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Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis.

AbdGawad, Mohamed LU ; Pettersson, Åsa LU ; Gunnarsson, Lena LU ; Bengtsson, Anders LU ; Geborek, Pierre LU ; Nilsson, Lars; Segelmark, Mårten LU and Hellmark, Thomas LU (2012) In PLoS ONE 7(3).
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,... (More)
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.

CONCLUSION:



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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
7
issue
3
publisher
Public Library of Science
external identifiers
  • wos:000303017700057
  • pmid:22403660
  • scopus:84857753305
ISSN
1932-6203
DOI
10.1371/journal.pone.0032439
language
English
LU publication?
yes
id
64966879-eb57-4933-bcff-caf9bf1d5290 (old id 2432093)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22403660?dopt=Abstract
date added to LUP
2012-04-03 09:44:39
date last changed
2017-07-09 04:10:46
@article{64966879-eb57-4933-bcff-caf9bf1d5290,
  abstract     = {BACKGROUND:<br/><br>
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.<br/><br>
<br/><br>
METHODS:<br/><br>
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.<br/><br>
<br/><br>
RESULTS:<br/><br>
AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50±14% vs. HBD 64±11%, p&lt;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.<br/><br>
CONCLUSION:<br/><br>
<br/><br>
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.},
  articleno    = {e32439},
  author       = {AbdGawad, Mohamed and Pettersson, Åsa and Gunnarsson, Lena and Bengtsson, Anders and Geborek, Pierre and Nilsson, Lars and Segelmark, Mårten and Hellmark, Thomas},
  issn         = {1932-6203},
  language     = {eng},
  number       = {3},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0032439},
  volume       = {7},
  year         = {2012},
}