Nature of the mononuclear infiltrate and the mechanism of muscle damage in juvenile dermatomyositis and Duchenne muscular dystrophy

McDouall, Rhoda; Dünn, Michael J.; Dubowitz, Victor

doi:10.1016/0022-510x(90)90156-h

Cited by 110 publications

(87 citation statements)

References 19 publications

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“…Muscle injury is accompanied by infiltration of macrophages and T lymphocytes [7]. Our previous work showed that the gene expression profile of TRAIL, an apoptosis-inducing ligand expressed on the surface of activate T lymphocytes and natural killer cells, was upregulated in children with JDM compared to children with Duchene disease [15].…”

Section: Discussionmentioning

confidence: 99%

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Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

Zhao

Fedczyna

McVicker

et al. 2007

Clinical Immunology

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Juvenile Dermatomyositis (JDM) is the most common myopathy in children with characteristic skin rash and muscle weakness, in which longer duration of untreated disease was associated with less muscle weakness. The duration of untreated inflammation may alter the apoptotic pathways involved in skeletal muscle damage. Diagnostic muscle biopsies from 14 untreated patients were stained for apoptosis markers. TUNEL-positive nuclei and caspase 3 were detected within the laminin layer, indicating apoptosis of skeletal muscle nuclei. Untreated JDM disease duration greater than 2 months ("long"), was associated with higher Fas positive cell counts in the perivascular region compared with the "short" disease duration group, 2 months or less. Within the "long" duration group, higher Fas positive cell counts were positively associated with increased TUNEL-positive nuclei and caspase 3. We conclude that the duration of untreated disease (chronic inflammation) influences the mode of continuing cell damage and death in children with JDM.

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Section: Discussionmentioning

confidence: 99%

“…Histological evidence of muscle cell death is less common, even in children with florid weakness, which is attributed to the fact that the muscle cells are multinucleated and thus more resistant to lethal insult. The cause of muscle cell death was ascribed to the infiltrating monocytes and T cells [7].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

Zhao

Fedczyna

McVicker

et al. 2007

Clinical Immunology

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“…The etiopathogenesis is still unknown, but it is believed to be autoimmune in origin. In muscle biopsy samples, the presence of a perivascular mononuclear cell infiltrate, including CD4-positive and CD8-positive T lymphocytes and macrophages, has been documented (2,3). Peripheral blood lymphocytes from patients with inflammatory myopathies, including juvenile DM, have been shown to cause muscle-specific injury in cytotoxicity assays (4)(5)(6).…”

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confidence: 99%

Self epitopes shared between human skeletal myosin and Streptococcus pyogenes M5 protein are targets of immune responses in active juvenile dermatomyositis

Massa

Costouros

Mazzoli

et al. 2002

Arthritis & Rheumatism

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Objective. To identify self T cell epitopes associated with proinflammatory immune responses and clinically active juvenile dermatomyositis (juvenile DM). The target of our search for relevant epitopes was represented by amino acid sequences shared between human skeletal myosin and Streptococcus pyogenes M5 protein. The long-term objective of the project is to identify suitable targets for immunotherapy of the disease.Methods. We used computerized algorithms to identify putative agretopes on both the human myosin and Streptococcus M5 proteins. Direct binding assays for homolog peptides were used to confirm such predictions. Antigenicity and functional cross-reactivity were evaluated by cytotoxicity assays and by measurement of cytokine levels. Specific T cells were isolated by T cell capture, and T cell receptor (TCR) V ␤ gene usage was identified by reverse transcriptase-polymerase chain reaction.Results. We identified peptides that are targets of disease-specific cytotoxic T cell responses. T cell reactivity against the self peptides correlates with clinical signs of early, active myositis. Such reactivity is accompanied by production of proinflammatory cytokines, which may contribute to the damage. T cell crossrecognition of bacterial and human homologs was shown functionally as well as by sorting peptide-specific T cells and identifying oligoclonal and largely overlapping TCR V ␤ gene usage.Conclusion. These findings represent the first identification of a self epitope in juvenile DM, providing a potential candidate for antigen-specific immune therapy.

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“…As shown in Figure 1, most of the deregulated pathways involved inflammatory/immune responses, including immune disease, immune system, and infectious disease. These immune/inflammatory pathways mainly indicated the infiltration of immune cells, such as T cells (McDouall et al, 1990;Spencer et al, 1997), macrophages (McDouall et al, 1990;Spencer et al, 1997), eosinophils (Cai et al, 2000), and mast cells (Granchelli et al, 1995;Nahirney et al, 1997), into muscles and elevated levels of various inflammatory cytokines. A previous study showed that in vivo depletions of CD4 or CD8 T cells or macrophages (Wehling et al, 2001) significantly reduced the pathology in mdx mice, and that the efficacy of the only drugs currently available for the treatment of DMD (glucocorticoids) in delaying DMD progression is mainly based on the suppression of inflammation (Serra et al, 2012), implicating the important roles of immune/ inflammation responses in aggravating the disease.…”

Section: B Discussionmentioning

confidence: 99%

Gene expression profiling of Duchenne muscular dystrophy reveals characteristics along disease progression

Tian¹,

Cao²,

Deng³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy with no cure currently available. In this study, using two microarray data sets obtained from the Gene Expression Omnibus database, we conducted a dysfunctional pathway-enrichment analysis and investigated deregulated genes that are specific to different phases of the disease in order to determine pathogenic characteristics in the progression of DMD. We identified 41 and 33 dysfunctional pathways that were enriched with differentially expressed genes in presymptomatic patients and in symptomatic patients, respectively. Over 70% of pathways were shared between both phases and many of them involved the inflammatory process, suggesting that inflammatory cascades were induced soon after the birth of the patients. Further investigation showed that presymptomatic patients performed better with respect to muscle regeneration and cardiac muscle calcium homeostasis maintenance. Neuronal nitric oxide synthase, dihydropyridine receptors, sarcoplasmic/ endoplasmic reticulum calcium ATPase, and phospholamban may serve as potential targets for further molecular diagnostic tests. Our results may provide a better understanding for the treatment of DMD.

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Nature of the mononuclear infiltrate and the mechanism of muscle damage in juvenile dermatomyositis and Duchenne muscular dystrophy

Cited by 110 publications

References 19 publications

Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

Self epitopes shared between human skeletal myosin and Streptococcus pyogenes M5 protein are targets of immune responses in active juvenile dermatomyositis

Gene expression profiling of Duchenne muscular dystrophy reveals characteristics along disease progression

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