The Tumor Necrosis Factor Superfamily of Cytokines in the Inflammatory Myopathies: Potential Targets for Therapy
Potential roles for tumor necrosis factor cytokines in the muscle damage associated with dermatomyositis. Based on current knowledge, a model is developed describing the possible involvement of tumor necrosis factor (TNF) cytokines in the sustained inflammation in perifascicular regions of muscle. Activation of the complement system leads to membrane attack complex (MAC) deposition on blood vessels and subsequent necrosis. Endothelial monocyte chemoattractant protein-1 (CCL2) recruits inflammatory cells that accumulate and organize in perimysial areas. Lymphocytes organize into functional compartments and produce lymphotoxins (LTs), TNFα and CD40L, which further recruit responsive immune cells from the circulation, leading to the buildup of perimysial inflammation. Dendritic cells (DCs) produce IFNα, which stimulates muscle fibers to secrete B-cell activating factor (BAFF). The latter activates B-cells that, in response, begin to produce autoantibodies. TNFα, mostly produced by Th-cells, provokes muscle fiber atrophy and stimulates major histocompatibility complex I (MHC-I) and expression of adhesion molecules.
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