Pathogenesis of inflammatory myopathy

The presence of inflammatory infiltrates in dermatomyositis, polymyositis, and inclusion body myositis primarily indicates the importance of autoimmune mechanisms in the pathogenesis of these diseases. Studies of HLA antigens have shown that patients with dermatomyositis and polymyositis more often have the HLA-DR3 antigen in linkage disequilibrium with HLA-B8. However, in none of these diseases has it been possible to identify an antigen that would be specific enough to meet the criteria for an autoimmune disease.

In dermatomyositis, severe angiopathy of the intramuscular vessels with marked B-lymphocyte infiltration is observed, and in the perimysial vessel wall, deposits of immunoglobulins and the complement component C3 are present. Components of the membrane attack complex (MAC) of complement C5b-9 can be detected immunohistochemically using light and electron microscopy. Macrophages and cytotoxic T lymphocytes are also present, but to a lesser extent. These data indicate that complement-dependent damage to intramuscular capillaries is mediated by immunoglobulins or immune complexes and probably leads to a decrease in capillary density with the development of ischemia, microinfarctions, and subsequent inflammatory muscle damage. In dermatomyositis (but not in polymyositis), local differences in cytokine activity are detected when studying the expression of signal transducer and activator of transcription 1 (STAT 1). The concentration of this compound is especially high in atrophic perifascicular muscle fibers. Since gamma interferon is known to activate STAT 1 in vitro, it is possible that it, along with ischemia, causes the development of pathological changes in perifascicular muscle fibers in dermatomyositis.

In polymyositis, unlike dermatomyositis, humoral immune mechanisms are less important than cellular ones, and the main target of immune attack is the endomysium, not the perimysium. Unnecrotic muscle fibers are surrounded and infiltrated by CD8 ⁺ cytotoxic lymphocytes, the oligoclonality of which is revealed by T-cell receptor typing. B lymphocytes, CD ⁺ lymphocytes, and macrophages are less common in the affected areas of the endomysium. These data indicate that muscle fiber damage in polymyositis is mediated by cytotoxic CD8 ⁺ lymphocytes, which recognize antigenic peptides associated with major histocompatibility complex (MHC) I molecules on the muscle fiber surface. One of the mechanisms of muscle fiber damage by cytotoxic cells is the release of the mediator perforin. In the study of muscle biopsies obtained from patients with dermatomyositis and polymyositis, using semiquantitative PCR, immunohistochemistry and confocal laser microscopy, it was found that in almost 50% of CD8 ⁺ lymphocytes, the perforin orientation vector is directed towards the muscle fiber with which these lymphocytes are in contact. In dermatomyositis, perforin in the cytoplasm of inflammatory T cells was oriented more chaotically. Thus, the interaction between the antigen on the surface of the muscle fiber and the T-cell receptor can initiate the secretion of perforin, which causes muscle fiber damage in polymyositis.

Another possible mechanism of muscle fiber damage involves activation of Fas, which initiates a cascade of programmed cell death (apoptosis). This process was studied in three patients with dermatomyositis, five patients with polymyositis, four patients with CF, and three patients with Duchenne muscular dystrophy (DMD). Fas was not detected in control muscle, but was detected in muscle fibers and inflammatory cells in all four diseases. In polymyositis and CF, Fas was detected in a higher percentage of muscle fibers than in dermatomyositis and DMD. However, B12, which protects cells from apoptosis, was also detected in a higher percentage of fibers in polymyositis and inclusion body myositis. Thus, potential sensitivity to Fas-induced apoptosis may be counterbalanced by the enhanced protective effect of B12. It should be noted that there is currently no evidence that an apoptotic cascade develops in muscle fibers or inflammatory cells in polymyositis, dermatomyositis, or inclusion body myositis.

Muscle fiber necrosis also occurs in polymyositis, but is less significant than non-necrotic fiber damage. Macrophages may predominate in necrotic areas, while CD8+ lymphocytes are much less common. Thus, a humoral immune process may also occur in polymyositis, with muscle fiber damage mediated by antibodies and possibly complement rather than cytotoxic T lymphocytes.

The antigen that triggers the immune response in polymyositis remains unknown at present. It has been suggested that viruses may play a provoking role, but all attempts to isolate specific viral antigens from muscle in polymyositis have failed. However, there are suggestions that viruses may still be involved in initiating an autoimmune reaction against muscle antigens in susceptible individuals. The inclusion bodies in inclusion body myositis were initially identified as "myxovirus-like structures," but no further evidence of a viral origin for the inclusions or filaments in Mstrong has been found. However, in inclusion body myositis, as in polymyositis, viruses may be responsible for initiating the host response that leads to muscle damage.

Autoimmune etiology of inclusion body myositis is considered the dominant hypothesis, given the inflammatory nature of the myopathy and clinical similarities to polymyositis. However, the relative resistance to immunosuppressive therapy and the unexpected presence of beta-amyloid, paired convoluted filaments, and hyperphosphorylated tau protein in muscle fibers suggest that the pathogenesis of inclusion body myositis may be similar to that of Alzheimer's disease and that altered amyloid metabolism may be a key factor in the pathogenesis. However, although inclusion body myositis is the most common myopathy in the elderly, the combination of Alzheimer's disease and inclusion body myositis is rare. Moreover, in inclusion body myositis, non-necrotic fibers infiltrated by cytotoxic T cells are several times more common than fibers with congophilic amyloid deposits. Furthermore, the muscle changes in inclusion body myositis are not completely specific - membranous vesicles and filiform inclusions have been described in oculopharyngeal dystrophy. Thus, an autoimmune reaction still seems to be a more likely initiating factor leading to muscle damage than specific disturbances in amyloid metabolism that are responsible for neuronal damage in Alzheimer's disease.

The autoimmune etiology is also supported by a report that non-necrotic fibers that expressed MHC-1 and were infiltrated with CD8+ lymphocytes were identified in seven patients with CF. The DR3 allele was identified in all seven patients. Another study noted a more limited use of the Va and Vb families of T-cell receptors in muscles compared with peripheral blood lymphocytes, indicating selective homing and local proliferation of T lymphocytes in areas of inflammation in inclusion body myositis. An increased incidence of paraproteinemia (22.8%) was also noted in patients with inclusion body myositis. However, many components of the amyloid plaques characteristic of Alzheimer's disease are present in muscle fibers in inclusion body myositis, which certainly requires an explanation. Direct transfer of the beta-amyloid precursor protein gene into normal human muscle fibre cultures can result in the appearance of congophilia, beta-amyloid-positive filaments and nuclear tubulofilamentous inclusions, suggesting that increased amyloid expression may trigger a pathological cascade. Furthermore, it has been shown that most of the proteins that accumulate in CF (including beta-amyloid and tau) are present at the human neuromuscular junction.

Hypotheses linking the development of inclusion body myositis with an autoimmune process and amyloid metabolism disorder are not mutually exclusive. It is possible that an autoimmune reaction initiates a pathological process, which is subsequently enhanced by amyloid hyperexpression. The resistance of most patients with inclusion body myositis to immunosuppressive therapy does not exclude the autoimmune hypothesis and can be explained by the fact that the autoimmune reaction only triggers a pathological cascade, including amyloid metabolism disorder, and then it proceeds independently of immunological processes. For example, 75% of vacuolated muscle fibers in patients with inclusion body myositis contain inclusions that are stained for neuronal and inducible nitric oxide synthetase and nitrotyrosine. This indicates the possibility of increased production of free radicals, which can play a certain role in pathogenesis, but is resistant to immunosuppressive therapy. Oxidative stress may contribute to the formation of multiple deletions in mitochondrial DNA found in inclusion body myositis. Even if the pathological process is assumed to be triggered by a response to an antigen, the unknown nature of the antigen activating cytotoxic T cells and the lack of clarity regarding the issue of amyloid deposition indicate that neither the autoimmune process nor the amyloid overexpression hypothesis alone can satisfactorily explain the pathogenesis of inclusion body myositis. Thus, these hypotheses cannot serve as a basis for rational choice of therapy for this disease.

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