Vijendra K. Singh

Circulating autoantibodies to neuronal and glial filament proteins in autism

Autoimmunity may be a pathogenic factor in autism, a behavioral disorder of early childhood onset. Circulating autoantibodies are produced in organ-specific autoimmunity; therefore, we investigated them in the plasma of autistic subjects, mentally retarded (MR) subjects, and healthy controls. Autoantibodies (IgG isotype) to neuron-axon filament protein (anti-NAFP) and glial fibrillary acidic protein (anti-GFAP) were analyzed by the Western immunoblotting technique. We found a significant increase in incidence of anti-NAFP (P = .004) and anti-GFAP (P = .002) in autistic subjects, but not in MR subjects. Clinically, these autoantibodies may be related to autoimmune pathology in autism.

Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism

Immune factors such as autoimmunity have been implicated in the genesis of autism, a neurodevelopmental disorder. Since autoimmune response involves immune activation, the plasma levels of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), interleukin-12 (IL-12), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble intercellular adhesion molecule-1 (sICAM-1) were measured in autistic patients and age-matched normal controls. The levels of IL-12 and IFN-gamma were significantly (P < or = 0.05) higher in patients as compared to controls. However, IFN-alpha, IL-6, TNF-alpha, and sICAM-1 levels did not significantly differ between the two groups. Because macrophage-derived IL-12 is known to selectively induce IFN-gamma in T helper type-1 (Th-1) cells, it is suggested that IL-12 and IFN-gamma increases may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism.

CIRCULATING CYTOKINES IN ALZHEIMER'S DISEASE

Immune factors may be involved in the pathophysiology of Alzheimers disease (AD), a neurodegenerative disease. Since immune activation precedes immune-mediated processes, we measured plasma levels of four selective cytokines: interleukin-6 (IL-6), interleukin-12 (IL-12), interferon-alpha (IFN-alpha), and interferon-gamma (IFN-gamma). The level of IL-6, but not other cytokines, was significantly elevated. The increase of circulating IL-6 indicates immune activation presumably related to pathophysiology of the disease.

Stimulatory effect of corticotropin-releasing neurohormone on human lymphocyte proliferation and interleukin-2 receptor expression

The supplementation of corticotropin-releasing factor (CRF) into the cultures of human blood lymphocytes caused increased proliferation both in the absence and presence of T cell mitogens such as concanavalin A and phytohemagglutinin. The stimulation of concanavalin A response was much higher with CRF ligand as compared to Tyr-CRF, CRF-antagonist and sauvagine, and this response was blocked by CRF-antagonist. The lymphocyte proliferative response to stimulation by pokeweed mitogen or monoclonal antibody to CD3 antigen (OKT3) and the activity of natural killer (NK) cells was not affected by CRF. However, this neuroendocrine hormone, in addition to its ability to stimulate lymphocyte proliferation, enhanced expression of interleukin-2 receptors (IL-2R) on T cells (activated T cells) as revealed by a 2-fold increase in the proportion of IL-2R+T cells after the culture of lymphocytes for 3-5 days in the presence of CRF. Based on these findings, we suggest that CRF plays an important role in the modulation of the neuroendocrine-immune circuity.

Enhancing effect of corticotropin-releasing neurohormone on the production of interleukin-1 and interleukin-2

Based upon an immunomodulatory role for Corticotropin-Releasing Factor (CRF), a low molecular weight neurohormone, we investigated the effect of CRF on the production of interleukin-1 (IL-1) and interleukin-2 (IL-2) activities of mononuclear cells isolated from the peripheral blood of healthy subjects. The production of both IL-1 and IL-2 was stimulated by a nanomolar concentration of CRF by itself. In addition, CRF augmented the production of IL-1 as induced by lipopolysaccharide and the production of IL-2 as induced by phytohemagglutinin. These results suggest that CRF modulates the function of the cells of the immune system presumably by acting as a blood-borne mediator of the neuroendocrine-immune pathways.

Prevalence of serum antibodies to caudate nucleus in autistic children

Autism may involve autoimmunity to brain. We studied regional distribution of antibodies to rat caudate nucleus, cerebral cortex, cerebellum, brain stem and hippocampus. The study included 30 normal and 68 autistic children. Antibodies were assayed by immunoblotting. Autistic children, but not normal children, had antibodies to caudate nucleus (49% positive sera), cerebral cortex (18% positive sera) and cerebellum (9% positive sera). Brain stem and hippocampus were negative. Antibodies to caudate nucleus were directed towards three proteins having 160, 115 and 49 kD molecular weights. Since a significant number of autistic children had antibodies to caudate nucleus, we propose that an autoimmune reaction to this brain region may cause neurological impairments in autistic children. Thus, the caudate nucleus might be involved in the neurobiology of autism.

Increased frequency of the null allele at the complement C4b locus in autism

Associations between C4 deficiency and autoimmune disorders have been found over the past several years. Since autism has several autoimmune features, the frequencies of null (no protein produced) alleles at the C4A and C4B loci were studied in 19 subjects with autism and their family members. The autistic subjects and their mothers had significantly increased phenotypic frequencies of the C4B null allele (58% in both the autistic subjects and mothers, compared with 27% in control subjects). The siblings of the autistic subjects also had an increased frequency of the C4B null allele, but this increase was not significant. The fathers had normal frequencies of this null allele. All family members had normal frequencies of the C4A null allele, all normal C4A and C4B alleles and all BF and C2 alleles.

Activation of indices of cell-mediated immunity in bipolar mania.

BACKGROUND Evidence supports that macrophages as well as lymphocytes and their products may be involved in the pathophysiology of psychiatric disorders. Whether patients with bipolar disorder have activation or reduction of immunity during a manic episode remains unclear. METHODS The purpose of this case-control study was to investigate the lymphocyte proliferation to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen, and plasma levels of soluble interleukin-2 receptor (sIL-2R) and sIL-6R in patients with bipolar mania (DSM-III-R). The subjects were 23 physically healthy patients with Young Mania Rating Scale (YMRS) scores > or = 26 as well as aged < or = 45 years and 23 age- and gender-matched normal control subjects. The above immune variables were measured in acute mania and consequent remission (YMRS scores < or = 12) among bipolar patients. RESULTS The lymphocyte proliferation to PHA and the plasma sIL-2R levels, but not sIL-6R, of bipolar patients were significantly higher in acute mania than in consequent remission. These elevations were not due to differences in medication status. Only in acute mania were the plasma sIL-2R levels of patients significantly higher than control subjects. A positive correlation between the changes of manic severity and plasma sIL-2R levels was observed. Remitted bipolar patients and normal control subjects did not differ in any of these measures. CONCLUSIONS Cell-mediated immunity activation in bipolar mania was demonstrated and may be through a specifically state-dependent immune response.

Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation

Autism is a biological disorder manifesting psychiatric symptoms in children. The etiology is not known, although diverse factors may contribute to the cause of autism. The major symptoms are impaired social interaction, communication, and language skills. Apparently, they are related to abnormal development of certain centers within the brain, in particular cerebellum, brain stem, and limbic region (Bauman 1991). Hyperserotoninemia is seen in 30-66% of autistic children (Yuwiler et al 1992; Laszlo et al 1994), and some also have autoantibodies to brain serotonin receptor (Todd and Ciaranello 1985; Yuwiler et al 1992). Since up to 60% of autistic children show mental retardation, we measured serotonin levels and brain serotonin receptor antibodies in the plasmas of autistic, mentally retarded, and normal children. The present study describes hyperserotoninemia and serotonin receptor antibodies in autistic children but not in mentally retarded children.

Immunogenetic studies in autism and related disorders

The major histocompatibility complex comprises a number of genes that control the function and regulation of the immune system. One of these genes, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. We previously reported that a deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) had an increased frequency in autism. In this study we attempted to confirm the increased incidence of the C4B null allele in autism and investigated the presence of a C4B null allele in two other childhood disorders, attention-deficit hyperactivity disorder and dyslexia (reading disability). In addition, we explored the relationship of autism to the DRβ1 gene, a gene located close to the C4B in autism. We confirmed the finding of an increased frequency of the C4B null allele in autism and found that the related disorders also had an increased frequency of this null allele. In addition, two alleles of the DRβ1 gene also had significantly increased representation in the autistic subjects.