Zhu Honglin, Xiao Yizhi, Xie Shasha, Meng Qiming, Ding Ting, Huang Ting, Liu Di, Liu Sijia, Zhang Xiaoli, Zhang Huali, Luo Hui
Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5):e70043. doi: 10.1002/jcsm.70043.
Idiopathic inflammatory myopathies (IIMs) exhibit diverse cellular microenvironments in muscle tissues, yet the full spectrum of cell populations and changes remains unclear. This study aimed to characterize cellular heterogeneity, explore cell-cell interactions and assess the prognostic value of cell subtype abundances across IIM subtypes in Han Chinese.
Muscle samples from six IIMs and three normal controls (NC) underwent single-cell RNA sequencing (scRNA-seq), whereas bulk RNA sequencing was performed on 203 IIMs and 19 NC. To avoid potential biases in cell proportion data from scRNA-seq, we used CIBERSORTx, a robust deconvolution method, to estimate cell subtype abundances in the large IIMs cohort. Cell-cell interaction, correlation and survival analysis were performed to investigate associations between cell subtypes, clinical features and disease progression.
We identified 10 T/NK cell types, eight monocyte/macrophage/dendritic cell types, 10 vascular-related cell types and four skeletal muscle cell types in IIM muscle tissues, with varying abundances across subgroups. Increased ISG T cells (1.42% vs. 0.075% in NC) and ISG monocytes (4.24% vs. 0% in NC) in dermatomyositis (DM), particularly in anti-MDA5 and anti-NXP2 patients, correlated with skin rashes and higher relapse rates. CD56CD16NK cells, exhibiting the highest cytotoxicity, were elevated most in anti-SRP (11.93% vs. 8.15% in NC) immune-mediated necrotizing myopathy (IMNM) and associated with severe muscle damage (p = 0.0001, rho = 0.267). Reduced angiogenesis-related SERPINB2 monocytes (37.12% vs. 46.69% in NC) predicted better outcomes in IMNM (p = 0.006, HR = 0.264), whereas decreased HIF3ACECs (14.29% in DM vs. 16.95% in NC), essential for endothelial barrier maintenance, negatively correlated with myofiber necrosis (p = 0.016, rho = -0.168) and were predictive of improved outcomes in DM (p = 0.014, HR = 0.412). Elevated endothelial-like pericytes in antisynthetase syndrome (ASS, 55.34% vs. 50.02% in NC) and IMNM (54.42%) were linked to muscle damage (p < 0.0001, rho = 0.272). Certain key pathways, such as angiogenesis-related pathways, were linked to better outcomes in DM (p = 0.002, HR = 0.405), whereas increased cytotoxicity scores, cell chemotaxis and regulation of inflammatory response were associated with a higher risk of relapse in both DM and IMNM. We also observed a reduction in Type I muscle fibres (22.66% in ASS vs. 66.68% in NC) that express MIF and MHC class I molecules and show extensive interactions with inflammatory cells via MIF-CD74 ligand-receptor signalling.
Our findings reveal significant shifts in cell subpopulations within IIM muscle tissues, which may contribute to muscle damage and influence disease outcomes.
特发性炎性肌病（IIMs）在肌肉组织中表现出多样的细胞微环境，但细胞群体的全貌及其变化仍不清楚。本研究旨在描述细胞异质性，探索细胞间相互作用，并评估汉族IIM各亚型中细胞亚型丰度的预后价值。
对6例IIM患者和3例正常对照（NC）的肌肉样本进行单细胞RNA测序（scRNA-seq），同时对203例IIM患者和19例NC进行批量RNA测序。为避免scRNA-seq细胞比例数据中的潜在偏差，我们使用了一种强大的反卷积方法CIBERSORTx来估计大型IIM队列中的细胞亚型丰度。进行细胞间相互作用、相关性和生存分析，以研究细胞亚型、临床特征与疾病进展之间的关联。
我们在IIM肌肉组织中鉴定出10种T/NK细胞类型、8种单核细胞/巨噬细胞/树突状细胞类型、10种血管相关细胞类型和4种骨骼肌细胞类型，各亚组中的丰度各不相同。皮肌炎（DM）中ISG T细胞（1.42% vs. NC中的0.075%）和ISG单核细胞（4.24% vs. NC中的0%）增加，特别是在抗MDA5和抗NXP2患者中，与皮疹和较高的复发率相关。细胞毒性最高的CD56CD16NK细胞在抗SRP（11.93% vs. NC中的8.15%）免疫介导的坏死性肌病（IMNM）中升高最多，并与严重肌肉损伤相关（p = 0.0001，rho = 0.267）。血管生成相关的丝氨酸蛋白酶抑制剂B2单核细胞减少（37.12% vs. NC中的46.69%）预示着IMNM的预后较好（p = 0.006，HR = 0.264），而对维持内皮屏障至关重要的缺氧诱导因子3A内皮细胞（ECs）减少（DM中为14.29% vs. NC中为16.95%）与肌纤维坏死呈负相关（p = 0.016，rho = -0.168），并预示着DM的预后改善（p = 0.014，HR = 0.412）。抗合成酶综合征（ASS，55.34% vs. NC中的50.02%）和IMNM（54.42%）中内皮样周细胞升高与肌肉损伤相关（p < 0.0001，rho = 0.272）。某些关键途径，如血管生成相关途径，与DM的较好预后相关（p = 0.002，HR = 0.405），而细胞毒性评分增加、细胞趋化性和炎症反应调节与DM和IMNM的较高复发风险相关。我们还观察到表达巨噬细胞移动抑制因子（MIF）和MHC I类分子并通过MIF-CD74配体-受体信号与炎症细胞广泛相互作用的I型肌纤维减少（ASS中为22.66% vs. NC中为66.68%）。
我们的研究结果揭示了IIM肌肉组织中细胞亚群的显著变化，这可能导致肌肉损伤并影响疾病预后。
