New insights into the genetics and epigenetics of systemic sclerosis

Angiolilli, Chiara; Marut, Wioleta; Kroef, Maarten van der; Chouri, Eleni; Reedquist, Kris A.; Radstake, Timothy R D J

doi:10.1038/s41584-018-0099-0

Cited by 84 publications

(84 citation statements)

References 149 publications

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“…An aberrant immune response, including type I IFN pathway activation, is evident from the earliest phases of SSc, before the development of clinically overt fibrosis ( 12 ). The link between immune response and fibrosis has been intensively studied ( 2 , 4 ); however, no treatment to date has managed to satisfactorily halt fibrosis progression in SSc patients. Thus, there is an imperative need to better understand the underlying pathogenetic mechanisms that may act as mediators or common denominators of immune activation and fibrosis in SSc in order to develop biomarkers for better patient risk stratification and to discover novel targets for targeted therapeutic approaches ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

et al. 2020

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Increased endogenous DNA damage and type I interferon pathway activation have been implicated in systemic sclerosis (SSc) pathogenesis. Because experimental evidence suggests an interplay between DNA damage response/repair (DDR/R) and immune response, we hypothesized that deregulated DDR/R is associated with a type I interferon signature and/or fibrosis extent in SSc. DNA damage levels, oxidative stress, induction of abasic sites and the efficiency of DNA double-strand break repair (DSB/R) and nucleotide excision repair (NER) were assessed in peripheral blood mononuclear cells (PBMCs) derived from 37 SSc patients and 55 healthy controls; expression of DDR/R-associated genes and type I interferon–induced genes was also quantified. Endogenous DNA damage was significantly higher in untreated diffuse or limited SSc (Olive tail moment; 14.7 ± 7.0 and 9.5 ± 4.1, respectively) as well as in patients under cytotoxic treatment (15.0 ± 5.4) but not in very early onset SSc (5.6 ± 1.2) compared with controls (4.9 ± 2.6). Moreover, patients with pulmonary fibrosis had significantly higher DNA damage levels than those without (12.6 ± 5.8 vs. 8.8 ± 4.8, respectively). SSc patients displayed increased oxidative stress and abasic sites, defective DSB/R but not NER capacity, downregulation of genes involved in DSB/R (MRE11A, PRKDC) and base excision repair (PARP1, XRCC1), and upregulation of apoptosis-related genes (BAX, BBC3). Individual levels of DNA damage in SSc PBMCs correlated significantly with the corresponding mRNA expression of type I interferon–induced genes (IFIT1, IFI44 and MX1, r =0.419-0.490) as well as with corresponding skin involvement extent by modified Rodnan skin score ( r =0.481). In conclusion, defective DDR/R may exert a fuel-on-fire effect on type I interferon pathway activation and contribute to tissue fibrosis in SSc.

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Section: Discussionmentioning

confidence: 99%

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

et al. 2020

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“…Genetic predisposition only partially explains the development of scleroderma. 70 Epigenetic processes in a genetically susceptible patient are likely to be involved in the development of SSc and its manifestations. 71,72 In summary, while there is evidence of susceptibility to SSc, the genetic risk factors specific to SSc-ILD and its progression remain unclear.…”

Section: Genetics Of Ssc-ildmentioning

confidence: 99%

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

Mackintosh

Stainer

Barnett

et al. 2019

Semin Respir Crit Care Med

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Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). SSc-ILD adversely impacts quality of life and is currently the leading cause of death in this multisystem disease. Identifying clinically significant SSc-ILD is critically important. Accurate staging and prognostication remain difficult; however, significant advances have been made in the last decade. Evidence supports the need to treat patients with extensive and/or progressive SSc-ILD, while only a subset of patients with limited ILD may require treatment. Research is urgently required to allow improved prediction of patients at risk of ILD progression at an early point in the disease, and ideally prior to its onset, to allow prevention. The last decade has seen the publication of landmark clinical trials for SSc-ILD. More effective strategies with less toxicity are under investigation. For those with refractory or very advanced disease, studies into disease-specific palliative approaches are in their infancy. Lung transplantation as an option for SSc-ILD remains patient- and center-specific, with data to suggest equivalent outcomes to other fibrotic lung diseases, in carefully selected cases. This review aims to provide a comprehensive overview of all key aspects of SSc-ILD.

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“…For this reason, the knowledge of epigenetic modifications as well as structural changes represents a great opportunity to contextualize genetic variations in the pathways where they are involved [17]. For instance, several methylation analyses in SSc considered DNA-methyltransferases (DNMT) as good targets for inhibitory drugs, such as 2-deoxy-5-azacytidine (5-aza) and 5-azacytidine (5-azaC) that were developed as treatment for leukemia and myelodysplastic syndrome [18]. A recent comparative analysis carried out by Carnero-Montoro and colleagues identified an interferon-related epigenetic signature in Mixed Connective Tissue Disease (MCTD), common with patients diagnosed with SLE, or Sjögren's syndrome, but significantly different to the ones observed in RA and SSc patients.…”

Section: Systemic Seropositive Rheumatic Diseases and Drug Repositioningmentioning

confidence: 99%

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases

Casares-Marfil

Martı́n

Acosta‐Herrera

2020

Expert Review of Clinical Immunology

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New insights into the genetics and epigenetics of systemic sclerosis

Cited by 84 publications

References 149 publications

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases

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