Inclusion body myositis: Laser microdissection reveals differential Up-regulation of IFN-γ signaling cascade in attacked versus nonattacked myofibers

Sporadic inclusion body myositis (IBM) is a muscle disease with two separate pathogenic components, degeneration and inflammation. Typically, nonnecrotic myofibers are focally surrounded and invaded by CD8 ⁺ T cells and macrophages. Both attacked and nonattacked myofibers express high levels of human leukocyte antigen class I (HLA-I) molecules, a prerequisite for antigen presentation to CD8 ⁺ T cells. However, only a subgroup of HLA-I ⁺ myofibers is attacked by immune cells. By using IHC, we classified myofibers from five patients with sporadic IBM as attacked (A _IBM) or nonattacked (N _IBM) and isolated the intracellular contents of myofibers separately by laser microdissection. For comparison, we isolated myofibers from control persons (H _CTRL). The samples were analyzed by microarray hybridization and quantitative PCR. HLA-I up-regulation was observed in A _IBM and N _IBM, whereas H _CTRL were negative for HLA-I. In contrast, the inducible chain of the interferon (IFN) γ receptor (IFNGR2) and several IFN-γinduced genes were up-regulated in A _IBM compared with N _IBM and H _CTRL fibers. Confocal microscopy confirmed segmental IFNGR2 up-regulation on the membranes of A _IBM, which positively correlated with the number of adjacent CD8 ⁺ T cells. Thus, the differential up-regulation of the IFN-γ signaling cascade observed in the attacked fibers is related to local inflammation, whereas the ubiquitous HLA-I expression on IBM muscle fibers does not require IFNGR expression.