Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from inflammatory myopathies

ABSTRACT: MHC-I overexpression in muscle biopsies is a hallmark of inflammatory myopathies.However the mechanisms of MHC-I overexpression in each disease is not well understood. Microarray analysis from MHC-I-microdissected myofibers showed a differential expression signature in each inflammatory myopathy. Innate immunity and IFN-I pathways are upregulated vs healthy controls, specifically in dermatomyositis (DM). RNA from MHC-I-positive myofibers were obtained from muscle biopsies of 5 patients with dermatomyositis, 5 with polymyositis, 4 with inclusion body myositis and normal looking fibers from healthy controls.

ORGANISM(S): Homo sapiens

SUBMITTER: Xavier SuM-CM-!rez-Calvet

PROVIDER: E-GEOD-48280 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.

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Expression data from inflammatory myopathies

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