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, Carmelo Carmona-Rivera, Lijing Xu, Noha Lim, Zhong Gao, Adam L. Asare, Ulrich Specks, John H. Stone, Philip Seo, Robert F. Spiera, Carol A. Langford, Gary S. Hoffman, Cees G M Kallenberg, E. William St. Clair, Nadia K. Tchao, Steven R Ytterberg, Deborah J. Phippard, Peter A. Merkel, Mariana J. Kaplan, Paul A. Monach

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62 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)1922-1932
Number of pages11
JournalArthritis and Rheumatology
Volume67
Issue number7
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology

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    Grayson, P. C., Carmona-Rivera, C., Xu, L., Lim, N., Gao, Z., Asare, A. L., Specks, U., Stone, J. H., Seo, P., Spiera, R. F., Langford, C. A., Hoffman, G. S., Kallenberg, C. G. M., St. Clair, E. W., Tchao, N. K., Ytterberg, S. R., Phippard, D. J., Merkel, P. A., Kaplan, M. J., & Monach, P. A. (2015). Neutrophil-related gene expression and low-density granulocytes associated with disease activity and response to treatment in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis and Rheumatology, 67(7), 1922-1932. https://doi.org/10.1002/art.39153