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PubMed2005

Association of haplotypes in the beta-chemokine locus with multiple sclerosis.

Linkage studies in multiple sclerosis (MS) identified several susceptibility loci. One of these regions includes chromosome 17q11 where a meta-analysis of data from three genome scans suggested linkage. This region encodes a cluster of genes for beta-chemokines or CC chemokine ligands (CCLs), which may be involved in the development of MS lesions. Here we aimed to test if CCL alleles and haplotypes are associated with MS. Using methods of linkage and association, we observed deviations from the expected 50% transmission of haplotypes from unaffected parents to their affected children at CCL2, CCL11-CCL8-CCL13 and CCL3 within the investigated 1.85 MB chromosomal segment. Analyses of the linkage disequilibrium map support that variants with possible relevance to MS can be located within these subregions. Identification of MS associated CCL variants may have direct clinical significance, as it can lead to the design of small competitive antagonists of these molecules with beneficial effects in the treatment of patients with early and active disease.

Chemokines, CC↗

PubMed1999

Recent developments in drug therapy for multiple sclerosis.

Symptomatic treatment of multiple sclerosis (MS) includes a diverse range of drugs intended to relieve the specific symptoms with which a patient may present at a particular point in the progression of the disease. These drugs, not specifically designed for the treatment of MS, may include antispastic agents (e.g. baclofen), drugs to reduce tremor (e.g. clonazepam), anticholinergics (e.g. oxybutynin) which relieve urinary symptoms, anti-epileptics (e.g. carbamazepine) to control neuralgia, stimulants to reduce fatigue (e.g. amantadine), and antidepressants (e.g. fluoxetine) to treat depression. The treatment of acute relapses or exacerbations is dominated by corticosteroids such as methylprednisolone. The most active area of current investigation is the development of drugs which will inhibit the progression of the disease process itself, and in this category the beta- and alpha-interferons are the most effective drugs currently available, although many new treatments are currently in trials, including immunoglobulin, copolymer-1. bovine myelin, T-cell receptor (TCR) peptide vaccines, platelet activating factor (PAF) antagonists, matrix metallo-proteinase inhibitors, campath-1, and insulin-like growth factor (IGF).

Adjuvants, Immunologic↗

PubMed1981

Segregation and linkage analysis of 40 multiplex multiple sclerosis families.

40 multiplex multiple sclerosis (MS) families were analyzed for evidence of an MS susceptibility gene linked to the HLA region of the sixth chromosome. We assumed that population associations between specific HLA alleles and MS are due to linkage disequilibrium, so preference was given to hypotheses compatible with tight linkage, and explanations were sought for conflicting evidence. The analyses proceeded in two steps: (1) segregation analysis using the computer program POINTER, and (2) linkage analysis using LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. The results of the segregation analyses were indeterminate. The results of the linkage analyses suggest that analyses that do not allow for disequilibrium lose substantial evidence on linkage. Of the models that were investigated under linkage disequilibrium, the best fit is with a model of complete linkage (theta= 0.0) in 75% of the pedigrees and no linkage in the remaining pedigrees. We were unable, however, to statistically reject another model involving loose linkage and no heterogeneity.

Chromosomes, Human, 6-12 and X↗

PubMed1993

Antigen processing gene polymorphisms in HLA-DR2 multiple sclerosis.

The association between multiple sclerosis (MS) and alleles of the HLA class II genes indicates that at least one MS susceptibility gene is linked to the HLA class II region. However, the actual locus responsible has not been precisely identified. The recent cloning of new genes involved in antigen processing that map within the HLA class II region led us to investigate--using the restriction fragment length polymorphism (RFLP) technique and sequence-specific oligonucleotide analysis--whether these genes might play a role in conferring susceptibility to MS. We studied large multifunctional protease (LMP) 2 and 7 and transporter associated with antigen processing (TAP) 1 and 2 gene polymorphisms in 60 HLA-DR2 MS patients and 60 HLA-DR2 healthy subjects and found no specific or preferential RFLP patterns or coding sequence variants in the patient group. Our data do not support a role for these genes in MS susceptibility.

Adult↗

PubMed1977

A possible association between house pets and multiple sclerosis.

29 patients with multiple sclerosis (M.S.) from families in New Jersey believed to have more than 1 member with this disease and 29 controls matched for age, sex, neighbourhood, and socio-economic status were questioned about their ownership of pets. No difference in ownership of cats or dogs was found. Exposure to small indoor pets (cats or dogs), however, was significantly higher in the M.S. group (P less than 0-001). Exposure to small indoor pets was particularly striking during the ten years before onset of initial symptoms of M.S. when the M.S. group was compared to the control group (P less than 0.01). 33 of 49 M.S. patients in these families had a cat or dog in the house within one year before onset of the first neurological symptom. 3 families had more than 1 member in whom initial symptoms of M.S. developed in the same year despite wide age ranges. These results suggest that exposure to house pets may sometimes be associated with subsequent M.S. Our findings should be interpreted with caution until they are confirmed by others.

Adult↗

PubMed1990

Fluctuations in T helper subpopulations in relapsing-remitting multiple sclerosis.

Patients with active multiple sclerosis (MS) have been reported to have a depletion of CD4+ CD45R+ cells, the immature resting CD4+ subpopulation. Using Leu 3a(anti-CD4) and Leu 18(anti-CD45R), the frequencies and absolute numbers of CD4+ CD45R+ and CD4+ CD45R- subsets were measured in 30 patients with MS and 17 healthy controls. These subsets were monitored every 6 weeks over a 6 month period. CD4+ CD45R- cells were found to be increased in relapse compared to remission (p less than 0.005) while CD4+ CD45R+ levels were not significantly altered in relapse. However, the CD4+ subset ratio (CD4+ CD45R-/CD4+ CD45R+) was significantly higher in relapse compared with remission (p less than 0.002). Furthermore, these findings were upheld when data from the same 6 patients in relapse and remission was compared. Increased disease activity was not associated with changes in any of the other parameters measured (total T cells, total CD4+ cells, suppressor cells or activated T cells). These results suggest that relapse in MS is accompanied by the conversion of CD4+ CD45R+ resting cells to CD4+ CD45R- primed cells.

Adult↗

PubMed1988

Correlations between clinical and magnetic resonance imaging findings in multiple sclerosis.

40 patients with multiple sclerosis were investigated by magnetic resonance imaging (MRI) and computer tomography (CT). Additionally, cerebrospinal fluid (CSF) findings and evoked potentials (EPs; visual, brainstem) were evaluated. MRI findings were abnormal in 85% of the patients, whilst CT scan showed pathological changes in only 23%. The sensitivity for detecting lesions was significantly higher for MRI than CT. 86% of 23 patients with a duration of disease of more than 1 year had pathological MRI findings, and MRI was abnormal in 82% of 17 patients with a duration of symptoms up to 1 year. All patients with abnormal MRI had at least one other pathological laboratory finding. CT revealed only large lesions, and in patients with abnormal CT MRI visualized lesions more extensively. Additionally, brainstem lesions could be verified in 6 patients and spinal cord lesions in 3 cases. CSF was abnormal in 86%, and positive MRI findings occurred in 26 of 31 patients with abnormal CSF. Abnormalities of EPs were found in 76%, and MRI was positive in 24 of 33 patients with abnormal EPs.

Adult↗

PubMed2006

Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years.

Reliable prognostic markers of primary progressive (PP) multiple sclerosis evolution are still needed. Diffusion tensor (DT) MRI can quantify normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis patients. We investigated whether conventional and DT-MRI-derived measures can predict the long-term clinical evolution of PP multiple sclerosis. In 54 PP multiple sclerosis patients, conventional and DT-MRI scans of the brain and T1-weighted scans of the cervical cord were acquired at baseline and after a median follow-up of 15 months. Another clinical evaluation was performed, 56 months after baseline, in 52 patients. Measures of lesion load, brain and cord atrophy were obtained. Histograms of the mean diffusivity (MD) and fractional anisotropy (FA) values from the NAWM and GM were analysed. At follow-up, 35 patients (65%) experienced a confirmed disability progression. Baseline expanded disability status scale score and average GM MD were independent predictors of subsequent clinical deterioration in a multivariable model (Nagelkerke R2: 0.44; discriminating ability: 81%). A lower level of disability and a more severe GM damage identify PP multiple sclerosis patients with an increased risk of disease progression over the subsequent 5 years. These data may be relevant to select patients for future exploratory phase II trials.

Adult↗

PubMed2006

[Pathophysiology and treatment of fatigue in multiple sclerosis].

Patients suffering from multiple sclerosis (MS) frequently complain of fatigue (53 to 92 percent depending on studies). Fatigue can be one of the most disabling symptoms of MS and presents as physical or mental fatigue in daily living activities. Besides this permanent feeling of exhaustion, MS patients can suffer from an abnormal tiredness and lack of energy after a given motor or mental task, which defines fatigability. A number of studies explored the origins of fatigue and fatigability by means of subjective and objective tools. The implication of central nervous system dysfunctions has been established in several studies; however the contribution of peripheral nervous system factors and systemic abnormalities associated with inflammatory and immunological parameters was also suggested. The aim of this review is to present the different types of fatigue and fatigability occurring in MS patients, their origins, the investigation tools which allow the quantification of fatigue and fatigability and characterization of their mechanisms. The currently available therapeutic strategies that have been proposed to relieve this disabling symptom are presented.

4-Aminopyridine↗

PubMed1991

Simultaneous recording of pattern electroretinogram (PERG) and visual evoked potential (VEP) in multiple sclerosis.

We studied 18 multiple sclerosis (MS) patients affected by retrobulbar neuritis (RBN). The patients were subdivided into two groups. Group 1: 14 patients with RBN. Group 2: 4 patients with optic atrophy. An ophthalmological examination (visual acuity, fundus oculi, visual field) was carried out in all the patients. A simultaneous visual evoked potential (VEP) and pattern electroretinogram (PERG) recording at two spatial frequencies (45' and 15') was performed. All the data obtained in Group 1 were compared (Student T-Test) with those of a control group of normal subjects matched for age and sex. Group 1. VEP: a comparison of the data in MS patients affected by RBN with the control group revealed a statistically significant P100 latency delay with both spatial frequencies (P less than 0.001). PERG: no "b" wave latency change at 45' and 15' spatial frequencies were seen. A "b" wave amplitude reduction was observed; this reduction reached significant values at 45' (P less than 0.001). Group 2. In optic atrophies the PERG was absent in 4 eyes at 45' and in 5 eyes at 15'.

Adult↗

PubMedDate not supplied

[Visual somatosensory and auditory evoked potentials in multiple sclerosis].

In a group of 15 patients with multiple sclerosis and in a control group of 20 healthy subjects visual evoked potentials produced with flashes or checkerboard pattern, auditory evoked potentials after stimulation with three different tones, and somatosensory evoked potentials after stimulation of the left, right or both median nerves, and reactions to stroboscopic stimulation at seven different frequencies were investigated. Recording was done with unipolar leads from frontal, central, occipital and temporal regions on the left and right side. In patients with multiple sclerosis the cortical responses to all these stimuli had lower amplitude than in healthy subjects, and the reponses to stroboscopic stimulation were also abnormal in the group of patients. Different clinical signs related to various defects of sensory functions showed a high correlation with electrophysiological anomalies. Non-linear discrimination analysis was carried out using 13 variants (the amplitudes were calculated from peak to peak and correlation coefficients were calculated between identical regions on the left and right side) comparing the group of patients with the control group. Using this method it was possible to establish the correct diagnosis in all cases of multiple sclerosis and 85% of healthy subjects could have been included into the asymptomatic group. Since the methods used in these investigations are easy and can be easily automated the authors think that they could be very useful in the clinical diagnosis of multiple sclerosis.

Acoustic Stimulation↗

PubMed1997

The effect of intrathecal MBP synthetic peptides containing epitope P85 VVHFFKNIVTP96 on free anti-MBP levels in acute relapsing multiple sclerosis.

Acute relapses of multiple sclerosis (MS) are characterized by elevated Free (F)/Bound (B) anti-MBP ratios during the initial phase, followed by a steady decline of F antibody as the recovery/remission phase develops. The (human) MBP epitope for MS anti-MBP is: Pro85-Val-Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro96. In phase one clinical research, synthetic peptides (p) containing this epitope, namely pMBP86-95 and/or pMBP82-98, were intrathecally administered to MS patients with monosymptomatic or polysymptomatic relapses to determine the dosage, frequency and duration of administration which will immediately neutralize F circulating CSF anti-MBP. Patients with monosymptomatic relapses required 50 mg of peptide administered daily for 4-5 days. In patients with polysymptomatic relapses, F anti-MBP can be neutralized with dosages between 50 mg peptide daily for 4 days up to 100 mg twice a day for 2 days; however due to the prolonged nature of polysymptomatic relapses, antibody neutralization could not be maintained by these short courses of intrathecal peptide administration. Intravenous administration of these same peptides did not prevent occurrence of future relapses.

Acute Disease↗

PubMed1999

A major influence of the T cell receptor repertoire as compared to antigen processing-presentation in the selection of myelin basic protein epitopes in multiple sclerosis.

We selected two multiple sclerosis (MS) patients, compatible for HLA-DR2 subtype, and differing for HLA-DM haplotype as well as for the myelin basic protein (MBP) epitope recognized by the vast majority of their T cell lines (TCL) (residues 16-38 and 86-99, respectively). TCL sharing the same restriction element were re-assayed in the presence of reciprocally mismatched antigen-presenting cells (APC). The TCL recognized both the whole MBP and the relevant peptide also in the presence of non-autologous APC, (compatibility for processing, despite a difference in the DM haplotype). The same protocol, performed in serum-free pulsing experiments or in the presence of 'fixed' APC, excluded extracellular processing or mutual T cell presentation, and confirmed the need for MBP processing in our system. The finding, that only TCL recognizing MBP peptide 16-38 (a region not previously related to the DR2 haplotype) used a novel Vbeta, supports the importance of the TCR repertoire over the processing-presentation machinery in the selection of MBP epitopes in MS.

Antigen-Presenting Cells↗

PubMed1981

Effect of ACTH treatment on CSF and blood lymphocyte subpopulations in patients with multiple sclerosis.

Patients with active multiple sclerosis (MS) were examined for T lymphocytes (E-rosette-forming cells, E-RFC) and IgG concentrations in cerebrospinal fluid (CSF) and in blood, and for other lymphocyte subpopulations in blood, before and after treatment with adrenocorticotropical hormone (ACTH). Patients who responded to treatment had higher initial percentages of CSF T lymphocytes (93.1 +/- 3.0%) compared to patients who showed no clinical improvement (88.2 +/- 3.2%). After treatment, the responders had decreased CSF T lymphocyte levels (83.1 +/- 6.6%) while those of the nonresponders were unchanged (90.2 +/- 2.2%). In blood, T cell counts were unchanged, but "active" T cell levels showed a tendency to increase in responders and decreased significantly in non-responders. The percentage of Fc receptor-positive cells increased after treatment in both responders and nonresponders, and that of complement receptor-positive cells increased slightly in responders, but these changes were not statistically significant. Serum IgG concentrations decreased in eight of nine patients after treatment. CSF IgG concentrations were found to be increased, unchanged or decreased, after treatment with no significant differences between responders and nonresponders. The results suggests an involvement of the T lymphocyte in active MS.

Adrenocorticotropic Hormone↗

PubMed1989

Multiple sclerosis: possible immunological mechanisms.

Multiple sclerosis is the principal demyelinating disease of the central nervous system. Although the prevalence of the disease is moderately low, averaging about 40 cases per 100,000 people in high risk areas, it is a particularly devastating disease. It primarily affects young adults, is chronic, and has an unpredictable course. Most discouraging, the cause of the disease is not known and an effective treatment has not been identified. Recently, however, research has yielded some important findings concerning the etiology of MS. Much evidence now points to an immunological process as one of the major elements in the disease. It is also likely that an environmental influence, possibly an infectious process, may contribute to the disease. Finally, it is now certain that genetic makeup influences susceptibility to the disease. At present, the strongest evidence is for a polygenic effect, not the effect of a single gene or gene locus. This review will examine some of the possible immunologically mediated disease processes that could be involved in MS, especially those that could account for a role for infectious and genetic factors in the disease.

Animals↗

PubMed1994

Environmental triggers in multiple sclerosis. Fact or fallacy?

Multiple Sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. In the early, most common course of the disease there are seemingly random attacks or exacerbations usually followed by partial or complete recovery. It has long been postulated that environmental events such as infection, emotional stress, or trauma play some role in triggering exacerbations, worsening of the disease, or even the onset of MS. Indeed there have been monetary awards by the courts based on possible influence on the disease following motor vehicle accidents. This paper will describe a prospective study undertaken at the UBC MS Clinic evaluating the impact of infection, emotional stress, and physical trauma on the course of the disease in 50 relapsing-remitting patients participating in the Betaseron trial. During the first two years of the clinical trail this cohort kept diaries documenting environmental "events". The participants were evaluated clinically and with Magnetic Resonance Imaging (MRI) every six weeks. The potential triggers or events are correlated with disease activity seen on MRI, relapse occurrence and disease progression according to the neurological exam. The results of the study and their implications for patient counselling will be presented.

Environment↗

PubMed1996

[Pathogenesis of multiple sclerosis: status of research].

Multiple sclerosis is considered an immune-mediated disease of the CNS white matter. Peripheral blood and CSF contain circulating autoreactive T lymphocytes recognizing a number of myelin antigens. When activated, e.g. through a viral infection, these cells can migrate across the blood-brain-barrier into the CNS. Upon encounter of microglial cells and local reactivation, they undergo clonal proliferation. Secreted Th1 cytokines (IFN-gamma and TNF-alpha) stimulate macrophages and microglia to heightened phagocytic activity and the release of proinflammatory mediators. This results in damage to the myelin sheath and oligodendrocytes. Autoantibodies directed to myelin antigens are of key importance in the demyelinative process by initiating the complement cascade. Early in the course of the disease, down-regulatory mechanisms can terminate an acute exacerbation and contain tissue damage. With repeated attacks, these mechanisms get overwhelmed and the reparative capacity of oligodendrocytes exhausted. This marks the transition to the chronic progressive phase of the disease characterized pathologically by demise of oligodendrocytes, secondary loss of axons and astroglial proliferation. A better understanding of the pathogenesis of MS allows to identify strategic targets for more specific and efficacious therapeutic immunointervention.

Autoantibodies↗

PubMed2006

The relation between menarche and the age of first symptoms in a multiple sclerosis cohort.

BACKGROUND: Previously, multiple sclerosis (MS) has been thought to be associated with changes in hormone levels. This study investigates the association between the age of menarche and the age of onset of the first symptoms of MS. METHODS: A complete list of patients diagnosed with MS in the province of Newfoundland and Labrador was constructed. The age of menarche for our entire relapsing remitting female MS (RRMS) population was requested by mailout survey. Age of symptom onset was ascertained by chart review. RESULTS: A 74% rate of return on the survey results was obtained (150 RRMS patients). A linear regression model demonstrated that the age of first symptoms increased by 1.16 years as the age of menarche increased by one year (R2 = 0.69, P = 0.04). Another analysis showed that the average age of first symptoms for women with reported menarche from 10 to 12 years was 28.96 years compared with 31.83 years for a reported menarche from 13 to 15 years, a significant difference (P = 0.047, t-test). CONCLUSIONS: This study suggests that menarche may be related to the pathogenesis of MS.

Adolescent↗