Multiple Sclerosis Abstracts

It has been shown that ProInflammatory & AntiInflammatory Cytokines correlate with disease activity in Multiple Sclerosis (MS).

To establish whether such correlations depend on the disease stage, in relation to monthly clinical and Magnetic Resonance Imaging monitoring.

We assessed in a longitudinal fashion the expression of:
1. InterLeukin-12 (IL-12)
2. Tumor Necrosis Factor-
3. Interferon-gamma (IFN-)
4. IL-10 mRNA

By competitive polymerase chain reaction in unstimulated peripheral blood MonoNuclear cells (MNCs) of Relapsing/Remitting (RR MS) and Secondary/Progressive (SP MS) patients.

MS patients had increased levels of IL-12p40 and decreased levels of IL-10 mRNA compared with controls; this difference was most pronounced in SP patients.

Both RR and SP patients had increased levels of IL-12p40 mRNA compared with controls during the development of active Lesions.

Moreover, in RR MS an increase was found before relapse. IL-12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL-12p40 mRNA.

In RR MS, IL-10 mRNA was low 4 weeks before Magnetic Resonance Imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent.

In contrast, SP patients showed low IL-10 mRNA levels constitutively, suggesting that IL-10 plays an important role in the control of disease progression.

Background
Both Genetic and Environmental factors play a role in the PathoPhysiology of MS and may influence the clinical expression of the disease.

Objective
To determine the contribution of familial factors to the clinical expression of MS.

Methods
The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded.

Disability was determined by the Progression Index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years.

Statistical analyzes were performed either with a group of patients (clinical features, relation between Human Lymphocyte Antigene and clinical features) or with a group of sibpairs (concordance for clinical features).

Results
The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03).

Conclusion
This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of Disability might be partly influenced by Familial Factors (Environmental or Genetic).

Objective
To determine whether Diffusion Tensor Imaging (DTI) can detect structural changes in Normal-Appearing White Matter, and to distinguish between Plaques of different pathologic severity, in patients with MS.

Background
Conventional MRI detects lesions sensitively in MS but has limited pathologic specificity.

The Diffusion of water molecules in Brain tissue, most fully expressed mathematically by a Tensor quantity, reflects its intrinsic MicroStructure.

It is now possible to estimate the Diffusion Tensor noninvasively in the human Brain using MR DTI.

This method is unique in providing precise and rotationally invariant measurements of the amount and directional bias (Anisotropy) of Diffusion in White Matter Tracts relating to tissue integrity and orientation.

Methods
DTI was performed in six patients with MS and in six age-matched control subjects.

Diffusion was characterized in Normal-Appearing White Matter in both groups, and in lesions of different pathologic subtypes (Inflammatory, NonInflammatory, T₁ HypoIntense, and T₁ IsoIntense).

Results
DTI identified significantly altered water Diffusion properties in the Normal-Appearing White Matter of patients compared with control subjects (p < 0.001), and distinguished between lesion types.

The highest Diffusion was seen in destructive (T₁ HypoIntense) lesions, whereas the greatest change in Anisotropy was found in Inflammatory (Gadolinium-Enhancing) lesions.

Conclusions
DTI detects diffuse abnormalities in the Normal-Appearing White Matter of MS patients, and the findings in Lesions appear to relate to pathologic severity.

Its use in serial studies and in larger clinical cohorts may increase our understanding of PathoGenetic mechanisms of reversible and persistent Disability.

Matrix MetalloProteinases (MMPs) comprise a family of ProteoLytic Enzymes. MMPs are capable of disrupting the Blood-Brain Barrier (BBB), mediating the destruction of ExtraCellular Matrix and Myelin components.

MMPs are also involved in the processing of a variety of cell surface molecules, including the Pro-Inflammatory Cytokine TNF-. Each of these mechanisms are thought to be important in the PathoGenesis of Multiple Sclerosis (MS).

We investigated mRNA expression of MMP-3, MMP-9 and two Tissue Inhibitors of MetalloProteinases (TIMP-1 and TIMP-2) in parallel in blood MonoNuclear Cells (MNC) from patients with MS and controls, using in situ hybridization.

Numbers of MMP-9 mRNA-expressing cells in blood were higher in patients with MS compared to Other Neurological Diseases (OND), Other Inflammatory Neurological Diseases (OIND) and healthy subjects (P<0.0001 for all comparisons).

Patients with MS had also higher levels of MMP-3 and TIMP-1 mRNA expressing blood MNC compared to patients with OND and healthy subjects. A positive correlation was observed for MMP-9 and TIMP-1 mRNA expression in MS.

These results demonstrate that MMPs and TIMPs are upregulated in MS and may contribute to the PathoGenesis of the disease.

Copyright 1999 Academic Press

Objectives
Stimulation of T-Lymphocytes via the T-Cell Receptor strongly enhances CD27 membrane expression and induces the release of a soluble 32 kDa form of CD27 (sCD27).

CD27 is a member of the TNF Receptor family, a group of molecules that have important roles in Lymphocyte differentiation and survival.

Raised concentrations of sCD27 have been reported in various ImmunoPathological conditions and there is evidence that this molecule can serve as a marker of T-Cell activation in vivo.

Concentrations of sCD27 in CSF were compared between patients with T-Cell mediated Neurological Disease and Non-Inflammatory controls. Also, the relation of CSF-sCD27 concentrations with clinical disease activity was investigated in patients with Multiple Sclerosis.

Methods
Four groups were studied: (1) eight patients with HTLV-1 Associated Myelopathy/ Tropical Spastic Paraparisis (HAM)/TSP), (2) eight HTLV-I carriers, (3) 41 patients with Multiple Sclerosis, and (4) 43 patients with Other Neurological Disease (OND).

Concentrations of CSF-sCD27 were determined by Enzyme Linked Immunosorbent Assay (ELISA).

Results
Quantification of CSF-sCD27 differentiates patients with HAM/TSP from HTLV-I carriers (p<0.01) and from patients with OND (p<0.001). Moreover, the Multiple Sclerosis patient group was different from the OND group (p<0.0001).

In patients with Multiple Sclerosis, CSF-sCD27 concentrations were higher in 24 patients with clinically active disease than in 17 with clinically stable disease.

In addition, most of the patients with Multiple Sclerosis with high sCD27 concentrations showed an increase in EDSS, whereas none of the patients with low sCD27 had an EDSS increase.

Conclusions
As a reliable marker of Immunological Disease activity in Inflammatory White Matter Disease is still not available, it is proposed that quantification of CSF-sCD27 concentrations is a good candidate.

Also, it may serve as a tool to stratify Neurological Diseases in Inflammatory and Non-Inflammatory states.

Oral administration of a Myelin component, Myelin Basic Protein (MBP), induces Immunological unresponsiveness to CNS Ags (Antigens) and ameliorates murine Relapsing Experimental AutoImmune EncephaloMyelitis (REAE).

However, a recent clinical trial in which Multiple Sclerosis patients were treated with repeated doses of oral Myelin was unsuccessful in reducing disease exacerbations.

Therefore, we directly compared the tolerizing capacity of Myelin vs MBP during REAE in B10.PL mice.

Oral administration of high doses of Myelin, either before disease induction or during REAE, did not provide protection from disease or decrease in vitro T-Cell responses.

In contrast, repeated oral administration of high doses of MBP suppressed established disease and MBP-specific T-Cell proliferation and Cytokine responses.

The frequency of IL-2-, IFN--, and IL-5-secreting MBP-specific T-Cells declined with MBP feeding, implicating anergy and/or deletion as the mechanism(s) of Oral Tolerance after high Ag doses.

We have previously shown that the dosage and timing of Ag administration are critical parameters in Oral Tolerance induction.