Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome
Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome
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DOI：
10.1002/art.22981
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发表时间：
2007-11-01
影响因子：
--
通讯作者：
Grom, Alexei A.
中科院分区：
文献类型：
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作者：
Fall, Ndate;Barnes, Michael;Grom, Alexei A.
目的。系统性幼年特发性关节炎（JIA）常与巨噬细胞活化综合征的发生相关。本研究旨在更好地了解系统性JIA与巨噬细胞活化综合征之间的关系。
方法。对17例未经治疗的新发系统性类风湿关节炎患者的基因表达谱进行了检测，其中5例有亚临床巨噬细胞活化综合征的证据（其中2例最终发展为显性巨噬细胞活化综合征）。通过菲可梯度分离外周血单个核细胞（PBMC），并使用Affymetrix基因芯片表达阵列分析纯化的RNA。一部分PBMC用于流式细胞术以确定样本的细胞组成。
结果。鉴定出225个差异表达基因（P < 0.05），这些基因可将系统性类风湿关节炎患者与健康对照（n = 30）区分开来。聚类分析表明，表达模式与血清铁蛋白水平相关。三个主要聚类将铁蛋白水平极高的系统性JIA患者（包括那些有亚临床巨噬细胞活化综合征的患者）与铁蛋白水平正常或仅中度升高的患者区分开来。第一个聚类包含参与血红蛋白合成和红细胞结构蛋白的基因。这种转录谱与未成熟有核红细胞一致，可能反映了红细胞的高转换率。还包括表明未成熟粒细胞的转录本。第二个聚类富含参与细胞周期调控的基因。第三个聚类富含参与先天免疫反应的基因，包括参与Toll样受体/白细胞介素 - 1受体触发的炎症级联反应的负调控以及巨噬细胞分化替代途径标志物的基因。其他感兴趣的差异表达基因是那些参与细胞溶解途径的基因，包括SH2D1A和Rab27a。
结论。这些数据表明，基因表达谱分析可作为识别系统性JIA患者早期巨噬细胞活化综合征的有用工具。
Objective. Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome.Methods. Gene expression profiles were examined in 17 patients with untreated new-onset systemic RA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples.Results. Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic RA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a.Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.