DNA double-strand breaks in inclusion body myositis

目的：检测S-IBM的DNA损伤反应。背景：散发性包涵体肌炎多项研究表明肌核异常可能与其发病机制密切相关。材料与方法：采用免疫组织化学方法检测17例S肌炎患者、15例多发性肌炎患者、10例皮肌炎患者及10例正常人的活检标本。针对1)磷酸化组蛋白H_2AX(DNAH_2AX)的抗体，它聚集在损伤部位，导致γ双链断裂；以及2)DNA-PK，它是一种参与DSB修复的酶。DNA-PK由催化亚基(DNA-PKcs)和调节亚基(Ku70和Ku80)组成。结果：在S-IBM型和其他肌炎对照组中，部分肌核呈强的γ、H_2AX和DNAPK免疫反应，而正常对照组的肌核呈弱阳性反应。在S-IBM的肌纤维中，有空泡的肌纤维中，γ-H_2AX和DNA-PK经常呈阳性反应。DNA-PKcs和Ku80在空泡化纤维中与DNA结合，Ku70以包涵体形式存在于细胞质中。结论：炎症性肌病的部分肌核存在DSB。在S-ibm中，DNA-PK的Ku70调控成分的细胞质积累可能阻止了它们向细胞核和DSB位点的移位。DSB的积累可能导致S-IBM的肌核变性。

Objectives: To examine DNA damage response in s-IBM. Background: In sporadic inclusion body myositis, several studies have indicated that myonuclear abnormality may be closely associated with its pathogenesis. Materials & Methods: Immunhistochemistry in biopsy materials from patients with s-IBM (n=17), polymyositis (15), dermatomyositis (10) and other controls (10). Antibodies against 1) phosphorylated histone H2AX (γH2AX) that accumulates to the damaged sites with DNA double-strand breaks (DSB); and 2) DNA-PK that is an enzyme involved in DSB repair. DNA-PK consists of a catalytic subunit (DNA-PKcs) and regulatory subunits (Ku70 and Ku80). Results: In s-IBM and other myositis controls, a proportion of myonuclei showed strong immunoreactivity of γH2AX and DNA-PK while normal controls showed weak myonuclear reactivity. In muscle fibers with vacuoles in s-IBM, vacuolar rims were frequently positive for γH2AX and DNA-PK. Whereas DNA-PKcs and Ku80 were associated with DNA in vacuolated fibers, Ku70 was observed in the cytoplasm as inclusions. Conclusions: DSB occurs in some myonuclei in inflammatory myopathies. In s-IBM, the cytoplasmic accumulation of Ku70 regulatory component of DNA-PK may prevent their translocation to the nucleus and DSB sites. Accumulation of DSB may lead to the myonuclear degeneration in s-IBM.