Differential roles of hypoxia and innate immunity in juvenile and adult dermatomyositis.
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.
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany.
Corinna
C
Preuße
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.
Yves
Y
Allenbach
Department of Neurology, St. Josefs Hospital, Potsdam, Germany.
Olaf
O
Hoffmann
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany.|Department of Neuropathology, University Medicine, Johannes Gutenberg University, Mainz, Germany.
Hans-Hilmar
HH
Goebel
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany.
Debora
D
Pehl
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany.
Josefine
J
Radke
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany.
Alexandra
A
Doeser
Department of Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Udo
U
Schneider
Department of Internal Medicine II, Schlossparkklinik, Berlin, Germany.
Rieke H E
RH
Alten
Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Tilmann
T
Kallinich
Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, Paris, France.
Olivier
O
Benveniste
Department of Pediatrics and Neuropediatrics, DRK Klinikum Westend, Berlin, Germany.
Arpad
A
von Moers
Friedrich-Baur-Institut, Ludwig Maximilians Universität, Munich, Germany.
Benedikt
B
Schoser
Department of Neuropediatrics, Universitätsklinikum, Essen, Germany.
Ulrike
U
Schara
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, D-10117, Berlin, Germany. werner.stenzel@charite.de.
Werner
W
Stenzel
D001284:Atrophy / Q000276:immunology / Q000473:pathology; D002196:Capillaries / Q000276:immunology / Q000473:pathology; D002648:Child; D003882:Dermatomyositis / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000276:immunology / Q000473:pathology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007370:Interferon Type I; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
Dermatomyositis; Hypoxia; Inflammation; Macrophages; Perifascicular atrophy; Type-I interferon