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Comparative Study
. 2015 Jul;67(7):1922-32.
doi: 10.1002/art.39153.

"VSports在线直播" Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Peter C Grayson  1 , Carmelo Carmona-Rivera  1 , Lijing Xu  2 , Noha Lim  2 , Zhong Gao  2 , Adam L Asare  2 , Ulrich Specks  3 , John H Stone  4 , Philip Seo  5 , Robert F Spiera  6 , Carol A Langford  7 , Gary S Hoffman  7 , Cees G M Kallenberg  8 , E William St Clair  9 , Nadia K Tchao  2 , Steven R Ytterberg  3 , Deborah J Phippard  2 , Peter A Merkel  10 , Mariana J Kaplan  1 , Paul A Monach  11 ; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group
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Comparative Study

V体育2025版 - Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Peter C Grayson et al. Arthritis Rheumatol. 2015 Jul.

Abstract

Objective: To discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV VSports手机版. .

Methods: The source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders) V体育安卓版. Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions. .

Results: Differential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2,346 transcripts at the baseline visit (P < 0. 05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders (P < 0. 01) and during active disease than during remission (P < 0. 01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0. 01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response (P < 0. 01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO V体育ios版. .

Conclusion: In AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV. VSports最新版本.

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Figure 1
Figure 1. Gene Set Enrichment Analyses
Venn diagram illustrates overlap in the number of differentially expressed genes identified in four independent datasets. The RAVE dataset compared whole blood gene expression between treatment responders and nonresponders in ANCA-associated vasculitis (AAV). The Cheadle and Lyons studies compared expression in PBMCs between patients with AAV and healthy controls (33,34). The Villanueva et al study compared expression between LDGs and autologous normal-density neutrophils in patients with SLE (25). Overlapping ovals indicates the number of common genes shared between datasets.
Figure 2
Figure 2. Differential Expression of Neutrophil Related mRNA in the PBMC Fraction
Expression of proteinase 3 (PR3) and calprotectin (S100A8) but not myeloperoxidase (MPO) or cathelicidin (CAMP) are differentially upregulated in PBMCs in treatment nonresponders compared to responders in the RAVE trial (Figure 2A). PBMCs expression of PR3 and S100A8 is differentially upregulated within the same patients with AAV during active disease compared to remission (Figure 2B).
Figure 3
Figure 3. Demonstration of LDGs in Patients with AAV
Immunofluorescence microphotographs of normal-density neutrophils from a healthy control, normal-density neutrophils and LDGs from a patient with AAV (Figure 3A). The top row depicts unstimulated neutrophils and the bottom row depicts neutrophils stimulated with PMA. NET formation (long strands) in the absence of PMA stimulation is observed in in both neutrophils and LDGs in AAV but not in control neutrophils, and is enhanced by PMA stimulation. Blue = DAPI stain (DNA); red = anti-myeloperoxidase stain. Unstimulated normal-density neutrophils (Vas-Neu) and LDGs (Vas-LDG) from patients with AAV undergo significantly more ex vivo NET formation than neutrophils from healthy controls (Ctrl-Neu) (p<0.01) and LDGs from patients with AAV undergo significantly more NET formation than autologous normal-density neutrophils (p<0.05) (Figure 3B). LDGs isolated from a patient with AAV demonstrate spontaneous NET formation and both PR3 and MPO co-localize within NETs (Figure 3C).
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References

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