Pathogenesis of inflammatory myopathy

The presence of inflammatory infiltrates with dermatomyositis, polymyositis and myositis with inclusions, first of all, demonstrates the importance of autoimmune mechanisms in the pathogenesis of these diseases. Studies of HLA antigens have shown that patients with dermatomyositis and polymyositis are more likely to have HLA-DR3 antigen in a non-equilibrium binding to HLA-B8. However, none of these diseases has been able to identify an antigen that is sufficiently specific to meet the criteria for an autoimmune disease.

With dermatomyositis, severe angiopathy of intramuscular vessels with severe infiltration of B-lymphocytes is detected, and in the wall of the vessels, perimisation is the deposition of immunoglobulins and the SZ component of complement. Components of the membrane- coagulation complex (MAK) of complement C5b-9 can be detected immunohistochemically by light and electron microscopy. There are also macrophages and cytotoxic T-lymphocytes, 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. With dermatomyositis (but not with polymyositis), local differences in cytokine activity are revealed when studying the expression of a signal transducer and transcriptional activator 1 (STAT 1). The concentration of this compound is particularly high in atrophic periphasicular muscle fibers. Since it is known that gamma interferon activates STAT 1 in vitro, it is possible that, along with ischemia, it 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 for an immune attack is endomysia, not periming. Non-necrosis muscle fibers are surrounded and infiltrated with CD8 ⁺ -cytotoxic lymphocytes, the oligoclonal character of which is revealed during typing of T-cell receptors. B-lymphocytes, CD ⁺ lymphocytes and macrophages are less common in affected areas of endomysia. These data indicate that damage to muscle fibers in polymyositis is mediated by cytotoxic CD8 ⁺ lymphocytes that recognize the antigenic peptides associated with the molecules of the main histocompatibility complex (MHC) I on the surface of the muscle fibers. One of the mechanisms of damage to muscle fibers by cytotoxic cells is the isolation of the mediator of perforin. In the study of muscle biopsies obtained in patients with dermatomyositis and polymyositis, using semi-quantitative PCR, immunohistochemical method and confocal laser microscopy, it was found that almost in 50% of CD8 ⁺ lymphocytes the orientation vector of perforin is directed towards the muscle fiber with which these lymphocytes contact. With dermatomyositis, perforin in the cytoplasm of inflammatory T cells was more randomly oriented. 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 damage to the muscle fibers in the polymyositis.

Another possible mechanism of damage to muscle fibers is associated with 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 MW and three patients with Duchenne muscular dystrophy (DMD). Fas was not detected in the muscles of the control group, but was found in muscle fibers and inflammatory cells in all four diseases. With polymyositis and MB, Fas was detected in a higher percentage of muscle fibers than with dermatomyositis and MDC. However, in polymyositis and myositis with inclusions in a higher percentage of fibers, B12 was also detected, which protects cells from apoptosis. Thus, the potential sensitivity to Fas- induced apoptosis can be counterbalanced by enhancing the protective effect of B12. It should be noted that there is currently no evidence that a cascade of apoptosis develops in muscle fibers or inflammatory cells in polymyositis, dermatomyositis or myositis with inclusions.

Necrosis of muscle fibers occurs with polymyositis, but inferior in importance to non-necrotic fiber damage. In the necrosis zones, macrophages may predominate, whereas CD8 + lymphocytes are much less common. Thus, in polymyositis, a humoral immune process can also occur in which damage to muscle fibers is mediated by antibodies and, possibly, by complement, rather than by cytotoxic T lymphocytes.

The antigen triggering an immune response in polymyositis is currently unknown. It was assumed that these or other viruses can provoke a provocative role, but all attempts to isolate specific viral antigens from muscles in polymyositis have failed. Nevertheless, there are suggestions that viruses can still participate in initiating an autoimmune reaction against muscle antigens in predisposed individuals. Inclusions in myositis with inclusions were first identified as "myxovirus-like structures," but subsequent confirmation of the viral origin of inclusions or filaments with Mstrong was not found. Nevertheless, with myositis with inclusions, as with polymyositis, viruses can be responsible for initiating a "host" reaction leading to muscle damage.

The autoimmune etiology of myositis with inclusions is considered to be the dominant hypothesis, given the inflammatory nature of myopathy and clinical similarity with polymyositis. However, the relative resistance to immunosuppressive therapy and the unexpected presence of beta amyloid, coupled crimped filaments and hyperphosphorylated tau protein in muscle fibers suggest that the pathogenesis of myositis with inclusions may be similar to the pathogenesis of Alzheimer's disease and that altered amyloid metabolism may be a key pathogenesis factor. Nevertheless, despite the fact that myositis with inclusions is the most common myopathy of the elderly, a combination of Alzheimer's and myositis with inclusions is rare. Moreover, with myositis with inclusions, non-necrotizing fibers infiltrated with cytotoxic T cells are several times more common than fibers with congophilic amyloid inclusions. In addition, changes in muscles with myositis with inclusions are not absolutely specific - membranous vesicles and filamentous inclusions are described in oculopharyngeal dystrophy. Thus, the autoimmune reaction still appears to be a more likely initiating factor leading to muscle damage than specific amyloid metabolic disturbances that cause neuronal damage in Alzheimer's disease.

Confirms the autoimmune etiology and the message according to which seven patients with MW had non-necrotizing fibers that expressed MHC-1 and were infiltrated with CD8 + lymphocytes. Allele DR3 was identified in all seven patients. In another study, there was a more limited use of Va- and Vb-families of T-cell receptors in muscles, as compared to peripheral blood lymphocytes, indicating selective homing and local proliferation of T lymphocytes in areas of inflammation in myositis with inclusions. There was also an increased detection of paraproteinemia (22.8%) in patients with myositis with inclusions. Nevertheless, in the muscle fibers of myositis with inclusions, many components of amyloid plaques characteristic of Alzheimer's disease are present, which certainly requires explanation. Direct transfer of the beta-amyloid precursor protein gene to the culture of normal human muscle fibers can lead to the appearance of congophilia, beta-amyloid-positive filaments and nuclear tubulo- filamentous inclusions. This indicates that increased expression of amyloid can trigger a pathological cascade. Moreover, it has been shown that most of the proteins that accumulate with MB (including beta amyloid and tau protein) are present in the neuromuscular synapse in humans.

Hypotheses linking the development of myositis with inclusions with an autoimmune process and a violation of amyloid metabolism do not exclude each other. It is possible that an autoimmune reaction initiates a pathological process, which is subsequently amplified by the overexpression of amyloid. Resistance of most patients with myositis with inclusions 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 including amyloid metabolism disturbance, and later it proceeds independently of immunological processes. For example, 75% of vacuolated muscle fibers in patients with myositis with inclusions contain inclusions that are stained for neuronal and inducible synthetase of nitric oxide and nitrotirozine. This indicates the possibility of increased production of free radicals, which may play a role in pathogenesis, but is resistant to immunosuppressive therapy. Oxidative stress can contribute to the formation of multiple deletions in the mitochondrial DNA found in myositis with inclusions. Even assuming that the pathological process is triggered by the response to the antigen, the unknown nature of the antigen that activates cytotoxic T cells and the lack of clarity on the issue of amyloid deposits suggest that neither the autoimmune process nor the amyloid overexpression hypothesis alone can satisfactorily explain the pathogenesis of myositis with inclusions. Thus, these hypotheses can not serve as the basis for a rational choice of therapy for this disease.

[1], [2], [3], [4], [5]