Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Abstract

Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8 ϩ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3 ϩ CD8 ϩ and CD3 ϩ CD4 ϩ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8 ϩ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest ( a ) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and ( b ) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin-and secretion-dependent mechanism of muscle fiber injury. ( J. Clin. Invest. 1996. 97:2905-2910.)

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Distinct from DM but consistent with lymphocytic infiltrates observed in PM, muscle‐invading CD8 + T cells stain positive for pore‐forming and cytolytic molecules such as perforin, granzyme A, and granulysin 46, 47, 48. It has been demonstrated that perforin‐polarization within endomysial CD8 + T cells occurs toward target myofibers indicative of immunosynapse formation and arguing strongly for a possible recognition of specific antigens presented via MHC class I expressing myofibers 49. In line with this, muscle fibers in IBM patients express co‐stimulatory molecules such as ICOS‐L, CD276, and BB1 on their surface 48, 50, 51…”

“…Short‐telomer‐bearing CD8 + CD28 − T cells are thought to comprise a highly differentiated oligoclonal subset arising from chronic antigen exposure as hypothesized for IBM19, 49, 73, 74, 75, 76, 77 and several autoimmune conditions are accompanied by increased frequencies of CD8 + CD28 − T cells 78, 79, 80. Furthermore, muscle‐infiltrating CD8 + T cells in patients suffering from PM and DM have been reported to be mainly CD28 − 81.…”

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective

“…In PM and IBM there is an endomysial inflammatory infiltrate with a predominance of CD8+ T cells surrounding and invading MHC-I expressing myofibers [16]. These cells putatively induce cytotoxic myonecrosis through an interaction between antigen-presenting MHC-I molecules and co-stimulatory molecules on CD8+ cells [6,17,18]. The infiltrating cells in PM also include CD68+ macrophages and myeloid dendritic cells, which are thought to participate in the cytotoxic process [2,19], as well as apoptosis-resistant CD8+CD28−/−, CD4+ CD28−/−, cells which have been suggested may contribute to treatment resistance [20].…”

Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR, and CDR3-spectratype analysis

“…In PM, CD8ϩ T lymphocytes surround, invade, and apparently destroy HLA class I-expressing muscle fibers (8)(9)(10)(11)(12). Typically, the inflammatory infiltrate contains putative effector CD8ϩ T cells, which make tight membrane contact with the muscle fiber, orient their cytotoxic granules toward the contact zone (13), and sometimes deeply invade into the HLA class I-positive target fiber (14). Bystander cells, which are not in direct contact with muscle fibers, are located in interstitial spaces.…”