Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto.
Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto.
Ann Neurol. 2017 Apr;81(4):512-525. doi: 10.1002/ana.24919. Epub 2017 Apr 3.
Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5'-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis.
We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies.
Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A-positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A-positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A-positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration.
Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512-525.
散发性包涵体肌炎（sIBM）是一种难以治疗的进行性肌肉疾病，常发生于老年人。sIBM 的发病机制可能涉及蛋白降解功能障碍和免疫异常。在 sIBM 患者的血浆和血清中发现了识别胞浆 5'-核苷酸酶 1A（cN1A）的自身抗体。然而，抗 cN1A 自身抗体是否在 sIBM 发病机制中发挥致病作用仍存在争议。本研究探讨了抗 cN1A 自身抗体在 sIBM 发病机制中的致病特性。
我们开发了一种基于细胞的检测方法来检测自身抗体，该方法是在包括 sIBM 在内的神经肌肉疾病患者的血清中发现的。我们还研究了具有和不具有自身抗体的 sIBM 患者的临床病理差异。我们使用被动体外和体内免疫接种模型来评估自身抗体的致病作用。
在 67 例 sIBM 患者中，有 24 例（35.8%）通过我们的基于细胞的检测方法检测到抗 cN1A 自身抗体。在抗 cN1A 阳性组中，丙型肝炎病毒抗体阳性率显著降低，2 型肌纤维的平均面积显著减小。在体外被动免疫接种模型中，抗 cN1A 阳性 sIBM 免疫球蛋白 G（IgG）补充细胞中 p62/SQSTM1 显著增加。在体内被动免疫接种模型中，抗 cN1A 阳性 sIBM IgG 注射小鼠的肌纤维中出现 p62/SQSTM1 阳性的肌浆内包涵体，并伴有巨噬细胞浸润。
我们的基于细胞的检测方法可用于检测抗 cN1A 自身抗体。具有抗 cN1A 自身抗体的患者表现出独特的临床病理特征。体外和体内被动免疫接种模型的结果表明，抗 cN1A 自身抗体可能影响肌纤维中的蛋白降解。
