FIGURE 2 Immunopathogenesis of polymyositis and inclusion-body myositis.
From the following article:
Mechanisms of Disease: signaling pathways and immunobiology of inflammatory myopathies
Marinos C Dalakas
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Figure 2. Immunopathogenesis of polymyositis and inclusion-body myositis.
Binding of leukocyte function-associated antigen 1 expressed by CD8+ T cells and intercellular adhesion molecule 1 expressed on the muscle fibers, initiates the formation of an immunological synapse between the muscle fiber and the antigen-receiving T-cell receptor of the CD8+ T cells. Stimulation is supported and enhanced by the engagement of CD80, inducible T-cell co-stimulator (ICOS), CD40, and additional co-stimulatory molecules with their ligands CD28, cytotoxic T-lymphocyte-associated protein 4, ICOS ligand and CD40 ligand. Metalloproteinases facilitate the migration of T cells and their attachment to the muscle surface. Muscle-fiber necrosis occurs via the perforin granules released by the autoaggressive T cells. A direct myocytotoxic effect exerted by the released interferon-
, interleukin-1, or tumor necrosis factor, might also have a role. Death of the muscle fiber is mediated by a form of necrosis rather than apoptosis, presumably because of the counterbalancing effect or protection by the antiapoptotic molecules B-cell leukemia/lymphoma 2, human inhibitor of apoptosis-like protein and FLICE (Fas-associated death domain-like interleukin-1 converting enzyme)-inhibitory protein, which are upregulated in the muscles of patients with polymyositis and inclusion-body myositis. Fas is also expressed, but it does not mediate apoptosis in the muscle. The upregulated expression of neural cell adhesion molecule 1 on regenerating muscle fibers might enhance regeneration. The cell transmigration and activation of adhesion molecules on the endothelial cell wall occurs by a similar process to that seen in dermatomyositis. CD40L, CD40 ligand; CTLA4, cytotoxic T-lymphocyte-associated protein 4; IFN-, interferon-; IL-1, interleukin-1; ICAM-1, intercellular adhesion molecule 1; ICOS, inducible T-cell co-stimulator; ICOSL, inducible T-cell co-stimulator ligand; LFA-1, leukocyte function-associated antigen 1; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; T (in circle), T cell; TCR, T-cell receptor; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule 1; VLA-4, very late activation antigen 4.
