Abstract
BackgroundEndogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.MethodsWe enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction before and after the initiation of immunosuppressive therapy. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure of eosinophil extracellular traps (EETs) and neutrophil extracellular traps (NETs) and stability against DNase were assessed in vitro. Platelet adhesion of EETs were also assessed.ResultsSerum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. The structure of EETs showed bolder net-like chromatin threads in vitro and EETs showed greater stability against DNase than NETs. EETs provided a scaffold for platelet adhesion.ConclusioncfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs in small-vessel thrombi might contribute to higher concentration of cfDNA and the occurrence of immunothrombosis in EGPA.
Highlights
Endogenous DNA derived from nuclei or mitochondria is released into the blood circulation as result of the damage or death of peripheral blood cells and tissues
The neutrophil count was significantly higher in patients with MPA compared with those with EGPA or GPA, and the eosinophil count and serum ECP were significantly higher in patients with EGPA
There was no correlation between serum cf-nDNA and DNase1 activity. These results indicated that the high levels of cell-free DNA (cfDNA) in patients with EGPA were not associated with decreased serum DNase1 activity
Summary
Endogenous DNA derived from nuclei or mitochondria is released into the blood circulation as result of the damage or death of peripheral blood cells and tissues. This extracellular DNA, referred to as cell-free DNA (cfDNA), is thought to derive primarily from dead cells of the hematopoietic lineage, with minimal contributions from other tissues [1, 2]. Levels of nuclear-derived cfDNA (cfnDNA) are significantly increased in cancer patients and can be used to monitor disease activity [3,4,5], while lower concentrations of cf-nDNA are present in peripheral blood from healthy individuals [6]. Endogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. This study aimed to evaluate the clinical significance of cfDNA in AAV
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