PMID- 25891759 OWN - NLM STAT- MEDLINE DCOM- 20150916 LR - 20191220 IS - 2326-5205 (Electronic) IS - 2326-5191 (Print) IS - 2326-5191 (Linking) VI - 67 IP - 7 DP - 2015 Jul TI - Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. PG - 1922-32 LID - 10.1002/art.39153 [doi] AB - 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. CI - (c) 2015, American College of Rheumatology. FAU - Grayson, Peter C AU - Grayson PC AD - National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. FAU - Carmona-Rivera, Carmelo AU - Carmona-Rivera C AD - National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. FAU - Xu, Lijing AU - Xu L AD - Immune Tolerance Network, Bethesda, Maryland. FAU - Lim, Noha AU - Lim N AD - Immune Tolerance Network, Bethesda, Maryland. FAU - Gao, Zhong AU - Gao Z AD - Immune Tolerance Network, Bethesda, Maryland. FAU - Asare, Adam L AU - Asare AL AD - Immune Tolerance Network, Bethesda, Maryland. FAU - Specks, Ulrich AU - Specks U AD - Mayo Clinic Foundation, Rochester, Minnesota. FAU - Stone, John H AU - Stone JH AD - Massachusetts General Hospital, Boston. FAU - Seo, Philip AU - Seo P AD - Johns Hopkins University, Baltimore, Maryland. FAU - Spiera, Robert F AU - Spiera RF AD - Hospital for Special Surgery, New York, New York. FAU - Langford, Carol A AU - Langford CA AD - Cleveland Clinic Foundation, Cleveland, Ohio. FAU - Hoffman, Gary S AU - Hoffman GS AD - Cleveland Clinic Foundation, Cleveland, Ohio. FAU - Kallenberg, Cees G M AU - Kallenberg CG AD - University of Groningen, Groningen, The Netherlands. FAU - St Clair, E William AU - St Clair EW AD - Duke University Medical Center, Durham, North Carolina. FAU - Tchao, Nadia K AU - Tchao NK AD - Immune Tolerance Network, Bethesda, Maryland. FAU - Ytterberg, Steven R AU - Ytterberg SR AD - Mayo Clinic Foundation, Rochester, Minnesota. FAU - Phippard, Deborah J AU - Phippard DJ AD - Immune Tolerance Network, Bethesda, Maryland. FAU - Merkel, Peter A AU - Merkel PA AD - University of Pennsylvania, Philadelphia. FAU - Kaplan, Mariana J AU - Kaplan MJ AD - National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. FAU - Monach, Paul A AU - Monach PA AD - Boston University School of Medicine, Boston, Massachusetts. CN - Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group LA - eng GR - KL2-TR-000158/TR/NCATS NIH HHS/United States GR - N01AI15416/AI/NIAID NIH HHS/United States GR - N01 AI015416/AI/NIAID NIH HHS/United States GR - M01 RR000533/RR/NCRR NIH HHS/United States GR - KL2 TR000158/TR/NCATS NIH HHS/United States GR - Z99 AR999999/Intramural NIH HHS/United States GR - M01 RR001066/RR/NCRR NIH HHS/United States GR - UL1 TR000439/TR/NCATS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (Biomarkers) RN - 0 (Glucocorticoids) RN - EC 1.11.1.7 (Peroxidase) RN - EC 3.4.21.37 (Leukocyte Elastase) RN - EC 3.4.21.76 (Myeloblastin) SB - IM CIN - Arthritis Rheumatol. 2015 Jul;67(7):1700-2. PMID: 25891203 MH - Adult MH - Aged MH - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/*drug therapy/metabolism/pathology MH - Biomarkers/metabolism MH - Extracellular Traps/metabolism MH - Female MH - Gene Expression Regulation MH - Glucocorticoids/therapeutic use MH - Granulocytes/metabolism/*pathology MH - Humans MH - Leukocyte Elastase/genetics/*metabolism MH - Leukocytes, Mononuclear/metabolism/pathology MH - Male MH - Middle Aged MH - Myeloblastin/genetics/*metabolism MH - Peroxidase/genetics/*metabolism MH - Randomized Controlled Trials as Topic MH - Severity of Illness Index MH - Treatment Outcome PMC - PMC4485551 MID - NIHMS684965 EDAT- 2015/04/22 06:00 MHDA- 2015/09/17 06:00 PMCR- 2016/07/01 CRDT- 2015/04/21 06:00 PHST- 2014/10/21 00:00 [received] PHST- 2015/04/07 00:00 [accepted] PHST- 2015/04/21 06:00 [entrez] PHST- 2015/04/22 06:00 [pubmed] PHST- 2015/09/17 06:00 [medline] PHST- 2016/07/01 00:00 [pmc-release] AID - 10.1002/art.39153 [doi] PST - ppublish SO - Arthritis Rheumatol. 2015 Jul;67(7):1922-32. doi: 10.1002/art.39153.