Lymphocyte transformation in the presence of myelin basic protein in multiple sclerosis and control subjects

The transformation of lymphocytes in vitro in the presence of human myelin basic protein has been investigated in normal people, patients with multiple sclerosis (MS) and controls with other neurological diseases. There was little or no response at low concentrations (1--10 microgram/ml) but significant transformation at higher concentrations (100--1000 microgram/ml) in all three groups. There was no significant difference among the groups as a whole, but those MS patients who had had disease for more than 10 years did show greater responses than normal subjects (P less than 0.05). Increased responses could not be correlated with any other aspect of disease activity: in particular they were not increased in patients with acute relapses. The use of autologous serum instead of homologous AB Rhesus positive serum did not significantly alter lymphocyte responsiveness. The absence of any response in the presence of purified calf thymus histone suggests that the response to myelin basic protein indicates a low level of lymphocyte sensitization to this antigen even in normal subjects. The present evidence does not support a primary pathogenetic role for such a reaction in MS. The increased response in patients with a long duration of disease might merely be an effect of white matter damage or might represent an amplification of the normal immune response contributing to myelin breakdown and leading to the emergence of the progressive stage of the disease. The study of lymphocyte responsiveness over a wide range of concentrations of myelin basic protein is considered to resolve some of the controversy surrounding this subject in the literature.     

Human T-cell response to myelin basic protein in multiple sclerosis patients and healthy subjects

In order to explore the T-cell repertoire to myelin basic protein (BP) of both multiple sclerosis (MS) patients and healthy subjects (HS), we raised BP reactive T-cell lines from blood mononuclear cells of eight MS patients and five HS. These lines were triggered in vitro by human BP. When analyzing their patterns of recognition of human BP versus heterologous BP, we could observe differences between healthy subjects and MS patients. Whereas T-cell lines from healthy subjects developed a response to heterologous BP, which was in most cases equal or higher than that elicited by human BP, T-cell lines from most MS patients displayed a low response, or no response at all, to one or several of the heterologous BP tested. A low response to bovine BP was only observed in active cases, whereas decreased responses to rat and/or monkey BP were observed both during remission and during active disease. This may indicate that T-cell repertoire to BP in MS patients differs from that of healthy subjects. BP-reactive T-cell clones were obtained by limiting dilution from two healthy subject lines. Their pattern of response to heterologous BP as compared to human BP suggest that T-cells from the same individual can recognize different BP epitopes.     

Abnormal sensorimotor control, but intact force field adaptation, in multiple sclerosis subjects with no clinical disability

In MS subjects with no clinical disability, we assessed sensorimotor organization and their ability to adapt to an unfamiliar dynamical environment. Eleven MS subjects performed reaching movements while a robot generated a speed-dependent force field. Control and adaptation performance were compared with that of an equal number of control subjects. During a familiarization phase, when the robot generated no forces, the movements of MS subjects were more curved, displayed greater and more variable directional errors and a longer deceleration phase. During the force field phase, both MS and control subjects gradually learned to predict the robot-generated forces. The rates of adaptation were similar, but MS subjects showed a greater variability in responding to the force field. These results suggest that MS subjects have a preserved capability of learning to predict the effects of the forces, but make greater errors when actually using such predictions to generate movements. Inaccurate motor commands are then compensated later in the movement through an extra amount of sensory-based corrections. This indicates that early in the disease MS subjects have intact adaptive capabilities, but impaired movement execution.     

Lipid composition of myelin in multiple sclerosis

Summary Myelin was isolated from histologically normal white matter and plaques from MS patients and from white matter of neurologically normal controls. No difference was found in the total lipid content. There were no detectable deficits in MS myelin of phosphoglycerides, plasmalogens or sphingolipids. Gangliosides and lysolecithin were not detected. Analysis of the fatty aldehyde composition of the phosphoglycerides and the fatty acid composition of the cholesteryl esters, phosphoglycerides and sphingolipids did not show any differences between the normal and MS myelin.This investigation was supported by Grant 484 from the National Multiple Sclerosis Society and by USPHS Grants HD 04575, NB 05464, GM-K6-19177.The postmortem specimens were provided from the International Tissue Bank supported by the National Multiple Sclerosis Society and administered by Wallace W. Tourtellotte, M.D., Ph.D.     

Spleen versus CNS immunoglobulin G in multiple sclerosis: an isoelectric focusing study

Immunoglobulin G (IgG) band patterns were investigated in a peripheral immune compartment, the spleen, and the central nervous system (CNS) compartment in 6 multiple sclerosis (MS) subjects and 3 controls in a search for systemic humoral immune response that may be related to the localized immune response seen in MS. Using the isoelectric focusing (IEF) technique with immunoperoxidase staining of proteins transferred to nitrocellulose membranes, we were not able to demonstrate any qualitative abnormalities of spleen or serum IgG in the MS cases, whilst all matched CNS tissues and CSF specimens were clearly positive for oligoclonal IgG bands. Our results suggest that there is no systemic oligoclonal IgG secretion in MS. This further supports the presence of a compartmentalized IgG intrathecal immune response in MS and emphasizes the organ specificity of MS.     

CSF myelin basic protein in multiple sclerosis

Cerebrospinal fluid (CSF) from 221 patients with multiple sclerosis (MS) and 85 patients with other neurological disorders (OND) was examined using a competitive radioimmunoassay for myelin basic protein (MBP) immunoreactivity. MBP was found in 46 of 55 MS patients (84%) examined within six weeks of relapse but in only 11 of 85 patients (13%) with OND. There was a significant correlation between the concentration of MBP in the CSF and relapse severity in patients seen within four weeks of the onset of symptoms (p less than 0.01). Of 44 patients in remission, MBP was detected in 12, and these patients had a significantly higher tendency to subsequent relapse (p less than 0.05). In 72 patients with progressive disease the presence of MBP in the CSF reflected the confidence of clinical diagnosis. The results of this study suggest that measurement of MBP in the CSF gives an objective method of monitoring disease activity in patient with MS.     

Increased frequency of restless legs syndrome in a French-Canadian population with multiple sclerosis

The authors evaluated the co-occurrence of multiple sclerosis (MS) and restless legs syndrome (RLS) using an RLS questionnaire. They evaluated 200 patients with MS, 100 with rheumatoid arthritis (RA), and 100 controls, all French-Canadians. They found that 37.5% of MS patients, 31% of RA patients, and 16% of controls fulfilled the criteria for RLS. MS can cause RLS, or MS and RLS may have common susceptibility factors.     

Water content and myelin water fraction in multiple sclerosis

BACKGROUND: Measurements of the T2 decay curve provide estimates of total water content and myelin water fraction in white matter in-vivo, which may help in understanding the pathological progression of multiple sclerosis (MS). METHODS: Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1 primary progressive) and 18 controls underwent MR examinations. T2 relaxation data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter and 6 grey matter structures were outlined in each of these subjects. The remaining 15 MS patients were scanned in other transverse planes. A total of 189 lesions were outlined in the MS patients. Water content and myelin water fraction were calculated for all regions of interest and all lesions. RESULTS: The normal appearing white matter (NAWM) water content was, on average, 2.2% greater than that from controls, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p<0.0006). On average, MS lesions had 6.3% higher water content than contralateral NAWM (p<0.0001). Myelin water fraction was 16% lower in NAWM than for controls, with significant differences in the major and minor forceps, internal capsules, and splenium (p<0.05). The myelin water fraction of MS lesions averaged 52 % that of NAWM. CONCLUSIONS: NAWM in MS has a higher water content and lower myelin water fraction than control white matter. The cause of the myelin water fraction decrease in NAWM could potentially be due to either diffuse edema, inflammation, demyelination or any combination of these features. We present a simple model which suggests that myelin loss is the dominant feature of NAWM pathology.     

Spatial frequency evoked visuograms in multiple sclerosis.

We obtained steady-state visual evoked potentials (VEPs) to sinusoidal gratings alternating at 4 Hz with spatial frequencies varying from 0.5 to 8 cpd in 21 normal controls and 21 patients with multiple sclerosis (MS), and analyzed responses by fast Fourier transform. Amplitude- and phase-spatial frequency functions were obtained and referred to as amplitude and phase "visuograms." We observed two types of abnormalities in the phase visuograms of MS patients: (1) abnormal responses at all spatial frequencies tested (37%), and (2) abnormal responses only at selective spatial frequencies (52%). Some patients had phase lag limited to low, middle, or high spatial frequencies. Steady-state and transient VEPs to 2 and 4 cpd showed a similar percent of abnormalities. The use of more than one spatial frequency stimulus increased the diagnostic yield by 17%. Our data confirm that MS may selectively affect specific neuronal channels within the visual pathways.     

IgG reactivity against citrullinated myelin basic protein in multiple sclerosis.

An increased level of citrullinated myelin basic protein (MBP-C8) has been reported in the brains of multiple sclerosis (MS) patients. However, the involvement of the immune response to post-translational modified MBP in the pathophysiology of MS remains speculative. The aim of this study was to compare the levels of immunoglobulin G antibodies to several MBP epitopes, before and after citrullination, in the cerebrospinal fluid (CSF) and sera of MS patients using enzyme-linked immunosorbent assay (ELISA). We analyzed antibody reactivity against various MBP-peptides in the CSF and sera of 60 MS patients, and 30 patients with other neurological diseases (OND) as controls. The peptides tested were: MBP(75-98) (peptide 1), native (peptide 2) and citrullinated (peptide 3) MBP(108-126) (ARG(122)-->Cit(122)), and native (peptide 4) and citrullinated (peptide 5) MBP(151-170) (ARG(159, 170)-->Cit(159, 170)). All selected peptides could support an immune reactivity in CSF and sera of MS and OND patients. A higher reactivity against peptide 4 was found in the CSF of MS patients compared with OND patients (P<0.0001), but not against citrullinated peptides (peptides 3 and 5). However, we observed that the citrullination state of peptide 2 modified the patterns of immune reactivity more markedly in MS patients (P<0.0001) than in OND patients (P<0.02). Although some MBP epitopes could be a potential target in MS, our data did not demonstrate any difference of antibody response to MBP peptides in their citrullinated forms.     

Increased CSF IgM in multiple sclerosis

CSF IgM levels have been measured by radioimmunoassay in 56 patients with MS, 62 patients with other neurologic diseases, and 31 normal controls. Forty-eight percent of the patients with MS had a raised CSF IgM level compared with 5 percent of the patients with other diseases. The IgM level did not correlate with the IgG level. Forty percent of the MS patients with normal IgG levels had high IgM levels. No relationship was found between the CSF IgM level and length or severity of the MS, relapses, or steroid therapy. Attempts to identify the IgM as being anti-measles were unsuccessful.     

对多发性硬化的再认识

中枢神经系统(CNS)脱髓鞘疾病特指一组病因不明确,通常认为与免疫相关的CNS炎症性疾病,多发性硬化(MS)是最典型的代表.既往研究认为,该疾病病理上主要累及CNS的白质,由髓鞘蛋白致敏的自身活化的CD4+T细胞导致髓鞘脱失和(或)髓鞘形成细胞的破坏,产生脱髓鞘斑块,而神经元和轴索相对保留.     

Visual object recognition in multiple sclerosis

Deficits in tasks measuring visual processing have been earlier reported in studies of MS. Yet, the nature and severity of visual-processing deficits in MS remains unclear. We used a new method in order to measure the different stages of visual processing in object recognition: shape recognition, familiarity recognition, semantic categorization, and identification with naming. Six two-choice reaction-time tasks were presented to 30 MS patients and 15 healthy controls. The patients were divided into cognitively preserved and cognitively deteriorated study groups according to their cognitive status. The purpose was to find out whether deficits at specific stages of visual processing can be found in cognitively deteriorated MS patients. Cognitively deteriorated MS patients did not perform as well as cognitively preserved MS patients or healthy controls. They were slower already at the early stage of visual processing where discrimination of whole objects from scrambled ones was required. They also had higher error rates in tasks requiring object familiarity detection and object identification with naming. Thus, cognitively deteriorated MS patients had difficulties in visual shape recognition and semantic-lexical processing. However, variation of performances was large within both of the patient groups indicating that even patients without a generalized cognitive decline may have deficits in some stages of the visual processing. We suggest that because of the heterogeneity of the patients, every single case needs to be examined separately in order to identify the possible deficits in visual processing.     

Overcoming remyelination failure in multiple sclerosis and other myelin disorders

Protecting axons from degeneration represents a major unmet need in the treatment of myelin disorders and especially the currently untreatable secondary progressive stages of multiple sclerosis (MS). Several lines of evidence indicate that ensuring myelin sheaths are restored to demyelinated axons, the regenerative process of remyelination, represents one of the most effective means of achieving axonal protection. Remyelination can occur as a highly effective spontaneous regenerative process following demyelination. However, for reasons that have not been fully understood, this process is often incomplete or fails in MS. Recognizing the reasons for remyelination failure and hence identifying therapeutic targets will depend on detailed histopathological studies of myelin disorders and a detailed understanding of the molecular mechanisms regulating remyelination. Pathology studies have revealed that chronically demyelinated lesions in MS often fail to repair because of a failure of differentiation of the precursor cell responsible for remyelination rather than a failure of their recruitment. In this article we review three mechanisms by which differentiation of precursor cells into remyelinating oligodendrocytes are regulated-the Notch pathway, the Wnt pathway and the pathways activated by inhibitor of differentiation in myelin debris-and indicate how these might be pharmacologically targeted to overcome remyelination failure.