Immune-Mediated Necrotizing Myopathy Is Characterized by a Specific Th1-M1 Polarized Immune Profile

Abstract

Immune-mediated necrotizing myopathy (IMNM) is considered one of the idiopathic inflammatory myopathies, comprising dermatomyositis, polymyositis, and inclusion body myositis. The heterogeneous group of necrotizing myopathies shows a varying amount of necrotic muscle fibers, myophagocytosis, and a sparse inflammatory infiltrate. The underlying immune response in necrotizing myopathy has not yet been addressed in detail. Affected muscle tissue, obtained from 16 patients with IMNM, was analyzed compared with eight non-IMNM (nIMNM) tissues. Inflammatory cells were characterized by IHC, and immune mediators were assessed by quantitative real-time PCR. We demonstrate that immune- and non-immune-mediated disease can be distinguished by a specific immune profile with significantly more prominent major histocompatibility complex class I expression and complement deposition and a conspicuous inflammatory infiltrate. In addition, patients with IMNM exhibit a strong type 1 helper T cell (T1)/classically activated macrophage M1 response, with detection of elevated interferon-γ, tumor necrosis factor-α, IL-12, and STAT1 levels in the muscle tissue, which may serve as biomarkers and aid in diagnostic decisions. Furthermore, B cells and high expression of the chemoattractant CXCL13 were identified in a subgroup of patients with defined autoantibodies. Taken together, we propose a diagnostic armamentarium that allows for clear differentiation between IMNM and nIMNM. In addition, we have characterized a Th1-driven, M1-mediated immune response in most of the autoimmune necrotizing myopathies, which may guide therapeutic options in the future.

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

“…In addition, there is diffuse expression of MHC-I antigens in muscle fibres, particularly in cases associated with statin therapy [29] or antibodies to 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) [30,31], signal recognition particle (SRP) or tRNA aminoacyl synthetases [28,41]. This finding is in keeping with an immune-mediated process in which muscle fibres participate in antigen presentation to the immune system.…”

“…+ macrophages are prominent in the endomysium and perimysium, and small numbers of CD4 + and CD8 + T cells and B cells may also be present (Table 1) [28]. In addition, there is diffuse expression of MHC-I antigens in muscle fibres, particularly in cases associated with statin therapy [29] or antibodies to 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) [30,31], signal recognition particle (SRP) or tRNA aminoacyl synthetases [28,41].…”

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

“…IMNM has been characterized by a Th1 immune response however this study did not assess IL-17/Th17 expression [14].…”

“…The majority of research to date has implicated CD4 + T-helper (Th1) cells or CD8 + cytotoxic effector T cells in the pathogenesis of the inflammatory myopathies, as evidenced by the detection of a type 1 interferon profile in both DM and PMand a Th1 immune profile in IMNM [13,14]. Interleukin-17 (IL-17) and the Th17 subset of CD4 + cells have been strongly implicated in the pathogenesis of a number of other autoimmune diseases including psoriasis, rheumatoid arthritis and multiple sclerosisleading to the development ofIL-17 targeted monoclonal antibody therapies.…”

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective

“…NAM may also occur in the absence of these antibodies in patients with malignancy, connective tissue diseases, or viral infections [29]. The inflammatory infiltrate is usually absent or sparse but when present comprises mainly CD68+ macrophages, with a type I helper T cell (Th1)/M1 macrophage response in the muscle tissue [30]. There can be upregulation of MHC-I antigens in myofibers, particularly in cases associated with statin drug therapy [31,32].…”