Cerebrospinal Fluid IgG Research Articles

Changes in cerebrospinal fluid IgG and apolipoprotein E indices in patients with multiple sclerosis during demyelination and remyelination.

Approximately 85% of patients with multiple sclerosis (MS) can be diagnosed by using magnetic resonance imaging and laboratory tests such as determination of the cerebrospinal fluid (CSF) IgG Index and electrophoresis to detect oligoclonal banding. However, these tests results are abnormal in MS patients whether they are in clinical remission or acute exacerbation. Because apolipoprotein E (apo E) is synthesized in the central and peripheral nervous system, particularly during remyelination, we propose that apo E might be a reliable marker of the remyelination that accompanies clinical remission in MS patients. We studied 33 patients with MS, 22 in remission and 11 in exacerbation, and 26 controls of comparable ages. The apo E Index, calculated from the concentrations of apo E and albumin in CSF and serum, allowed us to discriminate between MS patients in remission and MS patients in exacerbation (P less than 0.001); the IgG Index failed to show similar differences. However, combining the apo E and IgG indices gave maximum discrimination between controls, MS patients in remission, and those in exacerbation. This study suggests that apo E measurements should be included in the laboratory evaluation of MS patients.

Cerebrospinal fluid immunoglobulins and virus-specific antibodies in disorders affecting the facial nerve.

Sixty-two patients with acute idiopathic peripheral facial nerve palsy (AIPFP) and 31 patients with lymphocytic meningoradiculitis (Garin-Bujadoux or Bannwarth's syndrome) are described. Results of cerebrospinal fluid (CSF) analysis, including the measurement of immunoglobulins (Ig) G, A, and M, indicate that pleocytosis and/or disturbance of the blood-CSF barrier (BCB) and/or local immunoglobulin synthesis within the central nervous system (CNS) do occur in about 25% of patients with AIPFP. The commonest finding is a slight to moderate breakdown of BCB function without evidence of intrathecal immunoglobulin synthesis. In only about 10% of patients, further support for an inflammatory process within the CNS is found by intrathecal synthesis of oligoclonal IgG and/or localized synthesis of IgG and/or IgA. The majority of cases (75%) do not show any signs of an inflammatory process within the CNS. In contrast, lymphocytic meningopolyradiculitis (LMR) has a characteristic CSF profile with early impairment of BCB permeability as well as with rapid and predominant intrathecal IgM synthesis, which helps to distinguish monosymptomatic LMR from AIPFP. By applying a sensitive enzyme-linked immunosorbent assay to identical concentrations of IgG in serum and CSF, evidence of intrathecal synthesis of virus-specific antibodies was found only in 2 of 13 patients with AIPFP. In contrast, all 4 patients with herpes zoster oticus and peripheral facial palsy (Ramsay Hunt syndrome) showed an intrathecal IgG synthesis to varicella zoster virus lasting for up to 4 months after onset of disease.

Changes in cerebrospinal fluid cells, IgG and IgA during herpes simplex virus encephalitis in rabbits

Rabbits were infected with herpes simplex-type 1 virus either by corneal scarification or intrathecal inoculation. Encephalitis was induced predictably by either route but was most severe after intrathecal inoculation. Serial examination of the cerebrospinal fluid (CSF) demonstrated abnormalities reflecting two distinct phases of the immune response to this central nervous system infection. The acute phase was manifested by a mononuclear pleocytosis and transudation of serum proteins into the CSF. The recovery phase was manifested by increased amounts of IgG, IgA and antibody specific for herpes simplex virus in the CSF. These studies demonstrate that IgA is a significant component of the local immune response to viral encephalitis in the rabbit as well as in mice and man.

Isoelectric point restriction of cerebrospinal fluid and serum IgG antibodies to measles virus polypeptides in multiple sclerosis

Thirty consecutive isoelectric point (p I)-discrete IgG fractions were isolated from multiple sclerosis (MS) cerebrospinal fluid (CSF) and used to immune precipitate measles virus (MV) polypeptides. Most basic fractions were enriched in activity against nucleocapsid protein (NP), and to a lesser extent against hemagglutinin (H) protein; intermediate fractions were enriched in activity against H and fusion (F) proteins; and more anodic p I fractions were almost exclusively enriched in activity against the large (L) protein of MV. In MS there are marked differences between CSF and autologous serum in regard to antibody activity to MV. In contrast, there were similar profiles of antibody response to MV proteins in SSPE CSF and serum.

Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system

The cerebrospinal fluid (CSF)/serum concentration quotients of albumin and the immunoglobulins G, A and M have been determined for 396 patients with a normal blood CSF barrier function or a pure barrier impairment without a humoral immune response within the central nervous system. The ratios between the concentration quotients of the three immunoglobulins and that of albumin increase in a nonlinear fashion with progressive impairments of the blood CSF barrier, i.e. the molecular size dependent discrimination of the protein transfer (‘selectivity’) decreases. The upper reference values of the concentration quotients for the whole range of passive transfer comply with the hyperbolic function: Q( IgX) = a b √ Q(Alb) 2 + b 2 − c with different constants a b , b 2, c for IgG (0.8, 15 × 10 −6, 1.8 × 10 −3), IgA (0.72, 80 × 10 −6, 5.1 × 10 −3) and IgM (0.65, 150 × 10 −6, 7.5 × 10 −3). With these discriminatory functions the locally synthesized fractions IgX(loc) of IgG, IgA and IgM in CSF can be calculated by the general formula: IgX(loc) = [Q( IgX) − a b √Q( Alb) 2 + b 2 + c] . IgX(Ser).

Demonstration of locally synthesized Borrelia antibodies in cerebrospinal fluid

Antibodies against Borrelia burgdorferi develop slowly. Low titers can be anamnestic. In order to prove the etiology of manifestations of erythema chronicum migrans disease of the nervous system like meningopolyneuritis Garin-Bujadoux-Bannwarth or progressive borrelia encephalomyelitis we used the ELISA to measure specific IgG antibodies against Ixodes ricinus borrelia per microgram IgG in serum and cerebrospinal fluid. With the mentioned method we were able to demonstrate locally synthesized antibodies in the cerebrospinal fluid. Until the 110th day of illness a difference between serum and CSF in favour of the latter as high as five binary dilution steps could be found. Later on in time the difference decreased to four dilution steps or less.

Neurophysiological and CSF immunological study of 19 patients affected by acute idiopatic optic neuritis.

We studied 19 patients affected by acute idiopatic optic neuritis (ON), with neurophysiological tests: visual (VEP), somatosensory (SSEP), acoustic (ABR) evoked potentials and study of the blink reflex (BR), and with cerebrospinal fluid (CSF) examination, in order to detect "silent" lesions in the central nervous system (CNS) and/or immunological alterations, suggestive of multiple sclerosis (MS). The percentage of cases with at least one altered CSF IgG parameter (IgG index, IgG synthesis/day and IgG oligoclonal bands) has been higher than that of cases with one or more altered neurophysiological tests, regardless of the apparently intact eye VEP. If we also included this last test, the 2 percentages become identical. The validity of these tests in predicting the evolution of ON in MS is discussed.

Cerebrospinal fluid protein findings during prophylaxis and treatment of neuromeningosis in leukaemic patients

Methotrexate and Aracytin commonly employed in prophylaxis and treatment of leukaemic neuromeningosis, can induce neuromeningeal injury. Cerebrospinal fluid (CSF) protein disturbance may reflect the damage. In this study we have examined 141 CSF samples collected by lumbar puncture from 51 subjects: 15 normal controls and 36 leukaemic patients during the prophylaxis or the Central Nervous System (CNS) involvement treatment. In all the CSF samples, total proteins, IgG and IgA were examined. CSF total protein and albumin levels increased in the presence of leukaemic neuromeningosis and also after a prolonged CNS prophylaxis or therapy. The same behaviour was found in IgG levels. The IgA levels did not show any modification. We conclude that these parameters are not reliable indices of leukaemic CNS involvement.

Quantitative cerebrospinal fluid IgG measurements as a marker of disease activity in multiple sclerosis.

The value of various parameters of reporting quantitative cerebrospinal fluid (CSF) IgG levels to indicate disease activity in 34 patients with clinically definite multiple sclerosis was examined. IgG alone correlated significantly with increasing degree of disability and increasing number of clinical central nervous system lesions. There was also a trend toward higher mean IgG levels when the course was relapsing and progressive as opposed to progressive or relapsing. For the IgG index, the relationships were the inverse of that noted with IgG alone. IgG-albumin ratio and IgG synthetic rate did not correlate significantly with course, number of CNS lesions, or degree of disability, and there was no statistically significant relationship between any parameter of reporting quantitative CSF IgG and age, duration of disease, history of recent exacerbation, or area of first involvement in the nervous system. We conclude that although newer methods of reporting CSF IgG elevations in multiple sclerosis are more sensitive and some of them, more specific, in confirming a diagnosis than CSF IgG alone, this parameter remains the best marker of disease activity in individual patients.

Immunoglobulin heavy chain associated protein in multiple sclerosis cerebrospinal fluid

Immunoglobulins G, A, and M (IgG, IgA and IgM) were isolated from multiple sclerosis (MS) cerebrospinal fluid (CSF) and sera by Protein A-Sepharose (PAS) affinity chromatography or using solid-phase immunoabsorbents. An isoelectric point heterogenous protein with apparent mol. wt of 74,000–80,000 was seen consistently when CSF Igs were immunoaffinity purified but was never seen when PAS was used for Ig purification. Control experiments exclude the binding of this protein non-specifically either to Sepharose or to Igs or to other CSF proteins. Analysis of purified Igs under non-reducing conditions leads to some reduction in staining pattern indicating that a portion of the protein may be disulfide linked to itself or to other CSF proteins. Immunoblot analysis of CSF Igs separated on 2-DE gels is consistent with a portion of the total CSF Ig protein existing as “free” heavy (H)-chains. PAS requires dimeric Fc fragment of Ig for binding; the differences in 2-DE gels of PAS and immunoaffinity purified Igs may be due to interaction of the 74,000–80,000 protein with “free” H-chain, which nevertheless, still leaves this complex available for binding by anti-H chain antisera. It has been previously suggested that the cytotoxicity of “free” H-chains is abrogated in the absence of the complementary L-chains by H-chain binding proteins; the protein reported here has features similar to these proteins reported previously and may be involved in some way in regulating Ig production in the MS central nervous system.

Immunoglobulin abnormalities in the cerebrospinal fluid during bacterial meningitis

11 patients with bacterial meningitis, examined during the course of the disease for immunoglobulin (Ig) abnormalities in the cerebrospinal fluid (CSF), all had an increased CSF IgM index equal to (CSF/serum IgM):(CSF/serum albumin), indicating intrathecal IgM production. Seven patients had a slightly increased CSF IgG index, and 7 a slightly increased IgA index. Six of the 11 patients had an increased IgM index in the presence of normal indices for IgG and IgA. Follow-up revealed the return of these values to normal. Four patients had identical oligoclonal IgG bands in the CSF and serum, probably representing a systemic immune response, but in only one case were oligoclonal bands suggestive of intrathecal IgG production found. No oligoclonal IgA response was demonstrable in the 4 patients examined. Antigen-immunofixation or antigen-absorption studies revealed evidence of a specific, intrathecal IgG antibody response in only 2 patients, while a search for IgG antibodies against aetiologically unrelated bacterial and viral antigens was negative. With the exception of IgM production, therefore, a humoral intrathecal immune response is less common in bacterial than in aseptic meningitis.

Rapid diagnosis of central nervous systembrucellosis by ELISA

The diagnosis of central nervous system (CNS) brucellosis was made by determining Brucella-specific IgG, IgM and IgA in cerebrospinal fluid (CSF) specimens, using an enzyme-linked immunosorbent assay (ELISA) method. A total of 68 CSF specimens including 10 from patients with brucellosis of the nervous system, 4 with Brucella infection but without CNS involvement, 38 with meningitis other than due to Brucella and 16 with no meningitis were studied. Of the 10 CSF specimens from patients with CNS brucellosis, Brucella-specific IgG was detected in all 10, IgM in 7 and IgA in 8. The 10 patients were also seropositive for anti-Brucella IgG and IgM, and 9 were seropositive for IgA. No Brucella-specific IgG, IgM or IgA was detected in the CSF of 4 patients with brucellosis but without CNS involvement, even though the blood of these patients had high titres of anti-Brucella IgG, IgM and IgA. In addition, none of the CSF specimens from the 38 patients with meningitis other than due to Brucella, or from the 16 patients without meningitis, had detectable anti-Brucella antibodies. This study indicates that the Brucella ELISA on CSF is a reliable, rapid, sensitive and specific assay in the diagnosis of CNS brucellosis.

Specificity of CSF antibodies against components of Borrelia burgdorferi in patients with meningopolyneuritis Garin-Bujadoux-Bannwarth.

The specificity of immunoglobulin (Ig) for components of Borrelia burgdorferi was investigated in cerebrospinal fluid (CSF), serum and in CSF oligoclonal bands from nine patients with meningopolyneuritis Garin-Bujadoux-Bannwarth (MPN-GBB). All patients showed specific IgG and IgM antibodies in serum and CSF when incubated with a lysate of B. burgdorferi strain B 31. Specific antibody was detected in CSF but not in paired serum samples, indicating intrathecal synthesis. Investigation of the specificity of oligoclonal Ig in the CSF revealed oligoclonal bands with specificity for B. burgdorferi in one of the nine patients.

Ceftriaxone Therapy for Asymptomatic Neurosyphilis

A 27-year-old man with documented hypersensitivity to penicillin was treated intramuscularly for asymptomatic neurosyphilis with ceftriaxone (1 g daily for 14 days). After treatment the serum titer in the VDRL (Venereal Disease Research Laboratory) test declined from 32 to four dilutions. Lumbar punctures at months 3, 6, 9, and 28 after treatment revealed normalization of the cell count in cerebrospinal fluid and a decline in the VDRL titer in cerebrospinal fluid from four to one dilution(s). Western blot analysis revealed the presence in serum of IgG antibodies to at least 17 treponemal antigens and in cerebrospinal fluid of antibodies to at least ten treponemal antigens. Following ceftriaxone therapy serum and cerebrospinal fluid IgG reactivity to all antigens steadily decreased in intensity. These results indicate that ceftriaxone may provide a useful alternative therapy for penicillin-allergic patients with neurosyphilis.

Monosymptomatic sensory symptoms and cerebrospinal fluid immunoglobulin levels in relation to multiple sclerosis.

Of 53 patients with monosymptomatic paresthesiae, 55% had oligoclonal bands and 28% an elevated cerebrospinal fluid (CSF) IgG index. Over a mean observation period of 64 months, nine patients developed clinically definite multiple sclerosis (MS); all of these patients had IgG bands, illustrating the prognostic importance of this CSF aberration. Two lumbar punctures more than one year apart were performed in 31 of the patients, of whom 20 had oligoclonal bands. This abnormality was constant between the time of punctures in all subjects except one, thus behaving as in MS. Similarly, the CSF findings in the 11 patients without oligoclonal bands remained normal over the observation period. The majority of patients with oligoclonal bands had cells in their CSF producing immunoglobulin of one or more of the three main classes, while none of those without oligoclonal bands displayed immunoglobulin-producing cells in CSF. Occurrence of oligoclonal bands in CSF is common in patients with paresthesiae and increases the risk for future development of MS.

Immunoglobulins in serum and cerebrospinal fluid from patients with acute Guillain-Barré syndrome.

IgG, IgA, IgM and IgE were quantified in serum and IgG and total protein were quantified in cerebrospinal fluid (CSF) from 80 patients with acute Guillain-Barré syndrome. The serum concentrations of IgM and IgA were significantly increased in approximately 25% of the patients, whereas the concentrations of IgG and IgE were normal. Increased CSF concentrations of IgG were found in more than 90% of the patients and correlated with increased CSF total protein concentrations. The CSF IgG/total protein ratio, CSF IgG index and Tourtellotte's formula were used to determine intra-thecal IgG synthesis in 30 of the patients. In eight of the patients the results of the CSF IgG index and Tourtellotte's formula were significantly increased, while in the remaining seven patients increased values were obtained using only one of these formulae. The CSF IgG/total protein ratio was normal in all the patients. Oligoclonal bands were not detected in any of the sera or CSF. Antibodies to peripheral nerve tissue were detected in approximately 30% of the patient sera, but could not be detected in the CSF.

Multiple Sclerosis: Neuroimmunologic Puzzle

Epidemiologic, clinical, histopathologic, and laboratory findings in multiple sclerosis are briefly reviewed. Emphasis is placed on current clinical and experimental laboratory data demonstrating the presence of immunoregulatory abnormalities in the disease.

Effect of Methylprednisolone on CSF IgG Parameters, Myelin Basic Protein and Anti-Myelin Basic Protein in Multiple Sclerosis Exacerbations

Clinical exacerbations of multiple sclerosis (MS) are characterized by elevated levels of cerebrospinal fluid (CSF) myelin basic protein (MBP). The purposes of this study were to determine whether anti-MBP antibodies are present in increased titer in CSF of MS patients with exacerbations, and whether they can be suppressed by the administration of immunosuppressive dosages of methylprednisolone (MP). A solid phase radio-immunoassay (RIA) was used to detect free and total anti-MBP antibodies before and after acid hydrolysis of CSF. In MS exacerbations, the majority of elevated anti-MBP is in the free form. With the exception of subacute sclerosing panencephalitis (SSPE) and some cases of post infectious encephalomyelitis, anti-MBP antibodies are not present in either MS patients in remission or in non-MS controls. Anti-MBP levels remained elevated over a 10 day period when patients are managed by bed rest only or when treated with intravenous (IV) ACTH. IV administration of MP in "high" (160 mg/day) or "mega" (2 g/day) dosages produces a highly significant reduction of both MBP (p less than 0.01) and anti-MBP (p less than 0.001) levels. Total intrathecal IgG synthesis is also significantly suppressed by IV-MP but not by ACTH.

Immunological Disturbances in Psychiatric Patients-Reply

<h3>n Reply.—</h3> Our recent study¹showed no elevation of immunoglobulin levels or increased incidence of oligoclonal immunoglobulin in a group of psychiatric patients compared with controls. Although these data suggest that viruses and autoimmunity are not involved in the major psychoses, the study has certain limitations that are detailed in our article and reiterated in Dr DeLisi's letter. Most individuals with persistent CNS infections have raised cerebrospinal fluid (CSF) immunoglobulin levels, but immunosuppressed individuals may have chronic viral infections with little evidence of immunoglobulin level elevations. In addition, unconventional agents and autoimmune processes may not produce quantitative or qualitative immunoglobulin abnormalities. Most investigators have found, however, that CSF immunoglobulin level elevations and bands have been found consistently in persistent viral encephalitis caused by conventional agents in immunocompetent hosts, eg, 100% of patients with subacute sclerosing panencephalitis and herpes simplex encephalitis^2,3have increased CSF IgG levels and bands.⁴

Temporal invariance and clonal uniformity of brain and cerebrospinal IgG, IgA, and IgM in multiple sclerosis.

Elevated cerebrospinal fluid (CSF) IgG and oligoclonal IgG bands on electrophoresis are valuable clinical markers for B cell proliferation in the brains of patients with multiple sclerosis (MS). Using two-dimensional electrophoresis, (2DE) we have established that the humoral immune response in MS brain is characterized by finite clonal complexity for the major Ig classes. An important question is whether this immune response is clonally stable or varies with time, related to the development of new lesions and random entry of B cells into the MS brain. To investigate this, we performed serial electrophoretic studies on CSF obtained from 19 patients with MS; the intervals ranged from 7 to 12 yr, with a mean of 8 yr. These analyses included studies of IgG, IgA, and IgM, and revealed that the humoral immune response in MS is clonally stable over long periods. Spontaneous fluctuations or reduction in CSF IgG levels by drugs did not qualitatively affect B cell clonal proliferation in MS brain, in that dominant bands and spots were not obliterated. It has been asserted that IgG synthesis in MS is nonsense antibody because the spectotypes of IgG isolated from different regions of MS brains differ. Factors other than clonal heterogeneity could account for differences found using one-dimensional analysis. B cell clonal products resolve into unique and well-resolved spots by 2DE; the method is uniquely suitable for analysis of restricted immune responses. Therefore, Ig were isolated from 11 regions of three MS brains and the 2DE patterns were compared. The similarity of the 2DE patterns indicate unequivocally that major clones are distributed uniformly although some clones are more prominent in some brain areas. IgA and IgM isolated from the same areas also showed similar patterns. Furthermore, the patterns of light and heavy chains in brain regions differed from serum but were similar to the autologous CSF, providing new evidence that CSF IgG in MS derives from synthesis in situ. Our results indicate that, once initiated, B cell clonal proliferation persists indefinitely and is little altered qualitatively at a clonal level over time, even when CSF IgG levels change or are altered by drugs. Our results are consistent with allotype and idiotype analysis of Ig production in MS and conflict with nonsense antibody proposals of the origin and nature of in situ synthesized Ig in MS.