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

作者：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

来源：Arthritis & Rheumatology, 2015, 67(7): 1922-1932.

DOI：10.1002/art.39153

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.

• 出版日期2015-7