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

Inflammation and Atherosclerosis

X, 634 p.online resource

Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs), comprising polymyositis, dermatomyositis, and inclusion-body myositis, are characterized by inflammatory cell infiltrates in skeletal muscle tissue, muscle weakness, and muscle fatigue. The cellular infiltrates often consist of T lymphocytes and macrophages but also, in some cases, B lymphocytes. Emerging data have led to improved phenotypic characterization of the inflammatory cells, including their effector molecules, in skeletal muscle, peripheral blood, and other organs that are frequently involved, such as skin and lungs. In this review we summarize the latest findings concerning the role of T lymphocytes, B lymphocytes, dendritic cells, and other antigen-presenting cells in the pathophysiology of IIMs

Hypothetical involvement of T lymphocytes, B lymphocytes, and dendritic cells (DCs) in idiopathic inflammatory myopathies

<p><b>Copyright information:</b></p><p>Taken from "Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies"</p><p>http://arthritis-research.com/content/9/2/208</p><p>Arthritis Research & Therapy 2007;9(2):208-208.</p><p>Published online 26 Mar 2007</p><p>PMCID:PMC1906803.</p><p></p> (1) An unknown trigger (for example viral infection or ultraviolet radiation) in the respiratory tract or through the skin leads to the cleavage of histidyl-tRNA synthetase by granzyme B through antiviral CD8T lymphocytes in the lungs. (2) Immature DCs carry receptors on its surface that recognize common features of many pathogens. When a DC takes up a pathogen in infected tissue it becomes activated and migrates to the lymph node. (3) Upon activation, the DC matures into a highly effective antigen-presenting cell (APC) and undergoes changes that enable it to activate pathogen-specific lymphocytes in the lymph node. T lymphocytes become activated and B lymphocytes, with active help from CD4T lymphocytes, proliferate and differentiate into plasma cells. (4) Activated DCs, T lymphocytes, and B lymphocytes could release cytokines into the bloodstream. (5) The activated T lymphocyte, on which the DC-MHC-antigen complex is bound, itself binds to specialized endothelial cells called high endothelial venules (HEV). For this purpose it uses the VLA-4 (very late activation antigen-4) and LFA-1 (lymphocyte function associated antigen-1) molecules on its surface to interact with adhesion molecules (vascular cell-adhesion molecule-1 (VCAM-1) and intercellular cell-adhesion molecule-1 (ICAM-1)) on HEVs, where they can penetrate into peripheral lymphoid tissues. (6,7) Naïve T lymphocytes and B lymphocytes that have not yet encountered their specific antigen circulate continuously from the blood into the peripheral lymphoid tissues. (8,9) Various cytokines from the bloodstream or produced locally could affect the muscle tissue or cell in many different ways. However, it is not clear whether the muscle cell itself could produce and release cytokines. (10–12) DCs, macrophages (Mϕ), and B lymphocytes can interact with T lymphocytes in various ways. T lymphocytes could possibly also bind to muscle cells through inducible co-stimulators (ICOS), CD40 ligand (CD40-L), CD28, and CTLA-4 (CD152) on T lymphocytes to ICOS ligand (ICOS-L), CD40, and BB-1 antigen on the muscle cell. In that fashion, the muscle cell would function as an APC. (13) Plasma cells (CD138) can be found in the muscle tissue of certain subgroups of patients with idiopathic inflammatory myopathy, but whether these cells could produce autoantibodies locally is not yet known. (14) T lymphocytes have been shown to bind in close contact with muscle cells and to release perforin, granzyme A, and granulysin, which may cause necrosis of muscle tissue or cells

Effects of adalimumab treatment on endothelial cell activation markers in the skeletal muscle of patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA), particularly those with severe disease, have increased risk of cardiovascular disease (CVD). Previous studies suggest that endothelial cell activation may contribute to this co-morbidity, and that treatment with tumour necrosis factor (TNF) inhibitors could reduce the risk of CVD in these patients. The aim of this study was to investigate endothelial cell activation markers in muscle tissue of patients after adalimumab treatment