特发性炎性肌病患者不同肌炎特异性自身抗体中外周血单个核细胞和单核细胞中 1 型干扰素特征。
Type 1 interferon signature in peripheral blood mononuclear cells and monocytes of idiopathic inflammatory myopathy patients with different myositis-specific autoantibodies.
机构信息
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Radiology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
出版信息
Front Immunol. 2023 May 9;14:1169057. doi: 10.3389/fimmu.2023.1169057. eCollection 2023.
BACKGROUND
Myositis-specific autoantibodies (MSAs) are clinically used to diagnose and define idiopathic inflammatory myopathy (IIM) subsets. However, the underlying pathogenic mechanisms of patients with different MSAs remain unclear.
METHODS
A total of 158 Chinese patients with IIM and 167 gender- and age-matched healthy controls (HCs) were enrolled. Transcriptome sequencing (RNA-Seq) was performed with peripheral blood mononuclear cells (PBMCs), followed by the identification of differentially expressed genes (DEGs) and analysis of gene set enrichment analysis, immune cell infiltration, and WGCNA. Monocyte subsets and related cytokines/chemokines were quantified. The expressions of interferon (IFN)-related genes were validated using qRT-PCR and Western blot in both PBMCs and monocytes. We also performed correlation analysis and ROC analysis to explore the potential clinical significance of the IFN-related genes.
RESULTS
There were 1,364 genes altered in patients with IIM, including 952 upregulated and 412 downregulated genes. The type I interferon (IFN-I) pathway was remarkably activated in patients with IIM. Compared with patients with other MSAs, IFN-I signatures were significantly activated in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. In total, 1,288 hub genes associated with IIM onset were identified using WGCNA, including 29 key DEGs associated with IFN signaling. The patients had more CD14brightCD16- classical, CD14brightCD16+ intermediate, and fewer CD14dimCD16+ non-classical monocyte subsets. Plasma cytokines like IL-6 and TNF and chemokines including CCL3 and MCPs increased. The validation of IFN-I-related gene expressions was consistent with the findings from RNA-Seq. The IFN-related genes were correlated with laboratory parameters and helpful for IIM diagnosis.
CONCLUSION
Gene expressions were remarkably altered in the PBMCs of IIM patients. Anti-MDA5+ IIM patients had a more pronounced activated IFN signature than others. Monocytes exhibited a proinflammatory feature and contributed to the IFN signature of IIM patients.
背景
肌炎特异性自身抗体（MSAs）临床上用于诊断和定义特发性炎性肌病（IIM）亚型。然而，不同 MSA 患者的潜在致病机制尚不清楚。
方法
共纳入 158 例中国 IIM 患者和 167 名性别和年龄匹配的健康对照（HCs）。采用外周血单个核细胞（PBMCs）进行转录组测序（RNA-Seq），随后鉴定差异表达基因（DEGs），并进行基因集富集分析、免疫细胞浸润和 WGCNA 分析。量化单核细胞亚群及相关细胞因子/趋化因子。使用 qRT-PCR 和 Western blot 在 PBMCs 和单核细胞中验证干扰素（IFN）相关基因的表达。还进行了相关性分析和 ROC 分析，以探讨 IFN 相关基因的潜在临床意义。
结果
在 IIM 患者中，有 1364 个基因发生改变，包括 952 个上调基因和 412 个下调基因。I 型干扰素（IFN-I）途径在 IIM 患者中显著激活。与其他 MSA 患者相比，抗黑色素瘤分化相关基因 5（MDA5）抗体阳性患者的 IFN-I 特征明显激活。共鉴定出 1288 个与 IIM 发病相关的 WGCNA 枢纽基因，包括 29 个与 IFN 信号相关的关键 DEG。患者有更多的 CD14brightCD16-经典、CD14brightCD16+中间和更少的 CD14dimCD16+非经典单核细胞亚群。血浆细胞因子如 IL-6 和 TNF 以及趋化因子如 CCL3 和 MCPs 增加。IFN-I 相关基因表达的验证与 RNA-Seq 的结果一致。IFN 相关基因与实验室参数相关，有助于 IIM 诊断。
结论
在 IIM 患者的 PBMCs 中，基因表达明显改变。与其他患者相比，抗 MDA5+ IIM 患者的 IFN 信号更明显激活。单核细胞表现出促炎特征，并有助于 IIM 患者的 IFN 特征。
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