The Role of Cytotoxic Effector Molecules and Cytokines in Inflammatory Myopathies

The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). In DM, muscle fiber injury is secondary to an antibody- or immune-complex-mediated immune response against a vascular-endothelial component. In PM and IBM, initially non-necrotic muscle fibers are invaded and eventually destroyed by CD8+ T cells and macrophages. The autoaggressive T cells have the phenotype of activated (HLA-DR+) memory (CD45RO+) cells. T cell receptor (TCR) analyses revealed that the autoaggressive T cells are oligoclonal. In inflammatory lesions, muscle fibers express a number of cytoplasmic and surface molecules that are not detectable in normal muscle fibers. These molecules, which include HLA-class I antigens, heat-shock proteins, adhesion molecules and Fas, are probably induced by locally secreted cytokines. Although many of the muscle fibers invaded by CD8+ T cells express the Fas “death receptor”, signs of apoptosis are absent. However, the autoaggressive CD8+ T cells possess perforin-containing granules, which they orient towards the contact zone with the target muscle fiber. This is consistent with a perforin- and secretion-dependent mechanism of muscle fiber injury