Association and linkage studies have established the importance of the Major Histocompatibility Complex (MHC) in the susceptibility for Multiple Sclerosis (MS).

We carried out a case-control study to investigate the ancestral haplotype A30B18DR3 and MS in the Nuoro population of Sardinia, which is isolated and Genetically distinct from other populations in the Mediterranean basin.

And characterized by Genetic homogeneity, high level of inbreeding, low migration, high prevalence of MS, high frequency of the relevant haplotype, and high past Malaria prevalence.

Cases and controls were serologically typed for the currently recognized HLA-A, B, and DR Antigens. We used a log-linear approach to fit a wide class of models.

We tested our hypothesis comparing different models via a likelihood ratio test.

We overcame the complication due to unknown gametic phase using expectation-maximization (EM) algorithm as the estimation method.

We estimated confidence intervals for odds ratio by using a profile likelihood approach. We found that:

1. The ancestral haplotype A30B18DR3 was associated to MS after allowing for a possible stratification in cases and controls;

2. DR3 allele was conditional independent on disease status, given A30B18 haplotype;

3. There was a tendency for ORs for the high-risk haplotypes to be higher in the high Malaria strata; however, this indication did not achieve statistical significance (P = 0.11).

Copyright 2001 Wiley-Liss, Inc.

The MHC class II molecule H2-A(s), expressed in the SJL mouse strain, is the principle restriction element of autoreactive CD4⁺ T-Cells mediating Experimental AutoImmune EncephaloMyelitis, an animal model of Multiple Sclerosis.

We deduced the H2-A(s) Ligand motif from the analysis of naturally processed self peptides and from Peptide binding studies.

Major anchor residues were identified using various sets of substituted and truncated Peptides, derived from natural Peptide Ligands and known H2-A(s) binders like Myelin Basic Protein 81 - 99.

The nine-residue H2-A(s) core binding motif comprises an arrangement of anchors in relative positions P1, P4, P6, P7, and P9.

The P1 pocket is relatively unspecific and the P6 pocket favors hydrophobic-aliphatic side chains. The P1 pocket contributes little to Peptide binding.

Primary anchors were identified in P4, P7, and in particular in P9. The preferred anchor residues are Lys (P4), His / Arg (P7), and Pro (P9), respectively.

Ala-polysubstituted Peptides containing only one of these dominant anchor residues still retain the capacity to bind to H2-A(s).

Thus, the presence of only one suitable anchor side chain in P4, P7, or P9 is sufficient for high-affinity Peptide binding, at least in the absence of negatively charged side chains nearby.

The identified Ligand motif facilitates the analysis of Immunogenic Peptides interacting with H2-A(s) and will allow a better prediction of PathoGenetically relevant Peptide Antigens in the AutoImmune mouse model.

The common marmoset Callithrix jacchus (C. jacchus) is an outbred species characterized by a naturally occurring bone marrow chimerism and susceptibility to a form of Experimental AutoImmune EncephaloMyelitis (EAE) resembling Multiple Sclerosis (MS).

T-Cell clones specific for the Myelin Antigen, Myelin Basic Protein (MBP), can be derived from both naive and Immunized marmosets and can adoptively transfer EAE to compatible chimeric siblings.

Here, we demonstrate that severel different Antigenic determinants of MBP are recognized by these Encephalitogenic T-Cell clones. Furthermore, PCR-based analysis of TCR Vbeta families does not show the preferential usage of any Gene segment.

Characterization of third Complementarity Determining Regions (CDR3) fails to demonstrate a recurring motif characteristic of the T-Cell Immune Response to MBP in this species.

Nevertheless, brief Amino Acid motifs are shared among marmoset clones and CDR3 sequences from MS samples.

These data suggest that, due to its outbred condition, the C. jacchus marmoset mounts a diverse pathogenic response to MBP.

However, the findings that certain CDR3 sequences are identically expressed in different animals, or by different T-Cell clones, suggest that MBP-specific T-Cell populations may be clonally expanded following chronic Antigenic stimulation in vivo.

We have studied developing Oligodendrocytes in tissue sections as they initiate Myelination and have found that the transition from PreMyelinating Oligodendrocytes into Myelin-bearing cells is accompanied by a dramatic upregulation in expression of the RNA binding QKI proteins.

We show that in mature Oligodendrocytes in culture, the localization of cytoplasmic QKI isoforms requires an intact CytoSkeleton.

Together with previous observations, this indicates that cytoplasmic QKI proteins facilitate movement of mRNAs to Myelin via the CytoSkeleton.

In the adult rat brain, we found that a subset of Oligodendrocytes displays characteristics of actively Myelinating cells seen during development, i.e., connections to Myelin sheaths and elevated levels of QKI proteins and also MAP1B.

These observations suggest that instead of merely maintaining Myelin, Oligodendrocytes in the normal adult CNS are capable of responding to demands for new Myelin sheaths.

This has important implications for the prospect of repair of Myelin in DeMyelinating conditions such as Multiple Sclerosis.

Copyright 2001 Academic Press.

T-Cell activation requires clustering of a threshold number of T-Cell receptors (TCRs) at the site of Antigen Presentation, a number that is reduced by CD28 co-receptor recruitment of signalling proteins to TCRs.

Here we demonstrate that a deficiency in beta1,6 N-AcetylGlucoSaminylTransferase V (Mgat5), an enzyme in the N-GlycoSylation pathway, lowers T-Cell activation thresholds by directly enhancing TCR clustering.

Mgat5-deficient mice showed Kidney AutoImmune Disease, enhanced delayed-type HyperSensitivity, and increased susceptibility to Experimental AutoImmune EncephaloMyelitis.

Recruitment of TCRs to agonist-coated beads, TCR signalling, actin microfilament re-organization, and agonist-induced proliferation were all enhanced in Mgat5-/- T-Cells.

Mgat5 initiates GlcNAc beta1,6 branching on N-Glycans, thereby increasing N-AcetylLactoSamine, the Ligand for Galectins, which are proteins known to modulate T-Cell proliferation and Apoptosis.

Indeed, Galectin-3 was associated with the TCR complex at the cell surface, an interaction dependent on Mgat5.

Pre-treatment of wild-type T-Cells with Lactose to compete for Galectin binding produced a phenocopy of Mgat5-/- TCR clustering.

These data indicate that a Galectin-GlycoProtein lattice strengthened by Mgat5-modified glycans restricts TCR recruitment to the site of antigen presentation.

Dysregulation of Mgat5 in humans may increase susceptibility to AutoImmune diseases, such as Multiple Sclerosis.

Thirty-one patients were followed-up, at 3-month intervals for the first year and at 6-month intervals for the second year, after an episode of Optic Neuritis.

The object was to confirm previous evidence for a progressive shortening of Visual Evoked Potential (VEP) latencies and to determine whether this is associated with any change in the clinical Ocular examination, Visual fields or Contrast Sensitivity.

VEP latencies were found to decrease significantly during both the first and (less strikingly) the second year.

The most marked changes occurring between 3 and 6 months. Contrast sensitivity improved during the first 9 months, but subsequently tended (non-significantly) to deteriorate.

A similarly transient improvement in Central Visual Field sensitivity was seen in a subgroup of patients with clinically overt Multiple Sclerosis.

In the data from the acutely unaffected fellow eyes, no significant changes in VEP parameters or functional indices were observed.

The findings extend those of a previous study which showed significant shortening of VEP latencies between 6 months and 3 years without significant functional improvement.

Over this period, a significant prolongation of VEP latencies occurred in the asymptomatic fellow eye, accompanied by Contrast Sensitivity Deterioration.

Taken in conjunction, the two studies suggest that recovery processes involving ReMyelination or, possibly, ion channel reorganization proceed for at least 2 years.

The concurrent effects of insidious DeMyelination and/or Axonal Degeneration (also occurring in the fellow Optic Nerve) are initially masked by the recovery process, but gradually become more evident.

The functional benefits of the long-term recovery process are relatively minor and are usually reversed within a few years.

Nevertheless, it is suggested that long-term ReMyelination may perform an important role in protecting DeMyelinated Axons from degeneration.

Understanding the factors which promote long-term ReMyelination may have significant implications for therapy in Multiple Sclerosis.

AntiBodies directed against the ExtraCellular ImmunoGlobulin (Ig)-like domain of the Myelin Oligodendrocyte Glycoprotein (MOG (Igd)) mediate DeMyelination in Experimental AutoImmune EncephaloMyelitis (EAE) and are implicated in the ImmunoPathogenesis of Multiple Sclerosis (MS).

In this study we investigated the Epitope specificity of MOG (Igd)-specific AutoAntiBodies ImmunoPurified from MS patients (n=17) and normal healthy controls (HD; n=9).

ELISA, using a panel of synthetic MOG (Igd) peptides, revealed that the Epitope specificity of this response was heterogeneous in both groups.

The most frequently recognized Epitopes were located in Amino Acid sequences (a.a.) 1-26 (13/17) and 63-87 (15/17) in MS patients, and 14-39 (6/9) and 63-87 (6/9) in HDs, but there was no association between MS and any particular Peptide specificity.

We therefore investigated the ability of the ImmunoPurified AntiBodies to recognize native MOG (Igd) expressed on at the membrane surface by FACS.

Unexpectedly, AntiBodies fulfilling this essential criterion for a DeMyelinating AntiBody response were detected only in one of the MS samples.

These results indicate that the Epitope specificity of the human B-Cell response to MOG is not only heterogeneous, but may only mediate DeMyelination in a limited subset of MS patients.

IL-12/IL-12 receptor (IL-12R) system orchestrates the Th1 pathway of the Immune System by maintaining one of the major bridges between Innate and Adaptive Immune Responses.

Here, we studied both sides of this system in patients with Multiple Sclerosis (MS) and in controls. MS patients displayed elevated IL-12Rbeta1 and IL-12Rbeta2 expression on PHA-activated T-Cells compared to healthy subjects.

Higher percentages of IL-12Rbeta1 and IL-12Rbeta2 positive T-Cells in CerebroSpinal Fluid (CSF) compared to blood were observed both in MS and other neurological diseases (OND).

In contrast, numbers of IL-12 secreting blood MonoNuclear Cells (MNC) were similar in MS and controls.

The functional importance of high IL-12Rbeta2 in MS was underlined by the finding that IL-12 stimulated IFN-gamma production and proliferation of PHA-activated T-Cells correlated with levels of IL-12Rbeta2 expression.

Our data indicates a dysregulation of the IL-12/IL-12R system in MS. It is suggested that even in the absence of increased IL-12 levels, the net effect of IL-12 might be augmented in MS by elevated expression of its receptor.

Purpose
Analyzing a personal series of children with Acute Optic Neuritis (AON), a retrospective study of 28 eyes in 20 patients (mean age: 10;7 years), examined between 1982 and 1997, with a follow-up ranging from 6 months to 15 years (mean: 5;5 years).

We recorded Etiologic factors, clinical features (Ocular and Extra Ocular), Biological results, and NeuroImaging findings.

Results
Initial involvement was unilateral or bilateral with poor Visual Acuity (under 20/200 in 22 eyes of 28).

IntraCerebral inflammation was present in 9 of 13 cases where MRI was performed. We found a cause in only 7 cases (5 Viral diseases and 2 recent vaccinations against Hepatitis B).

Visual recovery was good (over 20/25 in 20 eyes of 28) whatever the treatment, but AON recurred in 5 children. Four children later developed Multiple Sclerosis.

Conclusions
The cause of AON is rarely found. After eliminating an infection, we retained Viral disease, complication of a recent vaccination against Hepatitis B, and Neurological diseases.

MRI was the imaging study of choice. Development of Multiple Sclerosis occurred in 4 cases of 20, the same frequency as in the literature. The risk of later development of Multiple Sclerosis was 20%.

Progression of AON was often excellent. Nevertheless, CortiCotherapy was added, in form of intravenous boluses followed by decreasing oral therapy for one month.

We have analyzed with localized proton Magnetic Resonance Spectroscopy (MRS) 31 lesions in 28 patients with Multiple Sclerosis (MS). The course of the disease was either Relapsing/Remitting, Secondary/Progressive, or Primary/Progressive.

Four patients had an Isolated Neurological Syndrome suggestive of MS. The decrease in the NAA/Cre ratio and the raise of the Cho/Cre ratio were more pronounced in patients with an acute Isolated Neurological Syndrome.

Suggesting the predominance of an inflammatory process, and the presence of an Axonal dysfunction in the initial course of the Lesion.

The NAA/Cre ratio was negatively correlated with clinical disability and thus could be used as an index of disease activity.

Patients with a Secondary/Progressive course exhibited a significant increase in the Myo/Cre ratio compared to those with a Relapsing/Remitting course.

Thus, there may be an association between the evolution towards a progressive disease and Axonal loss or the development of Gliosis.

The IsoIntense lesions to the CerebroSpinal Fluid on MRI T1 weighted sequences were characterized by a sharp raise in the Cho/Cre ratio suggesting DeMyelination and/or intense inflammation.

Gadolinium enhanced lesions were not characterized by a specific NeuroChemical profile.

Autoreactive T-Cells specific for candidate Myelin antigens, including Myelin Basic Protein (MBP) and ProteoLipid Protein (PLP), are thought to play an important role in the PathoGenesis of Multiple Sclerosis (MS).

Myelin-reactive T-Cells primed in vivo by Myelin breakdown products or microbial cross-reactive Antigens during the disease processes may exhibit a reactivity pattern and Cytokine profile different from those in the normal T-Cell repertoire.

In this study, we examined the precursor frequency, the reactivity pattern and Cytokine profile of Myelin-reactive T-Cells that were primed in vitro with overlapping peptides of MBP and PLP in patients with MS and healthy individuals.

The results revealed that T-Cells specific for peptides of MBP and PLP occurred at a relatively higher precursor frequency in patients with MS than that in healthy individuals.

We identified a number of dominant T-Cell epitopes within MBP and PLP, some of which were not previously detected using whole Myelin antigens as the primary stimuli.

Some residues represented common ImmunoDominant regions that were detected in both MS patients and healthy controls while others were associated only with MS.

MBP-reactive T-Cell lines generally exhibited a Th0 like Cytokine profile. There was significantly increased Th1 Cytokine production (ie. TNF- and IFN-) among MS-derived T-Cell lines.

PLP-reactive T-Cell lines had a distinct Cytokine profile, producing predominantly TNF- and little or not IFN- and IL-4.

The findings have important implications in the understanding of the role of Myelin-reactive T-Cells in MS.