Neutrophil‐Related Gene Expression and Low‐Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Issue 7 (July 2015)

• Record Type: Journal Article
• Authors: Grayson, Peter C.; Carmona‐Rivera, Carmelo; Xu, Lijing; Lim, Noha; Gao, Zhong; Asare, Adam L.; Specks, Ulrich; Stone, John H.; Seo, Philip; Spiera, Robert F.; Langford, Carol A.; Hoffman, Gary S.; Kallenberg, Cees G. M.; St.Clair, E. William; Tchao, Nadia K.; Ytterberg, Steven R.; Phippard, Deborah J.; Merkel, Peter A.; Kaplan, Mariana J.; Monach, Paul A.; for the Rituximab in ANCA‐Associated Vasculitis–Immune Tolerance Network Research Group
• Is Part Of: Arthritis & rheumatology. Volume 67:Issue 7(2015)
• Page Start: 1922
• Page End: 1932
• Publication Date: 2015-07
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39153
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art39153-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="art39153-sec-0002" sec-type="section"> <title>Methods</title> <p>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). 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.</p> </sec> <sec id="art39153-sec-0003" sec-type="section"> <title>Results</title> <p>Differential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2, 346 transcripts at the baseline visit (<italic>P</italic> < 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 (<italic>P</italic> < 0.01) and during active disease than during remission (<italic>P</italic> < 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 (<italic>P</italic> < 0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO.</p> </sec> <sec id="art39153-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>