Local Synthesis Of IgG Research Articles

Integrity of the blood-CSF barrier in dementia of Alzheimer type: CSF/serum ratios of albumin and IgG

Serum and cerebrospinal fluid (CSF) from 25 patients with dementia of Alzheimer type (DAT) and 25 controls were assayed for concentrations of albumin and IgG. The severity of dementia was rated with the Mini Mental State Examination. The CSF/serum ratio for albumin and IgG as well as the IgG index were used to evaluate blood-CSF barrier function in the respective groups. The control group was matched for age, sex and the indirect alcohol parameters, mean corpuscular volume and gamma-glutamyltranspeptidase. There were no signs of dysfunction of the blood-CSF barrier for proteins or signs of local synthesis of IgG in the central nervous system (CNS) of the demented patients. The permeability of the blood-CSF barrier appeared to be unrelated to dementia severity. The data do not support the hypothesis that a pathological leakage through the blood-CSF barrier facilitates the entry of extraneuronal proteins to the CNS, which might contribute to the pathophysiological process in DAT.

Isoelectric focusing versus quantitative measurements in the detection of intrathecal local synthesis of IgG

Specimens from 1007 patients with suspected neurological disturbances had quantitative and qualitative measurements made of cerebrospinal fluid and serum to investigate the presence of locally synthesised IgG. Qualitative measurement was recorded as the presence or absence of oligoclonal banding, and the quantitative measurement was derived by the use of the IgG index, the log index and the Reiber, Schuller and Tourtellotte formulae. The patients were divided into two categories, on the basis of banding: those with local synthesis and those without. The sensitivity, specificity and efficiency for each of the quantitative measurements were then calculated. Receiver-operator curves were also constructed for each of the quantitative measurements. 282 samples showed local synthesis of IgG by isoelectric focusing, whereas the best quantitative assay (log index) could only detect 198. Therefore, we conclude that oligoclonal banding should be adopted as the standard laboratory measurement of local synthesis of IgG in the diagnosis of neurological disorders, and that the diagnostic use of quantitative measurements should be abandoned for routine purposes. Furthermore, we suggest that quantitative analysis, at its current level, is misleading and has little value in the understanding of neurological disorders, but may be of use in serially monitoring individual patients as part of their therapeutic trials.

A STUDY OF IMMUNOGLOBULIN G IN THE CEREBROSPINAL FLUID OF 1007 PATIENTS WITH SUSPECTED NEUROLOGICAL DISEASE USING ISOELECTRIC FOCUSING AND THE LOG IgG-INDEX

Cerebrospinal fluid and serum immunoglobulin G from 1007 patients with suspected neurological disease were analysed by 2 methods: isoelectric focusing for the detection of oligoclonal banding, and quantitative measurement of IgG and albumin for the formulation of a Log IgG-Index. A comparison of the 2 methods in the detection of local synthesis of IgG showed that isoelectric focusing not only gave a much higher yield overall, with 282 patients showing local synthesis versus 225 for the Log IgG-Index, but also a higher specificity, with a false positive rate of 0% versus 3.5%. In addition, of the 282 patients positive by isoelectric focusing only 163 (58%) were positive by the Log IgG-Index. Of the 1007 patients studied, 206 had multiple sclerosis (MS), and isoelectric focusing showed local synthesis in 95% of clinically definite cases, with a 90% detection rate overall. The Log IgG-Index was positive in only 67% of clinically definite cases, with an overall 59% detection rate. Thus with the exceptions noted above, local synthesis of IgG as defined by isoelectric focusing is confined to demyelinating, inflammatory, infectious and postinfectious disorders. Our results compare very favourably with the published sensitivities of magnetic resonance imaging in the detection of abnormalities in multiple sclerosis, and better than those for evoked potentials. Where both these investigations are readily available isoelectric focusing provides a useful adjunct. For the majority of physicians and neurologists who do not have ready access to magnetic resonance imaging, isoelectric focusing is an excellent alternative. We would also recommend that it become the standard for the measurement of IgG abnormalities in the cerebrospinal fluid and that the use of quantitative data be abandoned for routine purposes.

Blood-cerebrospinal fluid barrier in schizophrenic patients.

A total of 15 young white male patients newly diagnosed as schizophrenic (DMS III) were examined for signs of blood-cerebrospinal fluid (CSF) barrier alteration and CNS IgG synthesis. Of the 15 patients, 8 exhibited signs of increased blood-CSF barrier permeability. There was a high correlation between the ratio for CSF/serum albumin concentration and the CSF total protein concentration. Local IgG synthesis in the CNS was not detected in any of the patients.

Effect of infection of the genital tract on the concentration of IgG and albumin in bull serum and semen.

Bovine IgG and albumin concentrations were determined from serum and semen of 59 bulls that were divided into 4 groups: 35 non-infected bulls (Group 1); 10 with vesiculitis due to Corynebacterium pyogenes (Group 2); 10 bulls with orchitis due to Chlamydia psittaci (Group 3); and 4 bulls with infectious vesiculitis (Group 4) sampled both before and after antibiotic treatment. Serum IgG concentrations (25 mg/ml approximately) were similar in non-infected (Gp 1) and infected bulls (Gp 2,3,4) whereas serum albumin concentrations were greater in infected than in non-infected bulls (51 mg/ml vs.41 mg/ml; p < 0.01). By contrast, both semen IgG and albumin concentrations in infected bulls (0.47 and 0.54 mg/ml respectively) were significantly different from those of non-infected bulls (0.14 and 0.32 mg/ml; p<0.01). In addition, bulls with chlamydial orchitis had both semen (but not serum) IgG and albumin levels higher than those suffering from vesiculitis (p< 0.01). Antibiotic therapy led to recovery and simultaneously to decreased concentrations of semen IgG and albumin. These results strongly suggest a local IgG synthesis or selective diffusion after such genital infections and further indicate that semen IgG and albumin assays could be a new and valuable tool for diagnosis and evaluation of genital infections.

Albumin and immunoglobulin in plasma and cerebrospinal fluid, and blood-cerebrospinal fluid barrier function in patients with dementia of alzheimer type and multi-infarct dementia

Plasma and cerebrospinal fluid (CSF) from 20 patients with Alzheimer's dementia or senile dementia of Alzheimer type (AD/SDAT), 23 with multi-infarct dementia (MID) and 16 controls were assayed for their content of immunoglobulins (Ig) and albumin (Alb). The concentrations of IgG and Alb were used to analyze the blood-CSF barrier function in the respective group. MID patients had significantly ( P < 0.001) elevated plasma IgG levels compared to controls and AD/SDAT patients. CSF concentration of Alb was significantly higher in MID ( P < 0.01) and AD/SDAT ( P < 0.05) patients compared to the controls. Concentration of CSF IgG was significantly ( P < 0.05) lower in AD/SDAT patients compared to the MID patients; no significant differences were found when CSF concentrations of IgG of demented patients were compared to controls. These findings may indicate a blood-CSF barrier dysfunction especially in cases with MID with significantly ( P < 0.001) elevated values of transudation. Also these findings indicate a non-specific and/or specific binding of IgG in CNS tissue and/or vessel walls in both forms of dementia on the basis of low IgG ratios compared to proportionally higher Alb ratios. There were no signs of local synthesis of IgG in CNS in either group of demented patients.

Chronic relapsing experimental allergic encephalomyelitis: Immunological and blood-cerebrospinal fluid barrier-dependent changes in the cerebrospinal fluid

Cerebrospinal fluid (CSF) and plasma were taken from strain 13 guinea pigs in various stages of chronic relapsing experimental allergic encephalomyelitis using techniques which allowed repeated sampling from the same animal. Samples were assayed for albumin and IgG and the corresponding CSF/plasma quotients evaluated graphically using a method which could discriminate between blood-CSF barrier dysfunction and local IgG synthesis in the central nervous system (CNS). During the disease a 2–3-fold increase in plasma IgG concentration developed and an increase in blood-CSF permeability was noted. Isoelectric focusing revealed an oligoclonal IgG pattern identical in both plasma and CSF. The results provided no evidence for a local production of IgG in the CNS like what which is known to occur in multiple sclerosis.

On the relationship of CSF pleocytosis to immunoglobulin levels as estimated by different techniques

One might expect a positive correlation between the number of CSF lymphocytes and the relative amount of CSF IgG, especially in cases of local synthesis of IgG within the CNS. However, previous attempts at correlating the number of CSF lymphocytes with IgG levels have yielded varying results. Since it is known that the estimation of CSF IgG levels can vary according to the method of immunoglobulin determination used, we decided to perform the analyses by three separate methods: (1) the commonly used, immunoprecipitation technique of radial immunodiffusion; (2) physico-chemical separation on the basis of hydrated size/charge using alkaline electrophoresis through the molecular sieving effects of polyacrylamide gels, followed by densitometry of the γ region of Coomassie Blue-stained proteins; (3) separation into constituent Ig heavy chains and light chains on the basis of unfolded chain lengths by molecular sieving using sodium dodecyl sulphate (SDS), followed by densitometry of heavy chains of immunoglobulins having been labelled with the fluorescent dye dansyl chloride. Our results show a correlation of white count with the latter two techniques but not the former. Possible reasons for discrepancies in the literature are discussed with regard to the peculiar physical properties of the selected CSF IgG molecules.

Local synthesis of CSF immunoglobulins: A neuroimmunological classification

The relationship between serum and CSF IgG has been analysed: 1. (1) In patients with a normal CSF concentration of albumin, no correlation can be demonstrated between serum IgG and CSF IgG. 2. (2) In cases where the CSF albumin concentration is elevated (i.e. transudation), local synthesis of IgG can be determined by reference to the degree of transudation of albumin and the serum IgG concentration. The combination of local IgG synthesis and transudation (meningitic pattern) is common. Most pure transudates are of “non-inflammatory” type. A very simple formula is proposed which evaluates the relationship between local and general immunity in all neurological diseases.

Cerebrospinal fluid G immunoglobulins in nervous system diseases

Cerebrospinal fluid IGG and the relations with total protein, and with prealbumin + albumin and the IGG index were studied in 160 patients with various neurological disorders. These patients were distributed in 8 groups according to diagnosis as follows: inflammatory (21 cases); demyelinating (31 cases); degenerative (10 cases); cerebrovascular (19 cases); tumoral (3 cases); convulsive (20 cases); headache (11 cases); other neurological disorders (45 cases). According to the results (table 1) the best applicability of IGG study is the group of chronic inflammatory diseases (neurosyphilis and neurocysticercosis) and the demyelinating disorders (multiple sclerosis). Emphasis is given to the possibility of the occurrence of local synthesis of IGG in the central nervous system in these 2 groups.

Immune complexes in serum and in cerebrospinal fluid in African trypanosomiasis. Correlation with polyclonal B cell activation and with intracerebral immunoglobulin synthesis.

The possible occurrence of immune complexes (IC) in serum and in cerebrospinal fluid (CSF) has been studied in 36 patients with African trypanosomiasis (Trypanosoma brucei gambiense). In serum, very high levels of IC were detectable by the (125)I-C1q-binding and by the conglutinin-binding assays with positive results in 94 and 87%, respectively, of untreated patients. Circulating IC were found in both early and late stages of the disease, without significant quantitative differences; their size was 15-25S. There was a significant negative correlation between C3 values and C1qBA. Our studies suggest that circulating IC occurring during trypanosomiasis may be the expression of a polyclonal B cell activation. Indeed, there was a significant correlation (P < 0.001) between the levels of circulating IC and either the levels of IgM (mean value 12.5+/-7.2 mg/ml) or with the levels of rheumatoid factor-like antiimmunoglobulin antibodies that were detected by solid phase radioimmunoassay in 74% of the patients.IC were detected in 31 of 35 CSF samples, with a marked elevation in patients with definite involvement of the central nervous system as compared with earlier stages of sleeping sickness. The occurrence of IC in CSF was not related to an impairment of the blood-brain barrier as shown by analysis of CSF/serum albumin ratios. The level of IC in CSF did not correlate with the serum level and, therefore, circulating IC do not appear to cross efficiently an unimpaired blood-brain barrier. The analysis of IgG, IgM, and albumin concentrations in serum and CSF demonstrates a marked intracerebral immunoglobulin synthesis in patients with manifestations of meningoencephalitis. There was a correlation between CSF-C1q binding assay and this local IgG synthesis. These data are consistent with a local formation of IC in CSF in patients with active meningoencephalitis. The results obtained in eight patients followed during therapy suggest that the presence of IC in CSF may be an indicator of a continuing central nervous system disease and that the quantitation of CSF-IC may be useful for monitoring patient care.

Serum and Cerebrospinal Fluid IGM in 203 Neurological Patients

Simultaneous serum and CSF IgM determinations were made by electroimmunodiffusion in 5 normals and 203 patients. Absent from normal CSF, IgM was found in 56 patients (27%): (1) A blood-CSF transudation was present in 25 patients (12%). IgM seems of no diagnostic value in these cases. (2) A purely local synthesis was demonstrated in 17 patients (8%), concerning proved (bacterial, viral, parasitic) or supposed (multiple sclerosis) persistent infectious aggressions. (3) In the last 14 patients with IgM in CSF, a transudation was associated with a local synthesis of IgG (meningitis pattern). (4) A ratio IgM .10(3)/albumin above 10 seems an argument for multiple sclerosis.

Changes in IgA and IgG Concentrations in Nasal Secretions Prior to the Appearance of Antibody during Viral Respiratory Infection in Man

Abstract To investigate the mechanisms of appearance of locally synthesized and plasmaderived proteins at the nasal membrane surface during upper respiratory viral infection, nasal secretions and sera from six volunteers experimentally infected with coxsackievirus A type 21 or rhinovirus type 15 were analyzed for their content of viral neutralizing antibodies, immunoglobulin and albumin. Nasal IgA increased significantly 24 hr after viral inoculation and before transudation started. In coxsackievirus infection, nasal secretion IgA concentrations continued to rise for 2 weeks to nearly twice baseline levels, whereas in rhinovirus infection a sustained rise in IgA began only after illness had subsided. Significant amounts of specific antibody did not appear in the nasal secretions during the same period. Marked transudation of albumin and IgG from plasma occurred during respiratory illness. Before illness half of the IgG in nasal secretions was synthesized locally; the remainder came from plasma as indicated by the quantity of isotopically labeled IgG which entered nasal secretions from the circulation. Viral infection inhibited local IgG synthesis; therefore, after illness subsided, nearly all IgG in nasal secretions came from the plasma. These results are consistent with the hypothesis that immunoglobulins are delivered to the nasal membrane surfaces by three different mechanisms: release of pre-formed secretory IgA during the incubation period of viral infection, transudation from the plasma before and after illness but particularly during the rhinorrhea phase of illness, and local synthesis of IgA and IgG. After illness subsides, local IgG synthesis is inhibited, but there is a marked stimulation of IgA synthesis, which, after a further period, develops specificity for the infecting virus.