Résumé :
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Normal muscle fibers do not express detectable levels of class I major histocompatibility complex (MHC-I). In contrast, high-level expression of MHC-I is a hallmark of muscle autoimmune diseases such as polymyositis, inclusion-body myositis or dermatomyositis. It is generally considered that damage of muscle fibers in myositis results from an auto-immune attack by auto-reactive cytotoxic T lymphocytes (cTL) that recognize muscle autoantigens presented by MHC-I molecules. However, the degree of inflammation does not consistently correlate with clinical severity or muscle structural alteration, and non-immunological processes could also contribute to the muscle damage in these pathologies. Using a MHC-Itransgenic mouse model (iMHC) in which a controllable muscle-specific promoter governs the conditional up-regulation of a MHC-I molecule (H-2Kb) in skeletal muscle, it was previously shown that forced H-2Kb expression resulted in a severe disease with important muscle fiber damage. Nevertheless, the paucity of muscle T cell infiltrates and the absence of direct evidence that the disease is indeed T cell-dependent prompted us to reappraise the role of the immune system in this model.iMHC mice were crossed into a T and B cell-deficient Rag-/- background. Surprisingly, in this setting, induction of muscle H-2Kb also provoked a severe clinical myopathy. Histological analysis evidenced necrotizing myopathy with myofiber structural changes suggestive of protein accumulation. Proteomic analysis of muscle samples (2-D gel electrophoreses followed by mass spectrometry, Orbitrap high resolution quantitative proteomics, Western blot) revealed activation of the unfolded protein response (UPR) with up-regulation of chaperones (HSP27, aBcrystallin) and UPR pathway proteins (BiP, calnexin, ATF-6) which are characteristic of endoplasmic reticulum stress. Also, augmented LC3-II expression suggested induction of autophagy. Hence, despite the absence of adaptive immune system, forced expression of H-2Kb by muscle fibers is per se pathogenic. These results may be relevant to human pathology since emerging data point to the up-regulation of autophagy markers and UPR proteins in inclusion-body myositis. Therefore, pharmacological strategies targeting these pathways may have therapeutic value in myositis.
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