Blockade of Granzyme B Remarkably Improves Mucocutaneous Diseases with Keratinocyte Death in Interface Dermatitis

Saito, Akimasa; Okiyama, Naoko; Kubota, Noriko; Nakamura, Yoshiyuki; Fujisawa, Yasuhiro; Watanabe, Rei; Ishitsuka, Yosuke; Bleackley, R. Chris; Fujimoto, Manabu

doi:10.1016/j.jid.2018.03.1507

Cited by 12 publications

(5 citation statements)

References 16 publications

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“…The analyses using the SIINFEKL peptide and OT-I CTLs have revealed the pathogenesis of a variety of CTL-mediated human diseases [24–27]. For example, a crucial role of Fas and Fas ligand, and the involvement of perforin and granzyme B, were demonstrated in human HCV infection and graft-versus-host skin disease, respectively, using OT-I CTLs [25, 26, 28–31]. This model should be useful to elucidate the mechanisms of antigen-dependent muscle injury by CTLs.…”

Section: Discussionmentioning

confidence: 99%

A new in vitro model of polymyositis reveals CD8+ T cell invasion into muscle cells and its cytotoxic role

et al. 2019

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ObjectivesThe hallmark histopathology of PM is the presence of CD8+ T cells in the non-necrotic muscle cells. The aim of this study was to clarify the pathological significance of CD8+ T cells in muscle cells.MethodsC2C12 cells were transduced retrovirally with the genes encoding MHC class I (H2Kb) and SIINFEKL peptide derived from ovalbumin (OVA), and then differentiated to myotubes (H2KbOVA-myotubes). H2KbOVA-myotubes were co-cultured with OT-I CD8+ T cells derived from OVA-specific class I restricted T cell receptor transgenic mice as an in vitro model of PM to examine whether the CD8+ T cells invade into the myotubes and if the myotubes with the invasion are more prone to die than those without. Muscle biopsy samples from patients with PM were examined for the presence of CD8+ T cells in muscle cells. The clinical profiles were compared between the patients with and without CD8+ T cells in muscle cells.ResultsAnalysis of the in vitro model of PM with confocal microscopy demonstrated the invasion of OT-I CD8+ T cells into H2KbOVA-myotubes. Transmission electron microscopic analysis revealed an electron-lucent area between the invaded CD8+ T cell and the cytoplasm of H2KbOVA-myotubes. The myotubes invaded with OT-I CD8+ T cells died earlier than the uninvaded myotubes. The level of serum creatinine kinase was higher in patients with CD8+ T cells in muscle cells than those without these cells.ConclusionCD8+ T cells invade into muscle cells and contribute to muscle injury in PM. Our in vitro model of PM is useful to examine the mechanisms underlying muscle injury induced by CD8+ T cells.

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Section: Discussionmentioning

confidence: 99%

A new in vitro model of polymyositis reveals CD8+ T cell invasion into muscle cells and its cytotoxic role

et al. 2019

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“…OVA-specific class I restricted T cell receptor transgenic mice (OT-I) and C57BL/6 mice were purchased from Charles River Japan (Kanagawa, Japan). The splenocytes from mutant OT-I mice lacking PRF1 or GZMB 66 were provided by Dr. Naoko Okiyama (Tsukuba University, Ibaraki, Japan). C57BL/6 Ripk3 −/− mice and C57BL/6 Mlkl −/− mice were described previously 67 , 68 .…”

Section: Methodsmentioning

confidence: 99%

Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

et al. 2022

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Muscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

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“…In a previous study, Saito et al (2018) reported that granzyme B e/e pathogenic CD8 T cells can infiltrate the skin but cannot induce interface dermatitis with KC apoptosis in a murine model (Saito et al, 2021). In this study, the authors showed that granzyme B e/e CD8 T cells can infiltrate the dermis but cannot induce sclerotic changes in cGvHD.…”

Section: Discussion Of Incorrect Answersmentioning

confidence: 58%

SnapshotDx Quiz: July 2021

Lázaro-Escudero

Chu

2021

Journal of Investigative Dermatology

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Blockade of Granzyme B Remarkably Improves Mucocutaneous Diseases with Keratinocyte Death in Interface Dermatitis

Abstract: Minner F, Poumay Y. Candidate housekeeping genes require evaluation before their selection for studies of human epidermal keratinocytes.

Cited by 12 publications

References 16 publications

A new in vitro model of polymyositis reveals CD8+ T cell invasion into muscle cells and its cytotoxic role

A new in vitro model of polymyositis reveals CD8+ T cell invasion into muscle cells and its cytotoxic role

Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

SnapshotDx Quiz: July 2021

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