title: Decreased neutrophil apoptosis in quiescent ANCA-associated systemic vasculitis.
abstract: BACKGROUND
  ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV.
  
  
  METHODS
  Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-α, C/EBP-β and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR.
  
  
  RESULTS
  AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 ± 14% vs. HBD 64 ± 11%, p<0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-α, C/EBP-β were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD.
  
  
  CONCLUSIONS
  Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.
authors.affiliation: Department of Nephrology, Clinical Sciences, Lund University, Lund, Sweden. Mohamed.Abdgawad@med.lu.se
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdgawad
authors.forename: Åsa
authors.initials: Å
authors.lastname: Pettersson
authors.forename: Lena
authors.initials: L
authors.lastname: Gunnarsson
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Pierre
authors.initials: P
authors.lastname: Geborek
authors.forename: Lars
authors.initials: L
authors.lastname: Nilsson
authors.forename: Mårten
authors.initials: M
authors.lastname: Segelmark
authors.forename: Thomas
authors.initials: T
authors.lastname: Hellmark
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007519:Isoantigens / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D055815:Young Adult
chemical_list: C000631012:ATRAID protein, human; D051017:Apoptosis Regulatory Proteins; C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface