活动性韦格纳肉芽肿患者外周血单个核细胞中蛋白酶3及相关骨髓生成基因的转录
Transcription of proteinase 3 and related myelopoiesis genes in peripheral blood mononuclear cells of patients with active Wegener's granulomatosis.
作者信息
Cheadle Chris, Berger Alan E, Andrade Felipe, James Regina, Johnson Kristen, Watkins Tonya, Park Jin Kyun, Chen Yu-Chi, Ehrlich Eva, Mullins Marissa, Chrest Francis, Barnes Kathleen C, Levine Stuart M
机构信息
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
出版信息
Arthritis Rheum. 2010 Jun;62(6):1744-54. doi: 10.1002/art.27398.
OBJECTIVE
Wegener's granulomatosis (WG) is a systemic inflammatory disease that is associated with substantial morbidity. The aim of this study was to understand the biology underlying WG and to discover markers of disease activity that would be useful for prognosis and treatment guidance.
METHODS
Gene expression profiling was performed using total RNA from peripheral blood mononuclear cells (PBMCs) and granulocyte fractions from 41 patients with WG and 23 healthy control subjects. Gene set enrichment analysis (GSEA) was performed to search for candidate WG-associated molecular pathways and disease activity biomarkers. Principal components analysis was used to visualize relationships between subgroups of WG patients and controls. Longitudinal changes in proteinase 3 (PR3) gene expression were evaluated using reverse transcription-polymerase chain reaction, and clinical outcomes, including remission status and disease activity, were determined using the Birmingham Vasculitis Activity Score for WG (BVAS-WG).
RESULTS
Eighty-six genes in WG PBMCs and 40 in WG polymorphonuclear neutrophils (PMNs) were significantly up-regulated relative to controls. Genes up-regulated in WG PBMCs were involved in myeloid differentiation, and these included the WG autoantigen PR3. The coordinated regulation of myeloid differentiation genes was confirmed by GSEA. The median expression values of the 86 up-regulated genes in WG PBMCs were associated with disease activity (P = 1.3 x 10(-4)), and WG patients with low-level expression of the WG signature genes showed expression profiles that were only modestly different from that in healthy controls (P = 0.07). PR3 transcription was significantly up-regulated in WG PBMCs (P = 1.3 x 10(-5), false discovery rate [FDR] 0.002), but not in WG PMNs (P = 0.03, FDR 0.28), and a preliminary longitudinal analysis showed that the fold change in PR3 RNA levels in WG PBMCs corresponded to changes in the BVAS-WG score over time.
CONCLUSION
Transcription of PR3 and related myeloid differentiation genes in PBMCs may represent novel markers of disease activity in WG.
目的
韦格纳肉芽肿（WG）是一种伴有严重发病率的系统性炎症性疾病。本研究的目的是了解WG的生物学基础，并发现对预后和治疗指导有用的疾病活动标志物。
方法
使用来自41例WG患者和23名健康对照者的外周血单个核细胞（PBMC）和粒细胞组分的总RNA进行基因表达谱分析。进行基因集富集分析（GSEA）以寻找与WG相关的候选分子途径和疾病活动生物标志物。主成分分析用于可视化WG患者亚组与对照之间的关系。使用逆转录-聚合酶链反应评估蛋白酶3（PR3）基因表达的纵向变化，并使用韦格纳肉芽肿的伯明翰血管炎活动评分（BVAS-WG）确定包括缓解状态和疾病活动在内的临床结果。
结果
与对照相比，WG患者的PBMC中有86个基因和WG多形核中性粒细胞（PMN）中有40个基因显著上调。在WG患者的PBMC中上调的基因参与髓系分化，其中包括WG自身抗原PR3。GSEA证实了髓系分化基因的协同调节。WG患者PBMC中86个上调基因的中位表达值与疾病活动相关（P = 1.3×10⁻⁴），并且WG特征基因低水平表达的WG患者显示出与健康对照仅略有不同的表达谱（P = 0.07）。PR3转录在WG患者的PBMC中显著上调（P = 1.3×10⁻⁵，错误发现率[FDR] 0.002），但在WG患者的PMN中未上调（P = 0.03，FDR 0.28），并且初步纵向分析表明，WG患者PBMC中PR3 RNA水平的倍数变化与BVAS-WG评分随时间的变化相对应。
结论
PBMC中PR3和相关髓系分化基因的转录可能代表WG中疾病活动的新标志物。
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