Central Nervous System IgG Synthesis Research Articles

Central nervous system IgG synthesis in multiple sclerosis. Application of a new formula.

A new formula for the determination of local central nervous system IgG synthesis has been applied to a group of 191 patients with multiple sclerosis. There were no correlations with sex, age, duration of disease, or clinical status but local IgG synthesis was significantly greater in patients with high levels of disability and a progressive clinical course than those with lower degrees of disability or a relapsing/remitting course. Significant correlations were found between oligoclonal aspect and local IgG synthesis; this synthesis was higher in CSF containing anti-viral and anti-nucleic acid antibodies than in CSF without such antibodies. There was also a lower local IgG synthesis when C-reactive protein (CRP) was present in serum.

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: The Mayo Clinic experience

The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.

Central Nervous System IgG Synthesis Rates in Alzheimer Disease

Central nervous system IgG synthesis rates were determined for 51 patients with autopsy-confirmed Alzheimer disease and 23 age-matched controls. Rates were no different between patients and controls when overall groups were compared. Age-at-dementia-onset data were available on 37 patients. Comparisons of 11 early-onset (< 65 years of age) patients with 26 late-onset patients revealed significantly increased intrathecal IgG synthesis rates for the late-onset group. These results suggest that IgG synthesis may be a contributing pathogenic factor in a subgroup of patients with late-onset Alzheimer disease.

Neoplastic Angioendotheliomatosis

A 60-year-old white man presented with aphasia, seizures, paraparesis, and incontinence. His serologic and hematologic profiles were unremarkable. His cerebrospinal fluid showed pleocytosis, increased daily central nervous system IgG synthesis, increased myelin basic protein, and negative cytology and cultures. Cerebral computed tomography exhibited multiple areas of hypodensity but spinal computed tomography and myelography showed no abnormalities. Cranial and spinal magnetic resonance imaging revealed areas of increased signal on T2-weighted images. The use of gadolinium-pentetic acid on T1-weighted images delineated smaller areas of cortical enhancement with surrounding rim of decreased signal. Brain biopsy showed intravascular malignant cells positive for leukocyte common antigen and B-cell markers. The diagnosis was neoplastic angioendotheliomatosis (intravascular lymphomatosis). To our knowledge, this is the first report on the use of both cranial and spinal magnetic resonance imaging in this condition.

Central nervous system involvement in early syphilis. Part 1. Intrathecal immunoglobulin production

The immunological activity in the cerebrospinal fluid (CSF) was studied in 47 patients with early syphilis. The immunoglobulin production within the central nervous system (CNS) was estimated by analysing immunoglobulin G and albumin in CSF and serum and constructing an IgG index according to Tibbling et al. and calculating daily CNS IgG synthesis, according to Tourtellotte. In 10 (21%) of the 47 patients, intrathecal immunoglobulin production was observed. The immunoglobulin production within the CNS was significantly correlated to the presence of syphilis antibodies and to pleocytosis. Eight of the patients demonstrated oligoclonal bands on electrophoresis. Total protein usually did not reveal an increased CNS immunoglobulin production but reflected a blood-brain barrier lesion. One year after penicillin treatment, 2 out of 9 patients still had slight intrathecal immunoglobulin production.

Quantification of de novo central nervous system IgG measles antibody synthesis in SSPE.

De novo central nervous system (CNS) IgG measles antibody synthesis rate was determined in two patients with subacute sclerosing panencephalitis (SSPE). Cerebrospinal fluid and sera were incubated with different concentrations of measles virus to determine maximum absorption of IgG. The difference in IgG concentration before and after incubation was considered the amount of measles-specific IgG antibody. Various tests were done to assess the immunological specificity of the absorption test. Using our empirical formula, the de novo CNS IgG measles antibody synthesis rate for one patient with SSPE was 57 mg/day, or 59% of the total CNS IgG synthesis rate; for the other it was 145 mg/day, or 82%. Daily determination of CNS measles antibody by empirical formula provides a quantification of humoral immunity in SSPE that corrects for both passage of measles antibody across a damaged blood-brain barrier and the effect of an elevated blood antibody level.

Measurement of complement components in cerebral spinal fluid by radioimmunoassay in patients with multiple sclerosis

Evidence for active immune processes occurring within the central nervous system (CNS) and involving complement has been found both in experimental animals and in humans. To examine the possible role of complement in the pathogenesis of multiple sclerosis (MS), we measured complement components C3 and C4 in cerebral spinal fluid (CSF) by the radioallergosorbent test (RAST). The method was found to be reproducible and specific. The effects of incubation time, temperature, pH of diluent, concentration of antibody used for coupling, and that of labeled anti-C3 and anti-C4 were studied. The normal range (mean ± 2 standard deviations) for CSF C4 and C3 were 0.09–0.4 and 0.46–1.4 mg/dl, respectively. The mean value of CSF C4 in neurologically normal control subjects did not differ from 45 patients; in contrast, the mean value of CSF C3 was significantly higher in MS patients. After measuring serum and CSF albumin, IgG, C3, and C4 on 20 neurologically normal subjects and on 102 coded specimens from 11 patients with MS, we calculated the rate of de novo CNS IgG, C3, and C4 synthesis. Synthesis of IgG was elevated in all patients. The measured increase in CSF C3 found in some MS patients appears in some instances to be due to an altered blood-brain barrier, and in other instances to increased CNS de novo synthesis of C3 in a manner analogous to that previously documented for CSF IgG.

Multiple sclerosis de novo CNS IgG synthesis: effect of ACTH and corticosteroids.

ACTH gel and corticosteroids were given to 28 clinically definite multiple sclerosis (MS) patients to determine whether de novo central nervous system (CNS) IgG synthesis (rate and cerebrospinal fluid [CSF] IgG oligoclonal bands) could be eradicated. The most effective treatments were ACTH gel and ACTH gel followed by prednisone, all 11 patients had a significant reduction in rate (p < 0.05), which became normal in eight patients (< 3.3 mg per day). In order of effectiveness, the other drugs used were: dexamethasone or prednisone given orally, and hydrocortisone administered intrathecally. For most treatments, reduction of the rate of CNS IgG synthesis occurred within days and persisted for months after cessation of treatment. The MS CNS immune reaction was not eradicated when IgG synthesis rate became normal, because CSF IgG oligoclonal bands persisted. None of the chronic progressive, severely disabled patients demonstrated significant change in neurologic function or persistent adverse effects.

Failure of intravenous and intrathecal cytarabine to modify central nervous system IgG synthesis in multiple sclerosis

To study the nature of the multiple sclerosis (MS) central nervous system (CNS) immune reaction, cytarabine (ara-C) was administered intravenously to three patients and intrathecally to another seven. Although intravenous administration severely suppressed circulating leukocytes derived fom the bone marrow, there was no change in de novo CNS IgG synthesis (rate or presence of CSF IgG oligoclones). Therefore, the MS CNS immune reaction can persist in the presence of severe granulocytopenia and severe monocytopenia of one to two weeks' duration. In four patients who were given ara-C intrathecally, cytotoxic levels (> 10 micrograms/ml) were present for a least 24 hours. A brief elevation in CSF albumin indicated transient damage to the blood-brain barrier. Leukopenia did not result in the seven patients treated intrathecally, and de novo CNS IgG synthesis did not change or was transiently increased. Assuming that cytotoxic levels in CSF diffused to the CNS sites responsible for synthesizing IgG, results indicate that CNS IgG synthesis does not depend on in situ rapid turnover of immune cells. None of the ten patients demonstrated neurological improvement or persistent adverse effects.

CSF "monoclonal" bands in chronic relapsing polyneuropathy.

The characteristics and temporal profiles of cerebrospinal fluid (CSF) and serum immunoglobulin patterns on agarose gel electrophoresis were studied in 47 patients with acute idiopathic polyneuropathy (AIP) and 15 patients with chronic relapsing polyneuropathy (CRP). Nineteen of 47 patients with AIP had transient oligoclonal IgG bands, which disappeared when the neurologic signs subsided. By contrast, 14 of 15 patients with CRP had a "monoclonal" (single) IgG band, which (1) was unchanged on repeated CSF examinations over 18 months, (2) was unaffected by corticosteroid therapy, and (3) did not correlate with the severity or chronicity of the disease. Serum protein patterns and in situ central nervous system IGG synthesis and IgG:albumin index were normal in the CRP patients. The origin of the band and the nature of the putative antigen(s) that the band may be directed against were not identified. Our findings suggest that different immunopathogenic mechanisms may be operating in CRP, compared with AIP. The stable IgG band in CRP may reflect response to a persisting antigenic stimulation and, with further experience, may prove to be of prognostic significance by furnishing early in the illness: (1) a clue to the subsequent course of the disease, and (2) possible guidance on therapeutic decisions.

Multiple sclerosis: measurement and validation of central nervous system IgG synthesis rate.

An empirical formula has been developed to calculate the de novo rate of synthesis of IgG in the central nervous system (CNS), based on physiologic principles that govern the passage of albumin and IgG across the blood-brain barrier (BBB). To validate the formula, radiolabeled IgG and albumin from pooled normal sera were followed from the blood to the cerebrospinal fluid (CSF) over 21 days in nine patients with definite multiple sclerosis (MS). IgG synthesis rates were calculated by the isotope exchange method and compared to values obtained with the empirical formula. There was excellent concordance, from a low rate of synthesis of 5 mg per day to a high rate of 120 mg per day. A double radiolabeled IgG experiment in two patients showed that the MS BBB processed normal serum IgG in the same way as IgG derived from autologous MS serum. Accordingly, the empirical formula, which requires only one sample of CSF and matched serum, can reliably and validly estimate the de novo rate of IgG synthesis in CNS of patients with MS.

Multiple sclerosis

This review deals with the blood-brain-barrier (BBB) as it relates to multiple sclerosis (MS). The MS BBB is discussed in relation to the following: postmortem perfusion utilizing trypan blue; circulating serum albumin as a marker of the normalcy of tight junctions of the endothelium of the CNS; CSF albumin as a marker of the BBB in MS; in vivo detection of an altered BBB of MS lesions utilizing computer tomography of the brain; detection of de novo central nervous system (CNS) IgG synthesis with or without an altered BBB; utilization of a formula to estimate de novo CNS IgG synthesis to evaluate putative therapies. In addition, a proposal is made that there exist within the BBB in MS two interlaced colonies of immunocytes capable of synthesizing IgG in concert or independently. Colony 1 consists of B lymphocytes that may be preprogrammed to antigens experienced by the core immune network, and that are recruited from the blood to the CNS by chemotaxis. This type of immunologic appearance could replicate the MS patient9s antigenic exposure and reward the CNS in MS with focal, in situ synthesized antibodies, hence imparting to the CNS an expeditious super-resistance. Colony 2 consists of resident plasma cells attributable to a persistent in situ antigenic stimulation, presumably owing to the MS antigen. Finally, since the CNS in MS has been provoked to become a type of immune organ-that is, it is able to synthesize IgG de novo—it is reasonable to propose the following: That de novo IgG in the CNSKSF, especially oligoclonal IgG, is antibody in excess of its antigen. We believe it can be used as an antibody reagent to search for the persistent antigenic stimulus present most appropriately at the periplaque edge, which might presumably turn out to be related to the cause of MS.

Aspects of the viral antibody response in multiple sclerosis.

It has been suggested that the intrathecal synthesis of viral IgG antibodies indicates the presence of the corresponding viral antigen(s) in the central nervous system (CNS) of MS patients (6). Although measles virus has predominantly been implicated in such studies, intrathecal IgG synthesis to rubella, mumps and vaccinia virus has also been detected (4, 7). Intrathecal viral IgG anti­body synthesis may, however, be a secondary, non-specific phenomenon in the pathogenesis of MS. Support for this idea comes from the fact that IgG antibodies against more than one virus are synthesized in the CNS of some MS patients (4). Moreover, not all MS patients have CNS IgG synthesis to a single virus i.e., measles virus (4) and of the oligoclonal IgG found in the CNS of MS patients, only a minor fraction is against a given virus i.e., measles virus (9).KeywordsMultiple SclerosisRheumatoid FactorMeasle VirusRubella VirusSubacute Sclerosing PanencephalitisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.