CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

C, Deb; LaFrance‐Corey, Reghann G.; Schmalstieg, William F.; Sauer, Brian M.; Wang, Huan; German, Christopher L.; Windebank, Anthony J.; Rodriguez, Moses; Howe, Charles L.

doi:10.1371/journal.pone.0012478

Cited by 35 publications

(43 citation statements)

References 30 publications

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“…In agreement with the present findings, β-APP-positive axons can be detected predominately in acute MS lesions and less frequent associated with chronic plaques [6,44,45]. In TME, the onset of axonopathy in the spinal cord during the initial stage is suggested to be a virus-induced effect [10] while axonal degeneration and loss at the later stages is more related to an immune-mediated attack [8,46,47], and a lack of glial-derived trophic support which induces neurodegenerative mechanisms in vulnerable, demyelinated axons [48]. Axonal degeneration is regarded as an active self-destructive response to TMEV infection to prevent further axonal spread of the virus [49].…”

Section: Discussionsupporting

confidence: 87%

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

et al. 2012

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Objectives: Theiler’s murine encephalomyelitis virus (TMEV) infection of mice is a widely used animal model for demyelinating disorders, such as multiple sclerosis (MS). The aim of the present study was to identify topographical differences of TMEV spread and demyelination in the brain of experimentally infected susceptible SJL/J mice and resistant C57BL/6 mice. Methods: Demyelination was confirmed by Luxol fast blue and cresyl violet staining and axonal damage by neurofilament-specific and β-amyloid precursor protein-specific immunohistochemistry. Viral dissemination within the central nervous system (CNS) was quantified by immunohistochemistry and in situ hybridization. Further, the phenotype of infected cells was determined by confocal laser scanning microscopy. Results: An early transient infection of periventricular cells followed by demyelination and axonopathies around the fourth ventricle in SJL/J mice was noticed. Periventricular and brain stem demyelination was associated with a predominant infection of microglia/macrophages and oligodendrocytes. Conclusions: Summarized, the demonstration of ependymal infection and subjacent spread into the brain parenchyma as well as regional virus clearance despite ongoing demyelination and axonal damage in other CNS compartments allows new insights into TME pathogenesis. This novel aspect of TMEV CNS interaction will enhance the understanding of region-specific susceptibilities to injury and regenerative capacities of the brain in this MS model.

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Section: Discussionsupporting

confidence: 87%

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

et al. 2012

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“…Perforin has been reported as a key mediator in the CTL-induced axonal/neuronal damage in various mice models of autoimmune diseases (53)(54)(55)(56)(57). In contrast, our study showed that GrB internalization into neurons as well as purified GrB and T cellmediated neuronal killing are independent of perforin (Figs.…”

Section: Discussioncontrasting

confidence: 67%

Granule-Derived Granzyme B Mediates the Vulnerability of Human Neurons to T Cell-Induced Neurotoxicity

Haile

Simmen

Pasichnyk

et al. 2011

The Journal of Immunology

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Multiple sclerosis (MS) is considered an autoimmune disease of the CNS and is characterized by inflammatory cells infiltrating the CNS and inducing demyelination, axonal loss, and neuronal death. Recent evidence strongly suggests that axonal and neuronal degeneration underlie the progression of permanent disability in MS. In this study, we report that human neurons are selectively susceptible to the serine-protease granzyme B (GrB) isolated from cytotoxic T cell granules. In vitro, purified human GrB induced neuronal death to the same extent as the whole activated T cell population. On the contrary, activated T cells isolated from GrB knockout mice failed to induce neuronal injury. We found that following internalization through various parts of neurons, GrB accumulated in the neuronal soma. Within the cell body, GrB diffused out of endosomes possibly through a perforin-independent mechanism and induced subsequent activation of caspases and cleavage of α-tubulin. Inhibition of caspase-3, a well-known substrate for GrB, significantly reduced GrB-mediated neurotoxicity. We demonstrated that treatment of neurons with mannose-6-phosphate prevented GrB entry and inhibited GrB-mediated neuronal death, suggesting mannose-6-phosphate receptor-dependent endocytosis. Together, our data unveil a novel mechanism by which GrB induces selective neuronal injury and suggest potential new targets for the treatment of inflammatory-mediated neurodegeneration in diseases such as MS.

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“…CSF levels of granzyme B (GzB) correlate with relapse rate in a sub-population of MS patients 23 and animal models of MS link CTL effector functions to axon loss and development of neurological deficits. In the Theiler’s murine encephalomyelitis model, genetic deletion of perforin (PFP) or the disruption of MHC-I surface expression by genetic deletion of β2-microglobulin result in protection of axons and preservation of neurologic function, despite extensive CNS demyelination 24-27 .…”

Section: Introductionmentioning

confidence: 99%

Axons are injured by antigen-specific CD8+ T cells through a MHC class I- and granzyme B-dependent mechanism

Sauer

Schmalstieg

Howe

2013

Neurobiology of Disease

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Axon injury is a central determinant of irreversible neurological deficit and disease progression in patients with multiple sclerosis (MS). CD8+ lymphocytes (CTLs) within inflammatory demyelinated MS lesions correlate with acute axon injury and neurological deficits. The mechanisms of these correlations are unknown. We interrogated CTL-mediated axon injury using the transgenic OT-I antigen-specific CTL model system in conjunction with a chambered cortical neuron culture platform that permits the isolated manipulation of axons. Interferon gamma upregulated the axonal expression of major histocompatibility complex class I molecules presenting immunologically-relevant peptides processed from endogenous proteins. Antigen-specific CTLs formed immune synapses with and directly injured axons in a mechanism dependent upon antigen presentation, T cell receptor specificity and granzyme B activity. These findings present a novel model of immune-mediated axon injury and offer anti-axonal CTLs and granzyme B as targets for the therapeutic protection of axons and prevention of neurological deficits in MS patients.

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CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

Cited by 35 publications

References 30 publications

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

Granule-Derived Granzyme B Mediates the Vulnerability of Human Neurons to T Cell-Induced Neurotoxicity

Axons are injured by antigen-specific CD8+ T cells through a MHC class I- and granzyme B-dependent mechanism

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