MS Abstracts 01b-2g8

Multiple Sclerosis (MS) is an inflammatory disease of the CNS White Matter associated with T-Cell infiltrates and alterations of Immune functions that can be measured in the Peripheral Immune System.

TIM-3 has been identified as a Central regulator of IFN-gamma-secreting type 1 Th (Th1) cells and Immune tolerance.

In this study, using a newly generated mAb against human TIM-3, we examined TIM-3 function on ex vivo CD4⁺ T-Cells isolated from the circulation of healthy subjects and patients with MS.

Blocking TIM-3 during T-Cell stimulation significantly enhanced IFN-gamma secretion in control subjects but had no effect in untreated patients with MS.

Demonstrating a defect in TIM-3 ImmunoRegulation. Treatment with Glatiramer Acetate or IFN-beta reversed this functional defect.

Reduced levels and altered kinetics of T-Cell TIM-3 expression, which was restored in treated patients, is one mechanism that can explain the loss of TIM-3 regulation of T-Cell function in untreated patients with MS.

These data provide functional, mechanistic data for dysregulated TIM-3 ImmunoRegulation in a human Autoimmune Disease and suggest that approved therapies for the treatment of MS may function in part by restoring TIM-3 ImmunoRegulation of T-Cell function.

PMID#

Background
Cerebellar dysfunction is common in patients with Multiple Sclerosis (MS). However, NeuroPsychological studies of this clinical feature are lacking.

Objective
We investigate the NeuroPsychological features in Relapsing/Remitting MS (RR-MS) patients with and without Cerebellar Dysfunction.

Methods
Twenty-one RR-MS patients with Cerebellar Dysfunction (RR-MSc), characterized by prevalent Ataxic gait and Nystagmus.

And 21 RR-MS patients without any Cerebellar manifestation (RR-MSnc) pair-matched for demographical and clinical variables were studied.

All patients from each group underwent an extensive battery of NeuroPsychological tests.

Magnetic Resonance Imaging analysis included HyperIntense fast Fluid-Attenuated Inversion-Recovery lesion load in the Whole Brain as well as in the Four Lobes separately.

Results
Any significant differences were detected in total and Regional Lesion Load measurements between the two groups. RR-MSc group performed equally as well as the RR-MSnc group on many of the Cognitive exploration measures.

Nevertheless, the RR-MSc group performed more poorly than the RR-MSnc group on Attention tests (Symbol Digit Modalities Test) and Verbal Fluency tests (Controlled Oral Word Association Test); neither of the test results proved to be affected by Regional Lesion Loads.

Conclusion
These results highlight the importance of considering Cognitive Deficits associated with the presence of Cerebellar Symptoms in RR-MS.

Objectives
To describe variations in Fatigue over the course of 2 years in a sample of persons with Multiple Sclerosis (MS).

And to investigate the predictive value of the following variables on variations in Fatigue: sex, age, sense of coherence, living with a partner, living with children, work status, ImmunoModulatory Treatment, mood, disease severity, disease course, time since diagnosis and time.

Methods
Every 6 months, 219 outpatients at an MS specialist clinic were assessed using the Fatigue Severity Scale (FSS).

Predictive values were explored with Generalised Estimating Equation employing proportional odds models; FSS scores were categorised as non-fatigue, borderline Fatigue or Fatigue.

Results
FSS scores varied significantly (p = 0.02); 54% changed FSS category one or several times, 27% were persistently fatigued and 19% persistently non-fatigued.

Independent predictors of increased fatigue were depressive symptoms, weak/moderate sense of coherence, living with a partner and not working. Furthermore, moderate disease severity predicted increase when combined with >10 years since diagnosis or a Progressive course.

Independent predictors of decreased Fatigue were no Depressive symptoms, strong sense of coherence, living alone and working.

Moreover, mild and severe disease predicted a decrease when combined with >10 years since diagnosis, and mild severity combined with a Progressive course.

Conclusion
Mood, sense of coherence and living with a partner were independent predictors of Fatigue in persons with MS.

In addition to monitoring disease related variables, health related services should apply a broad range of approaches and repeatedly assess Fatigue in persons with MS, to provide preventive care and appropriate interventions.

Objective
To explore variations and the capacity of selected factors - contextual factors, disease-related characteristics, Cognition, Fatigue, Mood and Time - to predict an increase in the perceived physical and Psychological impact of Multiple Sclerosis (MS) over a two-year period.

Methods
At an MS specialist clinic, 219 outpatients were included in the study and data were collected every 6 months.

The Multiple Sclerosis Impact Scale was used for assessment of the perceived physical and psychological impact of MS.

For statistical analysis of changes in impact during the study period, Friedman ANOVA was used and predictors of increased impact were explored with Generalized Estimating Equations employing proportional odds models.

Results
The majority had changes in perceived physical impact of established important magnitude and the Psychological impact varied significantly.

A period of more than 10 years since diagnosis, Cognitive Disability, Fatigue and signs of Depression were independent predictors of increase in physical impact.

Weak or moderate sense of coherence, absence of ImmunoModulatory Treatment, Fatigue and signs of Depression were independent predictors of increase in Psychological impact.

Conclusion
The fluctuation in perceived impact should be taken into account in clinical decision-making and when designing studies and interpreting the results.

This study identifies the predictors of increased perceived physical and Psychological impact that health-related services should pay special attention to, in order to provide interventions aimed at minimizing the perceived impact of MS.

Purpose
To investigate whether a recently improved version of the Three-Dimensional Double Inversion-Recovery (3D-DIR) technique enables the in vivo detection of Hippocampal lesions in Multiple Sclerosis (MS).

Materials And Methods
Magnetic Resonance Images of 16 patients and nine healthy control subjects were acquired at 1.5T.

Lesions were scored on 3D-DIR images and were anatomically classified as White Matter (WM), Cortical, or Hippocampal lesions.

Associations between Hippocampal, Cortical, and WM lesion numbers were evaluated. Also, Hippocampal lesions were retrospectively assessed on 3D-T₂ and Hippocampal and Brain Volumes were measured.

Results
No Hippocampal lesions were detected in control subjects. By contrast, 14 out of 16 MS patients had at least one Hippocampal lesion.

The mean number (+/-SD) of Hippocampal lesions detected with 3D-DIR was 2.6 +/- 1.8 in MS patients; only 56% of these lesions could be observed on 3D-T₂.

Conclusion
Hippocampal lesions can be visualized in vivo with 3D-DIR and occur frequently in MS.

The ability to visualize Hippocampal lesions in vivo is of fundamental importance to future studies focusing on the role of Gray Matter (GM) damage in Cognitive Deficits, which are common in MS.

J. Magn. Reson. Imaging 2008. (c) 2008 Wiley-Liss, Inc.

HLA-DRB1 is the major locus associated with risk for Multiple Sclerosis (MS). A recent genome-wide study showed three additional Single-Nucleotide Polymorphisms (SNPs), within the IL-2RA and IL-7RA genes respectively, also to be associated with MS.

Consistent association but lower significance was found for 13 other SNPs.

In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population.

Apart from the Human Leukocyte Antigen locus, the EVI5 gene on Chromosome 1 was confirmed as a novel risk gene, with Odds Ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P=0.01).

The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS.

On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P=0.03 and OR 1.15; P=0.04).

This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Genes and Immunity advance online publication, 10 April 2008; doi:10.1038/gene.2008.22.

Multiple Sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden.

MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene.

The well-established Human Leukocyte Antigen (HLA) association does not completely explain the genetic impact on disease susceptibility.

However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes.

Recently, associations with two Single Nucleotide Polymorphisms (SNPs) in the IL-2RA gene (rs12722489, rs2104286) and one SNP in the IL-7RA gene (rs6897932) have been reported by several groups.

These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA).

We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5.

The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Genes and Immunity advance online publication, 20 March 2008; doi:10.1038/gene.2008.14.

Macrophages respond to LPS by the rapid activation of ProInflammatory Cytokine that serve to initiate host defense against microbial invasion.

To prevent injury to the host from excess production of these Cytokines, IL-10 is up-regulated to feedback inhibit the ProInflammatory response.

However, the molecular events responsible for LPS-induced up-regulation of IL-10 remain to be elucidated.

In this study, we provide evidence that production of and signaling by Type 1 IFN is required for LPS-induced IL-10 up-regulation.

In addition, we demonstrate that defect in Type 1 IFN production and signaling results in a trend toward LPS-mediated superinduction of ProInflammatory genes and Cytokines in bone marrow-derived Macrophages.

Our findings suggest a novel AntiInflammatory role for the Type 1 IFN production and signaling pathway in regulating LPS response in bone marrow-derived Macrophages.

The Type 1 Interferons (IFNs), Interferon- and IFN-ß, are Cytokines that have AntiViral, AntiProliferative, and ImmunoModulatory activities. Data are now emerging that suggest that Type 1 IFNs are also important mediators of AntiInflammatory Responses.

These findings, largely driven by studies to explain the beneficial effects of IFN-ß in the treatment of Multiple Sclerosis, an Autoimmune Disease of the Central Nervous System, offer a number of mechanisms for the AntiInflammatory properties of Type 1 IFNs.

Type 1 IFNs, through their ability to induce the ImmunoSuppressive Cytokine InterLeukin-10 (IL-10), mediate the inhibition of ProInflammatory gene products.

In addition, Type 1 IFNs induce other ImmunoSuppressive mediators such as suppressor of Cytokine signaling–1 (SOCS-1) and TristeTraPolin (TTP), which act by divergent mechanisms to restore homeostasis to the Immune System.

Furthermore, Type I IFNs mediate AntiInflammatory and protective effects in a variety of Autoimmune Disease models such as Experimental Colitis, Experimental Allergic Encephalomyelitis, Experimental Arthritis, and Neonatal Inflammation.

Here, we discuss the molecular basis for the AntiInflammatory properties of Type 1 IFNs and their therapeutic potential in AutoImmune and Inflammatory Diseases.

Objective
Some patients with Relapsing/Remitting Multiple Sclerosis (RRMS) do not respond to treatment with Interferon-ß and continue to have relapses and new enhancing lesions on MRI.

The markers which would predict the treatment response are still not known.

The objectives of the study were to compare Cytokines levels (IFN-, IL-4, IL-6, IL-10) and expression of Adhesion Molecules before and during treatment in responders and nonresponders to IFN-ß treatment.

Methods
Twenty-nine patients with RRMS were enrolled in the study.

Cytokine levels were evaluated by ELISA in supernatants of IONO/PMA activated PBMC cultures (IFN-, IL-4, IL-6, IL-10), and by flow cytometry (IntraCellular IFN-, IL-4 and IL-2R expression) before and during treatment.

Expression of Adhesion Molecules (VLA-4, ICAM-1) was evaluated by flow cytometry (CD49⁺ and CD54⁺) before and during treatment.

Results
Only 9 of 29 patients were responders to treatment according to definition (no relapse in the first 2 years of treatment).

We found significant differences in the expression of IL-2R after 1 month of treatment, IntraCellular IFN- after 6 months of treatment and IL-10 level in nonactivated PBMC cultures after 1 week of treatment.

Conclusion
We concluded that the differences we had found between responders and nonresponders are most probably incidental and not predictive of treatment response.

Our study shows that Cytokines levels and expression of Adhesion Molecules cannot be used as markers for treatment response.

MS is thought to be mediated by CD4⁺ T-Helper Cells.

To investigate the importance of CD8⁺ CytoToxic T-Cells in MS we analyzed peripheral blood T-Cells by DNA microarray, and Plasma and CSF levels of Granzymes from MS patients and controls.

CytoToxic gene expression was decreased in peripheral T-Cells from RRMS patients whereas plasma levels of Granzymes were unchanged.

However, Granzyme levels were elevated in the CSF of RRMS patients at relapse compared with controls and remission.

Thus, CD8⁺ T-Cell-mediated CytoToxicity is confined to the CSF/CNS compartment in RRMS patients and may be involved in the ImmunoPathogenesis of clinical relapses.

Background
Individual Magnetic Resonance Imaging (MRI) disease severity measures, such as Atrophy or Lesions, show weak relationships to clinical status in patients with Multiple Sclerosis (MS).

Objective
To combine MS-MRI measures of disease severity into a composite score.

Design & Setting
Retrospective analysis of prospectively collected data. Community-based and referral subspecialty clinic in an academic hospital.

Patients
A total of 103 patients with MS with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom:
1. 62 (60.2%) had the Relapsing/Remitting
2. 33 (32.0%) the Secondary/Progressive, and
3.   8 (7.8%) the Primary/Progressive form

Main Outcome Measures
Brain MRI measures included baseline T₂ HyperIntense (T₂LV) and T₁ HypoIntense (T₁LV) Lesion Volume and Brain Parenchymal Fraction (BPF), a marker of global Atrophy.

The ratio of T₁LV to T₂LV (T₁:T₂) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T₂LV, BPF, and T₁:T₂.

Results
The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T₁:T₂, and MRDSS and weak for T₂LV.

The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the Relapsing/Remitting form from those with the Secondary/Progressive form.

Models containing either T₂LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)-year observation period, when adjusting for baseline EDSS score.

Conclusion
Combining Brain MRI lesion and Atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.