Recently, much has been learned about the Immunology of Multiple Sclerosis (MS). However, a mechanistic understanding of currently employed ImmunoModulatory therapies has lagged behind, hindering both the search for more effective agents and clearer insight into the ImmunoPathoGenesis of MS.

Christopher Karp and colleagues explore a unifying hypothesis for the mechanism of action of Interferon-ß in MS: suppression of InterLeukin-12 production.

Increasing body of evidence which suggests a crucial role for InterLeukin-12 (IL-12) in modulating Immune Responses in Multiple Sclerosis (MS) prompted us to analyze IL-12 in Serum from MS patients.

We measured the Sera concentrations of IL-12, Tumor Necrosis Factor (TNF)- and Transforming Growth Factor-ß1, in 21 MS patients and 13 patients with Non-Inflammatory Nervous Diseases.

In clinically active MS, Serum levels of IL-12 were detectable in 53% and TNF- in 40% of patients. None of the patients with clinically inactive MS had detectable IL-12 and TNF- Sera levels.

Analysis of Serum concentrations of all three Cytokines revealed no significant differences between MS patients and controls. These findings provide further evidence that both IL-12 and TNF- might have an active role in ImmunoPathoGenesis of MS.

Magnetic Resonance (MR) Diffusion imaging is a useful technique with which to increase our understanding of pathologic damage to the Central Nervous System.

To fully quantitate Diffusion and Anisotropy in the Spinal Cord, as in other tissues, it is necessary to determine the Diffusion Tensor.

If Spinal Cord Diffusion is assumed to be cylindrically symmetric and the orientation of the Cord in the gradient frame is known, then it is shown that full quantification is possible from only three images, two of which are Diffusion-weighted.

Mean Diffusivity and volume ratio were determined in the normal Cord of four healthy volunteers and in seven Cord lesions of three patients with Clinically Definite Multiple Sclerosis (MS) who had locomotor disability suggesting the presence of Spinal pathology.

MS Cord lesions exhibited increased Mean Diffusivity reflecting structural damage to the Cord White Matter.

Quantification of Diffusion and Anisotropy using Spinal Cord Diffusion imaging provides new structural information in relation to Spinal Cord pathology in vivo.

Localized short echo time Magnetic Resonance (MR) Spectra were obtained from patients with Multiple Sclerosis of Relapsing/Remitting or Secondary Chronic/Progressive course and from healthy controls.

Automated analysis using model Spectra, sensitivity correction, and subtraction of partial Ventricular volume yielded tissue concentrations of metabolites that were in line with findings of previous studies.

Additional findings were increased Creatine in chronic lesions and increased Myo-Inositol in Normal-Appearing White Matter. Regression analysis was performed to reveal concomitant changes of metabolite concentrations.

Differences in the correlations between Cholines and Myo-Inositol suggest increased expression of Myo-Inositol in chronic lesions or of Cholines in active, contrast-enhanced lesions.

A correlation between N-AcetylAspartate and Creatine, which is probably due to ExtraCellular Edema, was observed in active but not in chronic lesions.

Creatine and Cholines correlated in chronic lesions, which may be the result of Gliosis. The consequences of these findings for the interpretation of absolute concentrations and Creatine ratios are discussed.

Whereas co-stimulation of the T-Cell Antigen Receptor (TCR) and CD28 triggers T-Cell activation, stimulation of the TCR alone may result in an Anergic state or T-Cell deletion, both possible mechanisms of Tolerance induction.

Here we show that T-Cells that are deficient in the adaptor molecule Cbl-ß (ref. 3) do not require CD28 engagement for InterLeukin-2 production, and that the Cbl-ß-null mutation (Cbl-ß(-/-)) fully restores T-Cell-dependent AntiBody responses in CD28-/- mice.

The main TCR signalling pathways, such as Tyrosine Kinases Zap-70 and Lck, Ras/Mitogen-activated Kinases, Phospholipase Cgamma-1 and Ca²⁺ mobilization, were not affected in Cbl-ß(-/-) T-Cellls.

In contrast, the activation of Vav, a Guanine Nucleotide exchange factor for Rac1/Rho/CDC42, was significantly enhanced. Our findings indicate that Cbl-ß may influence the CD28 dependence of T-Cell activation by selectively suppressing TCR-mediated Vav activation.

Mice deficient in Cbl-ß are highly susceptible to Experimental AutoImmune EncephaloMyelitis, suggesting that the dysregulation of signalling pathways modulated by Cbl-ß may also contribute to human AutoImmune Diseases such as Multiple Sclerosis.

The mechanisms underlying Oligodendrocyte (OLG) loss and the precise roles played by OLG death in human DeMyelinating Diseases such as Multiple Sclerosis (MS).

And in the rodent model of MS, Experimental AutoImmune EncephaloMyelitis (EAE), remain to be elucidated.

To clarify the involvement of OLG death in EAE, we have generated transgenic mice that express the Baculovirus Anti-Apoptotic Protein p35 in OLGs through the Cre-loxP system.

OLGs from cre/p35 transgenic mice were resistant to Tumor Necrosis Factor-Tumor Necrosis Factor--, anti-Fas AntiBody- and Interferon--induced cell death.

cre/p35 transgenic mice were resistant to EAE induction by immunization with the Myelin Oligodendrocyte Glycoprotein.

The numbers of infiltrating T-Cells and Macrophages/Microglia in the EAE lesions were significantly reduced, as were the numbers of Apoptotic OLGs expressing the activated form of Caspase-3.

Thus, inhibition of Apoptosis in OLGs by p35 expression alleviated the severity of the neurological manifestations observed in AutoImmune DeMyelinating Diseases.

Maintenance of health is dependent on numerous regulatory interactions between organ systems.

This review discusses InterOrgan communication between the Nervous, Endocrine, and Immune Systems and Environmental and Genetic influences on this NeuroEndocrine Immune Circuitry.

Stresses of multiple types, including psychological and exposure to chemicals and infectious agents, may combine to enhance NeuroImmunoToxicology.

Altered Nervous System functions can alter immunity which could result in exacerbation of Infections, Cancers or other Immune-associated problems.

Inversely, abberant Immune System activities could lead to pathologies associated with altered nervous activities, such as Alzheimer's Disease, Chronic Fatigue, or Multiple Sclerosis.

The Nervous, Endocrine and Immune Circuitry is multi-directional, and a chemical, physical or emotional stress could upset the homeostasis.

The precise role of Tumor Necrosis Factor alpha (TNF) in Multiple Sclerosis (MS) is still controversial.

Most findings from the animal model Experimental Allergic EncephaloMyelitis have yet to be confirmed in Multiple Sclerosis.

The aim of this study was to define the significance of TNFalpha with respect to the hallmark of MS, that is DeMyelination. Therefore, 78 lesion areas from diagnostic Brain biopsies of 32 patients were analyzed.

Lesion DeMyelinating activity was classified by the presence of Myelin degradation products in Macrophages and Macrophage activation markers.

Non-radioactive in situ hybridisation was carried out to detect TNF mRNA expressing cells. DNA fragmentation was visualised by TdT-mediated X-dUTP nick end labeling.

A significantly higher number of cells expressed TNF mRNA in active DeMyelinating lesions than in inactive or ReMyelinating lesions irrespective of the extent of the inflammatory infiltrate.

TNF mRNA expression correlated with the appearance of DNA fragmentation in T-Lymphocytes and Oligodendrocytes within the lesions.

In the periplaque White Matter, expression of TNF mRNA negatively correlated with Oligodendrocyte numbers. These data support previous findings from animal models and in vitro experiments.

Although not proving, the current study strongly suggests a Pathogenic role of TNF in DeMyelination in human Multiple Sclerosis and gives further support for TNF-directed therapeutic strategies.

Copyright 2000 Wiley-Liss, Inc.

Among the Chemokine family, Fractalkine shows unusual properties: it exists as a membrane-bound and soluble protein, and both Fractalkine and its receptor CX(3)CR1 are expressed predominantly in the Central Nervous System.

In rat cell culture models, the Chemokine Fractalkine was expressed in Neurons and Microglia.

But not in Astrocytes and its receptor exclusively localized to Microglial Cells, where its expression was downregulated by treatment with the Bacterial EndoToxin (LPS).

In Microglial cultures, LPS (10 ng/ml) induced a marked increase in the release of the proinflammatory Cytokine Tumor Necrosis Factor-alpha (TNF-).

The effects of LPS on TNF- secretion were partially blocked (30%) by Fractalkine and the effects of fractalkine were reversed by a polyclonal anti-fractalkine AntiBody.

When Microglial-associated Fractalkine was neutralized by Anti-Fractalkine Antibody, the LPS response was increased by 80%, suggesting tonic activation of Microglial Fractalkine receptors by endogenous Fractalkine.

The effects of the AntiBody were antagonized by the addition of Fractalkine. LPS-activated Microglia were NeuroToxic when added to Neuronal Hippocampal culture, producing 20% Neuronal death, as measured by NeuN-positive cell counting.

An Anti-Fractalkine AntiBody produced NeuroToxic effects of similar magnitude in this co-culture system and also markedly potentiated the NeuroToxic effects of LPS-activated Microglia (40% Neuronal death).

These results suggest that endogenous Fractalkine might act tonically as an anti-inflammatory Chemokine in Cerebral tissue through its ability to control and suppress certain aspects of Microglial activation.

These data may have relevance to degenerative conditions such as Multiple Sclerosis, in which Cerebral inflammatory processes may be activated.

Copyright 2000 Wiley-Liss, Inc.

Even though the Immune privileged status of the Central Nervous System (CNS) limits access of Systemic Immune Cells through the Blood-Brain Barrier (BBB), an Immune Response can occur in this compartment with or without major breach of the BBB.

In this review, we consider properties of resident cells of the CNS, that participate in regulating the Neural Antigen (Ag)-directed Immune Responses implicated in AutoImmune Diseases such as Multiple Sclerosis (MS).

Under such conditions, the CNS is usually viewed as the target or victim of the Immune assault, because such Immune Responses are thought to be initiated and regulated within the Systemic Immune compartment.

The CNS-endogenous cells may themselves, however, initiate, regulate and sustain an Immune Response.

We consider the Immune Regulatory Functions within the CNS in terms of events occurring within the CNS Parenchyma (Microglia, Astroglia) and at the Vascular interface.

These regulatory functions involve Antigen presentation to T-Cells and polarization of the Cytokine response of these cells.

Such responses may contribute not only to the overall tissue injury in Primary Immune Disorders but also in a wide range of Traumatic, Ischemic and Degenerative Processes.

Copyright 2000 Wiley-Liss, Inc.

The relationship between Autobiographical Memory, Depression and Quality of Life (QoL) was investigated in a study of 30 persons with severe NeuroDisability resulting from Multiple Sclerosis.

Sixty percent (n = 18) of patients were found to have deficits in AutoBiographical Memory (AMI) for incidents in their earlier life; these deficits were associated with significant impairments in personal Semantic Memory of facts from their past life.

Patients with impaired AutoBiographical Memory who had been diagnosed for longer than 21 years reported significantly better QoL (SF-36: Role Physical) than those diagnosed more recently, or those with normal AutoBiographical Memory;
1. patients who had been diagnosed for longer were also significantly less depressed than patients diagnosed more recently.

2. Patients with normal AutoBiographical Memory reported the highest levels of Depression (HADS) and the lowest levels of QoL (Role Physical).