Optic neuritis and distribution of genetic markers of the HLA system

Thirty patients with optic neuritis (ON), in which neither multiple sclerosis (MS) nor any other etiology could be discriminated, were reexamined after a mean observeation period of 5 years. Eleven patients revealed oligoclonal IgG in the CSF and in five of them a measles virus antibody response within the CNS was demonstrable. the remaining 19 patients did not display oligoclonal CSF IgG and no local antibody production was detectable.
The occurrence of the HLA antigens A3 and B7 in ON did not correlate to the presence of oligoclonal IgG in CSF. the frequencies did not differ from those found in controls. the HLA-B7 linked lymphocyte defined antigen HLA-Dw2 occurred in ON at increased frequency, which was intermediate to that observed in MS and controls. an association was found in ON between oligoclonal IgG in CSF and Dw2. This association was of the same magnitude as in 22 MS patients who had ON as their first symptom of MS. In ON without oligoclonal CSF IgG the frequency of Dw2 was similar to that of controls.
No association was observed between the occurrence of the HLA antigens A3, B7 and Dw2, and increased measles antibody titers in serum or a measles virus antibody response in the CNS.
The occurrence of oligoclonal IgG in CSF in patients with ON may be assumed to increase the risk of developing MS.     

Myelinotoxic activity on tadpole optic nerve of cerebrospinal fluid from patients with optic neuritis

The myelinotoxic activity of unconcentrated cerebrospinal fluid (CSF) from eight optic neuritis (ON) and five multiple sclerosis (MS) patients with oligoclonal IgG, and from five ON patients without oligoclonal IgG, was tested in the tadpole optic nerve system. CSF from ON or MS patients with oligoclonal CSF IgG gave a significantly greater number of myelinotoxic lesions than did CSF from ON patients without oligoclonal CSF IgG, CSF from control patients, or physiologic saline. Induction of myelinotoxic lesions may be coupled with the presence of oligoclonal IgG. The findings support the hypothesis that there are two different forms of ON, of which one, characterized by oligoclonal IgG in the CSF, is more closely related to MS.     

OLIGOCLONAL IgG AND MEASLES ANTIBODY IN CSF OF MULTIPLE SCLEROSIS PATIENTS

Cerebrospinal fluid (CSF) was obtained from 50 neurological patients, 26 of whom suffered from multiple sclerosis (MS). Agar gel electrophoresis and determination of anti-measles antibody titre were performed on the CSF samples. The frequency of elevated measles antibody titre was higher among the MS patients than among the patients with other neurological diseases. Furthermore, oligoclonal IgG in CSF occurred more often among the MS patients than among the other neurological patients. An association between high measles antibody titre and the presence of oligoclonal IgG was observed in CSF from both the MS patients and the patients with other neurological diseases. However, the nature of the correlation between occurrence of oligoclonal IgG and high measles antibody titre remains to be explained.     

The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children

This article describes the association between previous infection and/or vaccination and the development of optic neuritis (ON) in 18 children. Ten of these children subsequently developed clinically definite multiple sclerosis (MS), while in 8 patients a clinically definite etiology could not be confirmed. Vaccination preceded the first ON attack in 6 patients, all but one of whom subsequently developed MS. It also preceded subsequent demyelinating events in 6 patients. Ten of the patients had a bacterial or viral infection within the 2 weeks prior to the first symptoms of ON. Intrathecal antibody synthesis against 2 or more viruses could be shown in 5 out of 8 patients studied; 5 out of 6 patients had oligoclonal antibodies in CSF and 12 out of 16 patients a high IgG index. Neither intrathecal antibody synthesis against 2 or more viruses nor elevated IgG indexes could be found in the control patients. Measles and mumps occurred at a significantly later age in the children who subsequently developed MS than in the control children, and these patients had significantly more events that might have impaired the blood-brain barrier than the controls. These results indicate that immunological events leading to MS may be triggered during childhood. Vaccination and infection often precede ON in childhood. Intrathecal viral antibody production can occur already in childhood at the time of the first symptoms of MS.     

Optic neuritis: findings on MRI,CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up

Optic neuritis (ON) is a common first manifestation of multiple sclerosis (MS), and examination of patients with ON provides opportunities to study the early clinical stages of MS. This prospective study compares results of brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) examinations and HLA-Dw2 phenotyping in 60 consecutive patients with ON. At a median of 17 days after the onset of ON, 69% had oligoclonal IgG bands, and at a median on 79 days after onset, 53% had multiple ( 3) white matter lesions on MRI. Subgroup analyses revealed that MRI abnormalities and oligoclonal IgG bands were equally common in patients examined early or late after the onset of ON. Strong correlations were found between the presence of MRI abnormalities and oligoclonal IgG bands. The HLA-Dw2 phenotype was significantly increased in ON patients compared with controls, but also significantly different from a group of MS patients from the same geographical area. A significant relation was found between Dw2 phenotype and oligoclonal IgG bands. During a mean follow-up time of about 2 years, the diagnosis in 17 of the patients changed to clinically definite MS. Initially, 16 of them had oligoclonal IgG bands and 12 had three or more MRI lesions. Both MRI and CSF studies are important diagnostic tools in the work-up of ON patients.     

Chronic progressive myelopathy associated with HTLV-I: oligoclonal IgG and anti-HTLV-I IgG antibodies in cerebrospinal fluid and serum

Among 22 patients with human T-lymphotropic virus type I (HTLV-I)-associated chronic progressive myelopathy, agarose isoelectric focusing (AIF) revealed oligoclonal IgG bands in 21: in 3 in CSF only; in 11 in CSF and to some extent in serum; and in 7, identical patterns in CSF and serum. By immunoblot after AIF of CSF and serum, we observed bands of anti-HTLV-I IgG antibodies in 19 patients: in 5 in CSF only; in 9 in CSF and partly in serum; and in 5, identical in CSF and serum. Oligoclonal anti-HTLV-I IgG antibody bands could only partly be traced to oligoclonal IgG bands. If, prior to AIF, serum and CSF were absorbed with HTLV-I antigen, practically all oligoclonal HTLV-I-specific IgG antibody activity was abolished, while the oligoclonal pattern of total IgG was affected only to a minor extent. Alongside with HTLV-I-specific oligoclonal B cell response, HTLV-I myelopathy is regularly accompanied by production of oligoclonal IgG of unknown antibody specificities.     

Genetic basis of multiple sclerosis: HLA antigens, disease progression, and oligoclonal IgG in CSF

The HLA antigens B7 and Dw2 occurred at elevated frequencies in 105 multiple sclerosis (MS) patients (49 and 47%, respectively), compared to healthy controls (29 and 30%), especially in MS patients with oligoclonal CSF-IgG (51 and 50%), in cases with CSF-IgG index values above 1.5 (64 and 64%), and in those with the most malignant course of the disease (47 and 59%). Normal or only slightly elevated frequencies of B7 and Dw2 were found in MS patients without oligoclonal CSF IgG (35 and 29%), normal CSF-IgG index (43 and 39%), and the most benign course (42 and 37%). No correlation was found between the HLA type and measles virus antibody titers in serum or a measles virus antibody response within the CNS.     

Chlamydia pneumoniae in multiple sclerosis: humoral immune responses in serum and cerebrospinal fluid and correlation with disease activity marker

Humoral immune responses to Chlamydia pneumoniae (C. pneumoniae) were studied in paired sera and cerebrospinal fluid (CSF) of patients with definite multiple sclerosis (MS) and other inflammatory and non-inflammatory neurological diseases. Seropositivity was not significantly different between these groups. However, C. pneumoniae-specific IgG titers were significantly higher in CSF of MS than in controls. Sixteen out of 52 seropositive MS patients (30.8%) showed intrathecal synthesis of C. pneumoniae-specific IgG but only one of 43 seropositive controls (2.3%). In MS, this was strongly associated with intrathecal synthesis of polyclonal IgG in 13/16 patients. However, these elevated C. pneumoniae antibody titers in CSF did not significantly correlate with disease duration, disease course, clinical or MRI disease activity, disability or presence of oligoclonal IgG in MS.     

Immunoglobulin class and light chain type of oligoclonal bands in CSF in multiple sclerosis determined by agarose gel electrophoresis and immunofixation.

Agarose gel electrophoresis and immunofixation of CSF and serum from 39 patients with multiple sclerosis (MS) revealed oligoclonal IgG in the CSF in all cases and oligoclonal IgA and IgM in 1 patient each. IgG kappa bands only were found in 10 patients, while no patient had IgG lambda bands alone. IgG kappa bands predominated in 20 patients and IgG lambda bands in 5, while 4 patients had the same number of IgG kappa and IgG lambda bands. Twenty-seven patients also displayed IgG bands with kappa and lambda present simultaneously. Bands of free lambda chains were found in 7 patients, while free kappa chain bands were not seen. One or 2 faint IgG bands in 4 patients constituted the only serum abnormality. In 4 additional MS patients selected on the basis of normal findings on agarose gel electrophoresis of the CSF, immunofixation did not reveal oligoclonal Ig, while isoelectric focusing showed bands in 1. Immunofixation is recommended for proving the presence of oligoclonal Ig in CSF and for characterizing oligoclonal Ig into classes and types of light chains.     

Optic neuritis: oligoclonal bands increase the risk of multiple sclerosis

ABSTRACT- In 1974 we examined 30 patients 0.5–14 (mean 5) years after acute unilateral optic neuritis (ON), when no clinical signs of multiple sclerosis (MS) were discernable. 11 of the patients had oligoclonal bands in the cerebrospinal fluid (CSF). Re-examination after an additional 6 years revealed that 9 of the 11 ON patients with oligoclonal bands (but only 1 of the 19 without this CSF abnormality) had developed MS. The occurrence of oligoclonal bands in CSF in a patient with ON is - within the limits of the present observation time - accompanied by a significantly increased risk of the future development of MS. Recurrent ON also occurred significantly more often in those ON patients who later developed MS.     

Relation between benign course of multiple sclerosis and low-grade humoral immune response in cerebrospinal fluid.

The prognosis in multiple sclerosis (MS) is related to the presence of an abnorma humoral immune response within the central nervous system: 14/17 MS patients (82%) without oligoclonal CSF IgG displayed no or slight disability after a mean duration of MS of 17 years, while 53% of 88 patients with oligoclonal CSF IgG had a benign course after a mean duration of 13 years (p less than 0.05). A benign course also was more often accompanied by a normal CSF IgG index. MS patients without oligoclonal CSF IgG had elevated CSF/serum ratios of albumin in 6%, and of the complement factors C3 in 0% and C4 in 6%, as against 20%, 27% and 37%, respectively, in MS patients with oligoclonal CSF IgG.     

HL–A HISTOCOMPATIBILITY ANTIGENS IN OPTIC NEURITIS

HL-A and MLC typing in 54 patients with optic neruitis showed increased frequencies of the HL-A3, 7 and LD-7a determinants of approximately the same magnitude as in patients with multiple sclerosis. The frequencies of the same three determinants were not different in the 11 patients who developed multiple sclerosis during the period of follow-up compared to the remaining patients. There was a significant increase in the frequency of the HL-A3 determinant in patients with oligoclonal IgG of the cerebrospinal fluid at the onset of disease. The connection between this determinant and the occurrence of cerebrospinal fluid changes is not clear. The results suggest that optic neuritis and multiple sclerosis represent different aspects of the same disease entity, rather than two distinct diseases. HL-A and MLC typing did not seem to offer prognostic information as to the later development of multiple sclerosis in these patients, but the observation period is still short.     

The occurrence of oligoclonal IgG in tears from patients with MS and systemic immune disorders

Using isoelectric focusing (IEF) and immunoperoxidase staining of proteins transferred to nitrocellulose membranes, we have examined the IgG band pattern in tears and matched serum and CSF specimens of 28 patients with MS, 4 patients with optic neuritis (ON), 30 individuals with systemic, inflammatory, or other neurologic diseases, and 5 patients with tension headache. We found no evidence of positive oligoclonal IgG in tears in any MS or ON patients, while 10 out of 16 cases with systemic immune disorders or infections of the CNS had positive tear oligoclonal bands. We are thus not able to support the hypothesis that tears from MS patients reveal abnormalities in their humoral immune response.     

Qualitative evidence of anti-Yo-specific intrathecal antibody synthesis in patients with paraneoplastic cerebellar degeneration

We investigated the presence of anti-Yo-specific oligoclonal antibody bands in cerebrospinal fluid (CSF) and serum samples of 9 patients with anti-Yo syndrome and 11 controls. Isoelectric focusing combined with affinity blotting, revealed anti-Yo-specific intrathecal antibody synthesis in all patients with anti-Yo syndrome: Four patients had positive anti-Yo-specific oligoclonal IgG bands in CSF which were not demonstrable in their sera; five CSF/serum pairs showed additional, more intensive, oligoclonal bands in CSF compared to the corresponding serum. Interestingly, four patients with absence of oligoclonal bands of total IgG in CSF revealed positive anti-Yo-specific oligoclonal bands in the same sample. This speaks for a higher sensitivity of detection of oligoclonal bands using an affinity blot loaded with Yo-specific antigen compared to an affinity blot coated with anti-human IgG used for the detection of oligoclonal bands of total IgG. In conclusion, the presence of anti-Yo-specific oligoclonal IgG bands in CSF which were absent, or less strong, in patients sera provides qualitative evidence of anti-Yo-specific IgG synthesis by intrathecal B-cell clones. These results could be of interest in detection of intrathecal-specific IgG synthesis in nervous system infectious diseases provided that the target antigen is known.     

Visual evoked responses and immunoglobulin abnormalities in the diagnosis of multiple sclerosis

Visually evoked responses (VERs), CSF IgG/albumin ratio and CSF oligoclonal IgG were examined in 136 patients with multiple sclerosis (MS) admitted to hospital for investigation, and compared to the CSF findings in 87 patients with other neurological diseases (OND). 33% of patients with OND had abnormal CSF IgG/albumin ratios but only 9% had CSF oligoclonal IgG banding. In clinically definite MS, VERs were abnormal in 87% and CSF oligoclonal banding was found in 80% of patients, but CSF oligoclonal banding was found significantly more frequently than abnormal VERs in patients with suspected MS. We were unable to show any relationship between benign MS and the absence or presence of CSF oligoclonal IgG. The significance of CSF oligoclonal IgG in the less clinically definite forms of MS will only emerge with prolonged follow-up.     

Multiple sclerosis is associated with enhanced B cell responses to the ganglioside GD1a

The occurrence and role of autoantibodies to gangliosides and other lipid-containing components of the central nervous system in Multiple Sclerosis (MS) are unsettled. Using sensitive ELISAs, we measured IgG and IgM antibody titers and absorbances to the three major gangliosides GD1a, GD1b and GM1, and to sulfatides, cardiolipin and myelin proteins in paired serum and cerebrospinal fluid (CSF) from patients with untreated MS, optic neuritis (ON), acute aseptic meningo-encephalitis (AM) and other neurological diseases (OND). Twenty-three per cent of 30 MS (P<0.04) and 18% of 32 ON patients (P<0.05) presented elevated IgG antibody titers to GD1a in serum compared to 9% of patients with OND. Six (40%) of the patients with malignant MS had elevated serum IgG antibody titers to GD1a compared to one (6%) of the patients with benign MS (P<0.04). In CSF, elevated IgG antibody titers to GD1a were measured in 13% of MS and 20% of ON patients compared to 4% of patients with OND (P<0. 03 and P<0.02, respectively). The augmented IgG response to GD1a in serum also separated MS from Guillain-Barré syndrome. Compared to OND increased IgM absorbances to sulfatides and cardiolipin were observed in CSF of patients with MS, but also in AM. Elevated IgG antibody titers to myelin proteins were found more often in MS patients' serum and MS, ON and AM patients' CSF compared to OND. The data implicate that among the multitude of enhanced B-cell responses occurring in MS and ON, that directed to GD1a is common and more discriminative, and should be evaluated in future MS treatment studies.     

Mumps meningitis: Specific and non-specific antibody responses in the central nervous system *

Intrathecal production of oligoclonal mumps-specific IgG was demonstrated in nine out of 10 children with mumps meningitis by imprint immunofixation (IIF) of sera and cerebrospinal fluids (CSF) separated by agarose electropheresis and by thin-layer electrofocusing. Four of the patients had intrathecal mumps antibody synthesis demonstrable also by conventional serological tests. Oligoclonal CSF IgG was demonstrable by agarose electrophoresis in four of the patients. A dominance of λ over κ type oligoclonal Ig and mumps antibodies was observed in the CSF of three of these patients. The bulk of the oligoclonal CSF IgG was concluded to represent mumps-specific antibodies on the basis of the IIF as well as virus absorption analysis. Intrathecal production of oligoclonal IgG antibodies to one, two, or three other (measles, rubella, herpes simplex) viruses was demonstrated by IIF in four patients. These antibodies were not associated with the oligoclonal CSF IgG present in three of the patients. It is concluded that a specific intrathecal IgG antibody response is a common feature in children with mumps meningitis. This response sometimes reaches a magnitude that permits detection of oligoclonal IgG in the CSF. In some patients, the specific response appears to be associated with a non-specific activation of cells producing antibodies of other (unrelated) specificity.     

Immunoglobulins within the central nervous system in primary Sjögren's syndrome

Cerebrospinal fluid (CSF) and sera from 17 patients with primary Sjögren's syndrome (PSS) with or without clinical evidence of nervous system involvement were studied. Intrathecal IgG synthesis as measured by oligoclonal IgG bands on agarose isoelectric focusing or elevated IgG index in CSF was found in 6 of 8 patients with clinical nervous system involvement but also in 5 of 9 patients without clinical nervous system involvement. Elevated IgM-index in CSF was found in 7 of 8 patients with clinical nervous system involvement and in 6 of 9 patients without clinical nervous system involvement. By immunoblotting, CSF IgG-antibodies against myelin basic protein (MBP) were found in 3 of 12 patients with multiple sclerosis (MS), but in none of the patients with PSS or in the 12 controls. Intrathecal anti-viral IgG-antibodies, as measured by immunoblotting against measles, mumps, varicella or herpes simplex, were found in 8 of 17 patients with PSS, and in 7 of 12 patients with MS, but were not detected in the controls. Our observations support the concept that the central nervous system (CNS) is included in the multiple immunological phenomena of PSS. Interestingly, in some PSS patients intrathecal IgG synthesis occurred without overt clinical nervous system involvement and thus the clinical significance of intrathecal IgG synthesis in PSS is uncertain. The similarities with MS regarding intrathecal antiviral antibody production may be interpreted as the result of polyclonal B-cell activation.     

Free light chains in the CSF in multiple sclerosis

Summary The presence of free light chains (FLC) was investigated in 32 patients with clinically definite or laboratory supported definite multiple sclerosis (MS), 2 patients with neurosyphilis and 10 normal controls. The detection of FLC in unconcentrated cerebrospinal fluid (CSF) was performed by means of agarose isoelectric focusing, followed by transfer of proteins to nitrocellulose membranes, double immunofixation, avidin-biotin amplification and peroxidase staining. Bands due to FLC were clearly demonstrated in the CSF of 28 MS patients; 3 of them showed only kappa FLC, 10 only lambda FLC, while 15 had both kappa and lambda FLC. The CSF of 4 MS patients was FLC negative. In both cases of neurosyphilis FLC bands were observed. FLC were never found in normal CSF. Among the indexes of intrathecal immunological activity (IgG oligoclonal bands, FLC, IgG index, intra-blood-brain barrier IgG synthesis rate, pleocytosis) the FLC proved to be the second most frequent abnormality in MS CSF, the presence of IgG oligoclonal bands being the first. In one MS case an FLC band was found, while all the other indexes of intrathecal IgG production were negative. A high correlation was found between an elevated number of FLC and pleocytosis. The presence of FLC in MS CSF seems to indicate a recent immunological stimulation leading to increased synthesis of FLC within the CNS.     

Immunoblot detection of oligoclonal anti-myelin basic protein IgG antibodies in cerebrospinal fluid in multiple sclerosis

Migration properties and occurrence of antibodies against myelin basic protein (MBP) in paired CSF and serum specimens from patients with multiple sclerosis (MS) were demonstrated after agarose isoelectric focusing, immunoblot transfer, and immunoperoxidase staining. Oligoclonal IgG antibody bands directed against MBP were found in the CSF of 9 of 28 patients with MS (32%), but not in the CSF of any of 34 patients with other neurologic diseases. No serum showed anti-MBP antibody bands. The CSF anti-MBP antibodies migrated to the anodal region of the IgG area in a different fashion from oligoclonal IgG and anti-measles IgG antibodies, which were detected in parallel. The anti-MBP bands were transient in three of seven patients whom we studied consecutively. Enzyme-linked immunosorbent assay (ELISA) of serum and CSF for detection of IgG reactivity against MBP showed absorbance values above 2 standard deviations of controls in 44% of the MS patients and in 21% of those with other neurologic diseases. Results of this assay correlated partly with those of the immunoblot assay. ELISA positive and immunoblot negative results might be due to a broad polyclonal anti-MBP antibody response.