Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease
Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease
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DOI：
10.1093/rheumatology/kes149
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发表时间：
2012-10-01
期刊：
影响因子：
5.5
通讯作者：
Koike, Takao
中科院分区：
文献类型：
--
作者：
Odani, Toshio;Yasuda, Shinsuke;Koike, Takao
目标。间质性肺疾病(ILD)是SSC的严重并发症。我们的目标是找出与SSc相关的ILDs相关的标记。从14例SSC患者外周血单个核细胞中提取RNA，根据有无ILD和治疗分为4个不同的RNA池，并进行基因芯片分析。应用实时定量聚合酶链式反应对43例SSc患者、42例自身免疫对照和10例健康对照的基因芯片结果进行验证。基因组DNA样本来自149例SSC患者(70例在北海道，79例在东京)，他们接受了高分辨率CT检查以评估ILD和230名健康对照。用序列特异性引物进行基因分型。微阵列分析显示，在两个对照组中，与非ILD患者相比，人类白细胞抗原DRB5基因是ILD患者中唯一普遍上调的基因。实时荧光定量聚合酶链式反应证实系统性红斑狼疮患者HLADRB5高表达。在两个队列中，伴有ILD的SSC患者的HLADRB5基因携带者的患病率均高于无ILD的SSC患者或健康对照组。在检测到的4个等位基因中，SLD患者的HLADRB5*01：05等位基因频率显著高于无ILD的SSC患者和健康对照组。这些关联在第二个队列中得到了证实。SLC相关性ILD患者PBMC中高表达HL A-DRB5。HLADRB5*01：05等位基因是SSc患者ILD的危险因素。
Objective. Interstitial lung disease (ILD) is a serious complication of SSc. We aimed to identify markers associated with SSc-related ILD.Methods. RNA was prepared from the peripheral blood mononuclear cells of 14 SSc patients, divided into four different RNA pools according to the presence or absence of ILD and to the treatment, and subjected to microarray analysis. Real-time quantitative PCR was used to confirm the microarray results in 43 SSc patients, 42 autoimmune controls and 10 healthy controls. Genomic DNA samples were collected from 149 patients with SSc (70 in Hokkaido and 79 in Tokyo) who underwent a high-resolution CT for the evaluation of ILD and from 230 healthy controls. Genotyping was performed using sequence-specific primers.Results. The microarray analysis revealed HLA-DRB5 to be the only gene commonly up-regulated in patients with ILD compared with those without ILD in both comparison groups. High expression levels of HLA-DRB5 in SSc patients with ILD were confirmed by real-time quantitative PCR. The prevalence of HLA-DRB5 gene carriers increased in the SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLA-DRB5*01:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls. These associations were confirmed in the second cohort.Conclusion. HLA-DRB5 was highly expressed in PBMCs from patients with SSc-related ILD. The HLA-DRB5*01:05 allele is a risk factor for ILD in patients with SSc.