Proinflammatory cell stress in sporadic inclusion body myositis muscle: overexpression of alpha B-crystallin is associated with amyloid precursor protein and accumulation of beta-amyloid

Abstract

Background: In the pathology of sporadic inclusion body myositis (sIBM), the relevance of cell stress molecules such as the heat shock protein alpha B-crystallin, particularly in healthy appearing muscle fibres, has remained elusive. Methods: 10 muscle biopsies from sIBM patients were serially stained for haematoxylin-eosin, trichrome and multi-immunohistochemistry for neural cell adhesion molecule ( NCAM), alpha B-crystallin, amyloid precursor protein (APP), desmin, major histocompatibility complex I, beta-amyloid and ubiquitin. Corresponding areas of all biopsies were quantitatively analysed for all markers. Primary myotube cultures were exposed to the proinflammatory cytokines interleukin (IL)-1 beta and interferon (IFN)-gamma. Results: In human myotubes exposed to IL-1 beta+IFN-gamma, overexpression of APP was accompanied by upregulation of alpha B-crystallin. In sIBM muscle biopsies, over 20% of all fibres displayed accumulation of beta-amyloid or vacuoles/inclusions. A clearly larger fraction of the fibres were positive for alpha B-crystallin or APP. In contrast with the accumulation of beta-amyloid in atrophic fibres, a major part of fibres positive for APP or alpha B-crystallin showed no morphological abnormalities. Expression of APP and alpha B-crystallin significantly correlated with each other and most double positive fibres displayed accumulation of beta-amyloid, vacuoles or an atrophic morphology. In almost all of these fibres, other markers of degeneration/regeneration such as NCAM and desmin were evident as additional indicators of a cell stress response. Some fibres double positive for APP and alpha B-crystallin displayed infiltration by inflammatory cells. Conclusion: Our results suggest that alpha B-crystallin is associated with overexpression of APP in sIBM muscle and that upregulation of alpha B-crystallin precedes accumulation of beta-amyloid. The data help to better understand early pathological changes and underscore the fact that a network of cell stress, inflammation and degeneration is relevant to sIBM.