I.I.3 Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: Which came first, the chicken or the egg?

Abstract

IBM is a disabled (but not lethal) muscle disease in persons over 50 years (median age of first symptoms: 60 years). No specific treatments are currently recommended and immunosuppressant drug therapies could even exacerbate progression of disability. The IBM muscle biopsy exhibits an unusual and specific pathologic phenotype, which combines multifaceted muscle fiber degeneration with an extracellular T-cell inflammation. IBM muscle-fiber degeneration is characterized by vacuolization and intra-muscle-fiber accumulation of ubiquitinated, congophilic multiple-protein aggregates evidenced by immunohistochemical studies with antibodies directed against e.g. ubiquitin, amyloid-beta protein, phosphorylated tau, Tar-DNA binding protein-43 (TDP-43) or p62 (the two latters beeing shown the most sensitive markers). These deposits are accompanied with protein degradation dysfunctions (at both proteasome and autophagy levels). It seems (at least in mouse models) that, when the protein degradation systems are overloaded, amyloids appear within muscle fibers, e.g. as misfolded and/or ubiquinated protein accumulations. The second hallmark of sIBM is the presence of inflammatory infiltrates. Effector cells can be clonally expanded and mostly consist of CD8+, CD28- T cells, which can exert cytotoxic activity and are found surrounding or invading muscle fibers. The latter may present so far unknown auto-antigens to these effector cells in a MHC class I restricted manner. MHC class I overexpression at the surface of muscle fibers has become a surrogate marker of inflammation. Most of these immune abnormalities are not only observable in muscle but also in the peripheral blood. Apart from the cellular immune response, auto-antibodies start to be also described in sIBM. In this context, the cytokines IFN-ϒ and IL-1 β have been demonstrated to be important inducers of accumulation of β -amyloid in muscle cells. The key question still remaining is the following: are the amyloid deposits cause or consequence of inflammation? Indeed, if amyloids are consequence of a primary immune reaction including secretion of cytokines that increased MHC class I expression to such an extent that protein degradation capabilities are overloaded, then a targeted immune intervention (such as by biotherapies) may be useful. To the contrary, if sIBM is a degenerative disease, where the accumulation of unfolded proteins causes a secondary immune reaction, an immunointervention may be of limited effect, if at all.