Multiple specificities of antibrain antibodies in multiple sclerosis and chronic myelopathy

The presence of complement-fixing antibodies against brain antigens was tested in paired serum and cerebrospinal fluid (CSF) samples from 60 multiple sclerosis (MS) patients, 15 patients with chronic myelopathy of undetermined cause (CM) and 60 control patients. Six MS sera, 34 MS CSF, 4 CM sera, 3 CM CSF, 4 control sera and 1 control CSF gave positive reactions either with a lipid extract or a saline extract of normal human brain. The proportion of anticomplementary CSF was significantly higher in the MS group than in the control group (15% vs 0%, P < 0.01). The reactivity of a large number of individual positive samples was further investigated. Seven antibody specificities were discerned in the MS samples. Most samples reacted with nonlipid antigens, the dominating being a heat-labile, nonlipid component associated with CNS myelin. Antibodies to cerebroside and sulfatide were detected in a few patients. A number of samples reacted with cholesterol in combination with a variety of lipids. Positive samples from the CM patients exhibited a similar heterogeneity. In the control group positive reactions were seen in one patient with systemic lupus erythematosus (SLE), two patients with rheumatoid arthritis (RA), and one with a spinal meningioma. The reaction patterns of these patients were different from those commonly seen in MS patients. The complement-fixing antibrain antibodies in MS CSF are usually of IgG class (Ryberg 1976). This applies also to the positive MS sera in this study. The distribution of the antibodies between serum and CSF indicated, in several cases, an intrathecal synthesis. All of a number of human brains, including one MS brain, contained all 6 antigens (haptens) reactive in saline extracts. Antibodies to tissues outside the CNS were rarely detected in MS patients. The varied humoral autoimmune response in MS might reflect a heterogeneity in the MS patients, the disease itself or its causative agent.     

A longitudinal study of immunological parameters in multiple sclerosis. Cytotoxic antibodies.

Complement-dependent gliotoxic antibody activity was determined in 22 patients with multiple sclerosis (MS) and 19 normal control persons. Peripheral blood serum was collected from MS patients at about 4-week intervals for one year, and the results of cytotoxicity tests correlated with the course of disease. For 10 MS patients with stable disease, complement-dependent cytotoxic antibodies directed against a noncytocidally infected mouse glial cell line (an as yet unidentified virus) were found in significantly higher than normal titer. For 12 MS patients with fluctuating clinical course, the gliotoxic antibody titer remained relatively constant before relapse. During relapse, the titer remained constant or dropped. With remission initially low titers increased appreciably.     

The ontogenetic mouse brain model employed in the characterization of antibrain antibodies in multiple sclerosis

The complement-fixing antibrain antibodies which may be found in patients with multiple sclerosis (MS) belong to several specificities, of which only two are as yet identified. In order to study three of the incompletely characterized specificities, the ontogenetic evolution of the corresponding antigens in mouse brain was followed. MS serum containing antibodies to sulfatide, a relatively myelin-specific glycolipid, served as a control. The studied antigens were virtually absent at birth and accumulated at different rates during the postnatal period. The results give valuable clues for the further study of the antibrain antibodies in MS.     

Different types of antibrain antibodies in multiple sclerosis: Studies employing myelin-deficient mutants of mice

The presence of complement fixing IgG class antibrain antibodies is a distinctive feature of multiple sclerosis (MS). Only two of the several specificities of these antibodies are yet identified. Testing a number of MS sera and CSF samples against homogenates of brain from two myelin-deficient mouse mutants, Jimpy and Quaking, and their littermate controls confirmed the occurrence of antibrain antibodies directed against both myelin-associated and non-myelin antigens.     

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

MRI measures of tissue atrophy within the central nervous system may reflect the neurodegenerative process which underpins the progressive phase of multiple sclerosis (MS). There has been limited longitudinal investigation of MRI-detected atrophy in secondary progressive MS. This study includes 56 subjects with secondary progressive MS. Subjects were followed up for 2 years and MRI analysis was conducted at 12 month intervals using the following measures: (1) whole brain (WB) volume change; (2) grey and white matter (WM) volumes; (3) central brain volume; (4) upper cervical spinal cord (SC) area; (5) T2 lesion volumes. Clinical measures included the Expanded Disability Status Scale and the MS Functional Composite. All volumetric MRI measures were assessed for sensitivity, responsiveness, reliability and correlation with disability. The mean annual atrophy rate of WB was 0.59% per year and this was the most responsive atrophy measure assessed. Grey matter (GM) atrophy (−1.18% per year) was greater and more responsive than WM atrophy (0.12% per year). The SC demonstrated the highest atrophy rate at 1.63% per year. WB, GM and SC atrophy all correlated with change in the Multiple Sclerosis Functional Composite z score (r = 0.35, 0.42, 0.34), and GM atrophy was the only correlate of change in the 9 Hole Peg Test and Paced Auditory Serial Addition Test performance. None of the MRI measures correlated with Expanded Disability Status Score progression. Measures of WB, GM and SC atrophy all have attributes for use as surrogate markers in secondary progressive MS trials and improvement in the reliability of the GM and SC volume measurements may enhance these further.     

A longitudinal study of ventricular volume in early relapsing-remitting multiple sclerosis

The specific aim of this study was to determine whether progressive brain atrophy could be detected within 18 months of establishing a diagnosis of relapsing-remitting multiple sclerosis (RRMS). Fifteen patients with clinically definite RRMS (mean disease duration from first symptom=6 months, mean EDSS=1.2) completed 6 - 14 monthly quantitative MRI sessions. The volume of the lateral ventricles was determined each month using a semi-automated thresholding technique from T1-weighted axial images. The number of new monthly gadolinium-enhancing (Gd+) lesions and EDSS scores were also recorded. Lateral ventricular volumes increased significantly during this study. When individual data were examined, statistically significant changes were observed in six of 15 patients. Monthly change in ventricular volume was related to baseline EDSS and total number of new Gd(+) lesions. These observations indicate brain atrophy, a putative imaging marker of diffuse demyelination and axonal loss, can occur as early as 18 months after first symptoms of RRMS, and is related to the baseline level of disability and to the number of new Gd+ lesions. Multiple Sclerosis (2000) 6 332 - 337     

Viral antibodies in multiple sclerosis. A nationwide co-twin study

Serum viral antibody titers against 21 viruses were studied in 19 of 23 same-sex twin pairs with multiple sclerosis derived from the Finnish Twin Cohort. Thorough neurologic examinations showed two monozygotic pairs to be concordant, whereas all dizygotic pairs were discordant. Special attention was given to measles, mumps, and rubella viruses, against which the antibody levels were determined with the complement fixation, hemagglutination inhibition, hemolysis-ingel, and enzyme immunoassay methods. Epstein-Barr virus antibody levels were determined by enzyme assay. In pairwise comparisons, the measles, mumps, and Epstein-Barr virus-IgG antibody levels were more often elevated in the patients with multiple sclerosis, compared with the healthy co-twins. The same antibody levels were more often above the median in the diseased twin, compared with the healthy twin, but the difference was not significant. No human T-cell lymphotropic virus type I antibodies were found in any of the individuals examined. The total IgG, IgA, and IgM levels did not differ between the diseased and healthy subjects. The HLA types, severity of the disease, and cell-mediated immunity parameters did not influence antibody levels.     

Maternal antibrain antibodies in autism

Autism is a neurodevelopmental disorder of prenatal onset that is behaviorally defined. There is increasing evidence for systemic and neuroimmune mechanisms in children with autism. Although genetic factors are important, atypical prenatal maternal immune responses may also be linked to the pathogenesis of autism. We tested serum reactivity in 11 mothers and their autistic children, maternal controls, and several groups of control children, to prenatal, postnatal, and adult rat brain proteins, by immunoblotting. Similar patterns of reactivity to prenatal (gestational day 18), but not postnatal (day 8) or adult rat brain proteins were identified in autistic children, their mothers, and children with other neurodevelopmental disorders, and differed from mothers of normal children, normal siblings of children with autism and normal child controls. Specific patterns of antibody reactivity were present in sera from the autism mothers, from 2 to 18 years after the birth of their affected children and were unrelated to birth order. Immunoblotting using specific antigens for myelin basic protein (MBP) and glial acidic fibrillary protein (GFAP) suggests that these proteins were not targets of the maternal antibodies. The identification of specific serum antibodies in mothers of children with autism that recognize prenatally expressed brain antigens suggests that these autoantibodies could cross the placenta and alter fetal brain development.     

Early onset multiple sclerosis: a longitudinal study

OBJECTIVE: To evaluate the clinical course of MS in individuals with onset of MS before age 16. METHODS: Patients with onset of MS before age 16 (n = 116) with complete clinical information on the clinical course from the MS Clinic at The University of British Columbia (UBC) Site Hospital computerized database (MS-COSTAR) were included in this study. The data were compared to those from the Canadian natural history study for MS clinic attendees, regardless of age at onset. RESULTS: The mean duration of observation was 19.76 +/- 0.90 years; the mean age at MS onset was 12.73 +/- 0.25 years. Only three cases (2.6%) had a primary progressive (PP) MS course. To date, 60 (53.1%) of 113 subjects have developed secondary progressive (SP) MS. The 50% probability for SPMS was reached 23 years after onset. For patients with relapsing remitting (RR) or SPMS the mean disease duration from onset to the time of confirmed Expanded Disability Status Scale (EDSS) 3.0 was 16.03 +/- 1.17 years (at mean age 28.47 +/- 1.14); mean duration from onset to the time of EDSS 6.0 was 19.39 +/- 1.43 years (at mean age 32.32 +/- 1.44). Annual relapse rate was 0.54 +/- 0.05 per year. The correlation between the number of relapses during the first year of disease and the course of the disease was also significant. CONCLUSIONS: The prevalence of early onset MS (3.6%) in our study confirms the previous findings on early onset MS. A RR course was seen in the majority of cases of early onset MS. A high frequency of relapses, early age at permanent disability, and the presence of malignant cases raise the question of possible early use of disease-modifying therapy in patients with early onset MS.     

A longitudinal study of callosal atrophy and interhemispheric dysfunction in relapsing-remitting multiple sclerosis

OBJECTIVES: To determine if callosal atrophy and interhemispheric dysfunction can be detected in the early stages of relapsing-remitting multiple sclerosis (MS) and to evaluate their progression in relation to the disability and evolution of lesions seen on magnetic resonance imaging during a 5-year period. METHODS: We compared 30 patients who had clinically definite early-onset replasing-remitting MS and mild disability with control subjects. Regional and segmental callosal size and extent of white matter abnormalities on magnetic resonance imaging, as well as performance on tasks exploring interhemispheric transfer of motor, auditory, and sensory information were assessed. Patients with MS were evaluated at baseline and after 5 years. Physical disability was determined at both times using the Expanded Disability Status Scale score. RESULTS: Patients with MS were seen with significant callosal atrophy and functional impairment of interhemispheric transfer at baseline that worsened during the 5-year study. A significant correlation was found between the magnitude of disability and the severity of morphological and functional callosal involvement at baseline. This association persisted at year 5. Baseline clinical characteristics such as age and prestudy relapse rate were unrelated to callosal size or interhemispheric performance. However, the number of baseline T2-weighted lesions was correlated with callosal involvement and this relation persisted at year 5. CONCLUSION: Patients who had relapsing-remitting MS in the early stages of the disease and mild disability had significant callosal involvement that progressed over time. The relationship between disability, T2-weighted lesions load, and degree of morphological and functional callosal impairment confirm the potential value of using callosal dysfunction as a surrogate marker of disease progression in MS.     

T cell subsets in multiple sclerosis. A longitudinal study of exacerbating-remitting cases

Twenty-four untreated MS patients with exacerbating-remitting disease were longitudinally studied for T-cell subset distribution within peripheral blood, using monoclonal antibodies OKT3, OKT4 and OKT8. A decreased percentage of OKT8 reactive cells, with a correlative increase of the OKT4/OKT8 ratio, was detected in relapsing MS patients, in most cases within 2 weeks before and 1 week after the onset of relapse. Longitudinal analysis of individual fluctuations allowed to detect during relapse an increase of OKT4/OKT8 ratio over the value recorded during remission in 78% of MS patients. Only 50% of patients however exhibited an OKT4/OKT8 ratio exceeding the 5% confidence upper limit of healthy control values. Relapse was more often associated with T-cell subset abnormalities in patients who suffered several attacks during the period of study. MS patients in remission, when considered as a group did not show significant abnormalities of the T-cell subset balance, although some individuals did present with wider T-cell subset fluctuations than healthy controls.     

A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions.

Severe tissue destruction is the presumed histopathological correlate of hypointense multiple sclerosis (MS) lesions. In this study we correlated changes of lesion hypointensity over time with initial histopathological features in 14 biopsied MS lesions. The extent of hypointensity increased in initially demyelinated plaques and decreased in remyelinating lesions. The initial axonal loss determined the increase of hypointensity over time. In conclusion, both axonal loss and demyelinating activity determine the evolution of hypointensity over time.     

Anti-ganglioside antibodies in multiple sclerosis

Serological activity against several purified brain gangliosides has been demonstrated in sera of a proportion of multiple sclerosis patients, but not in normal individuals. The activity was determined by the capacity of the sera to bring about complement-dependent lysis of liposomes containing the respective ganglioside in their lipid bilayer. An apparent correlation is indicated between the severity of the disease and the extent of liposome lysis. Cerebrospinal fluid of the patients did not induce lysis, probably due to low antibody concentration.     

Viral antibodies in multiple sclerosis

The sera of 176 MS patients and of 150 healthy adult controls were assayed for antibodies against mumps, rubella, Sendai and herpes simplex viruses, a higher prevalence of measles c.f.a. having already been demonstrated in the MS patients. The CSF of 48 of the MS patients were subjected to the same tests. The patients differed from the controls in a higher prevalence of h.i.a. to mumps and of c.f.a. to herpes simplex. For the latter, but not for the former, the prevalence was statistically higher only in patients treated with immunosuppressants. To date measles seems to be the most seriously incriminated virus in the etiopathogenesis of MS, mumps ranking second.

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Sommario Sono riportiti i risultati delle titolazioni anticorporali verso i virus della parotite, della rosolia, Sendai ed herpes simplex nel siero di 176 pazienti affetti da Sclerosi Multipla e di 150 soggetti sani di controllo, nonché nel liquor di 48 dei malati. In precedenza negli stessi gruppi di soggetti erano stati studiati gli anticorpi antimorbillo. Differenze tra i malati ed i controlli sono state riscontrate solo per la prevalenza nel siero degli anticorpi inibenti l'emoagglutinazione antiparotite e degli anticorpi fissanti il complemento verso l'herpes simplex. Va sottolineato che, al contrario di quanto si è verificato per il virus della parotite, solo i pazienti sottoposti a terapia con farmaci immunodepressivi presentavano una prevalenza degli anticorpi fissanti il complemento verso l'herpes simplex statisticamente maggiore dei controlli. Sulla base delle presenti e di precedenti osservazioni, sembra che il morbillo in primo luogo e la parotite siano i virus per i quali esistono maggiori evidenze di un coinvolgimento nell'eziopatogenesi della Sclerosi Multipla.