背景:系统性硬化症(SSc)是一种自身免疫性疾病(AD),与类风湿性关节炎(RA)相比,受到的关注较少,系统性红斑狼疮(SLE),和原发性干燥综合征(PSS)。这项研究旨在分析与其他AD相比,SSc患者外周血单核细胞(PBMC)中的转录谱和免疫细胞组成。
方法:来自119例未经治疗的患者的RNA-seq数据(8例SSc,42与RA,41与PSS,分析了28例SLE)和20例健康对照。生物信息学工具被用来识别差异表达基因(DEG),SSc特有并与其他AD共享的生物学功能和免疫细胞谱。
结果:在SSc中发现了1,148个DEG,与巨核细胞过程相关的上调基因和与中性粒细胞功能和免疫反应相关的下调基因。DEGs,包括ALDH1A1和MEGF9,与中性粒细胞减少相关。上调的转录因子(TFs)与胚胎造血有关,下调的TFs参与白细胞分化和免疫调节。与其他AD的比较分析揭示了常见的致病途径,强调巨核细胞增殖。与健康对照相比,AD中的中性粒细胞计数显著降低(p<0.001)。比较分析强调了常见的途径,特别是在巨核细胞增殖中,和SSc中的独特基因(MEGF9,MMP8和KRT家族成员),提示在中性粒细胞功能中的作用,皮肤完整性,和纤维化。
结论:本研究确定了与SSc中中性粒细胞功能和巨核细胞增加相关的基因表达失调(KRT和MMP8),突出了自身免疫性疾病的常见模式。这些发现为SSc的潜在发病机制提供了新的见解,并有助于探索新的治疗靶点。
BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease (AD), that receives less attention compared to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren\'s syndrome (pSS). This study aims to analyze transcriptional profiles and immune cell composition in peripheral blood mononuclear cells (PBMC) from SSc patients compared to other ADs.
METHODS: RNA-seq data from 119 untreated patients (eight with SSc, 42 with RA, 41 with pSS, 28 with SLE) and 20 healthy controls were analyzed. Bioinformatics tools were employed to identify differentially expressed genes (DEGs), biological functions and immune cell profiles unique to SSc and shared with other ADs.
RESULTS: 1,148 DEGs were found in SSc, with upregulated genes associated with megakaryocyte processes and downregulated genes associated with neutrophil function and immune response. DEGs, including ALDH1A1 and MEGF9, were associated with neutropenia. Upregulated transcription factors (TFs) were linked to embryonic hematopoiesis and downregulated TFs were involved in leukocyte differentiation and immune regulation. Comparative analysis with other ADs revealed common pathogenic pathways, emphasizing megakaryocyte proliferation. Neutrophils count was significantly decreased in ADs (p < 0.001) compared to healthy controls. Comparative analysis highlighted common pathways, particularly in megakaryocyte proliferation, and unique genes (MEGF9, MMP8, and KRT family members) in SSc, suggesting roles in neutrophil function, skin integrity, and fibrosis.
CONCLUSIONS: This study identifies dysregulated gene expression (KRT and MMP8) associated with neutrophil function and increased megakaryocytes in SSc, highlighting common patterns across autoimmune diseases. These findings offer new insights into the potential pathogenesis of SSc, and help to explore new targets for the treatment.