MS Abstracts: 3e-2g

Introduction And Objective
Discrimination and quantification of the environmental and Genetic components involved in developing Multiple Sclerosis (MS) have not been made.

In order to discriminate these components, which could demonstrate the relevance of the Genetic component, we have ascertained affected individuals by MS belonging to the Paisa community from Antioquia, Colombia, a state localized in the tropical area of South America, to detect eventual linkage disequilibrium to HLA, locus DQ alpha.

Development
A contingence analysis among case-control HLA DQ alpha Genotype distributions, by using Monte Carlo resampling method to solve small number sample, showed that there are significant differences between the two groups.

We observe that HLA DQ alpha 1.1, 1.2 allele frequencies were higher in the cases than in the controls. Also, there was significant HLA DQ alpha 3 allele lower frequency (p < 0.05) in the cases than in the controls.

Conclusions
Similar results have been described in other Caucasian populations living in non tropical areas.

Before results could indicate that the Caucasoid populations Genetic component implied in the susceptibility to MS have remained in Paisa community, whether the environmental component, being meaningful to develop MS.

Although the clinical manifestations and NeuroPathological signs of Multiple Sclerosis (MS) have been known for a century, the cause of this disease has not yet been determined.

The Epidemiological studies indicate that MS is of Multifactorial Etiology, including both environmental and inherited (Genetic predisposition) factors. The role of the HLA system in Genetic predisposition to MS has been known since the 1970s.

As a result of the progress made in human Genetics, it is now possible to study Genetic predisposition to MS.

Recent studies in chicken, rodents and transgenic mice have provided new insight on the nature of factors essential to Oligodendrocyte development.

Here we first review how sonic hedgehog (shh) graded signalling induces emergence of Oligodendrocytes in the Embryonic Spinal Cord from birds to man.

We then discuss the way in which Thyroid Hormone successively signals different thyroid receptors to control fate determination, growth and differentiation in the Oligodendrocyte lineage.

Platelet-Derived Growth Factor (PDGF) is a potent regulator of Oligodendrocyte Progenitor (OP) migration and proliferation, while Insulin-like Growth Factor 1 (IGF-1) acts both on Neurons and Myelin-forming cells to promote Myelination.

The balance between OP proliferation and differentiation appears to be controlled by different sets of Growth Factors locally synthesized in the Central Nervous System (CNS) as well as Glutamate.

In experimental models of Multiple Sclerosis (MS), the Neuregulin isoform Glial Growth Factor 2, IGF-1 and some NeuroTrophins can promote ReMyelination after an episode of inflammatory DeMyelination.

A future challenge is to determine how to induce multipotential Neural Precursors to generate migratory OP and enhance the ReMyelination process in the adult CNS.

In Multiple Sclerosis (MS), one of the most frequent DeMyelinating diseases in man, ReMyelination of DeMyelinating lesions exists but is often incomplete.

Also reported in experimental models of DeMyelination, this phenomenom confirms the regenerating potential of the DeMyelinated Central Nervous System (CNS) and, in particular, the existence of an endogenous mechanism of Oligodendrocyte renewal.

Failure in efficient ReMyelination could result from exhaustion of the pool of ReMyelinating cells, loss of Axons and absence of a permissive environment for ReMyelination.

Identifying the nature and the origin of the cells capable of generating new Oligodendrocytes for ReMyelination could contribute to strategies to activate these cells, and thereby enhance their potential for Myelin repair.

Within the adult CNS, several cell types are capable of generating new Oligodendrocytes following Myelin damage:

1. Post-Mitotic Oligodendrocytes frequently found at the lesion site
2. Oligodendrocyte Progenitors whose existence has been confirmed both in vitro and in vivo
3. Multipotent cells localized in the germinative areas of the Brain and the Spinal Cord

Although restricted to particular sites of the CNS, these multipotent cells, which maintain the capacity to self-renew and to migrate throughout adulthood, could constitute a powerful source of ReMyelinating cells.

The study of the mechanisms of proliferation, migration and differentiation of these cells in response to DeMyelination should allow the definition of new strategies to promote endogenous ReMyelination and develop therapeutic approaches for DeMyelinating Diseases such as MS.

This goal is an appealing alternative to the transplantation of Myelin-forming cells and should efficiently complement strategies aimed at reducing Neuronal Loss and inflammation.

The Myelination of the Axons of the Central Nervous System (CNS) is assumed by the Oligodendrocytes, which depend at least in part on signals of Axonal origin.

The Axonal influence on Myelination seems to consist of the sum of positive and negative factors, which can either act on the Axon or on the Oligodendrocyte, allowing the Neurons to decide when and where Myelinization is initiated.

The induction factors appear to be mediated, in some cases, by electrical activity.

Among the negative factors, certain factors such as the Adhesion Molecule PSA-NCAM seem to act by inhibiting the adhesion between the Axon and the Oligodendrocytic extension.

Others, such as the inhibitory signalling pathway, jagged1/Notch1, appear to trigger an inhibitory Oligodendroglial signalling, theraby preventing maturation and Myelination.

The recent determination of the role of these Axonal signals has provided a new approach to the mechanisms of normal Myelination.

These results could be extrapolated to the process of ReMyelination in human DeMyelinating Pathologies such as Multiple Sclerosis, and open up new therapeutic research possibilities aimed at Neuronal protection.

RetroViral involvement in the Pathogenic cascade in Multiple Sclerosis (MS) and a Cytotoxic activity with narrow specificity towards Glial Cells have been recently considered as credible working hypotheses to explain some of the complex PathoPhysiological and NeuroPathological features of MS.

The partial characterization of exogenous RetroViral sequences, thought to be associated with MS, has led us to the identification of new human endogenous RetroViruses closely related to the ExtraCellular Multiple Sclerosis associated RetroVirus (MSRV).

These endogenous RetroViruses (HERV-TcR and HERV-7q) have the potential to be transcribed into RNA and proteins. Interestingly, the env domain of HERV-7q could code for a 59.8 kDa secreted GlycoProtein (called Enverin) with an ImmunoRegulatory region.

The presence in various MS biological fluids of a Cytotoxic activity able to induce programmed cell death for Oligodendrocytes and Astrocytes suggests the possibility of a DeMyelination phenomenon as part of direct Glial Cell damage.

Moreover, both RetroViral expression and cytotoxic factor production have been evidenced in MS Monocyte/Macrophage cultures and MS CerebroSpinal Fluid.

It is now crucial to better characterize the endo/exo RetroViruses possibly involved in MS and their Pathogenic potential, and to identify the contributing factor(s) to the GlioToxicity found in the MS CerebroSpinal Fluid or Serum, as well as to elucidate the mechanism of induction of the observed programmed Glial Cell death.

This disease is characterized by the following:

1. An infiltration of the White Matter of the Brain and Spinal Cord by inflammatory cells;

2. The T and B-Lymphocytes, present in the lesions or in the CerebroSpinal Fluid of patients, show signs of activation; i.e., the classic IgG OligoClonal Bands of the CerebroSpinal Fluid (activation of B-Lymphocytes) and the presence of activation markers on the surface of the T-Lymphocytes;

3. The presence of an association, and a linkage between the disease and the Genes of the HLA complex.

4. The HLA molecules are implicated in the presentation of the Antigen to the T-Lymphocytes;

5. Finally, it should be noted that the therapeutic approaches aimed at reducing (ImmunoSuppressants) or at modulating (Interferon-ß, Copolymer 1) the Immune Responses have a positive effect on this disease.

Whereas those treatments which activate the Immune System (Interferon-gamma) have a negative effect.

Treatment with Interferon (IFN-ß) has been proposed as a therapeutic approach in Multiple Sclerosis (MS) patients, mostly in view of its ImmunoModulating actions.

At the same time, evidence has been provided that MS patients exhibit PolyMorphoNuclear Cell (PMN) deficits, which can explain the increased susceptibility to infections in these subjects.

Here, in 28 patients with Relapsing/Remitting (RR) MS under treatment with recombinant (r)-IFN-ß PMN polarization and PMN and Monocyte (MO) Phagocytosis and killing, as well as T-Cell mediated AntiBacterial activity, were evaluated before treatment and over a period of nine months of treatment.

Our results point out an enhanced rate of polarization (both "spontaneous" or N-formyl-methionyl-leucyl-phenylalanine-induced) in MS patients. After r-IFN-ß-1b treatment the polarization rate was further increased.

On the contrary, PMN and MO phagocytosis and killing were depressed in comparison to controls and values were further reduced by r-IFN-ß-1b treatment.

In patients T-Cell mediated antibacterial activity was decreased at T0 and dramatically dropped in the course of r-IFN-ß-1b therapy.

Oligodendrocyte cell migration is required for the development of the Nervous System and the repopulation of DeMyelinated lesions in the adult Central Nervous System.

We have investigated the role of the calcium-dependent Adhesion Molecules, the cadherins, in Oligodendrocyte-astrocyte interaction and Oligodendrocyte Progenitor migration.

Immunostaining demonstrated the expression of N-Cadherin on the surfaces of both Oligodendrocytes and Astrocytes, and Oligodendrocyte-like cells adhered to and spread on N-Cadherin substrates.

The blocking of Cadherin function by AntiSera or specific Peptides reduced adhesion of Oligodendroglia to Astrocyte Monolayers, diminished contact time between Oligodendrocyte processes and individual Astrocytes, and significantly increased the migration of Oligodendrocyte-like cells on Astrocyte Monolayers.

Furthermore, a soluble Cadherin molecule without adhesive properties increased Oligodendroglial proliferation on various ExtraCellular matrix substrates.

These data suggest that Cadherins are at least partially responsible for the poor migration-promoting properties of Astrocytes and that decreasing cell-cell adhesion might effect repopulation of DeMyelinated Multiple Sclerosis lesions by Oligodendrocyte progenitors.

Copyright 2000 Academic Press.

Myelin protein reactive CD4⁺ T-Cells are considered to be involved in the proposed ImmunoPathoGenesis of Multiple Sclerosis (MS). One particularly important molecule for T-Cell activation is the CD40L (gp39) that is expressed on the surface of T-Cells.

This study focuses on the CD40 and the CD40L expression on MonoNuclear Cells prepared from blood from patients with MS, Other Neurological Diseases (OND) and healthy subjects.

Immunostaining followed by a three channel flow cytometry was adopted. Patients with MS had higher levels of CD3⁺CD40L⁺, CD4⁺CD40L⁺ and CD8⁺CD40L⁺ T-Cells compared to patients with OND and healthy subjects.

Cross-sectional comparisons revealed that the elevation of CD40L⁺ T-Cell subtypes was confined to the patients with untreated MS and not observed in the patients with MS treated with Interferon-beta (IFN-ß).

Follow up studies showed that levels of CD3⁺CD40L⁺ and CD4⁺CD40L⁺ T-Cells decreased in individual patients after the initiation of the IFN-ß treatment.

The enhanced expression of CD40L on CD3⁺, CD4⁺ and CD8⁺ T-Cells in patients with MS may implicate a role for this molecule in disease ImmunoPathoGenesis.

Multiple Sclerosis (MS) is an Inflammatory Demyelinating Disease of the Central Nervous System (CNS) which results in DeMyelination and Axonal injury.

Conventional therapy for MS is Immune suppression in the absence of agents that promote Neural and Glial survival or ReMyelination.

Neuregulins are a family of Ligands that exert Trophic effects on both Neurons and Glia.

Using mice bearing a null mutation in the Neuregulin Gene, here we demonstrate that Neuregulins are necessary for the normal development of Oligodendrocytes.

In addition, Neuregulins are produced in the normal human CNS by Astrocytes as well as Neurons. Astrocyte-derived Neuregulin is functionally active in bioassays and exists in secreted and membrane-associated beta-Isoforms.

In active and chronic active MS lesions, however, the expression of Astrocyte Neuregulin is dramatically reduced. The absence of Neuregulin in active MS lesions may contribute to the paucity of ReMyelination in MS.

Copyright 2001 S. Karger AG, Basel