1. Structural dynamics of Oligodendrocyte lysis by Perforin in culture: Relevance to Multiple Sclerosis
    J NeuroSci Res 2001 May 15;64(4):380-91

  1. Perforin-dependent Neurologic injury in a Viral model of MS
    J NeuroSci 18: 7306-14 (1998)

  2. High numbers of Perforin mRNA expressing CSF cells in Multiple Sclerosis with Gadolinium-enhancing Brain MRI lesions
    Acta Neurol Scand 1999 Jul;100(1):18-24

  3. CytoToxic T-Lymphocytes in AutoImmune and degenerative CNS Diseases
    Trends NeuroSci 2002 Jun;25(6):313-9

  4. Fas Ligand (CD95L) protects Neurons against Perforin-mediated T-Lymphocyte CytoToxicity
    J Immunol 2001 Jul 15;167(2):674-81

  5. Multiple Sclerosis: pathogenesis and MR imaging features of T1 hypointensities in a [corrected] murine model
    Radiology 2008 Mar;246(3):790-5


Perforin-Dependent Neurologic Injury In A Viral Model Of Multiple Sclerosis

Murray PD; McGavern DB; Lin X; Njenga MK; Leibowitz J; Pease LR; Rodriguez M
J NeuroSci 18: 7306-14 (1998)
Mayo Clinic and Foundation, Dept of Immunology, Rochester, Minnesota 55905, USA
UI# 98409778

In this study we demonstrate Perforin-mediated CytoToxic Effector Function is necessary for Viral clearance and may directly contribute to the development of Neurologic deficits after DeMyelination in the Theiler's Murine EncephaloMyelitis Virus (TMEV) model of Multiple Sclerosis.

We previously demonstrated Major Histocompatability Complex (MHC) Class I-deficient (ß2m-deficient) mice with an otherwise resistant genotype develop severe DeMyelination with minimal Neurologic Disease when chronically infected with TMEV.

These studies implicate CD8+ T-Cells as the Pathogenic Cell in the induction of Neurologic Disease after DeMyelination.

To determine which Effector mechanisms of CD8+ T-Cells, granule ExocyTosis or Fas Ligand expression, play a role in the development of DeMyelination and clinical disease, we infected Perforin-deficient, lpr (Fas mutation), and gld (Fas Ligand mutation) mice with TMEV.

Perforin-deficient mice showed Viral persistence in the CNS, chronic Brain pathology, and DeMyelination in the Spinal Cord White Matter.

Perforin-deficient mice demonstrated severely impaired MHC Class I-restricted CytoToxicity against Viral Epitopes, but normal MHC Class II-restricted delayed-type hypersensitivity responses to Virus Antigen.

Despite DeMyelination, Virus-infected Perforin-deficient mice showed only minimal Neurologic deficits as indicated by clinical disease score, activity monitoring, and footprint analysis.

Perforin- and MHC Class II-deficient mice (with functional CD8+ T-Cells and Perforin molecules and an H-2(b) Haplotype) had comparable DeMyelination and Genotype, however, only the latter showed severe clinical disease.

Gld and lpr mice demonstrated normal TMEV-specific CytoToxicity and maintained resistance to TMEV-induced DeMyelinating disease. These studies implicate Perforin release by CD8+ T-Cells as a potential mechanism by which Neurologic deficits are induced after DeMyelination.


High Numbers Of Perforin mRNA Expressing CSF Cells In MS With Gadolinium-Enhancing Brain MRI Lesions

Kivisakk P, Stawiarz L, Matusevicius D, Fredrikson S, Soderstrom M, Hindmarsh T, Link H
Acta Neurol Scand 1999 Jul;100(1):18-24
Huddinge Univ Hospital, Karolinska Institutet, Division of Neurology, Sweden
PMID# 10416508; UI# 99342897

Enhanced expression of pro- and anti-inflammatory Cytokines is a common finding in MS, but attempts to correlate Cytokine expression with disease activity have produced conflicting results.

In this paper, Gadolinium-(Gd-)enhancing lesions on Brain MRI were used as markers for active inflammation in patients with MS not treated with any ImmunoModulatory Drugs.

In parallel, in situ hybridization was used to detect blood and CerebroSpinal Fluid (CSF) MonoNuclear Cells (MNC) expressing Cytokine mRNA.

An association was observed between numbers of Perforin mRNA expressing CSF MNC and numbers of Gd-enhancing Brain MRI lesions.

Perforin mRNA expressing CSF MNC were not detected in any of the patients lacking active Lesions on Brain MRI.

The expression of Tumor Necrosis Factor-alpha, InterLeukin-10 (IL-10) and IL-12 mRNA in CSF MNC did not differ between MS patients with and without active MRI lesions.

Based on the present finding, a role for Perforin in the disruption of the Blood-Brain Barrier in MS can be hypothesized.


CytoToxic T-Lymphocytes In AutoImmune And Degenerative CNS Diseases

Neumann H, Medana IM, Bauer J, Lassmann H
Trends NeuroSci 2002 Jun;25(6):313-9
European NeuroScience Institute Gottingen, NeuroImmunology Unit, Waldweg 33, 37073, Gottingen, Germany
PMID# 12086750

CytoToxic T-Lymphocytes (CTLs) with a CD8+ phenotype have the potential to recognize and attack Major Histocompatibility Complex (MHC) Class I-expressing Brain cells.

Most Brain cells, including Neurons, can be stimulated to present peptides to CD8+ CTLs by MHC Class I molecules, and are susceptible to CTL-mediated CytoToxicity in culture. In disease-affected Brain Parenchyma, CD8+ CTLs outnumber other T-Cell subtypes.

They show clonal expansion in several inflammatory and degenerative CNS diseases, such as Multiple Sclerosis (MS), virus-induced inflammatory Brain diseases and ParaNeoplastic Neurological Disorders.

In MS, damage of Axons is closely linked to the CD8+ CTLs, and protection against CTL-mediated damage should be considered as a new therapeutic approach in MS and Other NeuroInflammatory Diseases.


Fas Ligand (CD95L) Protects Neurons Against Perforin-Mediated T-Lymphocyte CytoToxicity

Medana I, Li Z, Flugel A, Tschopp J, Wekerle H, Neumann H
J Immunol 2001 Jul 15;167(2):674-81
Max-Planck Institute of NeuroBiology, Department of NeuroImmunology, Am Klopferspitz 18 A, 82152 Martinsried, Germany
PMID# 11441070

Previous work showed that Neurons of the CNS are protected against Perforin-mediated T-Cell CytoToxicity, but are susceptible to Fas-mediated Apoptosis.

In this study, we report that Fas Ligand (FasL) expression by Neurons is involved in protection against Perforin-mediated T-Cell CytoToxicity.

Gene transcripts for FasL were identified in single murine Hippocampal Neurons by RT-PCR combined with patch clamp ElectroPhysiology, and constitutive expression of FasL protein was confirmed in Neurons by ImmunoHistoChemistry.

Neurons derived from wild-type C57BL/6 (BL6) mice and mutant BL6.gld mice lacking functional FasL were confronted with AlloGeneic CTLs and continuously monitored in real time for changes in levels of IntraCellular Calcium ([Ca+](i)), an indicator of CytoToxic damage.

Perforin-mediated Plasma membrane Lysis, characterized by rapid, massive [Ca+](i) influx into the target cells within 0.5 h, was not detected in wild-type Neurons.

In striking contrast, FasL-deficient Neurons showed rapid increase in [Ca+](i) within 0.5 h, reflecting Perforin-dependent cell Lysis.

FasL seems to protect Neurons by blocking degranulation of CTLs, since CD3-induced release of CytoToxic granules was reduced by co-application of Fas-specific Abs or rFasL.


Multiple Sclerosis: Pathogenesis And MR Imaging Features Of T1 HypoIntensities In A [Corrected] Murine Model

Pirko I, Nolan TK, Holland SK, Johnson AJ
Radiology 2008 Mar;246(3):790-5
University of Cincinnati, Department of Neurology, 260 Stetson St. Suite 2300, PO Box 670525, Cincinnati, OH 45267-0525, USA
PMID# 18309014

To prospectively determine how T1 HypoIntensities (T1 Black Holes) on Brain Magnetic Resonance (MR) images are generated by the Immune System by using a Theiler murine Encephalitis Virus-induced model of Multiple Sclerosis and high-field-strength MR imaging.

Materials And Methods
All animal protocols and experiments were approved by the institutional animal care and use committee.

Volumetric MR imaging studies were conducted at 7T in six C57BL/6 mice and in Immune differentiation marker (recombination activation gene [RAG]-1)-, Immune Cell (CD4+, CD8+)-.

And Immune Effector molecule (Fas ligand, Perforin)-deficient mice (six mice in each group) to determine which Immune Cell types and effector molecules lead to T1 HypoIntensities.

The main outcome measure was the total T1 Black Hole Volume per animal, as determined with Volumetric Analysis, and was analyzed statistically by using software.

Compared with C57BL/6 mice, RAG-1-deficient mice showed a significant (P = .003) decrease in total T1 Black Hole Volume, suggesting a clear role for the Adaptive Immune System.

While CD4+-deficient mice did not show a significant decrease in T1 Black Hole Volume (P = .33), CD8+-deficient mice did (P = .003).

Perforin-deficient mice showed a significant reduction of T1 Black Hole Volume (P = .002), whereas Fas ligand-deficient mice did not (P = .77).

The data suggest that CD8+ T-Cells utilizing Perforin effector molecules are responsible for T1 Black Hole formation.

(c) RSNA, 2008.

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