Importance of intrathecal synthesis of IgD in multiple sclerosis. A combined clinical, immunologic, and magnetic resonance imaging study.

There is increasing evidence that soluble IgD has a certain role in the humoral immune response within the central nervous system. We report herein the results of a combined clinical, magnetic resonance imaging, and immunopathologic study to determine the clinical importance of intrathecal IgD synthesis. Intrathecal synthesis of IgD (detected through the calculation of index values) was studied in 64 patients with multiple sclerosis and in 50 neurologic control patients and normal subjects. Locally secreted IgD was detected in 30% of patients with clinically active multiple sclerosis, including two in whom magnetic resonance images of brain and spinal cord were normal and who had no evidence of intrathecal IgG synthesis. No intrathecal IgD production was detected in patients with clinically stable multiple sclerosis or those suffering from chronic progressive multiple sclerosis, while it significantly correlated with the interval from the last relapse and with the total duration of the disease process in patients with relapsing, remitting multiple sclerosis. Intrathecal IgD synthesis also correlated with the degree of cerebrospinal fluid pleocytosis and with the presence of free kappa and lambda light chain bands in cerebrospinal fluid. Present results supplement and expand earlier data and suggest that intrathecally secreted IgD is a putatively important part of the immune response in clinically active relapsing, remitting multiple sclerosis.

Oligoclonal immunoglobulin D in the cerebrospinal fluid of neurologic patients.

Oligoclonal immunoglobulin D (IgD) bands were observed in 20 of 110 CSF samples investigated by our method for isoelectric focusing (IEF) of IgD in unconcentrated CSF. These were mostly from demyelinating disorders, viral CNS infections, and CNS tumors. The patterns of expression of IgD were similar to that of IgG, except in cases with tumors where oligoclonal IgD may occur independently of IgG. The study shows for the first time the presence of oligoclonal IgD in CSF from neurologic patients.

Cerebrospinal fluid IgG, IgA, IgM, IgD, and IgE levels in central nervous system disorders.

Using a radioimmunoassay, we evaluated the cerebrospinal fluid content of IgG, IgA, IgM, IgD, and IgE in multiple sclerosis, viral meningitis, and tumors. Abnormal immunoglobulin levels occurred in all conditions, reaching 13 times the norm for IgM in multiple sclerosis and 5 times the norm in aseptic meningitis. Striking increases also occurred with IgA, IgM, and IgE in benign and malignant (both primary and metastatic) tumors of the CNS. Furthermore, the immunoglobulin-protein ratio was calculated. In aseptic meningitis and multiple sclerosis, the ratio was significant as compared to the norms.

A new qualitative method for detecting IgD in unconcentrated cerebrospinal fluid.

We report a method which is capable of demonstrating the isoelectric focusing (IEF) pattern of immunoglobulin D in unconcentrated cerebrospinal fluid (CSF) samples containing as little as 0.1-0.5 ng of total IgD. The method used was an immuno-sandwich technique, with alkaline phosphatase enzyme amplification. Oligoclonal and polyclonal IgD patterns were seen in CSF samples. No cross-reactivity with other immunoglobulins (IgG, IgA and IgM) was detected.

Measles virus-specific immunoglobulin D antibody in cerebrospinal fluid and serum from patients with subacute sclerosing panencephalitis and multiple sclerosis.

Quantitation of measles-specific immunoglobulin D (IgD) antibody was carried out in cerebrospinal fluid (CSF) and serum samples from 18 patients with subacute sclerosing panencephalitis (SSPE), 12 patients with multiple sclerosis (MS) and seven normal controls with high measles antibody titers in serum, using polyclonal and monoclonal antibodies specific for human IgD and enzyme-linked immunosorbent assay. Measles-specific IgD activity was significantly higher in CSF and serum from SSPE patients compared to that found in patients with MS or normal controls. The IgD antibody to measles virus was not due to high levels of measles-specific IgG since significant measles IgD activity was found after eluting IgG from SSPE serum. The increased level of measles-specific IgD found in SSPE sera is consistent with the levels observed in patients with acute and chronic viral infections.

Immunoglobulins in certain CNS disorders: a study of CSF Ig classes G, A, M, D, and E concentrations.

Concentrations of cerebrospinal fluid (CSF) Ig classes G, A, M, D, and E have been reported in various neurologic disorders, viz, aseptic meningitis, multiple sclerosis, benign tumor, malignant tumor, and hydrocephalus. In aseptic meningitis, IgG and IgM were found to be either normal or elevated, whereas concentrations of IgA, IgD, and IgE were normal. Multiple sclerosis patients had IgG, IgA, and IgM, either normal or elevated, but IgD and IgE were on the lower end of the normal. Malignant tumor patients had elevated concentrations of IgG, IgA, IgM, and IgE, but their IgD was on the lower end of the normal. In benign tumor population IgA and IgE, and in hydrocephalus IgG and IgA, were found to be elevated in most of the patients. On statistical analysis, significant differences were observed between the means of the normal group and that of the patients' group for all the five immunoglobulins. By linear regression, a statistical relationship was observed between IgA - IgG, IgM - IgG, IgA - IgM and IgA + IgM - IgG in these neurologic disorders.

Immunoglobulin D in cerebrospinal fluid.

Immunoglobulin D (IgD) was measured by radioimmunoassay in paired cerebrospinal fluid and serum samples from patients with various neurological diseases. The IgD index was calculated for every patient and compared with the IgG index. An increased IgD index was found in 18 out of 41 patients suffering from multiple sclerosis and in 52 out of all 122 patients investigated. An increased IgD index did not always coincide with an increased IgG index. An increased IgD index suggests an abnormal intrathecal synthesis of this immunoglobulin within the central nervous system. We conclude that the determination of IgD in the cerebrospinal fluid yields additional information on immunological reactions within the central nervous system.

Significance of de-novo IgD and IgM synthesis in CSF of patients with relapsing-remitting form of disseminated demyelinating disease of CNS.

Disseminated demyelinating disease of the central nervous system (DDD CNS) is immunologically mediated, with confirmed significant intrathecal immunoglobulin production. According to recently known immunopathogenic occurrences and activation of humoral immune response, we have assumed that the presence of oligoclonal immunoglobulins of M and D classes can be confirmed in cerebrospinal fluid (CSF) of patients with DDD CNS. With the aim of its further determination in CSF of relapsing-remitting DDD CNS patients in either remission and relapse phase, respectively, we have confirmed the presence of oligoclonal IgD and IgM bands, the association of this production and the presence of new demyelinating zones found by MRI of endocranium, as the time elapsed from the last relapse until the obtaining of CSF for further analyses. Method of isoelectric focusing with Western blott procedure was used for the confirmation of oligoclonal IgM and IgD bands presence in CSF. Significant presence of intrathecally synthetized oligoclonal IgM and IgD in patients with DDD CNS in exacerbation phase was presented. Almost in all patients in this phase was found at least one indicator of acute phase (positive MRI finding, presence of oligoclonal IgM or IgD bands). Significant decrease of positive findings of oligoclonal Ig bands in CSF was correlated with the time elapsed from the onset of relapse until the obtaining of CSF for the analysis due to short half-life of those Ig in CSF.

Immunoglobulins in the cerebrospinal fluid of patients with Guillain-Barré syndrome.

Increased immunoglobulin levels in the cerebrospinal fluid of patients with Guillain-Barré syndrome were found in association with increased protein levels. Evaluation of the immunoglobulin/protein ratios led us to conclude that the increase in immunoglobulin levels may be due to a leakage of plasma proteins and is unlikely to be caused by a local immune response to a preceding antigenic stimulus.

Radioimmunoassays for Ig classes G, A, M, D, and E in spinal fluids: normal values of different age groups.

Radioimmunoassay procedures of sufficient sensitivity (IgG, 0.5 mug per 100 mul; IgA, 25.0 ng. per 100 mul; IgM, 10.0 ng. per 100 mul; IgD, 0.5 U. per 100 mul; and IgE, 1.0 U. per 100 mul) were developed detect and quantitate all 5 immunoglobulin classes in the cerebrospinal fluid on small aliquots (1 ml.) of unconcentrated cerebrospinal fluid. All 5 immunoglobulin classes were routinely detected in normal individuals for the first time, the levels varying with different age groups for IgG and A but not for the remaining immunoglobulin classes. Race and sex had no effect. Standardization of techniques and establishment of normal values for different age groups sets the stage for determination of immunoglobulin changes related to central nervous system disease.

Meningeal involvement in IgD myeloma with cerebrospinal fluid paraprotein analysis.

Myelomatous meningitis is a rare occurrence in multiple myeloma. We report 2 cases of documented IgD myeloma with cytologic evidence of meningeal involvement in 1 and detailed paraprotein analysis in both. The occurrence of meningeal involvement in this rare form of plasma cell neoplasm may be more common than previously thought.

High-dose intravenous-penicillin in neurosyphilis: effect on intrathecal synthesis of IgG, IgM, IgA and IgD.

We evaluated occurrence and levels of intrathecal synthesis of IgG, IgM, IgA and IgD by calculating corresponding index values in 8 patients with definite and 4 with suspected or possible neurosyphilis, prior to, during and after high-dose intravenous penicillin therapy. Four patients with active neurosyphilis displayed intrathecal synthesis of IgG, IgM and IgA. Only 2 of them showed elevated IgD index, and both had taboparesis, pleocytosis and positive VDRL in CSF, and simultaneous elevation of the IgG, IgA and especially of the IgM indices. This suggests that intrathecal synthesis of IgD may occur in patients with severe CNS inflammation in response to diffuse CNS treponemal damage. Penicillin therapy incited transitory elevation of one or more of the immunoglobulin index values in most patients, possibly in response to massive treponemal lysis inside the CNS. Thereafter, the values became mostly normalized but exceptions occurred, including one patient who had elevated IgG and IgM index which persisted 31 months after therapy. Our data indicate that determinations of immunoglobulin indices performed on consecutive specimens from individual patients with neurosyphilis may be helpful in the evaluation of treatment.

Peripheral neuropathy in IgD myeloma. Cerebrospinal fluid paraprotein analysis in three cases.

High resolution polyacrylamide gel isoelectric focusing (IEF), followed by direct immunofixation with anti-delta chains monospecific antibodies, were used to detect and identify IgD paraprotein in the cerebrospinal fluid (CSF) of 3 patients affected by IgD myeloma. Two of these patients presented a paraproteinemic neuropathy. Blood-brain barrier damage was investigated by means of CSF/serum albumin ratio. IgG index and CSF and serum IgD/albumin ratio were also evaluated. An intrathecal origin of the IgD paraprotein was excluded. The correlation between the presence of the paraprotein in the CSF and the possible neurological involvement was also examined.

CNS tumours: oligoclonal immunoglobulin D in cerebrospinal fluid and serum.

Oligoclonal immunoglobulin D bands were detected by isoelectric focusing in 7 out of 25 unconcentrated cerebrospinal fluid (CSF) samples obtained from patients with tumours of the central nervous system (CNS). The tumours were confirmed by clinical and histological findings. Two patients with CNS malignancy had intrathecal synthesis of oligoclonal bands both IgD and IgG. Four patients with a variety of CNS tumours had a systemic IgD immune response but no oligoclonal IgG bands. One patient with the most malignant tumour histology had a systemic IgD response as well as local synthesis of IgG. The study reveals several new aspects regarding CNS tumours: they are immunologically active and are capable of invoking oligoclonal immunoglobulin production both within the CNS and systemically. Multiple immunoglobulin activation can be found in malignant CNS tumours, and systemic IgD production may occur independently from IgG synthesis and may represent an immune response to a neoantigen produced in the CNS compartment.

Immunological indices in the cerebrospinal fluid of patients with presenile dementia of the Alzheimer type.

In ten patients with presenile dementia of the Alzheimer type and in a control group the levels of the different immunoglobulins were determined in both serum and cerebrospinal fluid (CSF), and gel electrophoretic techniques used to determine possible oligoclonal bands in the gamma-globulin region. There is no indication that patients with Alzheimer disease produce immunoglobulins within the central nervous system.

Structure and biological functions of human IgD. XIV. The development of a solid-phase radioimmunoassay for the quantitation of IgD in human sera and secretions.

A simple but sensitive radioimmunoassay method for the quantitation of IgD in sera and body fluids has been developed. Specifically purified chicken anti-delta was covalently coupled to cyanogen bromide activated filter paper discs and the discs were incubated together with the samples to be analyzed. The washed discs were next incubated with 125-I-labeled specifically purified chicken or rabbit anti-human delta-antibodies. IgD on the disc was quantified by reference to a standard curve prepared with purified human IgD. The sensitivity of this assay was approximately 10 ng/ml IgD. IgD was demonstrable in cord sera (18 of 18), hypogammaglobulinemic sera (15 of 15), amniotic fluids (6 of 6), salivas (8 of 10), normal cerebrospinal fluids (12 of 13) and cerebrospinal fluids from patients with subacute sclerosing panencephalitis (5 of 5). The finding of IgD in human secretions raises the interesting possibility that IgD may be a secretory antibody.