Pathogenic mechanisms in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) are chronic inflammatory disorders characterized by muscle weakness, by low muscle endurance, and by inflammation in skeletal muscle tissue. The pathogenesis and etiology of these conditions are yet not fully understood and several different mechanisms are likely to be involved. The most characteristic histopathological finding is the presence of inflammatory cell infiltrates in muscle tissue together with degenerating and regenerating muscle fibers.

The main goal of this thesis was to increase our knowledge of the pathogenic mechanisms in IIMs, in particular how the immune reactions could cause impaired muscle performance. We characterized IIM patients and healthy subjects through muscle biopsies in different phases of disease, we performed detailed studies on the cellular level and in an animal model of IIMs, and correlated our results from in vivo studies with in vitro models.

Several new observations were made in this thesis. Firstly, we found a reduced number and morphologically changed capillaries in patients with short disease duration and without inflammatory cell infiltrates in muscle tissue. This finding correlated to an upregulated expression of the aniogenetic factor vascular endothelium growth factor (VEGF) in muscle fibers. These observations may suggest that local muscle hypoxia could be a contributing factor to the impaired muscle function seen in patients.

Secondly, we found that the pro-inflammatory cytokines interleukin (IL)-1 and high mobility group box chromosomal protein (HMGB)-1 were consistently expressed in muscle tissue of patients with IIMs not only in inflammatory cells but also in endothelial cells and the nuclei of muscle fibers. The expression of IL-1 and their receptors in muscle nuclei indicate that IL-1 could possess direct effects on muscle fibers and affect muscle fiber metabolism and function. In addition, HMGB-1 was found to reversibly induce major histocompatibility complex (MHC) class I expression on muscle fibers and irreversibly impair Ca2+ release from the sarcoplasmic reticulum during induction of fatigue, indicating a direct effect of HMGB-1 on generation of muscle force. Moreover, the expression of MHC class I in muscle fibers, which are a pathological finding in patients with IIMs, led to a specific muscle force reduction in an animal model.

In this model the reduced force was associated with decreased cross-sectional area in fast-twitch muscle whereas it was due to a decrease in the intrinsic force-generating capacity in slow-twitch muscles, indicating that MHC class I upregulation affects muscle fiber contractility with differential effects depending on muscle fiber properties.

In summary, we have identified different molecular pathways that might play a pathogenic role in these disorders and how they can lead to low muscle performance. These include tissue hypoxia as a consequence of a distorted microcirculation in skeletal muscle tissue as well as direct and indirect effects of the pro-inflammatory cytokines IL-1 and HMGB-1 on muscle fiber contractility. Thus, it is likely that both immune and non-immune-mediated pathways contribute to the impaired muscle function seen in IIMs and this needs to be recognized in the development of new therapeutic modalities.

List of scientific papers

I. Grundtman C, Salomonsson S, Dorph C, Bruton J, Andersson U, Lundberg IE (2007). Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies. Arthritis Rheum. 56(2): 674-87
https://pubmed.ncbi.nlm.nih.gov/17265504

II. Dastmalchi M, Grundtman C, Alexanderson H, Mavragani CP, Einarsdottir H, Barbasso Helmers S, Elvin K, Crow MK, Nennesmo I, Lundberg IE Md Phd (2008). A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis. Feb 13: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/18272672

III. Grundtman C, Tham E, Ulfgren A-K, Lundberg IE (2008). Vascular Endothelium Growth Factor (VEGF) is highly expressed in muscle tissue of patients with polymyositis and dermatomyositis. [Submitted]

IV. Salomonsson S*, Grundtman C*, Zhang S-J, Bruton J, Lanner J, Li C, Wedderburn L, Kanneboyina N, Lundberg IE, Westerblad H. (2008). Up-regulation of MHC class I in transgenic mice results in reduced force generating capacity in slow-twitch muscle. [Submitted]

V. Ulfgren AK, Grundtman C, Borg K, Alexanderson H, Andersson U, Harris HE, Lundberg IE (2004). Down-regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids. Arthritis Rheum. 50(5): 1586-94
https://pubmed.ncbi.nlm.nih.gov/15146429

VI. Grundtman C, Bruton J, Östberg T, Pisetsky DS, Erlandsson Harris H, Andersson U, Westerblad H, Lundberg IE (2008). High mobility group box chromosomal protein-1 (HMGB-1) induces MHC class I in muscle fibers and mediates muscle weakness - A possible key molecule in idiopathic inflammatory myopathies. [Submitted]