title: Overexpression of MHC class I in muscle of lymphocyte-deficient mice causes a severe myopathy with induction of the unfolded protein response.
abstract: Muscle fibers do not normally express major histocompatibility complex class I (MHC-I) molecules, and their reexpression is a hallmark of inflammatory myopathies. It has been shown in mice that overexpression of MHC-I induces a poorly inflammatory myositis accompanied by the unfolded protein response (UPR), but it is unclear whether it is attributable to T-cell-mediated MHC-I-dependent immune responses or to MHC-I forced expression per se. Indeed, besides presenting antigenic peptides to CD8(+) T cells, MHC-I may also possibly exert nonimmunologic, yet poorly understood pathogenic effects. Thus, we investigated the pathogenicity of MHC-I expression in muscle independently of its immune functions. HT transgenic mice that conditionally overexpress H-2K(b) in muscle were bred to an immunodeficient Rag2(-/-) background. The muscle proteome was analyzed by label-free high-resolution protein quantitation and Western blot. Despite the absence of adaptive immunity, HT Rag2(-/-) mice developed a very severe myopathy associated with the cytoplasmic accumulation of H-2K(b) molecules. The UPR was manifest by up-regulation of characteristic proteins. In humans, we found that HLA class I molecules not only were expressed at the sarcolemma but also could accumulate intracellularly in some patients with inclusion body myositis. Accordingly, the UPR was triggered as a function of the degree of HLA accumulation in myofibers. Hence, reexpression of MHC-I in normally negative myofibers exerts pathogenic effects independently of its immune function.
authors.affiliation: National Institute of Health and Medical Research (INSERM), U905, Rouen, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fréret
authors.forename: Laurent
authors.initials: L
authors.lastname: Drouot
authors.forename: Antoine
authors.initials: A
authors.lastname: Obry
authors.forename: Sandra
authors.initials: S
authors.lastname: Ahmed-Lacheheb
authors.forename: Claire
authors.initials: C
authors.lastname: Dauly
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
authors.forename: Pascal
authors.initials: P
authors.lastname: Cosette
authors.forename: François-Jérôme
authors.initials: FJ
authors.lastname: Authier
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D009132:Muscles / Q000276:immunology* / Q000473:pathology* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000276:immunology* / Q000473:pathology*; D018979:Myositis, Inclusion Body / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology*; D056811:Unfolded Protein Response; D015854:Up-Regulation
chemical_list: D015395:Histocompatibility Antigens Class I; D009124:Muscle Proteins