Pierre and Marie Curie University, Sorbonne Universities, National Institute of Health and Medical Research, National Center for Scientific Research, Myology Research Center, Pitié-Salpêtrière University Hospital, Paris, France.
Department of Internal Medicine and Clinical Immunology, University Hospital Department of Inflammation, Immunopathology, and Biotherapy, Pitié-Salpêtrière University Hospital, Public Hospital Network of Paris, Paris, France.
Ann Neurol. 2017 Apr;81(4):538-548. doi: 10.1002/ana.24902.
Immune-mediated necrotizing myopathies (IMNM) may be associated with either anti-signal recognition protein (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies (Abs), and the titer of these Abs is correlated with disease activity. We investigated whether anti-SRP and anti-HMGCR Abs could be involved in muscle damage.
Muscle biopsies of patients were analyzed for atrophy and regeneration by measuring fiber size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell coculture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles.
In muscle biopsies of patients with anti-SRP and anti-HMGCR Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed. In vitro, anti-SRP and anti-HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and TRIM63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: tumor necrosis factor, interleukin (IL)-6, and reactive oxygen species. In the presence of anti-SRP or anti-HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL-4 and IL-13. The addition of IL-4 and/or IL-13 totally rescued fusion capacity.
These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. Ann Neurol 2017;81:538-548.
免疫介导性坏死性肌病（IMNM）可能与抗信号识别蛋白（SRP）或抗 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）抗体（Abs）相关，且这些 Abs 的滴度与疾病活动度相关。我们研究了抗 SRP 和抗 HMGCR Abs 是否可能参与肌肉损伤。
通过测量纤维大小和进行新生儿肌球蛋白重链免疫染色，分析患者的肌肉活检以评估萎缩和再生。为了进一步了解 Abs 在病理学中的作用，我们进行了 Abs 与肌肉细胞的共培养。根据肌管表面积以及基因和细胞因子谱来评估萎缩和再生。
在抗 SRP 和抗 HMGCR Abs 的患者肌肉活检中，观察到大量的小纤维，这些小纤维对应于萎缩和再生纤维。在体外，抗 SRP 和抗 HMGCR Abs 诱导肌肉纤维萎缩，并增加 MAFbx 和 TRIM63 的转录。此外，肌肉纤维萎缩与高水平的炎症细胞因子（肿瘤坏死因子、白细胞介素（IL）-6 和活性氧）相关。在存在抗 SRP 或抗 HMGCR Abs 的情况下，由于成肌细胞融合缺陷，肌肉再生相关机制也受损。这种缺陷与 IL-4 和 IL-13 的产生减少有关。添加 IL-4 和/或 IL-13 可完全恢复融合能力。
这些数据表明，萎缩和再生的分子机制受到影响，并导致 IMNM 中发生的肌肉功能丧失。这强调了针对这些机制的靶向治疗的潜在意义。Ann Neurol 2017;81:538-548.
