Understanding the immunopathogenesis of inclusion-body myositis: present and future prospects

Sporadic Inclusion Body Myositis (s-IBM) is the most common acquired inflammatory myopathy. It has a stereotypic clinical presentation and a predictably progressive course that leads to severe muscle weakness and permanent disability. The combination of primary endomysial inflammation with autoimmune features identical to those seen in Polymyositis, and degenerative features with vacuolization of muscle fibers and deposits of tiny speckles of amyloid, are characteristic for the disease. In this review, the immunopathology of IBM is detailed. The inflammation which is prominent even late in the disease, is characterized by activated, CD8+ cytotoxic T cells that secrete perforin and invade MHC-I-expressing muscle fibers. The autoinvasive T cells are probably antigen driven because of specific rearrangement of their T Cell Receptor profile, restriction of the CDR3 region, upregulation of co-stimulatory molecules and their ligands on the muscle fibers, and activation of various cytokines, chemokines and adhesion molecules. The disease can be seen in association with HIV and HTLV-I infection, but viruses have not been amplified from the muscle fibers and the antigen or the factors that trigger inflammation are still unknown. The disease is mysteriously resistant to conventional immunotherapies in spite of the immunopathologic similarities with PM. The cause of the vacuolar formation in IBM is also unknown and the role, that the tiny amyloid deposits play in the disease remain unclear. The treatment approaches and the prospects for future immunotherapeutic interventions are discussed.