Dataset Information

Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.

ABSTRACT: Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.

SUBMITTER: Ryu C

PROVIDER: S-EPMC8088542 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.

Ryu Changwan C Brandsdorfer Caitlin C Adams Taylor T Hu Buqu B Kelleher Dylan W DW Yaggi Madeleine M Manning Edward P EP Walia Anjali A Reeves Benjamin B Pan Hongyi H Winkler Julia J Minasyan Maksym M Dela Cruz Charles S CS Kaminski Naftali N Gulati Mridu M Herzog Erica L EL

The European respiratory journal 20190829 2

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtD ...[more]

PMID: 31273041

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Project description:ObjectiveSystemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by variable clinical outcomes, activation of innate immune pattern-recognition receptors (PRRs), and accumulation of α-smooth muscle actin (α-SMA)-expressing myofibroblasts. The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs Toll-like receptor 9 (TLR-9) and cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING), which has yet to be determined.MethodsHuman lung fibroblasts (HLFs) from normal donors and SSc-ILD explants were treated with synthetic CpG DNA and assayed for α-SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in 2 independent SSc-ILD cohorts and demographically matched controls. The ability of SSc-ILD and control plasma to induce TLR-9 and cGAS/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin-6 (IL-6), and oxidized DNA were measured using electrochemiluminescence and enzyme-linked immunosorbent assay-based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography mass spectrometry.ResultsNormal HLFs and SSc-ILD fibroblasts developed increased α-SMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc-ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS/STING activation as well as type I IFN and IL-6 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin.ConclusionThese findings demonstrate a previously unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.

Project description:Circulating nucleic acids, alone and in complex with histones as nucleosomes, have been proposed to link systemic inflammation and coagulation after trauma to acute kidney injury (AKI). We sought to determine the association of circulating nucleic acids measured at multiple time points after trauma with AKI risk.DesignWe conducted a prospective cohort study of trauma patients, collecting plasma on presentation and at 6, 12, 24, and 48 hours, defining AKI over the first 6 days by Kidney Disease Improving Global Outcomes serum creatinine and dialysis criteria. We determined kinetics of plasma mitochondrial DNA (mtDNA), nuclear DNA (nDNA), and nucleosome levels across time points and associations with AKI using multivariable linear mixed-effects models, adjusted for injury characteristics and blood transfusions. We evaluated the association of presentation nucleic acid damage-associated molecular patterns (DAMP) concentrations with subsequent AKI, adjusting for injury severity using multivariable logistic regression.SettingAcademic level I trauma center.PatientsTrauma patients (n = 55) requiring intensive care for greater than or equal to 24 hours after presentation.InterventionsNone.Measurements and main resultsAKI developed in 17 patients (31%), a median of 12.0 hours (interquartile range, 6.2-24.1 hr) after presentation. mtDNA demonstrated a time-varying association with AKI (p = 0.022, interaction with time point), with differences by AKI status not emerging until 24 hours (β = 0.97 [95% CI, 0.03-1.90] log copies/uL; p = 0.043). Patients who developed AKI had higher nDNA across all time points (overall β = 1.41 log copies/uL [0.86-1.95 log copies/uL]; p < 0.001), and presentation levels were significantly associated with subsequent AKI (odds ratio [OR], 2.55 [1.36-4.78] per log copy/uL; p = 0.003). Patients with AKI had higher nucleosome levels at presentation (β = 0.32 [0.00-0.63] arbitrary unit; p = 0.048), a difference that was more pronounced at 24 hours (β = 0.41 [0.06-0.76]; p = 0.021) and 48 hours (β = 0.71 [0.35-1.08]; p < 0.001) (p = 0.075, interaction with time point).ConclusionsPlasma nucleic acid DAMPs have distinct kinetics and associations with AKI in critically ill trauma patients. nDNA at presentation predicts subsequent AKI and may be amenable to targeted therapies in this population.

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Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.

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Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.

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