Abstract
BackgroundANCA-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.MethodsNeutrophils 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.ResultsAASV, 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.ConclusionNeutrophil 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.
Highlights
Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, infiltration and accumulation of unscavenged apoptotic or necrotic neutrophils in perivascular tissues and fibrinoid necrosis of the vessel walls [1][2]
Vong et al showed that recombinant PR3 or the membrane fraction of cells stablytransfected with PR3 can cleave Annexin-A1 (AnxA1), suggesting that AnxA1 may be a physiologically relevant substrate for PR3 [11]; AnxA1 was recently recognized as an important inducer or promotor of neutrophil apoptosis
Neutrophil apoptosis in vitro Apoptosis, necrosis and survival of neutrophils from 44 patients with AASV, 93 Healthy Blood Donors (HBD), 20 transplant recipients (TP) recipients, 17 Polycythemia Vera (PV), 21 Systemic Lupus Erythematosus (SLE) and 21 Rheumatoid Arthritis (RA) patients was quantified after 20 h in culture as described in the method section
Summary
AASV is characterized by leukocytoclasis, infiltration and accumulation of unscavenged apoptotic or necrotic neutrophils in perivascular tissues and fibrinoid necrosis of the vessel walls [1][2]. Histological evidence suggests that neutrophil apoptosis may play a central role in the pathogenesis of AASV and production of ANCA (AntiNeutrophil Cytoplasmic Antibodies) [4][5]. Injection of brown Norway rats with syngenic apoptotic neutrophils was shown to induce ANCA but not AASV, suggesting that additional factors are required for disease pathogenesis [6]. Harper et al reported faster apoptosis in neutrophils from patients with active vasculitis compared to neutrophils from patients with quiescent vasculitis or from HBD; neutrophils from patients with active vasculitis had higher levels of mPR3 and superoxide production [12]. 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
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