DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis, Vassilis L.; Vlachogiannis, Nikolaos I.; Παππά, Μαρία; Argyriou, Alexandra; Ntouros, Panagiotis A.; Sfikakis, Petros P.

doi:10.3390/ijms21010055

Cited by 85 publications

(90 citation statements)

References 153 publications

(223 reference statements)

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“…Herein, we show that individual DNA damage levels in PBMCs are strongly associated with type I IFN expression in the same cells. Most studies to date concur that damaged DNA may induce an aberrant immune response through the cGAS/STING pathway, leading to IRF-3 phosphorylation and, consequently, type I IFN pathway activation ( 11 ). Other IFN regulatory factors, such as IRF-5, -7, or -8, as well as the downstream signal transducer STAT4, have also been implicated in SSc pathogenesis ( 20 ), further supporting the central role of type I IFN in SSc.…”

Section: Discussionmentioning

confidence: 99%

“…DDR/R is a hierarchically structured mechanism that determines the cell’s ability to repair DNA damage or to undergo apoptosis ( 10 ). It is triggered by the detection of DNA lesions through specific sensors, and the next step is the initiation of a signal transduction cascade, which activates DNA repair mechanisms, cell cycle control, and apoptosis ( 11 ). The DDR/R network and the immune response act synergistically to enhance cellular defenses, thus protecting multicellular integrity from both exogenous and endogenous threats.…”

Section: Introductionmentioning

confidence: 99%

“…The DDR/R network and the immune response act synergistically to enhance cellular defenses, thus protecting multicellular integrity from both exogenous and endogenous threats. Accumulating evidence suggests that aberrant activation of each one of these networks often leads to chronic and potentially fatal systemic autoimmune disease ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…At baseline, there were several pathways containing genes differentially expressed in patients compared with controls. For example, DNA repair pathway was upregulated in patients (with increased expression of BRCA2 and RMI2 ), probably reflecting DNA damage induced by inflammation-derived reactive oxygen and nitrogen species [ 25 , 26 ]. Interesting, mitochondrial DNA damage occurring in chronic inflammatory diseases can contribute to a positive feedback of inflammation, by stimulating the IFN pathway, and JAKinhibs have been proposed as possible anti-inflammatory agents in these settings [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors

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Pastore

et al. 2020

IJMS

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Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies.

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“…Reactive oxygen species and reactive nitrogen species are highly reactive chemical compounds that have the potential to damage lipids, proteins and DNA favoring expression of neoantigens and initiation of autoimmunity in predisposed individuals. Accordingly, exaggerated reactive oxygen species formation and increased levels of markers of protein and lipid oxidation have been reported in several systemic autoimmune diseases, including RA [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Biomarkers and Peripheral Endothelial Dysfunction in Rheumatoid Arthritis: A Monocentric Cross-Sectional Case-Control Study

et al. 2020

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Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. Objective: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. Methods: Paroxonase-1 (PON-1), protein-SH (PSH), and malondialdehyde (MDA) were measured in 164 RA patient s and 100 age- and sex-matched healthy controls without previous cardiovascular events. Peripheral ED, evaluated by flow-mediated pulse amplitude tonometry, was defined by log-transformed reactive hyperemia index (Ln-RHI) values < 0.51. Results: PON-1 activity and PSH concentrations were significantly reduced in RA patients compared to controls. In regression analysis, increased plasma MDA levels were significantly associated with reduced Ln-RHI [B coefficient (95% CI) = −0.003 (−0.005 to −0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06–2.88), p = 0.028). Contrary to our expectations, increased PON-1 activity was significantly associated, albeit weakly, with the presence of ED (OR (95% CI) = 1.00 (1.00–1.01), p = 0.017). Conclusions: In this first evidence of a link between oxidative stress and markers of atherosclerosis, MDA and PON-1 showed opposite associations with peripheral vasodilatory capacity and the presence of ED in RA. Further studies are needed to determine whether this association predicts atherosclerotic events in the RA population.

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DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Cited by 85 publications

References 153 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

Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors

Oxidative Stress Biomarkers and Peripheral Endothelial Dysfunction in Rheumatoid Arthritis: A Monocentric Cross-Sectional Case-Control Study

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