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.

In the idiopathic inflammatory myopathies (IIM), do reactive oxygen species (ROS) contribute to muscle weakness?

“…Muscle tissue from the murine H-2k b myositis model and from patients with myositis, displays ER stress-related markers such as increased Grp78 and Caspase12 8 22. Additional examination of the H-2k b murine model, which was generated to be immunodeficient, demonstrated profound muscle weakness, which further supports the hypothesis that non-immune mechanisms (eg, ER stress) could play a key role in muscle dysfunction in IIM 23. A recent study of muscle biopsies from patients with myositis confirmed colocalisation of the ER stress-related proteins Grp75 and Grp94, within fibres which show upregulated levels of MHC-I 8 24.…”

An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies

“…MHC-I molecules are necessary for antigen-specific T cell-mediated cytotoxicity and can mediate a response against surface antigens on myofibres [10]. Previous studies have also shown that MHC-I can behave as a pathogenic molecule in its own right since its expression can precede lymphocytic cell infiltration, and transgenic mice overexpressing MHC-I have been shown to develop a severe myopathy even in the absence of inflammation [11][12][13][14]. Unlike the inflammatory infiltrates, MHC-I expression is still detectable even after short-term immunosuppressive treatment and in patients with chronic myositis [9,15].…”

“…However, recent studies have shown that MHC-I overexpression can also mediate muscle fibre damage and dysfunction even in the absence of inflammation, through non-immune mechanisms such as endoplasmic reticulum (ER) stress and induction of the unfolded protein response [11,26,27]. This could explain the incomplete efficacy of immunosuppressive drugs in the treatment of IIM and the disparity between the severity of muscle damage and extent of inflammatory infiltrates in muscle biopsies, as well as the increased MHC-I expression in non-inflammatory myopathies.…”

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies – potential role of ER stress pathways

“…A recent mouse study has highlighted the potential importance of ER stress above inflammation in mediating IIM. Thus, even in a immunodeficient version of the H2-k b murine model of myositis, that is, ER stress-induced myopathic changes and muscle weakness still occurred in the absence of significant inflammatory cell infiltrations [20]. Collectively, these data suggest that activation of the ER stress pathway has an important role to play in the induction of nonimmune cell-mediated muscle weakness a process which may also apply in human IIM.…”