Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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DOI：
10.1002/art.39153
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发表时间：
2015-07
影响因子：
13.3
通讯作者：
Monach, Paul A.
中科院分区：
文献类型：
--
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.
发现参与 ANCA 相关性血管炎 (AAV) 病理生理学的生物标志物，并确定低密度粒细胞 (LDG) 是否有助于 AAV 的基因表达特征。临床数据和相关生物样本的来源是 AAV 的随机对照治疗试验。在基线访视 (BL) 的活动性疾病期间和 6 个月后的缓解期间 (6M) 对 AAV 患者的全血进行了 RNA 测序。对满足和不满足 6M 临床缓解主要试验结果的患者（有反应者与无反应者）之间的基因表达进行了比较。在 PBMC 中证实了中性粒细胞相关基因表达的测量，以验证全血中的发现。负选择策略从 PBMC 组分中分离出 LDG。在 BL 访视时，在 2,346 个转录本中检测到应答者 (n=77) 和无应答者 (n=35) 之间的差异表达 (p<0.05)。无监督的层次聚类显示了一组粒细胞相关基因，包括髓过氧化物酶 (MPO) 和蛋白酶 3 (PR3)。无应答者的粒细胞多基因综合评分显着高于应答者（p<0.01），活动性疾病期间的粒细胞多基因综合评分显着高于缓解者（p<0.01）。该特征与之前在狼疮中识别的 LDG 特征强烈重叠 (FDRGSEA<0.01)。 PBMC 中测量的 PR3 转录与活动性疾病和治疗反应相关 (p<0.01)。从 AAV 患者中分离出的 LDG 自发形成含有 PR3 和 MPO 的中性粒细胞胞外陷阱。在 AAV 中，粒细胞基因特征表达的增加与疾病活动性和治疗反应降低有关。该特征的来源可能是 LDG，这是 AAV 中的一种潜在致病细胞类型。
To discover biomarkers involved in the pathophysiology of ANCA-associated vasculitis (AAV) and determine if low-density granulocytes (LDGs) contribute to gene expression signatures in AAV. The source of clinical data and linked biospecimens 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 (BL) and during remission 6 months later (6M). Gene expression was compared between patients who met versus did not meet the primary trial outcome of clinical remission at 6M (responders vs. nonresponders). Measurement of neutrophil-related gene expression was confirmed in PBMCs to validate findings in whole blood. A negative selection strategy isolated LDGs from PBMC fractions. Differential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at BL visit (p<0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multi-gene composite score was significantly higher in nonresponders than responders (p<0.01) and during active disease compared to remission (p<0.01). This signature strongly overlapped an LDG signature identified previously in lupus (FDRGSEA<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. In AAV an 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.
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影响因子：
82.9
作者：
通讯作者：
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
7.3
作者：
Nakazawa D;Tomaru U;Yamamoto C;Jodo S;Ishizu A
通讯作者：
Ishizu A
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.6
作者：
Ohlsson, S;Hellmark, T;Segelmark, M
通讯作者：
Segelmark, M