Immunopathology for Inflammatory Myopathies

Pathogenesis of Dermatomyositis. A striking feature observed in muscle biopsies taken from patients with DM is the presence of a diverse collection of cell types: CD4⁺ T lymphocytes, B lymphocytes, plasma cells, macrophages, and dendritic cells located predominantly in a perivascular and perimysial distribution. The role of the macrophage and the dendritic cell is to present antigen—attached to a major histocompatibility (MHC) class II molecule—to a helper CD4⁺ T cell that, in turn, produces cytokines (such as the interleukins whose targets are principally leukocytes, type 1 interferons, and chemokines); these molecules amplify the immune response within the muscle microenvironment and have direct deleterious effects on muscle fiber function (see later). The interleukins stimulate B cells to multiply and mature into antibody-producing plasma cells. Additional hallmarks of the DM muscle biopsy are atrophy of muscle fibers occurring rather specifically on the edges of muscle fascicles, leading to a distinctive pathologic feature known as perifascicular atrophy, and there is the presence of membrane attack complex (MAC) with antibodies deposited in capillaries and small blood vessels throughout the endomysium.

One hypothesis proposes that the pathophysiology central to DM is a microangiopathy resulting from antibody and MAC-mediated injury of capillaries (see Plate 12-17). MAC is the end product of the complement cascade—consisting of complement components C5b, C6, C7, C8, and polymeric C9—that forms damaging transmembrane channels in the cell membranes of target cells, such as endothelial cells, and causes cell lysis and, ultimately, cell death. (The specific molecular agents that might trigger the complement cascade in DM have not been identified with certainty; however, antigen-antibody complexes are possible candidates.) The resulting necrosis and thrombosis of capillaries is postulated to result in muscle ischemia subsequently contributing to myofiber damage (see Plate 12-17).

A second pathogenic mechanism underlying muscle injury in DM proposes a central role for interferon (see Plate 12-17). Many CD4⁺ cells are plasmacytoid dendritic cells secreting type 1 interferon (type 1 INF), possibly in response to autoantibodies bound to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) located in DM muscle. There is strong evidence that type 1 INF, in turn, induces gene transcription of a host of proteins, some of which have the potential to injure muscle capillaries and muscle fibers and contribute to the pathologic picture of DM, although the precise mechanism of cell injury is not known.

Pathogenesis of Polymyositis. Examination of muscles biopsies from PM patients reveals an appearance rather different from that seen in DM. The population of inflammatory cells is variegated, but there is a predominance of CD8⁺ T cells, with a relative smaller percentage of CD4⁺ T lymphocytes; these cells, together with macrophages and dendritic cells, are located within the endomysium. A pathologic signature of PM is the presence of cytotoxic CD8⁺ T cells surrounding and invading non-necrotic muscle fibers. The CD8⁺ cytotoxic T lymphocytes recognize their targets by binding to antigen associated with major histocompatibility complex (MHC) class I on muscle fibers and may mediate muscle fiber damage by releasing toxic perforin granules that induce muscle fiber necrosis (see Plate 12-17). The precise character of the antigen or antigens that triggers the immune response and is presented to the T cell by the MHC I protein molecule in PM is not known; it may be an endogenous self-antigen or perhaps an antigen induced by a viral infection. Unlike DM, perifascicular atrophy is not seen, and there is no capillary deposition of complement and immunoglobulin.

Pathogenesis of Inclusion Body Myositis. The histopathology of IBM is notable for architectural changes within many fibers: eosinophilic inclusions in muscle fibers as well as rimmed vacuoles are seen, Congo red stains demonstrate amyloid deposits, and electron microscopy discloses tubulofilamentous inclusions in the cytoplasm and nucleus. These findings are perhaps more reminiscent of a neurodegenerative process than one that is immune mediated, and yet, a prominent feature is the presence of the invasion of muscle fibers by CD8+ cytotoxic cells with MHC class I antigen on the invaded fibers, similar to the cellular reaction in PM. Current thinking about the mechanism of myofiber damage in IBM—influenced largely by the lack of meaningful clinical response to vigorous immunosuppression, in contrast to the robust response seen in DM and PM—is that the disorder is more like neurodegeneration than immune-mediated injury.

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