MECHANISMS OF LYSIS BY ACTIVATED CYTOTOXIC-CELLS EXPRESSING PERFORIN AND GRANZYME-B GENES AND THE PROTEIN TIA-1 IN MUSCLE BIOPSIES OF MYOSITIS

Objective. Polymyositis (PM) and dermatomyositis (DM) are inflammatory muscle diseases of autoimmune origin. A chronic mononuclear cell infi ltrate is always present around PM and DM muscle damage. In PM, the pr edominant cells are activated cytotoxic cells, natural killer, and CD8 + T lymphocytes. Cytotoxic cells can kill the target cells via 2 mecha nisms. Both pathways induce target cell death by releasing the molecul es (granule exocytosis) perforin (PF), which attacks the target cell m embrane and causes cell death by necrosis, and TIA-1 protein and granz yme-B (GZB), possibly responsible for apoptosis. We studied the mechan isms of lysis in muscle biopsies of myositis. Methods. We used a panel of monoclonal antibodies to determine the phenotypes of reactive lymp hocyte subsets, in situ hybridization to study the expression of PF an d GZB genes, and immunohistochemistry to evaluate TIA-1 protein produc tion in muscle biopsies from 14 patients with myositis (11 PM/3 DM). R esults were compared to those obtained from muscle biopsies of 12 cont rol patients with muscle weakness, including patients with muscle dyst rophy and vasculitis, but without myositis. Results. Abundant CD8+ cel ls, especially in endomysial sites in PM, formed the predominant pheno type. The predominant mononuclear cells observed in DM were CD4+ T cel ls and CD22+ B lymphocytes, in perivascular sites. The GZB and PF gene s and the TIA-1 protein were expressed simultaneously in muscle sample s from patients with myositis. CZB, PF, and TIA-1 positive cells were predominantly located in endomysial sites of PM, in the nonnecrotic mu scle fibers. In DM, these positive cells were rare. Conclusion. In myo sitis, especially PM, cytotoxic cells may cause muscle damage and musc le cell necrosis and/or apoptosis by releasing several proteins (PF, G ZB, and TIA-1 proteins) responsible for the lysis of these stimulating target cells. Some drugs (prednisone and cyclosporine) inhibit the re lease of GZB and PF. Their efficacy may be due in part to this inhibit ory effect.