What are the possible links between degenerative and inflammatory changes in the pathophysiology of sporadic inclusion body myositis (s-IBM)?

Updated: Jun 08, 2018
  • Author: Michael P Collins, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Theoretically, the abnormal protein accumulations in s-IBM could be linked to the T-cell–mediated immune response by way of self-antigen presentation in MHC I/II-expressing myofibers. For example, immunoproteosome subunits are upregulated in s-IBM myofibers at sites of pathologic protein accumulation, sometimes colocalized with MHC I. [57] The immunoproteosome is specialized to produce antigenic peptides that can be presented by MHC class I molecules to CD8+ T cells. [58] Similarly, autophagosomes process intracellular antigens for MHC II presentation and CD4+ T cell recognition. [59] Thus, Aβ might be presented to CD4+ and CD8+ cells by degenerating myofibers in s-IBM, with an ensuing autoreactive T-cell response.

In addition, ER stress and the UPR can initiate inflammation via multiple intracellular signaling pathways. [60] However, the myofibers invaded by T cells in s-IBM are almost never vacuolated, and the vacuolated fibers are almost never surrounded by mononuclear inflammatory cells, arguing against a cytotoxic T-cell response to Aβ or any other abnormally accumulated protein in s-IBM. [5]

Alternatively, the inflammatory milieu within s-IBM muscle fibers might lead to the accumulation of misfolded MHC-related glycoproteins and trigger the overproduction of APP, Aβ, p-tau, and other such proteins, creating ER stress. [61, 4] In s-IBM, proinflammatory cytokines and chemokines correlate with the intramuscular accumulation of APP. [13] Exposure to IL-1β in particular might produce upregulation of APP with subsequent AB-associated degeneration. In a transgenic mouse model of IBM, lipopolysaccharide-induced inflammation increased steady state levels of APP and enhanced tau-phosphorylation in skeletal muscle, possibly secondary to proinflammatory cytokine (IL-1β, IL-6, and TNF-α)-mediated upregulation of the glycogen synthase kinase-3B (GSK-3B) signaling pathway. [45]

Of course, neither APP/Aβ-induced toxicity nor CD8+ T-cell–mediated cytotoxicity may be the primary event in s-IBM. In this regard, muscle biopsy specimens in patients with s-IBM harbor numerous alpha-B-crystallin-immunoreactive myofibers in the absence of any significant structural abnormality. [62] These "X fibers" are several-fold more frequent than necrotic, regenerating, vacuolated, and non-necrotic/invaded fibers and are many times more frequent than fibers with Congo red-, phosphorylated tau-, or ubiquitin-positive inclusions.

Alpha-B-crystallin is a small HSP, but the expression of other HSPs and markers of oxidative stress are not increased in X fibers, arguing against the presence of a nonspecific stress response or oxidative stress in these fibers. The implication of this finding is that increased expression of alpha-B-crystallin is an early event in the pathogenesis of s-IBM, triggered by an unidentified stressor acting upstream to the development of vacuolated, necrotic, invaded, and congophilic fibers. Engel has speculated that this stressor might be a viral infection or mutated gene. [62, 30] Muth et al demonstrated an association between alpha-B-crystallin and APP/Aβ in X-fibers, supporting an early inflammatory response, with subsequent degenerative Aβ accumulation and vacuolar changes. [63]


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