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  • Title: Mechanisms of lysis by activated cytotoxic cells expressing perforin and granzyme-B genes and the protein TIA-1 in muscle biopsies of myositis.
    Author: Cherin P, Herson S, Crevon MC, Hauw JJ, Cervera P, Galanaud P, Emilie D.
    Journal: J Rheumatol; 1996 Jul; 23(7):1135-42. PubMed ID: 8823683.
    Abstract:
    OBJECTIVE: Polymyositis (PM) and cermatomyositis (DM) are inflammatory muscle diseases of autoimmune origin. A chronic mononuclear cell infiltrate is always present around PM and DM muscle damage. In PM, the predominant cells are activated cytotoxic cells, natural killer, and CD8+ T lymphocytes. Cytotoxic cells can kill the target cells via 2 mechanisms. Both pathways induce target cell death by releasing the molecules (granule exocytosis) perforin (PF), which attacks the target cell membrane and causes cell death by necrosis, and TIA-1 protein and granzyme-B (GZB), possibly responsible for apoptosis. We studied the mechanisms of lysis in muscle biopsies of myositis. METHODS: We used a panel of monoclonal antibodies to determine the phenotypes of reactive lymphocyte subsets, in situ hybridization to study the expression of PF and GZB genes, and immunohistochemistry to evaluate TIA-1 protein production in muscle biopsies from 14 patients with myositis (11 PM/3 DM). Results were compared to those obtained from muscle biopsies of 12 control patients with muscle weakness, including patients with muscle dystrophy and vasculitis, but without myositis. RESULTS: Abundant CD8+ cells, especially in endomysial sites in PM, formed the predominant phenotype. The predominant mononuclear cells observed in DM were CD4+ T cells and CD22+ B lymphocytes, in perivascular sites. The GZB and PF genes and the TIA-1 protein were expressed simultaneously in muscle samples from patients with myositis. GZB, PF, and TIA-1 positive cells were predominantly located in endomysial sites of PM, in the nonnecrotic muscle fibers. In DM, these positive cells were rare. CONCLUSION: In myositis, especially PM, cytotoxic cells may cause muscle damage and muscle cell necrosis and/or apoptosis by releasing several proteins (PF, GZB, and TIA-1 proteins) responsible for the lysis of these stimulating target cells. Some drugs (prednisone and cyclosporine) inhibit the release of GZB and PF. Their efficacy may be due in part to this inhibitory effect.
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