Multiple Sclerosis Abstracts

  1. Microglia stimulate naive T-Cell differentiation without stimulating T-Cell proliferation
    J NeuroSci Res 1999 Jan 1;55(1):127-34

  2. Chemokines induce migration and changes in actin polymerization
    J NeuroSci Res 1999 Jan 1;55(1):17-23

  3. Distal versus proximal arm Tremor in Multiple Sclerosis
    J Neurol NeuroSurg Psychiatry 1999 Jan;66(1):43-7

  4. HLA-DR-restricted presentation by human B-Cells of alphaB-Crystallin, a candidate autoantigen in Multiple Sclerosis
    J Immunol 1999 Jan 1;162(1):129-35

  5. Theiler's virus alternatively initiated protein inhibits the generation of H-2K-restricted virus-specific cytotoxicity
    J Immunol 1999 Jan 1;162(1):17-24

  6. Structure & function of Myelin Oligodendrocyte Glycoprotein (MOG)
    J NeuroChem 1999 Jan;72(1):1-9

  7. SubCallosal striations: early findings of Multiple Sclerosis on Sagittal, thin-section, fast FLAIR MR images
    Radiology 1999 Jan;210(1):149-53

  8. CerebroSpinal Fluid Nitrate levels in Multiple Sclerosis
    Eur Neurol 1999 Jan;41(1):44-47

  9. Local delivery of TNF by RetroVirus-transduced T-Lymphocytes exacerbates Experimental AutoImmune EncephaloMyelitis
    Clin Immunol 1999 Jan;90(1):10-14

  10. Heat sensitivity of Sensory fibers in Carpal Tunnel Syndrome
    Muscle Nerve 1999 Jan;22(1):37-42


Microglia Stimulate Naive T-Cell Differentiation Without Stimulating T-Cell Proliferation

Carson MJ, Sutcliffe JG, Campbell IL
J NeuroSci Res 1999 Jan 1;55(1):127-34
The Scripps Research Institute, Dept of Molecular Biology, La Jolla, California 92037, USA

UI# 99105447

A major question relevant to the initiation and progression of inflammation and AutoImmune processes within the Central Nervous System (CNS) is whether resident Microglia or only infiltrating Macrophage can productively interact with T-Cells that enter the CNS.

Either actively through extravasation or passively through defects in the Blood-Brain Barrier (BBB).

We isolated Microglia and Macrophage from the Brains of healthy adult mice and transgenic mice that displayed many features of Multiple Sclerosis and HIV LeukoEncephalopathy.

Due to the Astrocytic expression of InterLeukin-3 (IL-3) and compared their Antigen-Presenting Cell (APC) functions.

We found that unactivated Microglia isolated from healthy nontransgenic mice and activated Microglia isolated from transgenic siblings are relatively weak stimulators of naive T-Cell proliferation compared to Macrophage populations.

The APC function of activated, but not unactivated, Microglia could be increased by treatment acutely with LipoPolySaccharide (LPS)/Interferon gamma (IFN-gamma).

However, this treatment also induced the apparent production of PostaGlandins, which reduced T-Cell proliferation when Indomethacin was absent from the assay cultures.

Strikingly, even in the absence of stimulated T-Cell proliferation, both unactivated and activated Microglia stimulated the differentiation of naive T-Cells into Th1 Effector Cells.

Although neither Microglial population was a more effective inducer than Macrophages or Splenic APCs. Thus, while Microglia are clearly capable of productively interacting with naive T-Cells, Macrophages have a more robust APC function.


Chemokines Induce Migration & Changes In Actin Polymerization In Adult Rat Brain Microglia & Human Fetal Microglial Cell Line In Vitro

Cross AK, Woodroofe MN
J NeuroSci Res 1999 Jan 1;55(1):17-23
Sheffield Hallam University, School of Science, Division of Biomedical Sciences, England

UI# 99105436

Microglia, the resident Macrophages of the Central Nervous System, are the primary cells to respond to injury in the Brain, both in inflammation, e.g., in Multiple Sclerosis, and trauma.

Chemokines are potential mediators of Microglial cell recruitment to sites of injury; thus, the ability of Microglia to migrate in response to a number of Chemokines was assessed.

The Chemokines Monocyte ChemoAttractant protein 1, Macrophage Inflammatory Protein 1alpha, Macrophage Inflammatory Protein 1beta, RANTES (regulated upon activation normal T-Cell expressed and secreted), InterLeukin 8, and IP-10 (Interferon gamma inducible protein-10), induce migration and changes in the distribution of f-actin in adult rat Microglia and a human Microglial Cells line, CHME3, in vitro.

Both cell types show a significant migration response, above control levels, to all the chemokines tested in a typical dose-dependent manner. These Chemokines also induced a reorganization of the actin cytoskeleton of the cells.

This study indicates that Chemokines play an important role in the recruitment of Microglia to areas of Central Nervous System inflammation.


Distal Versus Proximal Arm Tremor In MS
Assessed By Visually Guided Tracking Tasks

Liu X, Miall RC, Aziz TZ, Palace JA, Stein JF
J Neurol NeuroSurg Psychiatry 1999 Jan;66(1):43-7
UnivLaboratory of Physiology, Oxford, UK

UI# 99101540

To compare Action Tremor (AT) during manual tracking in normal subjects and patients with Multiple Sclerosis with Tremor (MS-Tremor group) and without Tremor (MS-no Tremor group).

And, to differentiate Tremor occurring predominantly around the distal joint from that involving the proximal joints of the arm.

Subjects performed both a visually guided ramp tracking task using wrist flexion/extension and a whole arm circle tracking task using shoulder movement.

Action Tremor at the wrist or shoulder was computed as the SD of the tracking velocity.

The ratio of wrist:arm Tremor was then calculated to differentiate distal from proximal Tremor in the tested arm. Frequency spectra of the records were also examined.

During wrist tracking, AT in patients with Multiple Sclerosis contained a major frequency component at 4-5 Hz; the frequency was slightly lower during whole arm tracking.

The ratio of wrist:arm Tremor was significantly higher in the MS-Tremor group.

Of 12 tested arms, eight had Tremor significantly weighted towards the distal joint, only one towards the proximal joint, and three had a ratio inside the control range.

AT in the arms of patients with Multiple Sclerosis can be effectively differentiated into proximal or distal using these two different tracking tasks.

Despite the variability of the effects of Multiple Sclerosis, most of the AT was distal rather than proximal in this group of patients. Possibly Conduction Block along the CorticoCerebelloCortical pathways caused this distal Tremor.


EBV-Induced Expression & HLA-DR-Restricted Presentation By Human B-Cells Of alphaB-Crystallin, A Candidate AutoAntigen In Multiple Sclerosis

van Sechel AC, Bajramovic JJ, van Stipdonk MJ, Persoon-Deen C, Geutskens SB, van Noort JM
J Immunol 1999 Jan 1;162(1):129-35
TNO Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands

UI# 99101469

The development of Multiple Sclerosis is most likely influenced by AutoImmune responses to Central Nervous System Myelin proteins as well as by infections with common Viruses such as EBV and Human HerpesVirus-6. However, much remains to be established on how these factors interact.

In this study, we show that upon EBV infection, human B-Cells start to express alphaB-Crystallin, a small stress protein that was identified previously as an Immunodominant Ag of CNS Myelin in Multiple Sclerosis patients.

EBV-induced expression of alphaB-Crystallin in B-Cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory alphaB-Crystallin-specific Th cells.

While alphaB-Crystallin is present in EBV-infected human B-Cells, the protein is absent from human Lymphoid tissues under normal conditions.

This is in sharp contrast to other stress proteins such as Heat-Shock Protein (hsp)27 and hsp60 that are ubiquitously expressed in these tissues.

In addition, the absence of alphaB-Crystallin from Lymphoid tissues in humans is unique as compared with other mammals.

All other species examined, including rodents, sheep, and primates, showed constitutive expression of alphaB-Crystallin in secondary Lymphoid tissues and sometimes even in the Thymus.

Since constitutive Lymphoid expression most likely results in Immunologic tolerance, such a state of tolerance to alphaB-Crystallin can be expected for all of these species, but not for humans.

When taken together, our data provide evidence for a novel mechanism by which common Viral infections can trigger Myelin-directed AutoImmunity in a way that is unique for humans.


A Theiler's Virus Alternatively Initiated Protein Inhibits The Generation Of H-2K-Restricted Virus-Specific Cytotoxicity

Lin X, Roos RP, Pease LR, Wettstein P, Rodriguez M
J Immunol 1999 Jan 1;162(1):17-24
Mayo Clinic, Dept of Immunology, Rochester, MN 55905, USA

UI# 99101456

In susceptible mouse strains, the wild-type Daniel's (wt-DA) strain of Theiler's Murine EncephaloMyelitis Virus induces a persistent Central Nervous System (CNS) infection with chronic DeMyelination.

The Virus is cleared from resistant mice with no resulting DeMyelination. We characterized the role of the DA L* protein in late DeMyelination and persistent infection. The DA genome has two alternative reading frames, encoding the virus polyprotein and L*, respectively.

The mutant virus DAL*-1 fails to synthesize L* and does not persist in the CNS of wt-DA-susceptible SJL/J or B10.S mice.

Since Class I-restricted CytoToxicity has been shown to determine resistance to virus persistence and DeMyelination in this model, virus-specific CytoToxicity in the CNS of DA-resistant (B6 or B10) and -susceptible (SJL/J and B10.S) mice during the acute stage of DA and DAL*-1 infection was characterized.

Following IntraCerebral inoculation with DAL*-1, virus-specific Db- and Kb-restricted CTLs were demonstrated in the CNS of resistant B10 mice, whereas only Db-restricted CTL were found in wt-DA-inoculated mice.

CTLs specific to wt-DA or DAL*-1 recognized Class I-presented peptides from either of the viruses.

Of particular interest, Ks-restricted virus-specific CytoToxicity-restricted CTLs were identified in the CNS of susceptible SJL/J (H-2s) and B10.S (H-2s) mice inoculated with DAL*-1.

In contrast, no virus-specific CTLs were identified in the CNS of SJL/J and B10.S mice inoculated with wt-DA.

We propose that L* inhibits the generation of H-2K-restricted Virus-specific CytoToxicity in the CNS, permitting a persistent infection in susceptible strains, with subsequent inflammatory DeMyelination in the CNS similar to that in human Multiple Sclerosis.


Structure & Function Of Myelin Oligodendrocyte Glycoprotein

Johns TG, Bernard CC
J NeuroChem 1999 Jan;72(1):1-9
LaTrobe University, NeuroImmunology Laboratory, Bundoora, Victoria, Australia

UI# 99101139

Myelin Oligodendrocyte Glycoprotein (MOG) is a quantitatively minor component of CNS Myelin whose function remains relatively unknown.

As MOG is an AutoAntigen capable of producing a DeMyelinating Multiple Sclerosis-like disease in mice and rats, much of the research directed toward MOG has been Immunological in nature.

Although the function of MOG is yet to be elucidated, there is now a relatively large amount of biochemical and molecular data relating to MOG.

Here we summarize this information and include our recent findings pertaining to the cloning of the marsupial MOG gene.

    On the basis of this knowledge we suggest three possible functions for MOG:
  1. Cellular Adhesive Molecule
  2. Regulator of Oligodendrocyte MicroTubule stability
  3. Mediator of interactions between Myelin and the Immune System, in particular, the Complement cascade

Given that AntiBodies to MOG and to the Myelin-specific Glycolipid GalactoCerebroside (Gal-C) both activate the same signaling pathway leading to MBP degradation, we propose that there is a direct interaction between the membrane-associated regions of MOG and Gal-C.

Such an interaction may have important consequences regarding the membrane topology and function of both molecules. Finally, we examine how polymorphisms and/or mutations to the MOG Gene could contribute to the PathoGenesis of Multiple Sclerosis.


SubCallosal Striations: Early Findings Of MS On Sagittal, Thin-Section, Fast FLAIR MR Images

Palmer S, Bradley WG, Chen DY, Patel S
Radiology 1999 Jan;210(1):149-53
Memorial MR Center, Long Beach Memorial Medical Center, Long Beach, CA 90806, USA

UI# 99102986

To determine how sensitive and specific the Magnetic Resonance (MR) Imaging finding of SubCallosal striations is for Multiple Sclerosis (MS).

Materials & Methods
In 18 patients with clinically suspected MS and 32 age-matched patients without MS, sagittal 2-mm fast Fluid-Attenuated Inversion-Recovery (FLAIR) imaging was added to the routine MR studies of the Brain.

The images were reviewed for the presence of SubCallosal striations, that is, linear, 1-mm-thick foci of HyperIntensity perpendicular to the Ependyma, like a stack of coins.

The images were masked to exclude the Hemispheric White Matter and were interpreted without knowledge of patient age or medical history.

Seventeen patients with clinical MS had SubCallosal striations (beneath the Corpus Callosum); one did not. Of the 32 patients without MS, five had SubCallosal striations and 27 did not.

SubCallosal striations were highly associated (P < .001) with clinical MS.

SubCallosal striations are thought to represent PeriVenular DeMyelination, that is, the same process that later produces the "ovoid" lesions visible on routine MR images.

SubCallosal striations are not seen on routine axial MR images and can be seen only on 2-mm Sagittal FLAIR images.


CerebroSpinal Fluid Nitrate Levels in Patients with Multiple Sclerosis

de Bustos F, Navarro JA, de Andres C, Molina JA, Jimenez-Jimenez FJ, Orti-Pareja M, Gasalla T, Tallon-Barranco A, Martinez-Salio A, Arenas J
Eur Neurol 1999 Jan;41(1):44-47
Hospital Doce de Octubre, Dept of BioChemistry, Madrid, Spain

PMID# 9885328

It has been suggested that Nitric Oxide (NO) could be implicated in the PathoGenesis of Multiple Sclerosis (MS). Recently, two groups reported increased CerebroSpinal Fluid (CSF) Nitrate levels (Oxidation product that provides an indirect estimation of NO) in MS patients.

However, another group did not confirm these findings. We studied the CSF and Plasma levels of nitrate with a kinetic cadmium reduction method in 11 MS patients and 25 matched controls.

The CSF Nitrate levels and the CSF/plasma Nitrate ratio did not differ significantly between the two study groups. Plasma Nitrate levels were nearly significantly lower in MS patients.

CSF and Plasma Nitrate levels did not correlate with age at onset and duration of the disease in the patient group. These data suggest that measurement of CSF levels of Nitrate is not a marker of the activity of MS.


Local Delivery of TNF by RetroVirus-Transduced T-Lymphocytes Exacerbates Experimental AutoImmune EncephaloMyelitis

Dal Canto RA, Shaw MK, Nolan GP, Steinman L, Fathman CG
Clin Immunol 1999 Jan;90(1):10-14
Stanford Univ, School of Medicine, Dept of Medicine, Stanford, California, 94305-5111

PMID# 9884347

Experimental AutoImmune EncephaloMyelitis (EAE) is an Inflammatory AutoImmune Disease of the Central Nervous System that serves as a model for the human disease Multiple Sclerosis. Paralysis is "induced" by CD4+ T-Cells of the Th1 phenotype.

Tumor Necrosis Factor (TNF ), a Th1 type Cytokine, has been shown to be upregulated in the CNS during the onset of EAE, and systemic manipulations of TNF have had substantial effects on disease progression.

However, the precise role of TNF in EAE has been called into question by recent experiments utilizing TNF and LymphoToxin knockout mice.

We demonstrate here that the local delivery of TNF by Myelin Basic Protein (MBP)-specific T-Cells, RetroVirally transduced to express TNF , exacerbated MBP-induced disease following adoptive transfer into syngeneic mice.

Copyright 1999 Academic Press.


Heat Sensitivity Of Sensory Fibers In Carpal Tunnel Syndrome

Wang AK, Raynor EM, Blum AS, Rutkove SB
Muscle Nerve 1999 Jan;22(1):37-42
Harvard Medical School, Dept of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA

UI# 99098324

Elevations in temperature may produce conduction block in DeMyelinated Neurons. A well-described phenomenon in Multiple Sclerosis, it has also been reported in some patients with inflammatory DeMyelinating PolyNeuropathies.

We used Carpal Tunnel Syndrome (CTS) as a model to study the effect of heat on nerves with focal DeMyelination secondary to chronic compression.

Compound Motor and Sensory responses were measured in 12 CTS patients and 12 normal subjects at 32 degrees C and with heating to 42 degrees C. Changes in relative motor response amplitude and area were similar for both normal subjects and CTS patients.

In CTS patients, however, Sensory response amplitude and area decreased 34.3% and 48.9%, significantly more than the 25.2% and 39.1% reductions in normal subjects (P=0.021 and P=0.018 respectively).

We hypothesize that these reductions in response amplitude are secondary to the occurrence of heat-induced Conduction Block in DeMyelinated Sensory Neurons.

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