Polymyositis and dermatomyositis : inflammation, muscle structure and immunosuppressive treatment
Sammanfattning: Polymyositis and dermatomyositis are chronic, inflammatory disorders characterized by muscle weakness, low muscle endurance and by inflammation in skeletal muscle tissues. The pathogenesis is not completely understood and several mechanisms are believed to be involved. Conventional immunosuppressive treatment for patients is primarily with glucocorticoids in combination with another immune-modulating drug. Although most patients respond to the treatment to some degree, persisting muscle weakness as well as continued presence of muscle tissue inflammation is often evident. The main aim was to investigate different pathways that may play a role in the disease pathogenesis and contribute to the muscle weakness in patients with polymyositis and dermatomyositis. We wanted to determine whether these mechanisms were associated with clinical outcome and if immunosuppressive treatment could alter the processes. Studies were thus performed by characterizing muscle tissue samples from patients before and after immunosuppressive treatment, and through comparison with samples from healthy individuals. We also collected in vivo samples from quadriceps muscles by microdialysis before and after exercise in both patients and healthy individuals. Some novel observations were made. Firstly, we determined that the pro-inflammatory cytokine interleukin (IL) 15 and the IL-15 receptor alpha (IL-15Rα) were over-expressed in muscle tissues from the patients compared to in healthy individuals. Immunosuppressive treatment had no effect on IL-15 expression in 1/3 of the patients along with a poorer functional outcome. Secondly, we investigated the prostaglandin (PG) E2 and leukotriene (LT) B4 pathways. Here we found that PGE2 pathway is up-regulated in muscle tissue from patients with polymyositis or dermatomyositis compared to healthy individuals. A higher expression of cyclooxygenase (COX) 1, COX-2 and microsomal PGE synthase (mPGES)-1 in the patients was apparent and while COX-2 was down-regulated by treatment, COX-1 and mPGES-1 levels remained high. LTB4 pathway was also found to be active in patients and the expression of both 5-lipoxygenase (5-LO) and the LTB4 receptor 1 (BLT1) were higher compared to in healthy individuals. 5-LO activating protein (FLAP), was highly expressed in a subgroup of patients who did not respond to immunosuppressive treatment. These results may suggest an involvement of PGE2 and LTB4 in vascular permeability and chemotaxis for infiltrating immune cells, but perhaps also to serve a purpose in skeletal muscle regeneration in patients with polymyositis and dermatomyositis. Lastly, we could report that patients with newly diagnosed polymyositis or dermatomyositis did not display a low proportion of oxidative type I muscle fibers typically seen in muscle tissue of patients in a chronic state of disease. This finding implies that the proportion of oxidative fibers does not contribute to the low muscle endurance, at least not in early polymyositis and dermatomyositis. The conclusions drawn from this thesis are that several mechanisms may contribute to the muscle weakness in different subgroups of polymyositis and dermatomyositis patients. New pathways discovered in this thesis include IL-15 and the eicosanoids PGE2 and LTB4, but the fiber type composition in the muscle tissue might play a lesser role, at least in early disease. The mechanisms identified could provide a basis for further studies and possibly new therapies.
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