Molecules, receptors, and ligands involved in exiting of the T cells through the endothelial cell wall and recognizing muscle antigens on the surface of muscle fibers

Sequentially, (1) LFA-1-intracellular adhesion molecule-1 binding anchors the cytoskeletal molecules in the nascent immunological synapse. This allows (2) the interaction of T cell receptor-MHC with the sampling of MHC-peptides complex and (3) the engagement of BB1, CD40, and ICOS costimulatory molecules with their ligands CD28, CTLA, CD40L, and ICOSL, the prerequisites for antigen recognition. (4) MMPs facilitate the attachment of T cells to the muscle surface. (5) Muscle fiber necrosis occurs through the perforin granules released by the autoinvasive T cells. (6) A direct myocytotoxic effect exerted by IFN-gamma, IL-1, or tumor necrosis factor-alpha released by the macrophages may also take place. (7) The muscle fiber cell-death is mediated through necrosis and not apoptosis, presumably because of the counterbalancing effect or protection by the antiapoptotic molecules Bcl-2, hILP, and FLIP that are upregulated in polymyositis and inclusion body myositis muscles. Fas is also expressed, but it does not mediate apoptosis in the muscle. The upregulated NCAM on degenerating muscle fibers may enhance regeneration. [ICAM = intracellular adhesion molecule; LFA = lymphocyte function-associated antigen; NCAM = neural cell adhesion molecule; VCAM = vascular cell adhesion molecule] (Contributed by Dr. Marinos Dalakas.)