Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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. 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). 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. 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.
Grayson, PC; Carmona-Rivera, C; Xu, L; Lim, N; Gao, Z; Asare, AL; Specks, U; Stone, JH; Seo, P; Spiera, RF; Langford, CA; Hoffman, GS; Kallenberg, CGM; St Clair, EW; Tchao, NK; Ytterberg, SR; Phippard, DJ; Merkel, PA; Kaplan, MJ; Monach, PA; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group,
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