Virus induced genetic changes in the pathogenesis of autoimmune myositis

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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.