MS Abstracts 04a-2g1

  1. Role of Calcium in Nitric Oxide-induced CytoToxicity: EGTA protects mouse Oligodendrocytes
    J NeuroSci Res 2001 Jan 15;63(2):124-135

  2. LPS/IFN-gamma CytoToxicity in Oligodendroglial cells: role of Nitric Oxide and protection by the AntiInflammatory Cytokine IL-10
    Eur J NeuroSci 2001 Feb;13(3):493-502

  3. Magnetization Transfer and Diffusion Tensor MR imaging of Basal Ganglia in Multiple Sclerosis
    J Neurol Sci 2001 Jan 15;183(1):69-72

  4. Interferon-ß-1a administration results in a transient increase of Serum Amyloid A protein and C-reactive protein: comparison with other markers of inflammation
    Immunol Lett 2001 Jan 15;75(3):191-197

  5. Multiple Sclerosis in the Faroe Islands. An epitome
    J Clin Epidemiol 2001 Jan;54(1):1-22

  6. Overexpression of the Apoptosis inhibitor FLIP in T-Cells correlates with disease activity in Multiple Sclerosis
    J NeuroImmunol 2001 Feb 15;113(2):268-274

  7. Analysis of InterLeukin-4 receptor alpha chain variants in Multiple Sclerosis
    J NeuroImmunol 2001 Feb 15;113(2):240-248

  8. Multiple Sclerosis: Genomic rewards
    J NeuroImmunol 2001 Feb 15;113(2):171-184

  9. Gray Matter T2 HypoIntensity is related to plaques and Atrophy in Multiple Sclerosis Brains
    J Neurol Sci 2001 Mar 15;185(1):19-26


Role Of Calcium In Nitric Oxide-Induced CytoToxicity: EGTA Protects Mouse Oligodendrocytes

Boullerne AI, Nedelkoska L, Benjamins JA
J NeuroSci Res 2001 Jan 15;63(2):124-135
Univ of Chicago, Pritzker School of Medicine, Dept of Neurology, Chicago, Illinois
PMID# 11169622

Active Nitrogen species are overproduced in inflammatory Brain lesions in Multiple Sclerosis (MS) and Experimental Allergic EncephaloMyelitis (EAE).

NO has been shown to mediate the death of Oligodendrocytes (OLs), a primary target of damage in MS.

To develop strategies to protect OLs, we examined the mechanisms of CytoToxicity of two NO donors, S-Nitroso-N-Acetyl-Penicillamine (SNAP) and Sodium NitroPrusside (SNP) on mature mouse OLs.

NitroSonium Ion (NO+) rather than NO. mediates damage with both SNAP and SNP, as shown by significant protection with Hemoglobin (HbO2), but not with the NO scavenger PTIO. SNAP and SNP differ in time course and mechanisms of killing OLs.

With SNAP, OL death is delayed for at least 6 hr, but with SNP, OL death is continuous over 18 hr with no delay.

Relative to NO release, SNP is more toxic than SNAP, due to synergism of NO with Cyanide released by SNP. SNAP elicits a Ca2 influx in over half of the OLs within min.

Further, OL death due to NO release from SNAP is Ca2+-dependent, because the Ca2+ chelator EGTA protects OLs from killing by SNAP, and also from killing by the NONOates NOC-9 and NOC-18, which spontaneously release NO.

SNP does not elicit a Ca2+ influx, and EGTA is not protective. In comparison to the N20.1 OL cell line (Boullerne et al., [1999] J. NeuroChem. 72:1050-1060), mature OLs are:

  1. More sensitive to SNAP
  2. Much more resistant to SNP
  3. Sensitive to Cyanide, but not Iron
  4. Exhibit a Ca2+ influx and EGTA protection in response to NO generated by SNAP
Copyright 2001 Wiley-Liss, Inc.


LPS/IFN-gamma CytoToxicity In Oligodendroglial Cells: Role Of Nitric Oxide And Protection By The AntiInflammatory Cytokine IL-10

Molina-Holgado E, Vela JM, Arevalo-Martin A, Guaza C
Eur J NeuroSci 2001 Feb;13(3):493-502
Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Neural Plasticity Unit, Avenida Doctor Arce 37, 28002 Madrid, Spain; and
Fisiologia i Immunologia, Facultad de Medicina, Unitat d'Histologia, Departament de Biologia Cellular, 08193 Bellaterra, Barcelona, Spain
PMID# 11168556

ProInflammatory mediators have been implicated in DeMyelinating Disorders, including Multiple Sclerosis.

Whereas it has been proposed that the AntiInflammatory Cytokines InterLeukins (IL-4) and IL-10 participate in disease recovery.

The present study analyzed the effect of Interferon-gamma (IFN-gamma) and Bacterial EndoToxin (LipoPolySaccharide, LPS) on proliferation and survival of progenitors and differentiated Oligodendrocytes.

We also investigated the presence of receptors for IL-4 and IL-10 in Oligodendroglial cells and explored a possible protective action of IL-4 and IL-10 in cultures following LPS/IFN-gamma.

Finally, the role of endogenous Nitric Oxide (NO) on cell viability and the modulatory action of IL-4 and IL-10 on inducible Nitric Oxide Synthase (iNOS) expression were also analyzed.

We report that LPS and/or IFN-gamma reduced proliferation and viability of Oligodendroglial cells.

Cell death, presumably by Apoptosis as evidence by TUNEL and Annexin V binding, was observed following LPS/IFN-gamma, progenitors being more sensitive than differentiated cells.

At both developmental stages, LPS/IFN-gamma-treated cultures expressed iNOS protein and released micromolar concentrations of NO.

In progenitors, LPS/IFN-gamma-mediated cell damage was partially dependent on endogenous NO production, whereas NO was fundamental for CytoToxicity of differentiated Oligodendrocytes.

Both cell types expressed mRNA for IL-4 and IL-10 receptors and expression of IL-10 receptors at the protein level was also demonstrated.

Treatment with either Cytokine inhibited the expression of iNOS resulting from the ProInflammatory stimulation.

IL-10 was more effective than IL-4 in suppressing iNOS expression and, interestingly, IL-10 conferred protection against Oligodendroglial death evoked by LPS/IFN-gamma.

Our data raise the question of whether IL-10 may play a protective role in DeMyelinating Diseases.

Not only downregulating the function of inflammatory cells but also promoting survival of progenitors and differentiated Oligodendrocytes.


Magnetization Transfer And Diffusion Tensor MR Imaging Of Basal Ganglia In Multiple Sclerosis

Filippi M, Bozzali M, Comi G
J Neurol Sci 2001 Jan 15;183(1):69-72
Scientific Institute, Ospedale San Raffaele, NeuroImaging Research Unit, Dept of NeuroScience, Via Olgettina, 60, 20132, Milan, Italy
PMID# 11166797

Although post-mortem studies have shown that lesions of Multiple Sclerosis (MS) can be detected in the Basal Ganglia, conventional T2-weighted Magnetic Resonance (MR) imaging is poorly sensitive for detecting such abnormalities.

This study was performed to investigate whether Magnetization Transfer (MT) and Diffusion Tensor MR imaging are able to detect in vivo Basal Ganglia changes in patients with MS.

After image coregistration, MT Ratio (MTR) and Mean Diffusivity (Diffusivity) maps were obtained and MTR and Diffusivity values of the Putamen, head of the Caudatus and Thalamus.

Measured from 31 patients with Clinically Definite MS and 14 age- and sex-matched healthy volunteers using region of interest analysis.

Although we found slightly decreased MTR and increased Diffusivity in the Basal Ganglia from patients compared to controls.

Suggesting increased extra-cellular water and reduced amount of 'barriers' restricting water molecular motion in the Basal Ganglia of patients with MS, none of the differences was statistically significant.

These data suggest that the more sophisticated MR probes of tissue disruption and cellular integrity are no more sensitive than current conventional imaging for detecting Basal Ganglia abnormalities in patients with MS.


Interferon-ß-1a Administration Results In A Transient Increase Of Serum Amyloid A Protein And C-Reactive Protein: Comparison With Other Markers Of Inflammation

Boylan MT, Crockard AD, Duddy ME, Armstrong MA, McMillan SA, Hawkins SA
Immunol Lett 2001 Jan 15;75(3):191-197
The Queen's Univ of Belfast, Royal Group of Hospitals Trust, Dept of Microbiology and Immunobiology, Microbiology Building, Grosvenor Road, BT12 6BA, Northern Ireland, Belfast, UK
PMID# 11166375

Putative markers of inflammation such as Serum beta2-MicroGlobulin and Neopterin have been shown to be transiently upregulated following Interferon-beta (IFN-ß) administration to Multiple Sclerosis (MS) patients.

However, to date the role of the important inflammatory mediators Serum Amyloid A Protein (SAA) and C-Reactive Protein (CRP) have not been described.

Here we show that SAA but not CRP is elevated in Relapsing/Remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-ß-1a (Avonex).

This pattern of expression was found to parallel that of beta2-MicroGlobulin and Neopterin following injection.

And was mirrored by a selective activation of peripheral Monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86).

Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated.

Following IFN-ß-1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients.

In addition, IFN-ß-1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.


Multiple Sclerosis In The Faroe Islands. An Epitome

Kurtzke JF, Heltberg A
J Clin Epidemiol 2001 Jan;54(1):1-22
Veterans Affairs Medical Center, NeuroEpidemiology Section, 50 Irving Street, NW, Washington, DC 20422, and Georgetown Univ, School of Medicine, Dept of Neurology, Washington, DC, USA
PMID# 11165464

The Faroe Islands are a semi-independent unit of the Kingdom of Denmark and are located in the North Atlantic Ocean between Norway and Iceland. Efforts to identify all cases of Multiple Sclerosis (MS) since 1900 among Faroese have been continuing for over a quarter century.

As of 1998 prevalence was 66 per 100,000, age adjusted to 1960 US population, with a rate of 100 for women and 34 for men. Median survival was at 29 to 34 years with no significant difference by sex.

Faroese with overseas residence indicated that at least 2 years of exposure from age 11 on in a high-risk area are required for acquisition of MS. Among native resident Faroese the first instance of symptom onset was in 1943, heralding a type 1 epidemic of 21 cases.

This was followed by three successive epidemics of 10, 10, 13 cases, with membership in each epidemic defined by calendar time and age of exposure.

Age at exposure for epidemic I was 11 to 45 years; for later epidemics age 11 was the minimum. We believe the source of MS on the Faroes was their occupation by British troops for 5 years in World War II.

We think they introduced a widespread, specific, persistent (but unknown) infection, probably asymptomatic, which we call the Primary Multiple Sclerosis affection (PMSA).

Only a small proportion of those affected with PMSA will years later show any clinical signs of MS. Models of transmission of PMSA through successive cohorts of Faroese fit the data for epidemics II and III, and predicted the occurrence of epidemic IV.

The Faroese provide an ideal location to determine the nature of PMSA, since the disease has remained geographically stable for 50 years without further spread throughout the islands.


OverExpression Of The Apoptosis Inhibitor FLIP In T-Cells Correlates With Disease Activity In Multiple Sclerosis

Semra YK, Seidi OA, Sharief MK
J NeuroImmunol 2001 Feb 15;113(2):268-274
Guy's Hospital, Guy's, King's and St Thomas' School of Medicine, Dept of NeuroImmunology, SE1 9RT, London, UK
PMID# 11164911

The cellular caspase-inhibitory protein FLIP has been recently identified as a potent regulator of T-Lymphocyte susceptibility to Fas-mediated programmed cell death (Apoptosis).

Since impairment of Apoptosis may be involved in Multiple Sclerosis (MS), we investigated the dynamics of cellular FLIP in unstimulated and activated T-Lymphocytes from MS patients, Inflammatory and Non-Inflammatory Neurological Disorders, and healthy subjects.

Cellular expression of the long and short forms of FLIP protein was similar in unstimulated T-Cells from MS patients and controls, but was significantly higher in activated T-Cells from patients with clinically active MS.

This high FLIP expression in active MS correlated with cellular resistance to Fas-mediated Apoptosis.

In contrast, cellular expression of the Anti-Apoptotic Protein Bcl-2 did not differ between active and stable disease, and was relatively similar between the MS group and controls.

These findings suggest that cellular overexpression of the Anti-Apoptotic protein FLIP is a feature of clinically active Multiple Sclerosis.


Analysis Of InterLeukin-4 Receptor alpha Chain Variants In Multiple Sclerosis

Hackstein H, Bitsch A, Bohnert A, Hofmann H, Weber F, Ohly A, Linington C, Maurer M, Poser S, Rieckmann P, Bein G
J NeuroImmunol 2001 Feb 15;113(2):240-248
Justus-Liebig University, Institute of Clinical Immunology and Transfusion Medicine, LanghansstraBe 7, D-35392, Giessen, Germany
PMID# 11164908

A recent candidate Gene study employing microsatellite markers suggested a possible linkage of Multiple Sclerosis (MS) with the InterLeukin-4 receptor (IL-4R) gene.

Consequently, we investigated the association of different IL-4R variants with MS in 341 German MS patients and 305 healthy controls.

Analysis of the first 100 MS patients for six IL-4R variants showed an increased frequency of the R551 variant in MS patients.

Versus healthy controls and carriage of the same IL-4R variant was weakly associated with Myelin Oligodendrocyte Glycoprotein (MOG) AutoAntiBody production.

However, further analysis of all 341 MS patients did not confirm the finding that this IL-4R variant represents a general Genetic risk factor for MS but revealed an increased frequency of the R551 variant in MS patients with Primary/Progressive MS (PPMS, n=48).

As compared to patients with Relapsing/Remitting MS or Secondary/Progressive MS (RR/MS, SP/MS n=284; P=0.005 for genotype differences) and to 305 healthy controls (P=0.001 for genotype differences).

This association was statistically independent of the presence of the well-known MS susceptibility allele HLA-DRB1*15. After correction for multiple comparisons only the genotype differences between PPMS patients and healthy controls remained statistically significant.

These results indicate, that the IL-4R variant R551 may influence the Genetic predisposition for PPMS but does not represent a general Genetic risk factor for MS.


Multiple Sclerosis: Genomic Rewards

Oksenberg JR, Baranzini SE, Barcellos LF, Hauser SL
J NeuroImmunol 2001 Feb 15;113(2):171-184
Univ of California, School of Medicine, Dept of Neurology, 94143-0435, San Francisco, CA, USA
PMID# 11164900

A large body of Immunologic, Epidemiologic, and Genetic data indicate that tissue inury in Multiple Sclerosis (MS) results from an abnormal Immune Response to one or more Myelin Antigens.

That develops in Genetically susceptible individuals after exposure to an as-yet undefined causal agent.

The Genetic component of MS etiology is believed to result from the action of several Genes of moderate effect.

The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other Genes, post transcriptional regulatory mechanisms, and significant nutritional and environmental influences.

Equally significant, it is also likely that Genetic heterogeneity exists, meaning that specific Genes influence susceptibility and PathoGenesis in some affects but not in others.

Results in multiplex MS families confirm the Genetic importance of the MHC region in conferring susceptibility of MS.

Susceptibility may be mediated by the Class II Genes themselves (DR, DQ or both), related to the known function of these molecules in the normal Immune Response, e.g. Antigen binding and presentation and T-Cell repertoire determination.

The possibility that other Genes in the MHC or the Telomeric region of the MHC are responsible for the observed Genetic effect cannot be excluded.

The data also indicate that although the MHC region plays a significant role in MS susceptibility, much of the Genetic effect in MS remains to be explained.

Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease.

The past few years have seen real progress in the development of laboratory and analytical approaches to study Non-Mendelian complex Genetic disorders and in defining the pathological basis of DeMyelination.

Setting the stage for the final characterization of the Genes involved in MS susceptibility and PathoGenesis.

Their identification and characterization is likely to define the basic Etiology of the disease, improve risk assessment and influence therapeutics.


Gray Matter T2 HypoIntensity is Related To Plaques And Atrophy In Multiple Sclerosis Brains

Bakshi R, Dmochowski J, Shaikh ZA, Jacobs L
J Neurol Sci 2001 Mar 15;185(1):19-26
Univat Buffalo, State Univ of New York, Dept of Neurology, Buffalo, NY, USA
PMID# 11266686

Cortical and SubCortical Gray Matter HypoIntensities on T2-weighted MR images (T2) occur commonly in MS Brains and have been related to disease duration, clinical course, and the level of Neurologic disability.

These HypoIntensities have been reported to occur in the Thalamus, Basal Ganglia, and Rolandic Cortex. We assessed whether T2 HypoIntensity is associated with the severity of White Matter plaques and Atrophy of MS Brains.

In 114 MS patients, HypoIntensity of the Thalamus, Putamen, Caudate, and SensoriMotor Cortex was ordinally rated against age- and gender-matched normal controls on 1.5-T MRI fast Spin-Echo axial T2.

Regional and global T2 HyperIntense and T1 HypoIntense Parenchymal lesion loads were ordinally rated.

Enlargement of SubArachnoid and Ventricular spaces (Atrophy) was ordinally rated vs. age- and gender-matched normal controls. T2 HypoIntensity was highly, positively correlated with many other MRI variables.

Regression modeling showed that T2 HypoIntensity was related to total Atrophy, total T2 lesion load, Third Ventricular Enlargement, Parietal Atrophy, and to a lesser extent, Frontal T1 lesions and Cerebellar T2 lesions, but not related to Gadolinium enhancement.

Ordinal ratings of T2 Lesions and Central Atrophy showed high correlations with quantitative computerized assessments.

We conclude that Gray Matter HypoIntensity on T2 may reflect pathologic Iron deposition and Brain degeneration in MS.

This T2 HypoIntensity is associated with Brain Atrophy and other MR markers of tissue damage.

Further study is warranted to determine if T2 HypoIntensity is predictive of disease course in MS and is a useful surrogate outcome measure in therapeutic trials.

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