TCRB-V gene usage in monozygotic twins discordant for multiple sclerosis.
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Biomedical subjects
Publications and source records attributed to M Clanet.
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In order to investigate whether genes coding for tumor necrosis factors (TNF) contribute to the pathogenesis of multiple sclerosis (MS) and also whether they have a non-random association with the MS associated HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype, 40 MS patients and their parents were characterized at four polymorphic loci in the region of the TNF genes: a NcoI RFLP and three microsatellites. We were able to determine the parental haplotypes and used those which were not transmitted to the proband as controls. Fifty percent of the HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotypes carried the TNFc1-n2-a11-b4 allelic combination in both the patient and the control groups. However, there was no association of any of these TNF polymorphisms with MS, independent of that already described for the class II region. This, with the lack of association of DP alleles with MS, effectively marks the boundaries of the MS associated haplotype.
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Multiple sclerosis (MS) is a demyelinating auto-immune disease of the central nervous system with a suspected genetic component. Previous publications have demonstrated that MS susceptibility is influenced by Major Histocompatibility Complex (MHC) genes and recent studies have focused on additional susceptibility genes. The accumulation of activated T-cells in demyelinating MS lesions, the possible auto-immune mechanism of this disease and the functional relationship between MHC and T cell receptor (TCR) molecules support the hypothesis that TCR genes are good candidates to influence MS development. Published results in this domain are conflicting and still a matter of controversy. In the present study we analysed the influence of V beta, C beta, P lambda G3 and V gamma gene polymorphisms defined by Restriction Fragments Length Polymorphism (RFLP) on 48 pairs of monozygotic and dizygotic twins with at least one of each pair affected, and also in 63 unrelated MS patients for V gamma gene polymorphism. These results have been compared with those in the non affected twins and with data from a control group (Beall et al., 1989) regarding C beta and V beta polymorphisms and with a local control population for V gamma. No significant correlation between C beta, V gamma or P lambda G3 polymorphisms and MS was found, only a non significant tendency to reduced P lambda G3 allele sharing among dizygotic non concordant twin pairs was observed. However one V beta 11, 25 kb allele and a haplotype defined by V beta 11 and C beta alleles showed a correlation with MS susceptibility of borderline significance.(ABSTRACT TRUNCATED AT 250 WORDS)
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A 30 year-old woman developed a postural and rest tremor of the left hand following a right peduncular post-traumatic hematoma. Two years later, positron emission tomography showed a marked decrease in [18F] fluorodopa uptake contrasting with a normal [76Br] bromolisuride uptake in the right striatum. This suggests that: 1) chronic unilateral dopaminergic striatal denervation may occur without persistent D2 dopaminergic receptor upregulation in humans; and 2) symptomatic mesencephalic tremor may be, at least in part, related to dopaminergic striatal denervation.
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A 20-year old man had three episodes of meningococcal meningitis. Complement assays showed a complete deficiency of the seventh component of the complement system. This case emphasizes the need to perform complement assays in young patients with recurrent bacterial meningitis.
Magnetic resonance imaging (MRI) has rapidly attained a major position among the examinations used in the diagnostic approach of multiple sclerosis because it is highly sensitive in demonstrating lesions. However, these lesional images may have several meanings, and there is the problem of distinguishing between oedema, which is said to reflect recent lesions, and gliosis which is thought to betray old lesions. The intrinsic MRI parameters studied (i.e. relaxation times) are unable to make this distinction, whereas it is provided by paramagnetic contrast media such as gadolinium. There is no correlation between the changes observed at MRI and the severity of the disease. Another problem is the accuracy of lesion localization, since visualization is predominantly macroscopic. This raises several questions about the demonstration of correlations between clinical signs and site of the lesion(s). At the moment, several teams of neuroradiologists are trying to find the most reliable method to determine the size of the lesion. The possible prognostic value of this size and its changes as time goes by are other parameters to be considered once the basic diagnosis has been made.
The polymorphism at the HLA-DPB1 locus has been characterized in a large number of patients with multiple sclerosis (n = 112) and in healthy controls (n = 115). Both patients and controls lived in the southwest of France (in the Pyrénées Atlantiques) and had similar ethnic background. The typing procedure involved the selective amplification of the second exon of the DPB1 locus by polymerase chain reaction, followed by hybridization of the amplified DNA with 14 sequence-specific oligonucleotide probes. Individual alleles were identified by the pattern of hybridization of the different probes. The distribution of the DPB1 alleles was not significantly different in multiple sclerosis patients and controls (p = 0.11). This does not corroborate the reported association of multiple sclerosis with the primed lymphocyte typing (PLT)-defined DPw4 specificity and is not in favour of a role played by polymorphic residues of the DP molecule in susceptibility to multiple sclerosis.
The Bereitschaftspotential (BP) recorded from 3 derivations (vertex, left and right precentral areas) in 20 right-handed, normal young subjects was compared in 2 kinds of motor task: a simple movement (task A) and a motor sequence (task B) starting with the simple movement (A). Differences in the onset time and amplitude of the BP were observed: the onset was earlier and the amplitude was larger in the sequential motor task (B) than in the simple one (A). These differences were more important at the vertex (Cz) and in the right precentral area (C4) than in the left contralateral precentral area (C3). These results suggest that the preparatory processes involved in a motor sequence do not exclusively concern the initial movement but also the remainder of the motor task and that the BP is dependent upon the duration or the complexity of the motor task to be executed. The BP seems on temporal grounds to be a global and not a partial expression of a motor task. The changes in the onset time and amplitude of the BP are maximal at the vertex and this could be related to a greater and perhaps earlier activation of SMA in complex sequential motor tasks.
Our purpose was to investigate possible interrelations between antibody titers against seven viruses (measles, rubella, herpes simplex, mumps, varicella-zoster, coronavirus, cytomegalovirus), HLA-class II antigens, and immunoglobulin Gm allotypes in multiple sclerosis (MS). We studied 57 MS patients and 59 controls with similar age and sex distributions. In MS patients, we found the classical increased frequency of HLA-DR2, HLA-DQw1 and also an excess of Gm (3; +/- 23; 5*). Mumps antibody levels were higher in MS patients than in controls; elevation was not significant for measles antibodies. Analysis suggests that an association between HLA-DQw1 and antibody titers against various viruses exists in controls but is absent in MS patients. In particular, we found that mumps antibody titers were higher in DQw1-positive than in DQw1-negative controls, while there was no significant difference among MS cases. Accordingly, we found that the overall difference between patients and controls was due to the fact that DQw1-positive patients had higher titers than controls, while DQw1-negative cases had similar titers as controls. These findings suggest that biological and molecular characteristics of DQw1 might differ in MS patients.
The frequency of square wave jerks (SWJ) was compared in eight patients with progressive supranuclear palsy (PSP), 25 patients with multiple system atrophy or Parkinson's disease plus (MSA/PP), 85 patients with idiopathic Parkinson's disease (PD) and 20 age-matched normal volunteers. In the control group, the mean (SD) SWJ frequency (SWJ larger than 1 degree amplitude) was 2.3 (2.4)/min. Abnormal ocular fixation (SWJ frequency greater than 10/min) was observed in a large proportion of PSP patients (7/8) and of MSA/PP patients (16/25) but in few PD patients (13/85). In the group of PD patients with abnormal ocular fixation, freezing of gait, falls and instability were more severe than in the group of PD patients with normal fixation. The study of ocular fixation may help to differentiate PD clinically from other Parkinsonian syndromes. SWJ are probably not related to the central degeneration of the dopaminergic nigrostriatal pathway observed in PD.
The interobserver variability of the expanded disability status scale (EDSS) was studied in 59 patients with multiple sclerosis (MS). Interrater agreement was measured by the kappa coefficient. Agreement was low in patients with mild disability (EDSS less than 5); it was higher in patients with EDSS equal to or greater than 5. The difference between ratings of 2 independent examiners was equal to at least 1 point in 34% of the MS cases. This variability must be taken into consideration in designing clinical trials in MS.
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Interferons (IFNs) are a family of proteins with antiviral, antitumoral and immunomodulating properties. Multiple Sclerosis (MS) is a CNS disease in which the immune reaction (IR) is the cause of the inflammatory demyelinating lesions. IFNs have been demonstrated in active lesions. The location of IFN gamma on astrocytes suggests an enhancing activity on IR by inducing Ia antigen expression on these cells. In contrast, IFN alpha/beta located on microglial cells and astrocytes might limit the growing lesion. MS patients frequently present a defective response of NK cell activity and an abnormally low production of IFNs reflecting immune dysregulation. The therapeutic trials available to date are discussed: IFN gamma possesses a severe deleterious effect but IFN alpha/beta are still under consideration due to a possible beneficial activity.
The aim of this study was to characterize autoantibodies produced in vitro by peripheral blood lymphocytes (PBL) of patients affected with multiple sclerosis (MS). We studied supernatants from man-mouse hybridomas established by fusion of PBL from 6 MS patients (group I) and from 13 individuals free of any neurological pathology (group II) with the mouse myeloma cell line P3X63 Ag8-653. They were screened for human IgG or IgM production by ELISA. Autoantibody activity against lymphocytes was studied by cell-binding ELISA. Anti-tissue reactivity was assessed by indirect immunofluorescence assay (IFA) on human cerebellum and peripheral nerve as well as on a panel of 8 non-nervous tissues. Additional ELISA tests were performed on 4 purified cellular antigens. Among 522 supernatants in group I, 13.7% contained Ig, mainly IgM, as compared to 25% among 1212 supernatants in group II; 8.3% in group I and 6.7% in group II contained anti-tissue autoantibodies. Antibodies against purified cellular antigens were found in 6% of the supernatants in group II versus 7% in group II. One human monoclonal anti-astrocyte antibody from group I was further studied. This IgM lambda (SAN-7) was particularly polyreactive and recognized glial fibrillar acid protein and other intermediate filaments, as well as tubulin and myosin. Moreover, cross-reactivity was observed with a hapten (TNP-BSA).