Pathogenesis of idiopathic inflammatory myopathies

Abstract

The idiopathic inflammatory myopathies, myositis, are characterized by a chronic course with decreased muscle endurance and by infiltrates of T lymphocytes and macrophages in muscle tissue. Treatment with immunosuppressives rarely leads to recovery of muscle function, despite abolishment of inflammatory cell infiltrates in muscle tissue. Therefore, other mechanisms than immune-mediated muscle fiber damage are likely to contribute to the pathogenesis. One such non-immune-mediated muscle dysfunction could be caused by a disturbed microcirculation due to capillary loss or to phenotypically changed endothelial cells in the capillaries. These aberrations may affect the micro-environment of muscle tissue and lead to local tissue hypoxia with development of a secondary metabolic myopathy. Another possible non-immune-mediated mechanism leading to muscle dysfunction is the newly identified endoplasmatic reticulum (ER) stress response in myositis. The ER stress response is thought to be a consequence of the up-regulation of major histocompatibility complex class I in muscle fibers. These newly identified molecular pathways could play a major role in the pathogenesis of myositis and could be important targets in the development of new therapies.

Skeletal Muscle Fiber-type Switching, Exercise Intolerance, and Myopathy in PGC-1α Muscle-specific Knock-out Animals

“…In particular, the rise in plasma TNF␣ levels paralleled the dramatic increase in muscle fiber damage post-exercise. TNF␣ is known to cause inflammatory myopathies in rodent models and human patients (30,31). Our hypothesis that increased systemic inflammation in MKOs might contribute to the myopathy is supported by other physiological and behavioral abnormalities in these mice.…”

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

“…Although a number of autoantibodies have been identified (Table 1), their roles are uncertain and the specific antigenic targets of the immune response are still largely unknown, with the exception of a subgroup of cases of IMNM associated with antibodies to the signal recognition particle (SRP) and 3-hydroxymethyl glutaryl co-enzyme A reductase (HMGCR), which are thought to be involved in the pathogenesis of the myositis. In addition, there has been increasing recognition of the importance of non-immune mechanisms such as the possible contribution of MHC-I expression to muscle dysfunction and damage through the induction of endoplasmic stress and the unfolded protein response [32,33] It is also recognized that immature myogenic cells involved in muscle regeneration may activate Toll-like receptor (TLR) pathways leading to cytokine and chemokine production in addition to their role in antigen presentation, and may also be a target of the immune response [16,32,33].…”

Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies

“…One such non-immune mechanism, endoplasmic reticulum stress, has been proposed, on the basis of observations both from human studies and from an animal model for myositis, the major histocompatibility complex (MHC) class I transgene [3]. These non-immune mechanisms have been addressed in a recent review paper [4]. …”