Evidence for an Early Inflammatory Response in the Central Nervous System of Mice With Scrapie

Betmouni, Samar; Perry, V.H.; Gordon, J.L

doi:10.1016/0306-4522(96)00212-6

Cited by 181 publications

(134 citation statements)

References 29 publications

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“…Within the few naïve CD3 + T cells found in the normal CNS, the CD4 + population was overrepresented (60%). However, a T cell recruitment that is dominated by CD8 + cells (66%) is triggered by the accumulation of PrP Sc in the brain of 139A-infected mice, confirming the earlier observations (Betmouni et al, 1996;Lewicki et al, 2003). In addition, as only activated T cells can enter the brain, peripheral CD8 + cytolytic T cells stimulated by 168 might be able to migrate and to be entrap into the brain when locally activated by antigen encounter.…”

Section: Discussionsupporting

confidence: 85%

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

Sacquin

Chaigneau

Defaweux

et al. 2012

Brain, Behavior, and Immunity

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a b s t r a c tPrion diseases are caused by the transconformation of the host cellular prion protein PrP c into an infectious neurotoxic isoform called PrP Sc . While vaccine-induced PrP-specific CD4 + T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8 + cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrP c -specific CTL was evaluated by stimulating a CD8 + T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H-2D b and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNc secreting CD8 + T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8 + T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3 + T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNc-secreting CD8 + T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8 + T cells interact with prions into the CNS during the clinical phase of the disease.

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Section: Discussionsupporting

confidence: 85%

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

Sacquin

Chaigneau

Defaweux

et al. 2012

Brain, Behavior, and Immunity

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“…Although the immune system is designed to be protective, excessive or inappropriate activation of immune cells can lead to severe inflammatory diseases. In the CNS, inappropriate activation of glial cells and elevated levels of inflammatory mediators including cytokines and adhesion molecules, the hallmarks of CNS inflammation, have been observed in various diseases, including ischemia (Rogers et al, 1996), Alzheimer's disease (McGeer et al, 1992a(McGeer et al, , 1992b, acquired immunodeficiency syndrome (AIDS)-related dementia (Gendelman et al, 1994), and prion diseases (Betmouni et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Lee

Park

Kim

et al. 2005

Glia

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PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-␤ through activation of NF-B, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.

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“…The misfolding and consequent aggregation of the protein is generally accepted to be responsible for spongiform encephalopathies (prion diseases), such as the human GerstmannSträussler-Scheinker's syndrome and Creutzfeldt-Jakob disease. These are characterized by the extracellular deposition of the pathological form of the PrP protein and in some cases, the co-existence of amyloid plaques, gliosis, vacuole formation, and neuronal cell death [7,20,59]. These changes parallel the pathological alterations in the brain of AD patients.…”

Section: Prion Proteinmentioning

confidence: 99%

“…Aggregated prion-related protein (PrP) and the amyloid-␤ peptides are two such cases in which the irreversible formation of beta sheeted fibrils lead to microglial activation [7,94].…”

Section: The Role Of Protein-metal Binding In Neurodegenerationmentioning

confidence: 99%

“…Microglia in turn produce ROS in response to PrP peptide (106 -126) and this fragment is toxic to neuronal cell cultures only in the presence of activated glial cells [14]. In vivo, the brain of mice infected with scrapie showed astrogliosis and microglial activation early in the course of the disease, followed by neuronal loss [7]. This sequence of events suggests that microglia associated inflammatory events may be contributing to the cell loss.…”

Section: Prion Proteinmentioning

confidence: 99%

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Mechanisms by which metals promote events connected to neurodegenerative diseases

Campbell

Smith

Sayre

et al. 2001

Brain Research Bulletin

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Although the exact causative phenomenon responsible for the onset and progression of neurodegenerative disorders is at present unresolved, there are some clues as to the mechanisms underlying these chronic diseases. This review addresses mechanisms by which endogenous or environmental factors, through interaction with redox active metals, may initiate a common cascade of events terminating in neurodegeneration.

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Evidence for an Early Inflammatory Response in the Central Nervous System of Mice With Scrapie

Cited by 181 publications

References 29 publications

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Mechanisms by which metals promote events connected to neurodegenerative diseases

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