Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027121 (myositis)
 4,538 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines have been shown to be potent inducers of major histocompatibility complexes (MHC) class I and II as well as of cell adhesion molecules in muscle tissue cultures, indicating that cytokines may play a role in mediating muscle fiber damage in inflammatory myopathies. We found in 21 cases of autoimmune myositis various amounts of inflammatory cells expressing interleukin (IL)-1 alpha and -beta, IL-2, IL-4, tumor necrosis factor (TNF) -alpha and -beta, and interferon (IFN)-gamma and its receptor. Muscle fibers displayed enhanced expression of IL-1 alpha and -beta, IL-2, and TNF-alpha. Upregulation of cytokines was strongest at sites of cellular infiltration typical for the respective myositis subtype. There was no correlation between the cytokine expression and the grade of inflammation. To a lesser extent, cytokines were also present in Duchenne muscular dystrophy expressed by muscle fibers positive for TNF-alpha and by phagocytic mononuclear cells. Expression of cytokines by the muscle fiber may enable the muscle fiber to induce and mediate the process of autoimmunization and antigen-expression by itself without primary presence of inflammatory cells. Cytokine-expressing muscle fibers may enhance the cytolytic potential of cytotoxic cells and the muscle fiber may serve as source and target.
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PMID:Cytokine expression profile in idiopathic inflammatory myopathies. 878 92

Cytokines and chemokines that upregulate major histocompatibility complex class I antigens, recruit lymphocytes, and enhance T-cell-mediated myotoxicity may be important in the pathogenesis of dermatomyositis and polymyositis. We searched for cytokine and chemokine transcripts in inflammatory muscle specimens from 14 newly diagnosed or treated patients. Control specimens from six patients without inflammatory muscle disease were analyzed for transcripts of interleukins-1 beta, -2, -4, -6, -10, and -15, and interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta 1, macrophage inflammatory proteins-1 alpha and -1 beta (MIP-1 alpha, MIP-1 beta), and the chemokine "regulated on activation, normally T expressed and secreted" (RANTES). Surprisingly, the proinflammatory and lymphocyte cytokines were detected only sporadically in myositis muscle specimens, and their presence did not correlate with disease activity or treatment status of the patient. In contrast, MIP-1 alpha and MIP-1 beta were detected in 13 and 6 myositis biopsies, respectively, and RANTES, another beta (CC) chemokine, was detected in eight myositis biopsies. This study and other reports of low levels of acute-phase cytokines in myositis patients suggest that the proinflammatory cytokines do not play a major role in ongoing muscle damage. The CC chemokines studied here, in particular MIP-1 alpha, might contribute to ongoing muscle inflammation, and the pathogenesis of inflammation in myositis may follow a previously unrecognized pathway.
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PMID:The predominance of beta (CC) chemokine transcripts in idiopathic inflammatory muscle diseases. 915 44

Cytokines, chemokines, and adhesion molecules are important mediators in chronic inflammation and in immune regulation. In idiopathic inflammatory myopathies (IIM), increased expression of proinflammatory cytokines particularly interleukin (IL)-1alpha and IL-1beta, tumor necrosis factor (TNF)-alpha and macrophage inflammatory proteins (MIP)-1alpha, as well as of the inhibitory cytokines transforming growth factor (TGF)-beta was observed in muscle. There was no difference in cytokine and chemokine pattern between polymyositis, dermatomyositis, and inclusion body myositis, which could indicate that similar pathogenetic mechanisms are involved in these subsets of myositis. A prominent finding of IL-1alpha expression in endothelial cells, both in patients with active inflammation and in patients with chronic persisting muscle weakness without inflammation, makes this an interesting molecule in understanding the mechanisms for the pathogenesis of muscle weakness. Involvement of the blood vessels in the pathogenesis of myositis was further supported by increased expression of adhesion molecules and by a phenotypical expression of endothelial cells, resembling high endothelium venules in all three subsets of IIM. The molecular studies to date indicate a role of the microvessels in the pathogenesis of IIM not only in DM, as was previously suggested, but also in PM and IBM. The studies also indicate that IL-1alpha could be a target molecule for new therapeutical interventions.
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PMID:The role of cytokines, chemokines, and adhesion molecules in the pathogenesis of idiopathic inflammatory myopathies. 1112 62

Juvenile dermatomyositis (JDM) is a multisystem disease characterized by acute and chronic lymphocytic inflammation of the skeletal muscle and skin. The disease is marked early in its course by the presence of a vasculopathy or vasculitis, and later by the development of calcinosis. Research has focused on the epidemiology, etiology, and pathogenesis of the disease with, until more recently, limited therapeutic interventions. This article highlights treatment regimens, both traditional and more recent interventions. Traditional treatment for JDM includes high dose corticosteroid treatment with additional agents used in resistant disease or children with unwarranted adverse effects. Traditional therapy begins with daily oral corticosteroids, with intravenous corticosteroids utilized in severe disease; however, recent data suggests that short-term use of intravenous corticosteroids will allow a short-term improvement in strength, with no long-term change in outcome. More recent investigations suggest that early intervention with additional immunomodulatory agents will allow for a faster recovery, with less medication and disease sequelae. Use of methotrexate as an agent early in the disease course is becoming common place. Methotrexate, in conjunction with oral corticosteroids, allows a rapid improvement in symptoms, and allows for a more rapid reduction in corticosteroid dose. Methotrexate is considered as a steroid sparing agent, whether oral or intravenous corticosteroids are used. Additional immunomodulatory agents include the use of cyclosporine with or without methotrexate. Intravenous immunoglobulin has been reported to have benefit in resistant disease. There are exciting new agents which have great potential in treating JDM. Many of these agents are termed biologics and are being tested in adult myositis and juvenile arthritis. These include tumor necrosis factor (TNF)-alpha inhibitors, such as a chimeric monoclonal antibody to TNF-alpha, and a recombinant soluble human TNF receptor (p75)-Fc fusion protein. Many other new biological agents are also being tested in myositis.
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PMID:Juvenile dermatomyositis: recognition and treatment. 1199 36

Adalimumab is a fully humanized IgG1 monoclonal antibody to tumor necrosis factor-a. We describe 2 patients (17 and 13 years of age) with refractory, steroid-dependent, recurrent nonspecific orbital myositis not controlled with standard immunosuppressive medications. Both improved with adalimumab treatment, allowing reduction in corticosteroid dosage without disease flare.
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PMID:Treatment of orbital myositis with adalimumab (Humira). 1599 84

Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven resistant to treatment. Tumor necrosis factor molecules have been detected in muscle biopsies from patients with IBM. Etanercept is a TNFalpha receptor fusion protein that binds and inactivates tumor necrosis factor. Nine patients were treated with etanercept at a dose of 25 mg, two times a week for an average of 17 +/- 6.1 months. Each patient was evaluated using quantitative strength testing. Their data were compared to two different control groups. The first control group consisted of patients who participated in trials of beta-interferon-1A and had received placebo. There was no significant difference. The second control group was a natural history cohort of IBM patients. There was no statistically significant difference between the treated group and the natural history group at 6 and 12 months when looking at elbow flexors, or 6 months when looking at hand grip. In the treated patients there was a small but significant improvement (p = 0.002) in handgrip at 12 months.
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PMID:Pilot trial of etanercept in the treatment of inclusion-body myositis. 1643 40

After background information about pathologic findings, this review focuses on the cytokine response in the pathogenesis of polymyositis and dermatomyositis. Cytokines are important mediators of the immune response and play a key role in these diseases by acting on inflammatory immune cells, muscle cells, and vessel cells. Various cytokines are found in myositis samples, in particular interleukin-1 and tumor necrosis factor-alpha, which are associated with the migration, differentiation, and maturation of inflammatory cells. Recent advances indicate that the muscle cell itself could participate in the inflammatory process. Cytokines promote changes in muscle metabolism resulting in a self-sustaining inflammatory response. Accordingly, cytokines may represent new targets for therapies.
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PMID:Cytokine response in inflammatory myopathies. 1768 37

Dysferlin deficiency causes limb-girdle muscular dystrophy type 2B (LGMD2B; proximal weakness) and Miyoshi myopathy (distal weakness). Muscle inflammation is often present in dysferlin deficiency, and patients are frequently misdiagnosed as having polymyositis. Because monocytes normally express dysferlin, we hypothesized that monocyte/macrophage dysfunction in dysferlin-deficient patients might contribute to disease onset and progression. We therefore examined phagocytic activity, in the presence and absence of cytokines, in freshly isolated peripheral blood monocytes from LGMD2B patients and in the SJL dysferlin-deficient mouse model. Dysferlin-deficient monocytes showed increased phagocytic activity compared with control cells. siRNA-mediated inhibition of dysferlin expression in the J774 macrophage cell line resulted in significantly enhanced phagocytosis, both at baseline and in response to tumor necrosis factor-alpha. Immunohistochemical analysis revealed positive staining for several mononuclear cell activation markers in LGMD2B human muscle and SJL mouse muscle. SJL muscle showed strong up-regulation of endocytic proteins CIMPR, clathrin, and adaptin-alpha, and LGMD2B muscle exhibited decreased expression of decay accelerating factor, which was not dysferlin-specific. We further showed that expression levels of small Rho family GTPases RhoA, Rac1, and Cdc 42 were increased in dysferlin-deficient murine immune cells compared with control cells. Therefore, we hypothesize that mild myofiber damage in dysferlin-deficient muscle stimulates an inflammatory cascade that may initiate, exacerbate, and possibly perpetuate the underlying myofiber-specific dystrophic process.
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PMID:Dysferlin deficiency enhances monocyte phagocytosis: a model for the inflammatory onset of limb-girdle muscular dystrophy 2B. 1827 88

Alphaviruses, such as chikungunya virus and Ross River virus (RRV), are associated with outbreaks of infectious rheumatic disease in humans worldwide. Using an established mouse model of disease that mimics RRV disease in humans, we showed that macrophage-derived factors are critical in the development of striated muscle and joint tissue damage. Histologic analyses of muscle and ankle joint tissues demonstrated a substantial reduction in inflammatory infiltrates in infected mice depleted of macrophages (i.e., "macrophage-depleted mice"). Levels of the proinflammatory factors tumor necrosis factor-alpha, interferon-gamma, and macrophage chemoattractant protein-1 were also dramatically reduced in tissue samples obtained from infected macrophage-depleted mice, compared with samples obtained from infected mice without macrophage depletion. These factors were also detected in the synovial fluid of patients with RRV-induced polyarthritis. Neutralization of these factors reduced the severity of disease in mice, whereas blocking nuclear factor kappaB by treatment with sulfasalazine ameliorated RRV inflammatory disease and tissue damage. To our knowledge, these findings are the first to demonstrate that macrophage-derived products play important roles in the development of arthritis and myositis triggered by alphavirus infection.
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PMID:Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus. 1843 28

Morphologically, muscle nociceptors are free nerve endings connected to the CNS by thin myelinated (group III) or unmyelinated (group IV) afferent fibers. Not all of these endings are nociceptive; approximately 40% have a low mechanical threshold and likely fulfill non-nociceptive functions. Two chemical stimuli are particularly relevant as causes of muscle pain. The first is a drop in tissue pH, i.e. an increase in proton (H+) concentration. A large number of painful patho(physio)logical alterations of muscle tissue are associated with an acidic interstitial pH (e.g. tonic contractions, spasm, inflammation). The second important cause of muscle pain is a release of adenosine triphosphate (ATP). ATP is present in all body cells, but in muscle its concentration is particularly high. Any damage of muscle cells (trauma, necrotic myositis) is accompanied by a release of ATP from the cells. Therefore, ATP is considered a general pain stimulus by some. ATP and protons are relatively specific stimuli for muscle pain; in cutaneous pain they play a less important role. The numerous agents that are released in pathologically altered muscle include substances that desensitize mechanosensitive group IV receptors. Capsaicin has a long-lasting desensitizing action, brain-derived neurotrophic factor, and tumor necrosis factor-alpha, a short-lasting one. Most of the agents exciting group IV units (e.g. low pH, ATP, capsaicin) activate not only nociceptive endings but also non-nociceptive ones. The only substance encountered that excites exclusively nociceptive group IV receptors is nerve growth factor (NGF). In rat muscle chronically inflamed with complete Freund's adjuvant, most group IV endings are sensitized to mechanical (and to some) chemical stimuli. However, stimulants such as ATP, NGF, and solutions of low pH were found to be less effective in inflamed muscle. A possible explanation for this surprising finding is that in inflamed muscle the concentrations of ATP and NGF and H+ are increased. Therefore, experimental administration of these agents is a less effective stimulus.
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PMID:Algesic agents exciting muscle nociceptors. 1913 71


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