Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease

Ercolini, Anne M.; Miller, Stephen D.

doi:10.4049/jimmunol.176.6.3293

Cited by 90 publications

(55 citation statements)

References 84 publications

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“…Third, preservation of conduction velocity and/or axonal sodium channel distribution should correlate with functional preservation in VP2 peptide-treated mice to a greater degree than either absolute axon number or retrograde transport (Rivera-Quinones et al, 1998;Waxman, 2006). Testing these predictions will help clarify the relationship between CD8+ T cells and axon injury Howe and Rodriguez, 2005) and may help rectify the contentious role of MHC class I in demyelinating disease (Begolka et al, 2001;Ercolini and Miller, 2006). Finally, we propose that a cytokine-secreting, reactive oxygen species-producing microglial intermediary positioned between cytotoxic CD8+ T cells and demyelinated axons may provide a highly relevant and highly manipulable therapeutic target for intervention in patients with MS (Craner et al, 2005;Miller et al, 2007;Peterson et al, 2001;Sriram and Rodriguez, 1997;Storch et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination

Howe¹,

Ure²,

Adelson³

et al. 2007

Journal of Neuroimmunology

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Demyelination, a pathological hallmark of multiple sclerosis, may be a necessary but not a sufficient condition for motor dysfunction associated with this disease. We favor a neurodegenerative model of multiple sclerosis and suggest that demyelination creates a permissive environment wherein the denuded axon becomes susceptible to immune-mediated injury. Unfortunately, the cellular effectors responsible for eliciting such axonal injury are currently unknown. Based on previous observations implicating cytotoxic T cells in this injury, we assessed motor function, axon dropout, and axon injury following peptide depletion of the immunodominant CD8+ antiviral T cell response in the IFNγ receptor-deficient mouse model of acute demyelination. We found that the targeted removal of this population of cytotoxic effector cells prior to infection with the Theiler's murine encephalomyelitis virus caused a substantial preservation of motor function at 45 days postinfection that was associated with preservation of retrograde axonal transport in a subpopulation of surviving axons within the spinal cord. We conclude that cytotoxic T cells may be responsible for the initiation of axon injury following demyelination.

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Section: Discussionmentioning

confidence: 99%

CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination

Howe¹,

Ure²,

Adelson³

et al. 2007

Journal of Neuroimmunology

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“…A role of both Th1 and Th17 T cell subsets in EAE has been demonstrated. The presence of Th1 cells in CNS of EAE-diseased mice and the ability of Th1 cells to transfer EAE are well-documented (13). However, the role of Th1 cells as the central mediators of EAE/MS was challenged by the observation that IFN-␥ and IFN-␥ receptor deficiency resulted in exacerbated EAE (14,15).…”

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confidence: 99%

Deficiency of Fatty Acid-Binding Proteins in Mice Confers Protection from Development of Experimental Autoimmune Encephalomyelitis

Reynolds

Liu

Brittingham

et al. 2007

The Journal of Immunology

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Fatty acid-binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. Recent studies have demonstrated the ability of FABPs to simultaneously regulate metabolic and inflammatory pathways. We investigated the role of adipocyte FABP and epithelial FABP in the development of experimental autoimmune encephalomyelitis to test the hypothesis that these FABPs impact adaptive immune responses and contribute to the pathogenesis of autoimmune disease. FABP-deficient mice exhibited a lower incidence of disease, reduced clinical symptoms of experimental autoimmune encephalomyelitis and dramatically lower levels of proinflammatory cytokine mRNA expression in CNS tissue as compared with wild-type mice. In vitro Ag recall responses of myelin oligodendrocyte glycoprotein 35–55-immunized FABP−/− mice showed reduced proliferation and impaired IFN-γ production. Dendritic cells deficient for FABPs were found to be poor producers of proinflammatory cytokines and Ag presentation by FABP−/− dendritic cells did not promote proinflammatory T cell responses. This study reveals that metabolic-inflammatory pathway cross-regulation by FABPs contributes to adaptive immune responses and subsequent autoimmune inflammation.

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“…Presently, there is no commercially available Ab to V␤19, which precludes us from sorting these T cells for analysis. Both MS and the murine model of this disease, experimental autoimmune encephalomyelitis, are driven by CD4 ϩ T cells that secrete Th1 or Th17-type cytokines (2,22). Thus, we decided to see whether V␤19/ p188 T cells are enriched in the population of T cells that secrete IFN-␥ in response to peptide.…”

Section: Functionality Of the V␤19/p188 Response In Hae 574 -586 /Cfamentioning

confidence: 99%

“…Mimicry between self-Ags and Ags found in infectious agents is postulated to either precipitate autoimmune disease or exacerbate already established disease symptoms (1)(2)(3)(4). For example, there is compelling evidence indicating that rheumatic heart disease is caused by molecular mimicry between T cell epitopes derived from streptococcal M proteins and epitopes from cardiac myosin (5,6).…”

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confidence: 99%

Molecular Mimics Can Induce Novel Self Peptide-Reactive CD4+ T Cell Clonotypes in Autoimmune Disease

Ercolini

Miller

2007

The Journal of Immunology

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It has been postulated that infectious agents may precipitate autoimmune disease when T cell responses raised against the pathogen cross-react with self-peptides, a phenomenon known as molecular mimicry. However, there are very little data available characterizing the similarity between the repertoire of the cross-reactive self-specific T cell population compared with the pathogen-specific T cell repertoire. In this study, we use immunoscope analysis to identify the T cell populations induced upon priming SJL/J mice with a pathogen-derived mimic of the immunodominant encephalitogenic myelin peptide PLP139–151, which is contained within the protease IV protein of Haemophilus influenzae (HAE574–586). We describe an IFN-γ-producing Vβ19+ T cell population in HAE574–586-primed mice that appears to be the “public clonotype” as it expanded in response to peptide in all mice tested. Critically this Vβ19+ T cell population is not expanded in mice primed with the self-peptide PLP139–151, indicating that mimics can induce the expansion of new self-reactive populations not initially present in the periphery of a host. This is the first description of the use of immunoscope analysis to characterize the cross-reactive anti-self T cell response induced by a molecular mimic.

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Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease

Cited by 90 publications

References 84 publications

CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination

CD8+ T cells directed against a viral peptide contribute to loss of motor function by disrupting axonal transport in a viral model of fulminant demyelination

Deficiency of Fatty Acid-Binding Proteins in Mice Confers Protection from Development of Experimental Autoimmune Encephalomyelitis

Molecular Mimics Can Induce Novel Self Peptide-Reactive CD4+ T Cell Clonotypes in Autoimmune Disease

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