Differential roles of hypoxia and innate immunity in juvenile and adult dermatomyositis

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Abstract

Dermatomyositis (DM) can occur in both adults and juveniles with considerable clinical differences. The links between immune-mediated mechanisms and vasculopathy with respect to development of perifascicular pathology are incompletely understood. We investigated skeletal muscle from newly diagnosed, treatment-naïve juvenile (jDM) and adult dermatomyositis (aDM) patients focusing on hypoxia-related pathomechanisms, vessel pathology, and immune mechanisms especially in the perifascicular region. Therefore, we assessed the skeletal muscle biopsies from 21 aDM, and 15 jDM patients by immunohistochemistry and electron microscopy. Transcriptional analyses of genes involved in hypoxia, as well as in innate and adaptive immunity were performed by quantitative Polymerase chain reaction (qPCR) of whole tissue cross sections including perifascicular muscle fibers.

Through these analysis, we found that basic features of DM, like perifascicular atrophy and inflammatory infiltrates, were present at similar levels in jDM and aDM patients. However, jDM was characterized by predominantly hypoxia-driven pathology in perifascicular small fibers and by macrophages expressing markers of hypoxia. A more pronounced regional loss of capillaries, but no relevant activation of type-1 Interferon (IFN)-associated pathways was noted. Conversely, in aDM, IFN-related genes were expressed at significantly elevated levels, and Interferon-stimulated gene (ISG)15 was strongly positive in small perifascicular fibers whereas hypoxia-related mechanisms did not play a significant role.

In our study we could provide new molecular data suggesting a conspicuous pathophysiological ‘dichotomy’ between jDM and aDM: In jDM, perifascicular atrophy is tightly linked to hypoxia-related pathology, and poorly to innate immunity. In aDM, perifascicular atrophy is prominently associated with molecules driving innate immunity, while hypoxia-related mechanisms seem to be less relevant.

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Most cited references 30

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119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.

Jessica E Hoogendijk, Anthony Amato, Bryan R Lecky … (2004)

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Oxidative stress in angiogenesis and vascular disease.

Young-Woong Kim, Tatiana V. Byzova (2014)

Despite the damaging effect on tissues at a high concentration, it has been gradually established that oxidative stress plays a positive role during angiogenesis. In adults, physiological or pathological angiogenesis is initiated by tissue demands for oxygen and nutrients, resulting in a hypoxia/reoxygenation cycle, which, in turn promotes the formation of reactive oxygen species (ROS). The ROS can be generated either endogenously, through mitochondrial electron transport chain reactions and nicotinamide adenine dinucleotide phosphate oxidase, or exogenously, resulting from exposure to environmental agents, such as ultraviolet or ionizing radiation. In many conditions, ROS promotes angiogenesis, either directly or via the generation of active oxidation products, including peroxidized lipids. The latter lipid metabolites are generated in excess during atherosclerosis, thereby linking atherogenic processes and pathological angiogenesis. Although the main mechanism of oxidative stress-induced angiogenesis involves hypoxia-inducible factor/vascular endothelial growth factor (VEGF) signaling, recent studies have identified several pathways that are VEGF-independent. This review aims to provide a summary of the past and present views on the role of oxidative stress as a mediator and modulator of angiogenesis, and to highlight newly identified mechanisms.

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Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy.

Remedios Nazareno, R. Walsh, K. Parker … (2009)

We investigated interferon-stimulated gene 15 (ISG15), a poorly understood ubiquitin-like modifier, and its enzymatic pathway in dermatomyositis (DM), an autoimmune disease primarily involving muscle and skin. We generated microarray data measuring transcript abundance for approximately 18,000 genes in each of 113 human muscle biopsy specimens, and studied biopsy specimens and cultured skeletal muscle using immunohistochemistry, immunoblotting proteomics, real-time quantitative polymerase chain reaction, and laser-capture microdissection. Transcripts encoding ISG15-conjugation pathway proteins were markedly upregulated in DM with perifascicular atrophy (DM-PFA) muscle (ISG15 339-fold, HERC5 62-fold, and USP18 68-fold) compared with 99 non-DM samples. Combined analysis with publicly available microarray datasets showed that >50-fold ISG15 transcript elevation had 100% sensitivity and specificity for 28 biopsies from adult DM-PFA and juvenile DM patients compared with 199 muscle samples from other muscle diseases. Free ISG15 and ISG15-conjugated proteins were only found on immunoblots from DM-PFA muscle. Cultured human skeletal muscle exposed to type 1 interferons produced similar transcripts and ISG15 protein and conjugates. Laser-capture microdissection followed by proteomic analysis showed deficiency of titin in DM perifascicular atrophic myofibers. A large-scale microarray study of muscle samples demonstrated that among a diverse group of muscle diseases DM was uniquely associated with upregulation of the ISG15 conjugation pathway. Exposure of human skeletal muscle cell culture to type 1 interferons produced a molecular picture highly similar to that seen in human DM muscle. Perifascicular atrophic myofibers in DM were deficient in a number of skeletal muscle proteins including titin.

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Author and article information

Contributors

Werner Stenzel: +49 (0)30 450-536 073 , werner.stenzel@charite.de

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 27 April 2016

Publication date PMC-release: 27 April 2016

Publication date Collection: 2016

Volume: 4

Electronic Location Identifier: 45

Affiliations

[ ]Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117 Berlin, Germany

[ ]Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, Paris, France

[ ]Department of Neurology, St. Josefs Hospital, Potsdam, Germany

[ ]Department of Neuropathology, University Medicine, Johannes Gutenberg University, Mainz, Germany

[ ]Department of Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany

[ ]Department of Internal Medicine II, Schlossparkklinik, Berlin, Germany

[ ]Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany

[ ]Department of Pediatrics and Neuropediatrics, DRK Klinikum Westend, Berlin, Germany

[ ]Friedrich-Baur-Institut, Ludwig Maximilians Universität, Munich, Germany

[ ]Department of Neuropediatrics, Universitätsklinikum, Essen, Germany

Article

Publisher ID: 308

DOI: 10.1186/s40478-016-0308-5

PMC ID: 4847347

PubMed ID: 27121733

SO-VID: bf328ca3-a3e3-45c4-a07c-c801b4ac7d8d

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 March 2016

Date accepted : 6 April 2016

Funding

Funded by: St4/3

Custom metadata

Keywords: dermatomyositis,perifascicular atrophy,hypoxia,macrophages,inflammation,type-i interferon

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Keywords: dermatomyositis, perifascicular atrophy, hypoxia, macrophages, inflammation, type-i interferon

Differential roles of hypoxia and innate immunity in juvenile and adult dermatomyositis

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Biomarkers for Inflammatory Lung Disease

Most cited references 30

119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.

Oxidative stress in angiogenesis and vascular disease.

Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy.

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