concanavalin-a and Schizophrenia

Numerous studies have demonstrated brain region- and subunit-specific abnormalities in the expression of subunits of the AMPA subtype of glutamate receptors in schizophrenia. In addition, abnormalities in the expression of proteins that regulate the forward trafficking of AMPA receptors through the cell have been reported. These findings suggest abnormal trafficking of AMPA receptors as a mechanism underlying dysregulated glutamate neurotransmission in schizophrenia. AMPA receptor subunits (GluR1-4) assemble to form AMPA receptor complexes in the lumen of the endoplasmic reticulum (ER). These subunits undergo the posttranslational modification of N-linked glycosylation in the ER and the Golgi apparatus before the assembled receptors are transported to the plasma membrane. In this study, we measured expression of AMPA receptors and the extent of their N-glycosylation using Western blot analysis in the dorsolateral prefrontal cortex in subjects with schizophrenia (N = 35) and a comparison group (N = 31). N-glycosylation was assessed using molecular mass shift assays following digestion with endoglycosidase H (Endo H), which removes immature high mannose-containing sugars, and with peptide-N-glycosidase F (PNGase F), which removes all N-linked sugars. Of the four AMPA receptor subunits, only GluR4 was significantly increased in schizophrenia. GluR2 and GluR4 were both sensitive to Endo H and PNGase F treatment. Endo H-mediated deglycosylation of GluR2 resulted in a significantly smaller pool of GluR2 protein to shift in schizophrenia, reflecting less N-linked high mannose and/or hybrid sugars on the GluR2 protein in this illness. This was confirmed by immunoisolation of GluR2 and probing with Concanavalin A, a mannose specific lectin; in subjects with schizophrenia GluR2 was significantly less reactive to Concanavalin A. Altered N-linked glycosylation of the GluR2 subunit in schizophrenia suggests abnormal trafficking of AMPA receptors from the ER to the synaptic membrane in schizophrenia.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Concanavalin A; Female; Glycosylation; Humans; Male; Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; Middle Aged; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; Prefrontal Cortex; Protein Binding; Protein Subunits; Receptors, AMPA; Schizophrenia

Previous studies from this and other laboratories have shown that abnormal glycosylation of several acute-phase proteins can be detected in various pathological conditions including autoimmune diseases. In the present study, we have investigated if abnormal glycosylation is limited to acute-phase proteins. We used the concanavalin A (Con A) blots in conjunction with the peptide mapping techniques to analyze serum samples and cerebrospinal fluids (CSF) obtained from patients with autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), scleroderma (SCL), Sjögren's syndrome (SS), and polymyositis (PM); diseases of probable autoimmune origin: hepatopathies (HP); diseases of suspected autoimmune origin: schizophrenia and Alzheimer's disease (AZ); and conditions not related to autoimmunity: pregnancy (PG) and elevation of the carcinoembryonic antigen (CEA), in comparison to normal donors (NHS). We have micropurified two human proteins; alpha 2-macroglobulin, a non-acute-phase protein and beta-chain of haptoglobin, a known acute-phase protein, from serum samples of individual patients with SLE, RA, MCTD, SCL and SS, and from PG and NHS for analysis. The identity of the purified proteins was confirmed by immunoblots using either monospecific polyclonal or monoclonal antibodies, and by direct N-terminal amino acid sequencing. Peptide maps for each of these proteins were generated using Staphylococcus aureus protease V8, a Glu-C endopeptidase. When the peptide fragments of alpha 2-macroglobulin were resolved by SDS-PAGE and visualized using silver staining, no differences were noted between patient samples and controls. However, when they were examined by lectin blots using Con A, the Con A-reactive fragments increased specifically and significantly in samples derived from patients of SLE, SCL, MCTD, and RA. Similarly when the peptide fragments of the beta-chain of haptoglobin were visualized by silver staining, no differences were noted; however, the Con A reactivity of specific fragments increased in SLE, RA, SCL, and SS patients. Analysis of these results indicated that there has been a selective increase in Con A-reactive fragments in both acute-phase and non-acute-phase proteins in autoimmune conditions. Thus, the study of changes in glycosylation patterns in selected serum proteins may be a valuable diagnostic approach to define the pathophysiology of inflammatory and autoimmune disorders.

Topics: Acute-Phase Proteins; alpha-Macroglobulins; Amino Acid Sequence; Autoimmune Diseases; Blood Proteins; Cerebrospinal Fluid Proteins; Concanavalin A; Female; Glycosylation; Haptoglobins; Humans; Molecular Sequence Data; Peptide Fragments; Pregnancy; Reference Values; Schizophrenia

In a first approach to measure the activity of the interferon system in schizophrenic patients, leucocyte cultures of schizophrenic patients and normal control individuals were set up using a whole blood assay. In this system both lymphoproliferation and the induction of interferon was tested. The lymphoproliferation (LP) test was performed with one bacterial recall antigen (PPD) and four different mitogens (phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and a novel mitogen derived from mycoplasma arthritidis - MAS). For induction of interferon two inducers of interferon alpha (Corynebacterium parvum and Newcastle disease virus (NDV] and two inducers of interferon gamma (PHA and Con A) were tested. Leucocytes of the patients responded to C. parvum, NDV and Con A with significantly lower titers of interferon, whereas the responses to PHA were lower than those of normals, but this difference was not significant. Regarding the LP test, significantly lower responses of the patients were obtained with PHA and Con A, whereas there were no significant differences when the responses to MAS, PWM or PPD were compared. Although our data cannot rule out a role of the medications in the defects observed, they may be indicative of a defect in the interferon system of schizophrenic patients.

Topics: Adult; Concanavalin A; Female; Humans; Interferon Type I; Interferon-gamma; Leukocytes; Male; Mycoplasma; Newcastle disease virus; Phytohemagglutinins; Pokeweed Mitogens; Propionibacterium acnes; Schizophrenia

The study of T lymphocyte suppressors in juvenile continuously progressive schizophrenia showed that the number of suppressor cells in patients was significantly decreased as compared to a group of mentally normal donors; 20.4% and 28.9% respectively. The parallel study of the number of suppressor cells in the peripheral blood and the proliferative activity of T lymphocytes upon their stimulation with mitogenic lectins of PHA and Con A demonstrated that in the mentally normal donors, these parameters were inversely correlated, whereas in the patients with juvenile continuously progressive schizophrenia, there was no such correlation between the above indices. The data obtained are indicative of the impaired regulatory activity of T lymphocyte suppressors in this group of schizophrenic patients.

Topics: Adult; Cell Division; Cells, Cultured; Concanavalin A; Female; Humans; Leukocyte Count; Male; Middle Aged; Phytohemagglutinins; Schizophrenia; Schizophrenia, Paranoid; Schizophrenic Psychology; T-Lymphocytes; T-Lymphocytes, Regulatory

The results of studying the properties of peripheral blood lymphocytes in schizophrenic patients are reviewed. Three parameters are specified in which the patients' lymphocytes differ substantially from those of healthy donors: these are the resistance to osmotic shock and responses of the cells to stimulation with phytohemagglutinin and concanavalin A. It is shown that all the three parameters are controlled by different factors of the schizophrenics' blood serum. Two of them correlate with the clinical manifestations of the disease. It is concluded that the lymphocytes of schizophrenic patients can serve as a biological indicator of the pathophysiological processes taking place in that disease.

Topics: Autoantibodies; Brain; Concanavalin A; Cross Reactions; Humans; Lymphocytes; Membrane Proteins; Osmotic Fragility; Phytohemagglutinins; Schizophrenia

The reaction of lymphocytes to Con A and PHA and combined action of these 2 T-mitogens in the peripheral blood was studied in schizophrenic patients (25 cases) and normal donors (21 cases). It was demonstrated that study of lymphocyte function in the peripheral blood with the aid of the 2 mitogens makes it possible to differentiate more distinctly the lymphocytes of schizophrenic patients and normals. It was established that the lymphocyte subpopulation capable of responding to both mitogens used is 4 times less in schizophrenics than in normal donors. The proportion of cells reacting only to one of these mitogens is significantly higher than in normals. The total content of mitogen-sensitive T-lymphocytes in schizophrenic patients and normal donors is approximately the same and equals about 40% of the whole lymphocyte population in the peripheral blood.

Topics: Adult; Concanavalin A; Humans; Leukocyte Count; Phytohemagglutinins; Schizophrenia; T-Lymphocytes

Studies were performed on an equivalent age group of schizophrenic patients and normal donors to detect the lymphocyte reaction of the peripheral blood to concanavalin A stimulation. It was demonstrated, that in the blood of schizophrenic patients, the part of lymphocytes capable of reacting to stimulation, is 2,3 times less than in the group of normals. The studies showed that the capability of cells to react to stimulation does not depend upon the duration of the disease, the duration of the postmanifest or initial periods, but differs in patients with different forms of schizophrenia. A significant negative correlation was demonstrated between the severity of positive disorders and the lymphocyte response to stimulation.

Topics: Adolescent; Adult; Cells, Cultured; Concanavalin A; DNA; Humans; Lymphocytes; Schizophrenia

The action of various doses of PHA and Con A on 3H-thymidine incorporation in DNA of blood lymphocytes was studied in health and schizophrenia. The dose-response curves in schizophrenia treated with various doses of PHA and Con A lie beneath the respective curves characteristic for the cells from normal subjects. The most discriminant results with respect to the proliferative activity of lymphocytes of the two groups were obtained in the course of administering low doses of the stimulants. In schizophrenic patients, the shift of the optimal dose towards higher concentrations was seen both for PHA and Con A.

Topics: Adolescent; Adult; Concanavalin A; DNA; Dose-Response Relationship, Drug; Humans; Lymphocytes; Middle Aged; Mitosis; Phytohemagglutinins; Schizophrenia

The author studied the proliferative abilities of lymphocytes in the peripheral blood of schizophrenic patients and normals in cultures not containing autologous plasma. The reactivity of lymphocytes in schizophrenic patients to PHA and rabbit serum to human thymocytes (ATS) appeared to be decreased. The level of their proliferative response to concavaline A was significantly the same as in normals. The assumption is made that in schizophrenic patients there is a blocking of lymphocyte receptors, binding PHA and ATS. The possibility of a deficit of a subpopulation of T lymphocytes in the organism of patients highly sensitive to stimulation by PHA and ATS is not excluded.

Topics: Adolescent; Adult; Antilymphocyte Serum; Binding Sites, Antibody; Cells, Cultured; Concanavalin A; Humans; Lectins; Lymphocyte Activation; Lymphocytes; Receptors, Drug; Schizophrenia; T-Lymphocytes

Topics: Adult; Autoantibodies; Concanavalin A; Female; Humans; Lymphocyte Activation; Male; Phytohemagglutinins; Schizophrenia; T-Lymphocytes

The capability of the schizophrenic patients' lymphocytes and lymphocytes of healthy persons to respond to the stimulating action of T-mutagens -- concanavalin A and PHA -- was studied. The T-cell count was determined by the method of rosette formation; the influence of adhesive cells on the lymphocyte response to mitogens was ascertained. The response to both the mitogens in the patients' lymphocyte cultures was reduced as compared to control, and the T-cell count failed to differ from the normal. The removal of adhesive lymphocytes results in the disappearance of differences between the response of the patients' lymphocytes and normal lymphocytes to both the mitogens.

Topics: Concanavalin A; Humans; Immune Adherence Reaction; Lectins; Lymphocytes; Rosette Formation; Schizophrenia; T-Lymphocytes