中性粒细胞相关基因表达与低密粒细胞与抗中性粒细胞胞浆抗体相关性血管炎的疾病活动和治疗反应相关。
Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
机构信息
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
Immune Tolerance Network, Bethesda, Maryland.
出版信息
Arthritis Rheumatol. 2015 Jul;67(7):1922-32. doi: 10.1002/art.39153.
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.
目的
发现与抗中性粒细胞胞浆抗体相关性血管炎（AAV）病理生理学相关的生物标志物，并确定低密粒细胞（LDG）是否有助于 AAV 的基因表达特征。
方法
临床数据和相关生物样本的来源是 AAV 的一项随机对照治疗试验。在基线就诊时处于活动期以及 6 个月后缓解期对 AAV 患者的全血进行 RNA 测序。比较了在 6 个月时达到主要临床试验缓解终点（应答者与未达到者）的患者之间的基因表达。为了验证全血中的发现，在外周血单核细胞（PBMC）中证实了中性粒细胞相关基因表达的测量。从 PBMC 部分中使用负选择策略分离 LDG。
结果
在基线就诊时（P < 0.05），应答者（n = 77）和无应答者（n = 35）之间检测到 2346 个转录本之间存在差异表达。无监督层次聚类显示出一个粒细胞相关基因簇，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复合评分明显高于应答者（P < 0.01），并且在活动期比缓解期更高（P < 0.01）。该特征与先前在狼疮中确定的 LDG 特征强烈重叠（基因集富集分析的错误发现率 <0.01）。PBMC 中测量的 PR3 转录与疾病活动和治疗反应相关（P < 0.01）。从 AAV 患者中分离的 LDG 自发形成含有 PR3 和 MPO 的中性粒细胞细胞外陷阱。
结论
在 AAV 中，粒细胞基因特征的表达增加与疾病活动度和对治疗的反应降低有关。该特征的来源可能是 LDG，这是 AAV 中的一种潜在致病性细胞类型。
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