Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken

Abstract

Sporadic inclusion body myositis (sIBM) is the most frequently acquired myopathy in patients over 50 years of age. It is imperative that neurologists and rheumatologists recognize this disorder which may, through clinical and pathological similarities, mimic other myopathies, especially polymyositis. Whereas polymyositis responds to immunosuppressant drug therapy, sIBM responds poorly, if at all. Controversy reigns as to whether sIBM is primarily an inflammatory or a degenerative myopathy, the distinction being vitally important in terms of directing research for effective specific therapies. We review here the pros and the cons for the respective hypotheses. A possible scenario, which our experience leads us to favour, is that sIBM may start with inflammation within muscle. The rush of leukocytes attracted by chemokines and cytokines may induce fibre injury and HLA-I overexpression. If the protein degradation systems are overloaded (possibly due to genetic predisposition, particular HLA-I subtypes or ageing), amyloid and other protein deposits may appear within muscle fibres, reinforcing the myopathic process in a vicious circle.

Fig. 1

Clinical features of sIBM. a Finger flexors weakness (arrow maximum obtained by this patient: 5.6 kg, normal >21 kg for a woman at 70 years old), and b atrophy (arrows). c Quadriceps atrophy (arrows) for a man at 75 years old

Fig. 2

Pathological features of sIBM: a partial invasion of a myofiber by inflammatory cells (Gomori trichrome; original magnification ×600). b Intracytoplasmic rimmed vacuoles (H&E; original magnification ×400). c Evidence of intracytoplasmic and intravacuolar amyloid by staining with pFTAA (original magnification ×400). d Intracytoplasmic paired helical filaments illustrated by ultrastructural examination (scale bar represents 0.5 μm). e, f Immunohistochemical evidence of P62⁺ aggregates in muscle fibres (e original magnification ×400, f original magnification ×200)

Fig. 3

In sIBM, misfolded proteins start to accumulate into aggregates that are positive for P62 and NBR1. The presence of P62-positive aggregates is a consequence of impaired protein clearance of proteasome and autophagy/lysosome (Ly) systems that further impacts on their activities. Overload of the autophagy system with subsequent exhaustion, aspecific absorption and sequestration of the proteasome on the surface of inclusions describe how aggregates negatively affect these systems. Autophagy is characterized by membranes that are committed to growth, thus becoming double membrane vesicles, named autophagosome, that surround a ‘portion’ of cytoplasm, organelles, glycogen and protein aggregates. Autophagy is triggered by the activation of a regulatory complex (containing Vps34, Beclin 1, Vps15, Ambra1, Atg14) that induces LC3 recruitment to the nascent autophagosome (isolation membrane). Selective removal of organelles including mitochondria (mitophagy, a specific form of autophagy) requires several signals. For example in mitophagy, Bnip3 factors are recruited on damaged mitochondria and by binding LC3 allow the recruitment of the vesicle on the surface of the altered mitochondria. Proteins that are committed for lysosomal degradation are labelled by polyubiquitin chains and delivered to the autophagosome by the p62/NBR1 scaffold proteins that bind LC3. Finally, upon autophagosome fusion with lysosome the cargo is destroyed and constituents are recycled by the cell to rebuild organelles/proteins or for energy purposes. Whether inflammation triggers protein misfolding aggregation or blocks the autophagy and proteasome system is still an open issue and will certainly be subject of future studies. Dotted lines represent unknown mechanisms (Ub = ubiquitin)

Fig. 4

Composition of the inflammatory infiltrate in sIBM muscle: a CD8⁺ cells. b CD68⁺ macrophages. c CD4⁺ cells. d CD20⁺ B cells. e Clonally Vβ1 expanded cells. f CD138⁺ plasma cells

Fig. 5

A possible scenario for the pathogenesis of sIBM is that it may start with inflammation within muscle (the different actors are represented in red). The rush of leukocytes attracted by chemokines and cytokines may induce fibre injury and HLA-I overexpression. If the protein degradation systems are overloaded (due to genetic predisposition, particular HLA-I subtypes or ageing), amyloid and other protein deposits (represented in green) may appear within muscle fibres, reinforcing the myopathy in a vicious circle. The opposite scenario where amyloid deposits come first leading to a secondary inflammatory reaction is less probable since (apart some rare exceptions) neither hereditary inclusion body myopathy nor animal models of forced amyloid deposits (with proteasomal and/or autophagosomal pathway deficiencies) are accompanied by inflammation