Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis

Neutrophil is a key cell in pathophysiology of granulomatosis with polyangiitis. Recently, neutrophil extracellular traps were described in this disease. Mitochondrial DNA is also released during traps formation. We measured circulating cell‐free mitochondrial and genomic DNA in serum of patients with granulomatosis with polyangiitis. Subjects with the disease (14 active and 11 in remission stage) and 10 healthy controls were enrolled. Quantitative real‐time polymerase chain reaction (PCR) was used to measure 79 base pairs (bp) and 230 bp mtDNA fragments. Alu repeats were quantified to evaluate abundance of nuclear DNA in serum at the presence of plasmid control. Both fragments of mtDNA (79 bp and 230 bp) and genomic DNA were elevated significantly in granulomatosis with polyangiitis compared to controls. Only the shorter 79bp mtDNA correlated with active stage of granulomatosis with polyangiitis and clinical symptoms. A mechanism of extracellular release of mitochondrial DNA accompanies the active stage of the disease. Circulating mtDNA is extremely high in untreated patients. This suggests that biomarker properties of mtDNA are useful for monitoring of treatment.

[1]  Z. Balogh,et al.  Cell necrosis–independent sustained mitochondrial and nuclear DNA release following trauma surgery , 2015, The journal of trauma and acute care surgery.

[2]  Z. Balogh,et al.  Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. , 2014, Journal of critical care.

[3]  M. Gelb,et al.  Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. , 2014, Blood.

[4]  A. Buser,et al.  Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility , 2014, Arthritis Research & Therapy.

[5]  M. Segelmark,et al.  Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti‐neutrophil cytoplasmic antibodies , 2014, Clinical and experimental immunology.

[6]  M. Asaduzzaman,et al.  Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo , 2012, Nature Medicine.

[7]  R. Kettritz.  How anti‐neutrophil cytoplasmic autoantibodies activate neutrophils , 2012, Clinical and experimental immunology.

[8]  Z. Werb,et al.  Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. , 2012, The Journal of clinical investigation.

[9]  J. Ellinger,et al.  Circulating mitochondrial DNA in serum: a universal diagnostic biomarker for patients with urological malignancies. , 2012, Urologic oncology.

[10]  M. Sanak,et al.  Expression profile of proinflammatory genes in neutrophil-enriched granulocytes stimulated with native anti-PR3 autoantibodies. , 2012, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[11]  A. Bengtsson,et al.  Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis , 2012, PloS one.

[12]  H. Krishnamurthy,et al.  Neutrophil extracellular traps contain mitochondrial as well as nuclear DNA and exhibit inflammatory potential , 2012, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[13]  L. Crinò,et al.  Increased levels of circulating DNA in patients with systemic autoimmune diseases: A possible marker of disease activity in Sjögren’s syndrome , 2011, Lupus.

[14]  C. Savage,et al.  Immunoglobulin subclass determines ability of immunoglobulin (Ig)G to capture and activate neutrophils presented as normal human IgG or disease‐associated anti‐neutrophil cytoplasm antibody (ANCA)‐IgG , 2011, Clinical and experimental immunology.

[15]  M. Surette,et al.  A Novel Mechanism of Rapid Nuclear Neutrophil Extracellular Trap Formation in Response to Staphylococcus aureus , 2010, The Journal of Immunology.

[16]  H. Simon,et al.  Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps , 2009, Cell Death and Differentiation.

[17]  P. Albers,et al.  Circulating mitochondrial DNA in the serum of patients with testicular germ cell cancer as a novel noninvasive diagnostic biomarker , 2009, BJU international.

[18]  Z. Werb,et al.  Netting neutrophils in autoimmune small-vessel vasculitis , 2009, Nature Medicine.

[19]  J. Ellinger,et al.  Mitochondrial DNA in serum of patients with prostate cancer: a predictor of biochemical recurrence after prostatectomy , 2008, BJU international.

[20]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[21]  D. Schroeder,et al.  Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis , 2007, Annals of Internal Medicine.

[22]  Volker Brinkmann,et al.  Beneficial suicide: why neutrophils die to make NETs , 2007, Nature Reviews Microbiology.

[23]  A. Giuliano,et al.  Prediction of breast tumor progression by integrity of free circulating DNA in serum. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  W. Holzgreve,et al.  Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. , 2005, Human immunology.

[25]  Eric Buel,et al.  Development of an Alu-based, real-time PCR method for quantitation of human DNA in forensic samples. , 2003, Journal of forensic sciences.

[26]  D. Chan,et al.  Increased plasma DNA integrity in cancer patients. , 2003, Cancer research.

[27]  D. Alcorta,et al.  Expression profile of leukocyte genes activated by anti-neutrophil cytoplasmic autoantibodies (ANCA). , 2002, Kidney international.

[28]  P. Cockwell,et al.  Neutrophil priming and apoptosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis. , 2001, Kidney international.

[29]  P. Merkel,et al.  A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). , 2001, Arthritis and rheumatism.

[30]  F. O. Fackelmayer,et al.  DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. , 2001, Cancer research.