摘要

BACKGROUND: Systemic sclerosis is an autoimmune disease characterized by immunological abnormalities, vascular damage, and fibroblast proliferation. We have previously shown that a molecular mimicry mechanism links antibodies against the human-cytomegalovirus-derived protein UL94 to the pathogenesis of systemic sclerosis. The UL94 epitope shows homology with NAG-2, a surface molecule highly expressed on endothelial cells. Anti-UL94 peptide antibodies purified from patients' sera induce apoptosis of endothelial cells upon engagement of the NAG-2-integrin complex. METHODS AND FINDINGS: We show here that NAG-2 is expressed on dermal fibroblasts and that anti-UL94 antibodies bind to fibroblasts. We have used the gene array strategy (Affimetrix oligonucleotide microarrays) to analyze the transcriptional profile in response to a 4-h and an 8-h treatment with antibodies against the UL94 peptide in endothelial cells and dermal fibroblasts. Exposure of endothelial cells to anti-UL94 antibodies had a profound impact on gene expression, resulting in the upregulation of 1,645 transcripts. Several gene clusters were upregulated including genes encoding adhesion molecules, chemokines, colony-stimulating factors (CSFs), growth factors, and molecules involved in apoptosis. Following antibody stimulation, dermal fibroblasts showed an upregulation of 989 transcripts and acquired a "scleroderma-like" phenotype. Indeed, genes involved in extracellular matrix deposition, growth factors, chemokines, and cytokines were upregulated. We confirmed the microarray results by real-time quantitative polymerase chain reaction and by measuring some of the corresponding proteins with ELISA and Western blotting. CONCLUSION: Our results show that anti-human-cytomegalovirus antibodies may be linked to the pathogenesis of systemic sclerosis not only by inducing endothelial cell activation and apoptosis but also by causing activation of fibroblasts, one of the hallmarks of the disease.

译文

背景: 系统性硬化症是一种以免疫异常、血管损伤和成纤维细胞增殖为特征的自身免疫性疾病。我们先前已经表明,分子模拟机制将抗人巨细胞病毒衍生蛋白 UL94 的抗体与系统性硬化症的发病机制联系起来。UL94 表位与内皮细胞高度表达的表面分子 NAG-2 具有同源性。从患者血清中纯化的 Anti-UL94 肽抗体在 NAG-2-integrin 复合体结合时诱导内皮细胞凋亡。方法和结果: 我们在此表明,NAG-2 在真皮成纤维细胞上表达,anti-UL94 抗体与成纤维细胞结合。我们使用基因阵列策略 (afficmetrix 寡核苷酸微阵列) 在内皮细胞和真皮成纤维细胞中使用针对 UL94 肽的抗体进行 4-h 和 8-h 处理后分析转录谱。内皮细胞暴露于 anti-UL94 抗体对基因表达有深远的影响,导致 1,645 转录本的上调。几个基因簇被上调,包括编码粘附分子、趋化因子、集落刺激因子 (CSFs) 、生长因子和参与细胞凋亡的分子的基因。抗体刺激后,真皮成纤维细胞显示 989 个转录本的上调,并获得 “硬皮病样” 表型。事实上,参与细胞外基质沉积、生长因子、趋化因子和细胞因子的基因被上调。我们通过实时定量聚合酶链反应和用 ELISA 和 Western blotting 测量一些相应的蛋白质来确认芯片结果。结论: 我们的结果表明,抗人巨细胞病毒抗体可能与系统性硬化症的发病机制有关,不仅通过诱导内皮细胞活化和凋亡,而且通过引起成纤维细胞活化, 这种疾病的标志之一。

systemic sclerosis

免疫 系统性硬化症 疾病
概述  :  

系统性硬化症是一类病因不明的自身免疫性疾病,以广泛纤维化、血管病变以及针对多种细胞抗原的自身抗体为其主要特点。除常见的皮肤肿胀,继以变厚、变硬,最终萎缩外,还累及血管、肺、消化道、肾脏、心脏等多种内脏器官造成内脏受损的表现,严重影响预后。但其患病率偏低。   发病机制 1.遗传因素:有研究表明,系统性硬化症具有遗传性。家族中有系统性硬化症或其他自身免疫性疾病的患者,其亲属患系统性硬化症的风险增加,若为一级亲属,则风险更高

systemic 英 [sɪˈstiːmɪk; sɪˈstemɪk] 美 [sɪˈstemɪk]

释    义    adj. 系统的;全身的;体系的

例    句    Without a resolution of this global debt burden, systemic risk will fester and grow.没有这个全球债务负担的解决,系统性风险将恶化和生长。

 

Sclerosis 英 [skləˈrəʊsɪs] 美 [skləˈroʊsɪs]

释    义    n. [病理] 硬化,[医] 硬化症;细胞壁硬化

例    句    Labs are using such cells to study amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and even autism.实验室通过这些细胞来研究肌萎缩性脊髓侧索硬化、帕金森氏症、亨廷顿氏病,甚至自闭症。

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