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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0308-5) contains supplementary material, which is available to authorized users.

Diagnostic potential of sarcoplasmic myxovirus resistance protein A expression in subsets of dermatomyositis

“…RIG‐I and ISG15 are known to be upregulated in muscle cells of DM patients as well as MxA . The present findings suggest a more important benefit from the use of MxA immunostaining in pathological practice rather than the use of these other markers.…”

“…There are several limitations in this study. The previous studies demonstrated the overexpression of type 1 IFN‐related genes in DM muscle tissue including MxA, ISG‐15 and RIG‐I by means of transcriptome analyses and immunohistochemistry . The current study was based upon these findings.…”

“…The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, revealing that it had a higher sensitivity than that of PFA and complement membrane attack complex (C5b‐9) deposition on capillaries (47% and 35% respectively) with an equal or higher specificity . MxA is one of the type 1 interferon‐inducible proteins, which plays an important role in the pathogenesis of DM but presumably not of other idiopathic inflammatory myopathies, similar to the proteins retinoic acid‐inducible gene I (RIG‐I) and interferon‐stimulated gene 15 (ISG15) . However, the comparison with MxA and other interferon‐inducible proteins in terms of the utility as a pathological marker has not been explored to date.…”

The IgG2 Isotype of Anti–Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis

“…Since anti TIF1γ IgG2 identified patients with poorer prognosis, the presence of anti TIF1γ IgG2 autoantibodies may reflect a helper T cell response associated with an inefficient antitumor response, which warrants further study. On the contrary, disease evolution in adult patients with out cancer resembles that of juvenile DM, raising the question of a different pathophysiologic process (57)(58)(59).…”

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

“…Routine stains were performed in 7 µm cryostat sections, according to standard procedures. Immunohistochemical and double immunofluorescence stains were obtained as described previously . The following antibodies were used for staining procedures: (Primary antibody, Dilution; Company/Clone): αB‐crystallin, dil.…”