Institutionen för medicin / Department of Medicine
Abstract
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