FIGURE 2 Sequence of immunopathological changes in sporadic inclusion body myositis.
From the following article:
Sporadic inclusion body myositis—diagnosis, pathogenesis and therapeutic strategies
Marinos C Dalakas
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Figure 2. Sequence of immunopathological changes in sporadic inclusion body myositis.
It is hypothesized that the disease begins when viruses break tolerance, and CD8+ T cells, on receiving putative antigens by macrophages that serve as antigen-presenting cells, become activated. The released cytokines upregulate VCAM1 and ICAM1, thereby allowing the transgression of T cells through the endothelial cell wall to reach the muscle fiber. The released cytokines upregulate MHC class I, chemokine receptors, costimulatory molecules and ICAM1 on the muscle fibers, allowing the invading T cells to scan for antigens and initiate the formation of immunological synapses between MHC class I and the T-cell receptors. The engagement of the costimulatory molecules BB1, ICOS and CD40 on the muscle fibers with their ligands CD28, CTLA4, ICOSL and CD40L on the autoinvasive T cells completes the synapse and activates the T cells. Muscle fiber necrosis occurs via perforin granules released by the autoinvasive cytotoxic T cells. The muscle fibers are also active modulators because they secrete cytokines and chemokines, which further activate the invading CD8+ T cells thereby contributing to the persistence and chronicity of the immunopathologic process. Abbreviations: CTLA4, cytotoxic T-lymphocyte-associated protein 4; ICAM1, intercellular adhesion molecule 1; ICOS, inducible T-cell costimulator; ICOSL, inducible T-cell costimulator ligand; IL-1, interleukin-1; LFA-1, leukocyte function-associated antigen 1; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; TCR, T-cell receptor; TGF-
, transforming growth factor-; TNF, tumor necrosis factor; VCAM1, vascular cell adhesion molecule 1; VLA-4, very late activation antigen 4.
