Chen Shaoqi, Fan Yu, Wu Qiulin, Zhang Guohong, Wang Yukai, Li Weiping, Yang Shengli, Matucci-Cerinic Marco, Furst Daniel E
The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
Arch Med Res. 2025 Jan;56(1):103072. doi: 10.1016/j.arcmed.2024.103072. Epub 2024 Aug 28.
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.
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.
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.
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.
系统性硬化症（SSc）是一种自身免疫性疾病（AD），与类风湿关节炎（RA）、系统性红斑狼疮（SLE）和原发性干燥综合征（pSS）相比，受到的关注较少。本研究旨在分析与其他自身免疫性疾病相比，系统性硬化症患者外周血单个核细胞（PBMC）中的转录谱和免疫细胞组成。
分析了119例未经治疗的患者（8例系统性硬化症患者、42例类风湿关节炎患者、41例原发性干燥综合征患者、28例系统性红斑狼疮患者）和20例健康对照的RNA测序数据。采用生物信息学工具鉴定系统性硬化症特有的以及与其他自身免疫性疾病共有的差异表达基因（DEG）、生物学功能和免疫细胞谱。
在系统性硬化症中发现了1148个差异表达基因，上调基因与巨核细胞过程相关，下调基因与中性粒细胞功能和免疫反应相关。包括醛脱氢酶1A1（ALDH1A1）和多个表皮生长因子样结构域蛋白9（MEGF9）在内的差异表达基因与中性粒细胞减少有关。上调的转录因子与胚胎造血有关，下调的转录因子参与白细胞分化和免疫调节。与其他自身免疫性疾病的比较分析揭示了共同的致病途径，突出了巨核细胞增殖。与健康对照相比，自身免疫性疾病患者的中性粒细胞计数显著降低（p<0.001）。比较分析突出了共同途径，特别是在巨核细胞增殖方面，以及系统性硬化症中独特的基因（MEGF9、基质金属蛋白酶8（MMP8）和角蛋白家族成员），提示它们在中性粒细胞功能、皮肤完整性和纤维化中的作用。
本研究确定了与系统性硬化症中中性粒细胞功能相关的基因表达失调（角蛋白和MMP8）以及巨核细胞增加，突出了自身免疫性疾病的共同模式。这些发现为系统性硬化症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。
