Multiple Sclerosis Journal

In recent years we have seen growing evidence for the role of chemokines in the pathogenesis of several infectious and non-infectious inflammatory CNS disease states, including Multiple Sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). An increase in proinflammatory chemokines has been associated with demyelinating lesions and clinical neurological dysfunction in patients with MS; these chemokines could be potential targets for MS therapy. Besides a clearly defined role in mediating leukocyte migration, these and other chemokines may act as immunoregulatory molecules in the driving to Th1/Th2 responses, switch of cytokine profiles, and the induction of tolerance. Since chemokine receptors have now been identified on macrophages, microglia, astrocytes, and endothelial cells as well as neurons in the CNS, chemokine/receptor interactions may mediate functional responses in a variety of CNS cell types during the course of inflammatory disease states. Therefore, clarification of the roles of chemokines and their receptors in the pathogenesis of EAE and MS will be useful in establishing immunotherapeutic strategies for these neurological autoimmune disorders.

The pathogenesis of multiple sclerosis is under strong genetic control involving several or more genes each of modest effect. Whilst the mechanisms underlying the pathogenesis of MS remain unknown, it has been hypothesised that either decreased apoptosis of autoreactive T cells in the CNS, or increased apoptosis of oligodendrocytes may play an important role. The Apo-1/Fas antigen (CD95), the gene for which is located in a chromosomal region showing linkage in MS genome screens, is a critical inducer of apoptosis and studies have shown aberrant expression of this molecule in MS, correlating with a decrease in T cell apoptosis or increase in CNS tissue damage. This study investigated an Mva I polymorphism in the Apo-1/Fas promoter region in a group of 124 Australian patients with relapsing-remitting MS and in 183 normal controls. Whilst there were increases in the Mva I*2 allele in MS individuals overall (59% vs 52%, P not corrected=0.08), and in HLA-DRB1*1501 negative MS patients (62% vs 55%), these were not significantly different from controls. Interactions were investigated between the Mva I alleles and T cell receptor beta chain variable region (TCRBV) germline polymorphisms, with a trend in MS individuals towards a decrease of the Mva I*1 allele when combined with the TCRBV3S1*2 allele (Relative Risk=0.25, P=0.067), and with the TCRBV8S1*1 allele (Relative Risk=0.44, P=0.12). Overall, the findings of this study indicate a possible effect of the Apo-1/Fas promoter Mva I polymorphism in MS susceptibility, which needs to be confirmed in further studies.

The proinflammatory cytokine interferon gamma (IFG) is elevated in body fluids of multiple sclerosis patients but its variation range is broad. The reason for this wide scatter of IFG production is not yet known. We looked for the relation between clinical parameters such as disability, exacerbation frequency, disease duration, course of the disease and IFG producing blood lymphocytes. Forty-one consecutive, clinically stable multiple sclerosis patients with primary relapsing course of the disease and without immunomodulatory or immunosuppressive treatment in the last 3 months were investigated for IFG in blood lymphocytes by flow cytometry. A significant positive correlation between IFG production and disability (r = 0.45, P50.01, Spearman's rho coefficient) was found. Pathophysiological implications and therapeutical relevance of this unexpected finding are discussed.

Rapid correction of chronic hyponatremia can cause osmotic brain demyelination in animals and humans. Why demyelination develops is unknown, but blood brain-barrier disruption might expose oligodendrocytes to substances normally excluded from the brain. To test this hypothesis, chronic hyponatremia was induced and corrected using a new, reproducible rat model for producing osmotic brain demyelination. Blood brain barrier integrity was assessed by NMR imaging at either 3, 16 or 24 h during the first day of correction. Demyelination was determined histopathologically 5-6 days later. Of 96 rats studied, demyelination developed 5-6 days later in 37 rats, 89% of whom showed barrier disruption. In the 59 rats who did not develop demyelination, 45 (76%) had no barrier disruption. Thus, blood-brain barrier disruption during the first 24 h of correction was associated with a 70% risk of developing demyelination. By contrast, the risk of developing subsequent demyelination was only 8% when the barrier was intact. This strong association between barrier disruption and subsequent demyelination provides new insights into the role of blood brain barrier function in demyelinative disorders such as the osmotic demyelination syndrome and by extension to other demyelinative disorders such as multiple sclerosis.

Allelic variants of the apolipoprotein E (APOE) gene influence the course of several neurological diseases. In multiple sclerosis the concentration of APOE in cerebrospinal fluid and its intrathecal synthesis is reduced. Specific isoforms of APOE may also be important and it has been suggested that possession of the e4 allele may be associated with a more aggressive disease process. These data prompted us to re-examine, in a large group of patients with multiple sclerosis, the proposal that allelism in the apolipoprotein gene influences disease course. Genotypes were determined in a well-defined group of 370 unrelated Caucasians with clinically definite multiple sclerosis and in 159 healthy controls. Age at onset, sex, disease duration, disease subtype were recorded. Disability was measured using the Kurtzke expanded disability status score in patients with a disease duration of 10 years or greater. There was no significant difference in APOE allele or genotype frequencies between patients and controls, between disease subtypes or between genders. APOE genotype did not significantly influence age of onset, and no significant relationship between genotype, allele frequency and disease severity was found. This study suggests that individual APOE alleles or genotypes do not determine disease susceptibility or the clinical course of multiple sclerosis.

There are still questions regarding whether macrophages found in MS lesions are agents of recovery or of destruction. To address this, we examined in aggregate cultures prepared from dissociated embryonic spinal cord tissue, with or without addition of exogenous macrophages, the effect of menadione-induced oxidative stress. Similar to findings of other laboratories, we observed that in the absence of oxidative stress macrophage enrichment promoted myelinogenesis. In macrophage-poor cultures, menadione at 5 μM had very little effect upon the status of the aggregate cultures; however, increasing this to 10 and 20 μM did result in some damage to axons and myelin. By contrast, in macrophage enriched cultures, menadione at a concentration as little as 5 μM caused the complete destruction of the aggregates. We suggest that in neural tissues that have sufficiently high macrophage numbers, oxidative stress results in a positive inflammatory feedback loop that results in massive tissue destruction. We further suggest that what we see in macrophage-enriched aggregates subjected to oxidative stress may represent what happens in the Marburg-type of MS lesion.

Magnetic resonance imaging (MRI) has been used to study the history of multiple sclerosis (MS). We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months. Monthly enhanced MRI was performed in 103 relapsing remitting (RR) MS patients for 6 months. Thirty-five per cent of patients had an inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months. Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRI's. The relationship between the first scan and all subsequent scans demonstrates a clear weakening over time. Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months. These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in an individual RRMS patient.

Patients suffering from multiple sclerosis have a high frequency of cognitive deficits usually attributable to demyelination and axonal loss in the subcortical white matter. Neurologic abnormalities referable to cortical function are uncommon but have been described. The present study describes three patients with clinically definite MS with deficits in cognitive function referable to cortical location. Two of the patients underwent positron emission tomography and showed profound cortical hypometabolism adjacent to subcortical white matter lesions seen on MRI. This paper points out that neurologic deficits referable to cortical sites may be caused by subcortical white matter lesions and that cognitive dysfunction in patients with MS may progress rapidly in the absence of motoria deficits or other evidence of clinical deterioration.

Phosphodiesterase inhibitors (PDEIs), when used in combination, synergistically suppress TNFa production by various cells and also suppress experimental demyelination at very low concentrations. We conducted a pilot study to determine whether the combination of three PDEIs suppresses the relapse of MS at the usual therapeutic doses. Of the 12 relapsing remitting MS, the mean relapse rate/year dropped remarkably (from 3.08+3.32 to 0.92+1.86) after PDEI treatment. Seven out of 12 (58.3%) were relapse-free in the follow up period (499+142 days). The combination of three PDEIs can be safe and useful strategy for the future treatment of MS.