Immune mechanisms in polymyositis and dermatomyositis and potential targets for therapy

Abstract

PM and DM are characterized clinically by weakness and low endurance of skeletal muscle. Other organs are frequently involved, suggesting that idiopathic inflammatory myopathies (IIMs) are systemic inflammatory diseases. Involvement of immune mechanisms in IIMs is supported by the presence of T cells, macrophages and dendritic cells in muscle tissue, by the presence of autoantibodies and by HLA-DR being a strong genetic risk factor. T cells may have direct and indirect toxic effects on muscle fibres, causing muscle fibre necrosis and muscle weakness, but the target of the immune reaction is not known. A newly identified T cell subset, CD28(null) T cells, may have cytotoxic effects in the CD4(+) and CD8(+) T cell phenotype. These cells are apoptosis resistant and may contribute to treatment resistance. Several myositis-specific autoantibodies have been identified, but they are all directed against ubiquitously expressed autoantigens and the specificity of the T cell reactivity is not known. These autoantibodies are associated with distinct clinical phenotypes and some with distinct molecular pathways; e.g. sera from patients with anti-Jo-1 autoantibodies may activate the type I IFN system and these sera also contain high levels of B cell activating factor compared with other IIM subsets. The characterization of patients into subgroups based on autoantibody profiles seems to be a promising way to learn more about the specificities of the immune reactions. Careful phenotyping of infiltrating immune cells in muscle tissue before and after specific therapies and relating the molecular findings to clinical outcome measures may be another way to improve knowledge on specific immune mechanism in IIMs. Such information will be important for the development of new therapies.

Cell death, clearance and immunity in the skeletal muscle

“…7,8 In contrast, the accumulation of conventional CD4 + or CD8 + T lymphocytes reflects persistent inflammatory and immune-mediated injury, such as that taking place as a consequence of muscular dystrophy or inflammatory myopathies. 72,73 Figure 3 depicts some cellular players of muscle regeneration. Muscle stem cells fail to activate their regenerative potential in the absence of the inflammatory response.…”

“…110,111 Available evidence strongly supports the autoimmune underpinnings of IIM and commonly targeted autoantigens include proteins involved in DNA transcription or protein synthesis, such as the histidyl-tRNA synthase (HisRS). 73,[112][113][114] Regenerating fibers appear a preferential …”

The role of interleukin-17 in immune-mediated inflammatory myopathies and possible therapeutic implications

“…IL-6 is a key factor in the differentiation of CD8 + Tc17 and Th17 cells [67] and studies suggest the cytokine plays an important role in myositis, in particular in PM [120]. Overexpression of IL-6 has been detected in the serum and muscle tissue of patients with IBM, PM and DM [121][122][123].…”

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

“…Other subtypes include overlap syndromes and cancer-associated myositis [1,2] An autoimmune origin for these conditions is supported by immune cell-mediated myocytotoxicity, the presence of autoantibodies and over-expression of major histocompatibility complex (MHC) class I and II molecules in myositis tissue [3][4][5][6]. However, there is still debate as to whether IBM is primarily autoimmune in origin or a degenerative myopathy with associated inflammatory features and an immune component.…”