Myopathies

Editor's Notes

1. Pathogenesis An autoimmune etiology of the inflammatory myopathies is indirectly supported by an association with other autoimmune or connective tissue diseases; the presence of various autoantibodies; an association with specific major histocompatibility complex (MHC) genes; demonstration of T cell-mediated myocytotoxicity or complement-mediated microangiopathy; and a response to immunotherapy. Autoantibodies and Immunogenetics Various autoantibodies against nuclear antigens (antinu-clear antibodies) and cytoplasmic antigens are found in up to 20% of patients with inflammatory myopathies. The antibodies to cytoplasmic antigens are directed against ribonucleoproteins involved in protein synthesis (anti-synthetases) or translational transport (anti-signal- recognition particles).The antibody directed against the histidyl-transfer RNA synthetase, called anti-Jo-1, accounts for 75% of all the anti-synthetases and is clinically useful because up to 80% of patients with anti-Jo-1 antibodies have interstitial lung disease. Some patients with the anti-Jo-1 antibody also have Raynaud’s phenomenon, nonerosive arthritis, and the MHC molecules DR3 and DRw52. DR3 haplotypes (molecular designation DRB1*0301,DQB1*0201) occur in up to 75% of patients with PM and IBM, whereas in juvenile DM there is an increased frequency of DQA1*0501 (Chap. 2). Immunopathologic Mechanisms In DM, humoral immune mechanisms are implicated, resulting in a microangiopathy and muscle ischemia (Fig. 16-1). Endomysial inflammatory infiltrates are composed of B cells located in proximity to CD4 T cells, dendritic cells, and macrophages; there is a relative absence of lymphocytic invasion of nonnecrotic muscle fibers. FIGURE 16-1 Immunopathogenesis of dermatomyositis. Activation of complement, possibly by autoantibodies (Y), against endothelial cells and formation of C3 via the classic or alternative pathway. Activated C3 leads to formation of C3b, C3bNEO, and membrane attack complexes (MAC), which are deposited in and around the endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction of capillaries, ischemia, or microinfarcts most prominent in the periphery of the fascicles, and perifascicular atrophy. B cells, CD4 T cells, and macrophages traffic from the circulation to the muscle. Endothelial expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) is induced by cytokines released by the mononuclear cells. Integrins, specifically very late activation antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1, bind VCAM and ICAM and promote T-cell and macrophage infiltration of muscle through the endothelial cell wall. Activation of the complement C5b-9 membranolytic attack complex is thought to be a critical early event that triggers release of proinflammatory cytokines and chemokines, induces expression of vascular cell adhesion molecule (VCAM) 1 and intracellular adhesion molecule (ICAM) 1 on endothelial cells, and facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces. Necrosis of the endothelial cells, reduced numbers of endomysial capillaries, ischemia, and muscle-fiber destruction resembling microinfarcts occur. The remaining capillaries often have dilated lumens in response to the ischemic process. Larger intramuscular blood vessels may also be affected in the same pattern. Residual perifascicular atrophy reflects the endofascicular hypoperfusion that is prominent in the periphery of the muscle fascicles. By contrast, in PM and IBM a mechanism of T cell-mediated cytotoxicity is likely. CD8 T cells, along with macrophages, initially surround and eventually invade and destroy healthy, nonnecrotic muscle fibers that aberrantly express class I MHC molecules. MHC-I expression, absent from the sarcolemma of normal muscle fibers, is probably induced by cytokines secreted by activated T cells and macrophages. The CD8/MHC-I complex is characteristic of PM and IBM; its detection can aid in confirming the histologic diagnosis of PM, as discussed below. The cytotoxic CD8 T cells contain perforin and granzyme granules directed towards the surface of the muscle fibers and capable of inducing myonecrosis. Analysis of T-cell receptor molecules expressed by the infiltrating CD8 cells have revealed clonal expansion and conserved sequences in the antigen-binding region, both suggesting an antigen-driven T-cell response. Whether the putative antigens are endogenous (e.g., muscle) or exogenous (e.g., viral) sequences is unknown. Viruses have not been identified within the muscle fibers. Co-stimulatory molecules and their counterreceptors, which are fundamental for T-cell activation and antigen recognition, are strongly upregu-lated in PM and IBM. Key molecules involved in T cell-mediated cytotoxicity are depicted in Fig. 16-2. FIGURE 16-2 Cell-mediated mechanisms of muscle damage in polymyositis (PM) and inclusion body myositis (IBM). Antigen-specific CD8 cells are expanded in he periphery, cross the endothelial barrier, and bind directly to muscle fibers via T-cell receptor (TCR) molecules that recognize aberrantly expressed MHC-I. Engagement of co-stimulatory molecules (BB1 and ICOSL) with their ligands (CD28, CTLA-4, and ICOS) along with ICAM-1/LFA-1, stabilize the CD8-muscle fiber interaction. Metalloproteinases (MMP) facilitate the migration of T cells and their attachment to the muscle surface. Muscle fiber necrosis occurs via perforin granules released by the autoaggressive T cells. A direct myocytotoxic effect exerted by the cytokines interferon (IFN) γ, interleukin (IL) 1, or tumor necrosis factor (TNF) α may also play a role. Death of the muscle fiber is mediated by necrosis. MHC class I molecules consist of a heavy chain and a light chain [ß2 microglobulin (ß2m)] complexed with an antigenic peptide that is transported into the endoplasmic reticulum by TAP proteins.