Immune-mediated pathology in Duchenne muscular dystrophy

Rosenberg, Amy S.; Puig, Montserrat; Nagaraju, Kanneboyina; Hoffman, Eric P.; Villalta, S. Armando; Rao, V. Ashutosh; Wakefield, Lalage M.; Woodcock, Janet

doi:10.1126/scitranslmed.aaa7322

Cited by 234 publications

(269 citation statements)

References 108 publications

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“…Ablation or impaired recruitment of macrophages severely compromises muscle repair. Chronic muscle injury entails analogous shifts in innate immune system cell populations (68–70). …”

Section: Skeletal Muscle Tregs: Facilitators Of Repairmentioning

confidence: 99%

“…Though far less markedly, lymphocytes also accumulate in skeletal muscle after acute injury, as well as in the dystrophin-deficient muscles of mice harboring the mdx mutation or humans with Duchenne’s muscular dystrophy (DMD) (63, 68, 71). Their function has not been well studied, although both CD4 + and CD8 + T cells seem to promote the mdx pathology, and blocking their activities with immunosuppressants can ameliorate disease (72).…”

Section: Skeletal Muscle Tregs: Facilitators Of Repairmentioning

confidence: 99%

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Tissue Tregs

Panduro

Benoist

Mathis

2016

Annu. Rev. Immunol.

457

431

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The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3+CD4+ regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations—those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work—as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.

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“…Ablation or impaired recruitment of macrophages severely compromises muscle repair. Chronic muscle injury entails analogous shifts in innate immune system cell populations (68–70). …”

Section: Skeletal Muscle Tregs: Facilitators Of Repairmentioning

confidence: 99%

Section: Skeletal Muscle Tregs: Facilitators Of Repairmentioning

confidence: 99%

Tissue Tregs

Panduro

Benoist

Mathis

2016

Annu. Rev. Immunol.

457

431

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“…Presently, the only pharmacological therapy available to DMD patients is glucocorticoids , the administration of which has been associated with improved muscle strength and function and, crucially, a delay in the age at which patients become wheelchair‐bound . The beneficial effects of glucocorticoids are mostly due to their immunosuppressive effect , supporting the notion that the immune response plays an important role in the disease pathogenesis . Studies of the muscle infiltrate in DMD patients' biopsies have shown that it is composed of mostly macrophages and T cells and that corticosteroid treatment reduces their number .…”

Section: Introductionmentioning

confidence: 99%

Targeting early PKCθ‐dependent T‐cell infiltration of dystrophic muscle reduces disease severity in a mouse model of muscular dystrophy

Lozanoska-Ochser

Benedetti

Rizzo

et al. 2018

The Journal of Pathology

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Chronic muscle inflammation is a critical feature of Duchenne muscular dystrophy and contributes to muscle fibre injury and disease progression. Although previous studies have implicated T cells in the development of muscle fibrosis, little is known about their role during the early stages of muscular dystrophy. Here, we show that T cells are among the first cells to infiltrate mdx mouse dystrophic muscle, prior to the onset of necrosis, suggesting an important role in early disease pathogenesis. Based on our comprehensive analysis of the kinetics of the immune response, we further identify the early pre-necrotic stage of muscular dystrophy as the relevant time frame for T-cell-based interventions. We focused on protein kinase C θ (PKCθ, encoded by Prkcq), a critical regulator of effector T-cell activation, as a potential target to inhibit T-cell activity in dystrophic muscle. Lack of PKCθ not only reduced the frequency and number of infiltrating T cells but also led to quantitative and qualitative changes in the innate immune cell infiltrate in mdx/Prkcq muscle. These changes were due to the inhibition of T cells, since PKCθ was necessary for T-cell but not for myeloid cell infiltration of acutely injured muscle. Targeting T cells with a PKCθ inhibitor early in the disease process markedly diminished the size of the inflammatory cell infiltrate and resulted in reduced muscle damage. Moreover, diaphragm necrosis and fibrosis were also reduced following treatment. Overall, our findings identify the early T-cell infiltrate as a therapeutic target and highlight the potential of PKCθ inhibition as a therapeutic approach to muscular dystrophy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disorder caused by a mutation in the dystrophin gene . The absence of functional dystrophin protein is responsible for membrane fragility and repeated myocytic damage which lead to progressive muscle tissue destruction, associated with inflammation, ionic homeostasis dysregulation, energy metabolism alterations, exhaustion of regenerative capacities and, ultimately, replacement by fatty and fibrotic tissue. The nature and extent of how these mechanisms interact, however, are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

¹H NMRS of carnosine combined with ³¹P NMRS to better characterize skeletal muscle pH dysregulation in Duchenne muscular dystrophy

2017

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In recent years, quantitative nuclear magnetic resonance imaging and spectroscopy (NMRI and NMRS) have been used more systematically as outcome measures in natural history and clinical trial studies for Duchenne muscular dystrophy (DMD). Whereas most of these studies have emphasized the evaluation of the fat fraction as an assessment for disease severity, less focus has been placed on metabolic indices measured by NMRS. P NMRS in DMD reveals an alkaline inorganic phosphate (P ) pool, originating from either leaky dystrophic myocytes or an increased interstitial space. H NMRS, exploiting the pH-sensitive proton resonances of carnosine, an intracellular dipeptide, was used to distinguish between these two hypotheses. NMR data were obtained in 23 patients with DMD and 14 healthy subjects on a 3-T clinical NMR system. Both P and H NMRS data were acquired at the level of the gastrocnemius medialis muscle. A multi-slice multi-echo imaging acquisition was performed for the determination of water T and fat fraction in the same region of interest. Whereas nearly all patients with DMD showed an elevated pH compared with healthy controls when using P NMRS, H NMRS-determined pH was not systematically increased. As expected, the carnosine-based intracellular pH was never found to be alkaline in the absence of a concurrent P -based pH elevation. In addition, abnormal intracellular pH, based on carnosine, was never associated with normal water T values. We conclude that, in one group of patients, both H and P NMRS showed an alkaline pH, originating from the intracellular compartment and reflecting ionic dysregulation in dystrophic myocytes. In the other patients with DMD, intracellular pH was normal, but an alkaline P pool was still present, suggesting an extracellular origin, probably revealing an expanded interstitial volume fraction, often associated with fibrotic changes. The data demonstrate that H NMRS could serve as a biomarker to assess the normalization of intramyocytic pH and sarcolemmal permeability following therapy inducing dystrophin expression in patients with DMD.

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Immune-mediated pathology in Duchenne muscular dystrophy

Cited by 234 publications

References 108 publications

Tissue Tregs

Tissue Tregs

Targeting early PKCθ‐dependent T‐cell infiltration of dystrophic muscle reduces disease severity in a mouse model of muscular dystrophy

¹H NMRS of carnosine combined with ³¹P NMRS to better characterize skeletal muscle pH dysregulation in Duchenne muscular dystrophy

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Immune-mediated pathology in Duchenne muscular dystrophy

Cited by 234 publications

References 108 publications

Tissue Tregs

Tissue Tregs

Targeting early PKCθ‐dependent T‐cell infiltration of dystrophic muscle reduces disease severity in a mouse model of muscular dystrophy

1H NMRS of carnosine combined with 31P NMRS to better characterize skeletal muscle pH dysregulation in Duchenne muscular dystrophy

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¹H NMRS of carnosine combined with ³¹P NMRS to better characterize skeletal muscle pH dysregulation in Duchenne muscular dystrophy