Virus induced genetic changes in the pathogenesis of autoimmune myositis

摘要： 特发性炎症性肌病的病因目前尚不清楚。肌炎的时间关联性 在某些人身上出现环境因素，如病毒，表明特定的暴露，在 某些遗传背景的背景下，可引发肌肉炎症。尝试识别病毒在 通过聚合酶链式反应等敏感技术检测IIM患者的组织失败，使病毒病原学受到质疑 并排除持续的病毒感染作为持续的肌肉炎症的原因 这些病人。然而，先前的研究并不排除病毒可能改变 受影响细胞的表观基因组，并在被宿主免疫消除之前启动致病过程 应答，从而解释了病毒基因组的缺失和I型干扰素签名基因的存在 在肌炎肌肉组织中的表达。我们在这里提出，一种独特的环境因素不太可能 引发肌炎的疾病表型，但很可能是一组不同的共同环境 药物导致组织特异性表观遗传学和基因表达改变，细胞内稳态，存活和 死亡基因，导致具有易感基因的人表现出疾病表型 背景资料。也有重要证据表明，基因组水平上的表观遗传变化可能是 负责病因不明的复杂炎症性疾病的发病机制。在体外初步试验中 实验中，我们发现柯萨奇B病毒感染改变了DNA甲基化和基因表达 控制细胞膜和细胞骨架的稳定性、细胞死亡和细胞凋亡。在这里，我们假设持续了 HRK的表达增加导致线粒体功能障碍，从而损害肌膜的完整性。 导致细胞内钙离子增加，膜渗漏，细胞死亡和炎症，从而增强 肌炎时肌肉退化和消瘦。目的1：检测HRK表达的变化是否会改变 体外培养的人骨骼肌膜修复和细胞死亡信号，目标2：确定 骨骼肌中HRK表达降低可改善肌炎易感患者的肌肉损伤和无力 小鼠和目标3：确定骨骼肌中HRK表达增加是否诱导肌肉 易患肌炎和野生型(C57BL/6)小鼠的损伤和虚弱。拟议的研究将会有所帮助。 阐明疾病表型的遗传基础，他们的结果可能从根本上改变我们目前的 常见环境因子在慢性自身免疫性疾病发病和维持中的作用 比如肌炎。

Abstract: The etiology of idiopathic inflammatory myopathies is currently unknown. Temporal association of myositis onset with environmental agents such as viruses in certain individuals suggests that specific exposure, in the context of certain genetic backgrounds, can initiate muscle inflammation. Attempts to identify viruses in the tissues of IIM patients by sensitive techniques such as PCR have failed, bringing into question the viral etiology of these diseases and ruling out continual viral infection as a cause of the ongoing muscle inflammation in these patients. However, the previous studies do not exclude the possibility that viruses may alter the epigenome in affected cells and initiate pathogenic processes prior to their elimination by the host’s immune response, thus explaining the absence of viral genomes and presence of type I interferon signature gene expression in the myositis muscle tissue. Here we propose that it is unlikely that a unique environmental agent initiates the myositis disease phenotype, but it is highly likely that a diverse group of common environmental agents causes tissue specific epigenetic and gene expression alterations in cell homeostasis, survival and death genes, resulting in the manifestation of the disease phenotype in persons with a susceptible genetic background. There is also significant evidence that epigenetic changes at the genomic level could be responsible for the pathogenesis of complex inflammatory diseases of unknown etiology. In preliminary in vitro experiments, we found that Coxsackie B virus infection alters the DNA methylation and expression of genes controlling membrane and cytoskeletal stability, cell death and apoptosis. Here we hypothesize that sustained increased expression of HRK causes mitochondrial dysfunction that compromises sarcolemmal integrity, leading to increased cytosolic calcium, membrane leakiness, cell death and inflammation, which enhance muscle degeneration and wasting in myositis. Aim 1:To test whether changes in the expression of HRK alter membrane repair and cell death signaling in vitro in human skeletal muscle, Aim 2:To determine whether decreased expression of HRK in skeletal muscle improves muscle damage and weakness in myositis-prone mice and Aim 3:To determine whether increased expression of HRK in skeletal muscle induces muscle damage and weakness in myositis prone and wild-type (C57BL/6) mice. The proposed studies will help elucidate the genetic basis for the disease phenotype, and their results may radically change our current concepts on the role common environmental agents in initiating and sustaining chronic autoimmune diseases such as myositis.