Local expression of cytokines in idiopathic inflammatory myopathies

Lépidi, Hubert; Francès, V.; Figarella‐Branger, Dominique; Bartoli, Catherine; Machado-Baeta, A; Pellissier, Jean‐François

doi:10.1046/j.1365-2990.1998.00092.x

Cited by 109 publications

(79 citation statements)

References 42 publications

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“…TNF-␣ is readily detectable and predominantly expressed in macrophages as well as in the endomysium and perimysium of affected muscle fibers from patients with polymyositis, dermatomyositis, and sIBM (20,27,(31)(32)(33). The monokine mediates inflammation by increasing vascular permeability and endothelial cell adhesiveness as well as via activation of antigen-presenting cells such as dendritic cells and macrophages, which initiate and orchestrate adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

TNF-α Induces Macroautophagy and Regulates MHC Class II Expression in Human Skeletal Muscle Cells

Keller

Fokken

Turville

et al. 2011

Journal of Biological Chemistry

104

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Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to deliver antigens for presentation on major histocompatibility complex (MHC) class II molecules. Skeletal muscle fibers show a high level of constitutive macroautophagy and express MHC class II molecules upon immune activation. We found that tumor necrosis factor-␣ (TNF-␣), a monokine overexpressed in inflammatory myopathies, led to a marked up-regulation of macroautophagy in skeletal myocytes. Furthermore, TNF-␣ augmented surface expression of MHC class II molecules in interferon-␥ (IFN-␥)-treated myoblasts. The synergistic effect of TNF-␣ and IFN-␥ on the induction of MHC class II surface expression was not reflected by higher intracellular human leukocyte antigen (HLA)-DR levels and was reversed by macroautophagy inhibition, suggesting that TNF-␣ facilitates antigen processing via macroautophagy for more efficient MHC class II loading. Muscle biopsies from patients with sporadic inclusion body myositis, a well defined myopathy with chronic inflammation, showed that over 20% of fibers that contained autophagosomes costained for MHC class II molecules and that more than 40% of double-positive muscle fibers had contact with CD4 ؉ and CD8 ؉ immune cells. These findings establish a mechanism through which TNF-␣ regulates both macroautophagy and MHC class II expression and suggest that macroautophagy-mediated antigen presentation contributes to the immunological environment of the inflamed human skeletal muscle.Autophagy is a homeostatic process that enables eukaryotic cells to deliver cytoplasmic constituents for lysosomal degradation, for example to recycle nutrients for survival during starvation. In addition to this original function, autophagy has emerged as a key mechanism in orchestrating innate and adaptive immune responses. During macroautophagy, the major route of degradation of cytoplasmic constituents, proteins, and organelles are sequestered inside double-membrane vesicles (autophagosomes) that fuse with lysosomes/late endosomes. In the fusion vesicles, often multivesicular and multilamellar amphisomes, the captured material is degraded, and antigenic fragments are loaded onto major histocompatibility complex (MHC) class II molecules for presentation to CD4 ϩ T cells. In turn, innate and adaptive immune signals are capable of regulating macroautophagy via cytokine secretion and cell contact-dependent mechanisms (1-3).In vivo analysis of macroautophagy in transgenic mice expressing the GFP-coupled specific autophagosome marker light chain 3 (LC3), one mammalian homologue of yeast autophagy-related gene 8 (Atg8), demonstrated that the regulation of macroautophagy is organ-dependent and that some tissues produce LC3-positive autophagosomes even in the absence of nutrient starvation. Such constitutive autophagosomal activity has been observed in metabolically active tissues such as liver, thymus, and skeletal muscle (4).Skeletal myocytes are facultative antigen-p...

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Section: Discussionmentioning

confidence: 99%

TNF-α Induces Macroautophagy and Regulates MHC Class II Expression in Human Skeletal Muscle Cells

Keller

Fokken

Turville

et al. 2011

Journal of Biological Chemistry

104

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“…Overexpression of IL-6 has been detected in the serum and muscle tissue of patients with IBM, PM and DM [121][122][123]. Furthermore, in mouse models of myositis inhibiting IL-6 by gene knockout or with an anti-IL-6 receptor antibody ameliorated myositis severity.…”

Section: Targeting Of Th17 Related Moleculesmentioning

confidence: 99%

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

Moran

Mastaglia

2014

Neuromuscular Disorders

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The role of interleukin-17 in immune-mediated inflammatory myopathies and possible therapeutic implications. Neuromuscular Disorders, 24 (11) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Granulomatous inflammation is driven by T helper 1 (Th1) cytokines such as IFN gamma and interleukin-2, a pattern consistent with the immuno-histochemical pattern of local cytokine expression demonstrable in the inflammatory myopathies. 9 The demonstration that idiotype-specific T cells in patients with myeloma frequently express Th1 cytokines 10 raises the possibility that a skewed immune response to myelomaspecific antigens leads to a perturbation of the cytokine milieu which, in turn, is capable of inducing a granulomatous reaction or inflammatory myopathy. Whether or not specific biological features of extramedullary disease influence the host immune response or increase the risk of certain paraneoplastic complications is not known.…”

Section: Discussionmentioning

confidence: 99%

Dermatomyositis and sarcoid-like reaction associated with multiple myeloma treated effectively by high-dose chemotherapy and autologous peripheral blood stem cell transplantation

Chakraverty

Rabin

Peggs

et al. 2001

Bone Marrow Transplant

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Summary:We report the case of a 46-year-old male who developed dermatomyositis and a sarcoid-like reaction in association with testicular relapse of multiple myeloma. The myositis progressed despite chemotherapy directed at the underlying malignant disorder and immunosuppressive treatment. There was, however, a dramatic and sustained response to high-dose chemotherapy and autologous peripheral blood stem cell transplantation which resulted in resolution of the myopathy and partial resolution of the sarcoid-like reaction. This case report highlights the potential of autologous stem cell transplantation as treatment for para-neoplastic disorders associated with haematological malignancies. Bone Marrow Transplantation (2001) 27, 1215-1217. Keywords: multiple myeloma; autologous PBSCT; dermatomyositis; sarcoidosis The presenting clinical features of multiple myeloma are protean and reflect the direct effects of clonal plasma cell proliferation (eg bone marrow failure), the activity of monoclonal antibody (eg amyloid deposition), or the consequence of a complex inter-relationship between the abnormal clone and the host bone marrow micro-environment (eg bone disease). The pathogenesis of the various 'paraneoplastic' disorders which occur in association with myeloma, such as axonal or demyelinating neuropathy, is less certain although antibodies with specificity for proteins expressed by affected tissues, amyloid deposition or changes in cytokine production patterns have all been proposed as potential mechanisms. The optimal treatment for this group of disorders has not been defined and their impact upon prognosis is not known. We report for the first time the effectiveness of high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) as treatment for a para-neoplastic disorder associated with multiple myeloma. Case reportA 46-year-old man presented with a 3 month history of general malaise and 2 week history of vomiting in March 1998. There was no significant past medical history. On examination he appeared unwell and short of breath at rest. He had a raised venous pressure, peripheral oedema and bilateral inspiratory crepitations on chest examination. FBC at presentation was: Hb 8.2 g/dl, white cell count 5.2 × 10 9 /l and platelets 163 ϫ 10 9 /l. Renal function tests confirmed acute renal failure with a creatinine of 844 umol/l (normal range 62-130) and urea 46.4 mmol/l (normal range 2.8-7.6). Corrected serum calcium was 3.43 mmol/l. Chest Xray showed changes consistent with pulmonary oedema. Serum electrophoresis confirmed an IgG lambda paraprotein of 70 g/l. No urinary Bence-Jones protein was detected. Skeletal survey revealed no lytic lesions. Bone marrow trephine was diffusely fibrotic with deposition of collagen (grade 4) and heavy infiltration by neoplastic plasma cells (CD138 positive, lambda light chain restriction). Most plasma cells had the features of plasmblasts. Renal biopsy showed a cast nephropathy.The diagnosis was of IgG lambda myeloma complicated by hypercalcaemia and acute rena...

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Local expression of cytokines in idiopathic inflammatory myopathies

Cited by 109 publications

References 42 publications

TNF-α Induces Macroautophagy and Regulates MHC Class II Expression in Human Skeletal Muscle Cells

TNF-α Induces Macroautophagy and Regulates MHC Class II Expression in Human Skeletal Muscle Cells

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

Dermatomyositis and sarcoid-like reaction associated with multiple myeloma treated effectively by high-dose chemotherapy and autologous peripheral blood stem cell transplantation

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