Nucleosomes in the pathogenesis of systemic lupus erythematosus

Koutouzov, Sophie; Jerônimo, Antônio Luiz C.; Campos, Henry de Holanda; Amoura, Zahir

doi:10.1016/j.rdc.2004.04.001

Cited by 71 publications

(77 citation statements)

References 163 publications

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“…During apoptosis, chromatin is cleaved by specific DNases and nucleosomes (the fundamental units of chromatin), are released [13]. Nucleosomes contain structures (DNA and histones) that are targeted in lupus and it provides a link between apoptosis and SLE.…”

Section: Introducctionmentioning

confidence: 99%

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

et al. 2009

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Section: Introducctionmentioning

confidence: 99%

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

et al. 2009

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“…Chromatin is degraded to mono-and oligonucleosomes, and subsequently down to component histone and free DNA (18), where they function as DAMPs. Initial studies focused on the role of nucleosomes in autoimmune disorders (21) and oncologic processes (17). More recently, circulating histones have been implicated as mediators of endothelial and organ dysfunction in sepsis (38), and several clinical studies have demonstrated their relevance to critical illness.…”

Section: Discussionmentioning

confidence: 99%

Circulating nucleosomes are associated with mortality in pediatric acute respiratory distress syndrome

Yehya

Thomas

Margulies

2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Nucleosome levels were not associated with either Berlin (P ϭ 0.845) or PALICC (P ϭ 0.886) oxygenation categories, nor with etiology of PARDS (P ϭ 0.527). Nucleosomes were correlated with increasing numbers of nonpulmonary organ failures (P ϭ 0.009 for trend), and were higher in patients whose PaO 2 /FiO 2 worsened (P ϭ 0.012) over the first 72 h of PARDS. In regression analysis, nucleosome levels were independently associated with mortality after adjusting for either age, severity of illness score, number of nonpulmonary organ failures, vasopressor score, or Pa O 2 /FiO 2 (all P Ͻ 0.05). In conclusion, plasma nucleosome levels in early PARDS were associated with increased mortality, correlated with number of nonpulmonary organ failures, and preceded worsening oxygenation. The potential utility of this biomarker for prognostication, risk stratification, and mechanistic insight should be investigated further.acute respiratory distress syndrome; ARDS; pediatric acute respiratory distress syndrome; PARDS; nucleosomes MECHANISMS UNDERLYING pediatricacute respiratory distress syndrome (PARDS) remain elusive. While PARDS was historically defined by adult ARDS criteria (6, 25), it possesses a distinct epidemiologic, comorbidity, and outcome profile, prompting the Pediatric Acute Lung Injury Consensus Conference (PALICC) to develop pediatric-specific definitions in 2015 (23). Among other differences, the PALICC definition of PARDS uses oxygenation index (OI), rather than Pa O 2 /Fi O 2 , for risk stratification, despite the inconsistent relationship between oxygenation and outcome (1, 31). Common to both adult (35, 36) and pediatric (13, 39) ARDS is the significance of nonpulmonary organ failures as a predictor of poor outcome. While several investigations have focused on the systemic inflammatory response and the associated neutrophil activation and cytokine release (9, 36), the pathogenic mechanisms invoked remain incomplete for explaining the development of lung injury and multisystem organ failure (MSOF).Recent studies in adult ARDS have implicated circulating nucleosomes, the histone/DNA complexes resulting from nuclear chromatin degradation released after cellular damage, as potentially pathogenic in sepsis (4, 12, 24, 38), aspiration (41), and trauma-related ARDS (2). Normally located within the nucleus, nucleosomes released into the circulation act as damage-associated molecular patterns (DAMP), and have been shown to be toxic to multiple cell types (2,12,24), offering a novel mechanism linking diverse inciting insults with subsequent lung injury and organ failure. However, whether nucleosomes are associated with PARDS development or progression is unknown.Rapid identification of children with PARDS who are most at risk of a poor outcome is essential for accurate risk stratification in clinical trials, as it allows redirection of aggressive interventions toward the sickest cohort. Unlike adult ARDS, few studies address the utility of biomarkers in PARDS. The reduced incidence of PARDS [12.8 per 100,000 person-ye...

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“…Apoptosis defects are well known to be associated with certain animal models of lupus, and have also been discussed in connection with human SLE. [28][29][30][31] Recent evidence obtained in murine models of SLE suggests that nucleosome core particles are a preferential target for lupus autoantibodies and they are accepted as genuine autoantigens triggering the production of antibodies against the nucleosome core particles themselves, dsDNA and histones. [32][33][34] According to recent literature data, the presence of glomerular extracellular nucleosomes derived, for instance, from apoptotic cells is a pre-requisite for the binding of antichromatin antibodies to the glomeruli and may be involved in nephritic processes.…”

Section: Discussionmentioning

confidence: 99%

Desempenho diagnóstico e associações clínicas dos anticorpos contra componentes da cromatina no lúpus eritematoso sistêmico juvenil

Keusseyan¹,

Silva²,

Hilário³

et al. 2012

Rev. Bras. Reumatol.

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Objectives: To determine the frequency of antibodies to chromatin components in juvenile systemic lupus erythematosus (JSLE), and to correlate the presence of these autoantibodies with clinical manifestations and disease activity. Methods: Anti-chromatin (anti-CHR), anti-nucleosome core particle (anti-NCS) and anti-dsDNA antibodies were measured in 175 individuals, including 37 patients with active JSLE and 41 with inactive disease, 47 non-lupus autoimmune disease patients (non-lupus AD), and 50 healthy children. An in-house ELISA was developed with purifi ed nucleosome core particles from calf thymus to determine IgG and IgG3 anti-NCS antibodies. Anti-CHR and anti-dsDNA antibodies were detected by commercial ELISA kits (INOVA). Results: Anti-NCS and anti-CHR antibodies exhibited high specifi city for JSLE and similar frequency in active and inactive JSLE. Anti-CHR and IgG/IgG3 anti-NCS serum levels did not differ between active and inactive JSLE. SLEDAI correlated with anti-dsDNA antibodies but not with antibodies to other chromatin components. There was association of anti-dsDNA, anti-CHR and IgG/IgG3 anti-NCS antibodies with proteinuria and low C4 serum levels. Anti-NCS antibodies in the absence of anti-dsDNA were observed in 14% of the JSLE patients. Conclusions: Our data indicate that anti-NCS and anti-CHR antibodies are relevant diagnostic markers for JSLE and appear to be correlated with JSLE lupus nephritis activity. IgG3 isotype anti-NCS antibodies do not seem to be more relevant than IgG anti-NCS antibodies as markers of disease activity or active nephritis in JSLE.

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Nucleosomes in the pathogenesis of systemic lupus erythematosus

Cited by 71 publications

References 163 publications

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

Circulating nucleosomes are associated with mortality in pediatric acute respiratory distress syndrome

Desempenho diagnóstico e associações clínicas dos anticorpos contra componentes da cromatina no lúpus eritematoso sistêmico juvenil

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