Journal
ARTHRITIS & RHEUMATOLOGY
Volume 67, Issue 7, Pages 1922-1932Publisher
WILEY
DOI: 10.1002/art.39153
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Funding
- Immune Tolerance Network (NIH), an international clinical research consortium headquartered at the University of California San Francisco [N01-AI-15416]
- NIH through National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program
- National Center for Advancing Translational Sciences (Boston University-Clinical and Translational Science Institute) [KL2-TR-000158]
- Rheumatology Scientist Development Award from Rheumatology Research Foundation
- Genentech
- ChemoCentryx
- GlaxoSmithKline
- Eli Lilly
- MedImmune
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ObjectiveTo 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. MethodsThe 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). 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. ResultsDifferential 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. ConclusionIn 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.
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