viral infections.

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Section: Resultsmentioning

confidence: 99%

Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis

Jamali

Sendra

et al. 2020

Cell Reports

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“…Significant negative correlations are observed between the model and FVC (% pred) and TLC (% pred). The negative correlation is still significant and even stronger between the model computed with T1 measurements and TLC (% pred) quantified at T2 (but not with FVC at T2), which means that the model could be a predictor of disease progression for TLC (% pred) at T2 significant increase in cell-free nucleosomic biomarkers in SSc with a specific correlation with the skin involvement [13]. In our study, instead of using total cell-free circulating nucleosomes, we used a specific H3 variant assay (Nu.Q™ H3.1) which seems to increase sensibility compared to our previous study [5].…”

Section: Table 3 Correlations Between the Model And Pft At Baselinementioning

confidence: 88%

“…Even if elevated levels of circulating cell-free nucleosomes (cf-nucleosomes) does not appear to be specific to a unique pathological state and correlate with different mechanisms of release, it may be of a particular interest for differential diagnosis and may serve as a guiding biomarker for prognosis in association with other biomarkers as it is sensitive and linked with inflammatory processes [9][10][11][12]. Reinforcing this hypothesis, Yoshizaki et al identified a significant increase in cell-free nucleosomic biomarkers in SSc with a specific correlation with the skin involvement [13].…”

Section: Introductionmentioning

confidence: 99%

A new nucleosomic-based model to identify and diagnose SSc-ILD

et al. 2020

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Background: Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the evolution of the lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease. Nucleosomes are stable DNA/protein complexes that are shed into the blood stream making them ideal candidates for biomarkers. Methods: We studied circulating cell-free nucleosomes (cf-nucleosomes) in SSc patients, 31 with ILD (SSc-ILD) and 67 without ILD. We analyzed plasma levels for cf-nucleosomes and investigated whether global circulating nucleosome levels in association with or without other biomarkers of interest for systemic sclerosis or lung fibrosis (e.g., serum growth factors: IGFBP-1 and the MMP enzyme: MMP-9), could be suitable potential biomarkers for the correct identification of SSc-ILD disease. Results: We found that H3.1 nucleosome levels were significantly higher in patients with SSc-ILD compared SSc patients without ILD (p < 0.05) and levels of MMP-9 were significantly increased in patients with SSc-ILD compared to SSc patients without ILD (p < 0.05). Conversely, IGFBP-1 was significantly reduced in patients with SSc-ILD compared to SSc without ILD (p < 0.001). The combination of cf-nucleosomes H3.1 coupled to MMP-9 and IGFBP-1 increased the sensitivity for the differential detection of SSc-ILD. High levels of accuracy were reached with this combined model: its performances are strong with 68.4% of positive predictive value and 77.2% of negative predictive value for 90% of specificity. With our model, we identified a significant negative correlation with FVC % pred (r = −0.22) and TLC % pred (r = −0.31). The value of our model at T1 (baseline) has a predictive power over the Rodnan score at T2 (after 6-18 months), showed by a significant linear regression with R 2 = 19% (p = 0.013). We identified in the sole group of SSc-ILD patients a significant linear regression with a R 2 = 54.4% with the variation of DLCO between T1 and T2 (p < 0.05). Conclusion: In our study, we identified a new blood-based model with nucleosomic biomarker in order to diagnose SSc-ILD in a SSc cohort. This model is correlated with TLC and FVC at baseline and predictive of the skin evolution and the DLCO. Further longitudinal exploration studies should be performed in order to evaluate the potential of such diagnostic and predictive model.

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“…TLR8 stimulation by ssRNA increases the production of TIMP-1 in monocytes from SSc patients or healthy controls, and thus inhibits the breakdown of ECM 3. Nucleosome, which can stimulate TLR9, induces T cell expression of IL-4 and IL-17, and B cell Ig production 11. Serum nucleosome levels are elevated in SSc, and TLR9 is upregulated in T cells and B cells from SSc patients 11.…”

Section: Systemic Sclerosismentioning

confidence: 99%

“…Nucleosome, which can stimulate TLR9, induces T cell expression of IL-4 and IL-17, and B cell Ig production 11. Serum nucleosome levels are elevated in SSc, and TLR9 is upregulated in T cells and B cells from SSc patients 11. TLR7 and TLR9 induce type I IFN-regulated genes, such as Siglec in SSc monocytes, and Siglec expression is increased in tissue macrophages in SSc 12…”

Section: Systemic Sclerosismentioning

confidence: 99%

Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis

Sakkas¹

2016

DDDT

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Systemic sclerosis (SSc) is a multisystem disease characterized by extensive collagen deposition in skin and internal organs, fibrointimal microvasculopathy, and activation of the immune system. T cells and B cells can promote fibrosis in SSc. Interleukin (IL)-6 is implicated in the pathogenesis of SSc. IL-6 is increased in the peripheral blood and lesional skin from patients with SSc, and induces fibroblast collagen production directly and indirectly by inducing profibrotic M2 macrophages. IL-6 also induces Th17 differentiation and promotes B cell differentiation toward Ig-producing plasma cells. IL-6 is also implicated in the pathogenesis of SSc in animal models as it is increased in mice with bleomycin-induced fibrosis, whereas neutralization of IL-6 in these mice prevents skin fibrosis. IL-6 acts on cells by binding to IL-6 receptor (IL-6R) which is transmembrane or soluble, and then recruits the signal-transducing glycoprotein 130 which is ubiquitously expressed. Tocilizumab is an anti-IL-6R humanized monoclonal antibody that blocks IL-6-mediated signaling. Tocilizumab has been approved for the treatment of moderate-to-severe rheumatoid arthritis, for polyarticular and systemic juvenile idiopathic arthritis, and for Castleman’s disease, and is well tolerated. Case reports and a Phase II, randomized trial in SSc have shown some improvement of skin tightness and delayed deterioration of lung function. A Phase III randomized trial in SSc is anticipated.

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Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells

Abstract: These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.

Cited by 14 publications

References 45 publications

Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis

Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis

A new nucleosomic-based model to identify and diagnose SSc-ILD

Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis

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