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Inclusion Body Myositis Laser Microdissection Reveals Differential Up-Regulation of IFN-gamma Signaling Cascade in Attacked versus Nonattacked Myofibers

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons38907

Ivanidze,  Jana
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38897

Hohlfeld,  Reinhard
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38805

Dornmair,  Klaus
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

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Citation

Ivanidze, J., Hoffmann, R., Lochmueller, H., Engel, A. G., Hohlfeld, R., & Dornmair, K. (2011). Inclusion Body Myositis Laser Microdissection Reveals Differential Up-Regulation of IFN-gamma Signaling Cascade in Attacked versus Nonattacked Myofibers. AMERICAN JOURNAL OF PATHOLOGY, 179(3), 1347-1359. doi:10.1016/j.ajpath.2011.05.055.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-3C0C-F
Abstract
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. HIA-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) gamma receptor (IFNGR2) and several IFN-gamma-induced 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-gamma 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. (Am J Pathol 2011, 179:1347-1359; DOI:10.1016/j.ajpath.2011.05.055)