Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inducible co-stimulator ligand (ICOSL), a member of the B7 family of co-stimulatory molecules related to B7.1/2, regulates CD4 as well as CD8 T-cell responses via interaction with its receptor ICOS on activated T cells. Here we examined the expression and the functional relevance of ICOSL in human muscle cells in vivo and in vitro. We investigated 25 muscle biopsy specimens from patients with polymyositis, dermatomyositis, inclusion body myositis, Duchenne muscular dystrophy and non-myopathic controls for ICOSL expression by immunohistochemistry. Normal muscle fibres constitutively express low levels of ICOSL. However, ICOSL expression is markedly increased in muscle fibres in inflammatory myopathies. Cell surface staining was most prominent in the contact areas between muscle fibres and inflammatory cells, which in turn show expression of ICOS as a marker of T-cell activation. Muscle endothelial cells show constitutive expression of ICOSL under normal and pathological conditions. We also detected mRNA and cell surface protein expression of ICOSL on myoblasts cultured from control subjects and patients as well as in TE671 muscle rhabdomyosarcoma cells. ICOSL expression was upregulated by tumour necrosis factor-alpha (TNF-alpha), whereas interferon-gamma (IFN-gamma) had no such effect. Co-culture experiments of major histocompatibility complex (MHC) class II-positive myoblasts with CD4 T cells together with superantigen demonstrated that the expression of muscle-related ICOSL has functional consequences: the production of Th1 (IFN-gamma) and Th2 cytokines [interleukin (IL)-4 and IL-10] by CD4 T cells was markedly reduced in the presence of a neutralizing anti-ICOSL monoclonal antibody (mAb HIL-131), thus showing the importance of ICOSL co-stimulation for T-cell activation. Taken together, our results demonstrate that human muscle cells express ICOSL, a functional co-stimulatory molecule distinct from B7.1 and B7.2. ICOSL-ICOS interactions may play an important role in inflammatory myopathies, providing further evidence for the antigen-presenting capacity of muscle cells.
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PMID:Muscle fibres and cultured muscle cells express the B7.1/2-related inducible co-stimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies. 1269 43

B7-H1 is a novel B7 family protein attributed to costimulatory and immune regulatory functions. Here we report that human myoblasts cultured from control subjects and patients with inflammatory myopathies as well as TE671 muscle rhabdomyosarcoma cells express high levels of B7-H1 after stimulation with the inflammatory cytokine IFN-gamma. Coculture experiments of MHC class I/II-positive myoblasts with CD4 and CD8 T cells in the presence of antigen demonstrated the functional consequences of muscle-related B7-H1 expression: production of inflammatory cytokines, IFN-gamma and IL-2, by CD4 as well CD8 T cells was markedly enhanced in the presence of a neutralizing anti-B7-H1 antibody. This observation was paralleled by an augmented expression of the T cell activation markers CD25, ICOS, and CD69, thus showing B7-H1-mediated inhibition of T cell activation. Further, we investigated 23 muscle biopsy specimens from patients with polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM), and nonmyopathic controls for B7-H1 expression by immunohistochemistry: B7-H1 was expressed in PM, IBM, and DM specimens but not in noninflammatory and nonmyopathic controls. Staining was predominantly localized to areas of strong inflammation and to muscle cells as well as mononuclear cells. These data highlight the immune regulatory properties of muscle cells and suggest that B7-H1 expression represents an inhibitory mechanism induced upon inflammatory stimuli and aimed at protecting muscle fibers from immune aggression.
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PMID:Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies. 1292 66