From the Departments of Neuropathology (Y.A., C.P., H.R., H.-H.G., W.S.) and Pathology (P.H., N.Z.), Charité-Universitätsmedizin, Berlin, Germany; Internal Medicine Department (Y.A., N.C., K.M., A.R., O. Benveniste), Reference for Neuro-muscular Diseases, Paris Est, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; Myology Research Center (Y.A., L.A.-D., G.B.-B., D.A., O. Benveniste), Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Pitié-Salpêtrière University Hospital; Department of Neuropathology (T.M., S.L.-L., C.D.) and Institut de Myologie (B.E.), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Paris; and Department of Immunology (C.B., L.D., O. Boyer), UNIROUEN, INSERM, U1234, Normandie University, Rouen University Hospital, France.
Neurology. 2018 Feb 6;90(6):e507-e517. doi: 10.1212/WNL.0000000000004923. Epub 2018 Jan 12.
To characterize muscle fiber necrosis in immune-mediated necrotizing myopathies (IMNM) with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) antibodies and to explore its underlying molecular immune mechanisms.
Muscle biopsies from patients with IMNM were analyzed and compared to biopsies from control patients with myositis. In addition to immunostaining and reverse transcription PCR on muscle samples, in vitro immunostaining on primary muscle cells was performed.
Creatine kinase levels and muscle regeneration correlated with the proportion of necrotic fibers ( = 0.6, < 0.001). CD68iNOS macrophages and a Th-1 immune environment were chiefly involved in ongoing myophagocytosis of necrotic fibers. T-cell densities correlated with necrosis but no signs of cytotoxicity were detected. Activation of the classical pathway of the complement cascade, accompanied by deposition of sarcolemmal immunoglobulins, featured involvement of humoral immunity. Presence of SRP and HMGCR proteins on altered myofibers was reproduced on myotubes exposed to purified patient-derived autoantibodies. Finally, a correlation between sarcolemmal complement deposits and fiber necrosis was observed ( = 0.4 and = 0.004). Based on these observations, we propose to update the pathologic criteria of IMNM.
These data further corroborate the pathogenic role of anti-SRP and anti-HMGCR autoantibodies in IMNM, highlighting humoral mechanisms as key players in immunity and myofiber necrosis.
对伴有抗信号识别颗粒（SRP）或抗 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）抗体的免疫介导坏死性肌病（IMNM）中的肌纤维坏死进行特征描述，并探讨其潜在的分子免疫机制。
分析伴有 IMNM 患者的肌肉活检，并与肌炎患者的活检进行比较。除了对肌肉样本进行免疫染色和逆转录 PCR 外，还对原代肌肉细胞进行了体外免疫染色。
肌酸激酶水平和肌肉再生与坏死纤维的比例相关（ = 0.6， < 0.001）。CD68iNOS 巨噬细胞和 Th1 免疫环境主要参与坏死纤维的持续吞噬作用。T 细胞密度与坏死相关，但未检测到细胞毒性迹象。补体经典途径的激活，伴有肌膜免疫球蛋白的沉积，是体液免疫的特征。在暴露于纯化的患者源性自身抗体的肌管上，改变的肌纤维上存在 SRP 和 HMGCR 蛋白。最后，观察到肌膜补体沉积物与纤维坏死之间存在相关性（ = 0.4 和 = 0.004）。基于这些观察结果，我们建议更新 IMNM 的病理标准。
这些数据进一步证实了抗 SRP 和抗 HMGCR 自身抗体在 IMNM 中的致病作用，突出了体液机制作为免疫和肌纤维坏死的关键因素。
