Immune dysfunction & mercury toxicity in autism

Posted in Studies

A selection of journal articles regarding immune dysfunction and/or mercury toxicity in autism

Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol. 2004 Jul;152(1-2):176-82.

Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, Vicente AM.

Instituto Gulbenkian de Ciencia, Rua da Quinta Grande 6, 2781-196 Oeiras, Portugal.

The hypothesis of an immune dysfunction in autism spectrum disorders has previously been put forward without, however, compelling evidence of a direct relation to its etiology or pathogenesis. To further understand if autoimmunity could play a significant role in autism, we analyzed autoantibody repertoires to brain tissue extract in the plasma of 171 autism children, their parents, and 54 controls, by quantitative immunoblotting. Multiparametric analysis revealed significant differences between patients and controls, and showed that one single reactivity in Section 32 of the blot had the most power to discriminate between these samples. Family correlation coefficients and heritability estimates did not provide any evidence that this reactivity was genetically determined. While the molecular weight of the target protein suggested that it might be an isoform of Myelin Basic Protein (MBP), inhibition assays with human MBP argued against this hypothesis. The study evidences the widespread occurrence of autoreactivities to brain tissue in autism patients, which may represent the immune system's neuroprotective response to a previous brain injury occurred during neurodevelopment. The molecular identification of the target protein in Section 32 will contribute to the understanding of the role of immune responses against brain antigens in autistic patients.

Neurotoxic effects of postnatal thimerosal are mouse strain dependent.Mol Psychiatry. 2004 Sep;9(9):833-45.

Hornig M, Chian D, Lipkin WI.

Jerome L and Dawn Greene Infectious Disease Laboratory, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease.Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL.

Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Suite 200, Beverly Hills, CA 90211, USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

Searching for a mechanism underlying autoimmunity in autism, we postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK) bind to different peptidases resulting in autoantibody production against these components. We assessed this hypothesis in patients with autism and in those with mixed connective tissue diseases. Associated with antigliadin and anti-HSP antibodies, children with autism and patients with autoimmune disease developed anti-dipeptidylpeptidase I (DPP I), anti-dipeptidylpeptidase IV (DPP IV [or CD26]) and anti-aminopeptidase N (CD13) autoantibodies. A significant percentage of autoimmune and autistic sera were associated with elevated immunoglobulin G (IgG), IgM, or IgA antibodies against three peptidases, gliadin, and HSP-60. These antibodies are specific, since immune absorption demonstrated that only specific antigens (e.g., DPP IV absorption of anti-DPP IV), significantly reduced IgG, IgM, and IgA antibody levels. For direct demonstration of SK, HSP-60, and gliadin peptide binding to DPP IV, microtiter wells coated with DPP IV were reacted with SK, HSP-60, and gliadin. They were then reacted with anti-DPP IV or anti-SK, anti-HSP, and antigliadin antibodies. Adding SK, HSP-60, and gliadin peptides to DPP IV resulted in 27 to 43% inhibition of the DPP IV-anti-DPP IV reaction, but DPP IV-positive peptides caused 18 to 20% enhancement of antigen-antibody reactions. We propose that (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens. Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity.

Prevalence of serum antibodies to caudate nucleus in autistic children.

Singh VK, Rivas WH.

Department of Biology, Biotechnology Center Building , Utah State University, 4700 Old Main Hill, Logan , UT 84322-4700 , USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

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.

J. Van de Water, P. Ashwood, R. Hansen, B. Goodlin-Jones, K. Lam, and M.E. Gershwin.Reduced IgG Response to Common Vaccine Antigens for Patients with Autism Spectrum Disorder (ASD); May, 2004.

Summary:

Internal Medicine and M.I.N.D. Institute, UC Davis, Davis , CA 95616.

There is a growing awareness of an immunological involvement in some ASD children. To better define the immune status of children with ASD, we examined by ELISA the serologic response of patients and age-matched typically developing (TD) controls to common vaccine antigens. These included Bordetella, Diptheria, Tetanus, Measles, Mumps and Rubella. All children analyzed were vaccinated with DTaP and MMR. Based on vaccination schedules, comparisons were made between patients and controls in three age groups: 2-5 yrs, 5-8 yrs and 8-14 yrs.

The most striking differences were observed in the 2-5 age group where patients with ASD had a significantly lower IgG response to Bordetella (p = 0.0003), Diptheria (p = 0.006), and Mumps (p = 0.043) than TD controls. There was also a trend for a lower IgG responses against Measles and Tetanus in the ASD group. In the 5-8 age group, there were no differences in the response to any of the test antigens. In the over 8 age group, while there was a trend towards lower IgG responses to Bordetella, Tetanus and Mumps antigens, only the IgG response to Measles was significantly reduced (p = 0.016). Interestingly, the response to Rubella was equal in groups over time. Finally, at no time point did the median of the response of the ASD group exceed that of the TD population. In conclusion, all patients with ASD were immunopositive for the vaccine antigens tested, their responses were significantly lower than the TD controls suggesting an immune dysregulation in these children.

Vojdani A, Pangborn JB, Vojdani E, Cooper EL.: Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

Abstract:

Lab. Comparative Immunology, Dept. Neurobiology, UCLA Medical Center, Los Angeles, CA, USA.

Similar to many complex autoimmune diseases, genetic and environmental factors including diet, infection and xenobiotics play a critical role in the development of autism. In this study, we postulated that infectious agent antigens such as streptokinase, dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69, streptokinase (SK), gliadin and casein peptides and against ethyl mercury bound to human serum albumin in patients with autism. A significant percentage of children with autism developed anti-SK, anti-gliadin and casein peptides and anti-ethyl mercury antibodies, concomitant with the appearance of anti-CD26 and anti-CD69 autoantibodies. These antibodies are synthesized as a result of SK, gliadin, casein and ethyl mercury binding to CD26 and CD69, indicating that they are specific. Immune absorption demonstrated that only specific antigens, like CD26, were capable of significantly reducing serum anti-CD26 levels. However, for direct demonstration of SK, gliadin, casein and ethyl mercury to CD26 or CD69, microtiter wells were coated with CD26 or CD69 alone or in combination with SK, gliadin, casein or ethyl mercury and then reacted with enzyme labeled rabbit anti-CD26 or anti-CD69. Adding these molecules to CD26 or CD69 resulted in 28-86% inhibition of CD26 or CD69 binding to anti-CD26 or anti-CD69 antibodies. The highest % binding of these antigens or peptides to CD26 or CD69 was attributed to SK and the lowest to casein peptides. We, therefore, propose that bacterial antigens (SK), dietary peptides (gliadin, casein) and Thimerosal (ethyl mercury) in individuals with pre-disposing HLA molecules, bind to CD26 or CD69 and induce antibodies against these molecules. In conclusion, this study is apparently the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism.

Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ.: Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics. 2003 Nov;112(5):e420.

Summary:

Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children Indianapolis 46202-4800, USA.

OBJECTIVES: Increased prevalence of familial autoimmune disease is a common finding among probands with various autoimmune disorders. Autistic disorder (autism) is a highly genetic disorder with known immune and immunogenetic abnormalities. Previous research has found an increased frequency of autoimmune disorders in families with autistic probands. We further investigated this association by determining the frequency of autoimmune disorders in families that have probands with pervasive developmental disorders (PDDs), including autism, compared with 2 control groups. METHODS: Three well-defined study groups, including 1) families that have a child with a PDD, 2) families that have a child with an autoimmune disorder, and 3) families with a healthy control child, constituted the sample. A questionnaire inquiring about which first- and second-degree family members had received a diagnosis of having specific autoimmune disorders was completed by 101 families in each group. RESULTS: The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto's thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. CONCLUSIONS: Autoimmunity was increased significantly in families with PDD compared with those of healthy and autoimmune control subjects. These preliminary findings warrant additional investigation into immune and autoimmune mechanisms in autism.

Singh VK, Jensen RL.: Elevated levels of measles antibodies in children with autism. Pediatr Neurol. 2003 Apr;28(4):292-4.

Abstract:Department of Biology and Biotechnology Center, Utah State University, Logan, Utah, USA.

Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P Lipkin WI, Hornig M.: Microbiology and immunology of autism spectrum disorders. Novartis Found Symp. 2003;251:129-43; discussion 144-8, 281-97.

Abstract:Center for Immunopathogenesis and Infections Diseases, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, USA.

Both generic and environmental factors are likely to contribute to the pathogenesis of neurodevelopmental disorders. Even in heritable disorders of high penetrance, variability in timing of onset or severity of disease indicate a role for modifying principles. Investigation in animal models of the consequences of interactions between host response genes and microbes, toxins, and other environmental agents in a temporal context may elucidate the pathophysiology of a wide spectrum of chronic diseases. Here we review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline plans for translational research in animal models and prospective human birth cohorts.

Holmes AS, Blaxill MF, Haley BE.: Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol. 2003 Jul-Aug;22(4):277-85.

Abstract: SafeMinds, Cambridge, Massachusetts, USA.

Reported rates of autism have increased sharply in the United States and the United Kingdom. One possible factor underlying these increases is increased exposure to mercury through thimerosal-containing vaccines, but vaccine exposures need to be evaluated in the context of cumulative exposures during gestation and early infancy. Differential rates of postnatal mercury elimination may explain why similar gestational and infant exposures produce variable neurological effects. First baby haircut samples were obtained from 94 children diagnosed with autism using Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) criteria and 45 age- and gender-matched controls. Information on diet, dental amalgam fillings, vaccine history, Rho D immunoglobulin administration, and autism symptom severity was collected through a maternal survey questionnaire and clinical observation. Hair mercury levels in the autistic group were 0.47 ppm versus 3.63 ppm in controls, a significant difference. The mothers in the autistic group had significantly higher levels of mercury exposure through Rho D immunoglobulin injections and amalgam fillings than control mothers. Within the autistic group, hair mercury levels varied significantly across mildly, moderately, and severely autistic children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively. Hair mercury levels among controls were significantly correlated with the number of the mothers' amalgam fillings and their fish consumption as well as exposure to mercury through childhood vaccines, correlations that were absent in the autistic group. Hair excretion patterns among autistic infants were significantly reduced relative to control. These data cast doubt on the efficacy of traditional hair analysis as a measure of total mercury exposure in a subset of the population. In light of the biological plausibility of mercury's role in neurodevelopmental disorders, the present study provides further insight into one possible mechanism by which early mercury exposures could increase the risk of autism.

Geier DA, Geier MR.: An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil. 2003 Apr-Jun;6(2):97-102.

Abstract:

The Genetic Centers of America, 14 Redgate Court, Silver Spring, MD 20905, USA.

The prevalence of autism in the US has risen from 1 in approximately 2500 in the mid-1980s to 1 in approximately 300 children in the mid-1990s. The purpose of this study was to evaluate whether mercury from thimerosal in childhood vaccines contributed to neurodevelopmental disorders. Neurodevelopmental disorder dose-response curves for increasing mercury doses of thimerosal in childhood vaccines were determined based upon examination of the Vaccine Adverse Events Reporting System (VAERS) database and the 2001 US' Department of Education Report. The instantaneous dosage of mercury children received in comparison to the Food and Drug Administration (FDA)'s maximum permissible dose for the oral ingestion of methylmercury was also determined. The dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other. Controls employed in the VAERS and US Department of Education data showed minimal biases. The evidence presented here shows that the occurrence of neurodevelopmental disorders following thimerosal-containing childhood vaccines does not appear to be coincidental.

Singh VK, Lin SX, Newell E, Nelson C., Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci 2002 Jul-Aug;9(4):359-64.

Abstract:

Department of Biology and Biotechnology Center, Utah State University, Logan, Utah, USA.

Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.

Korvatska E, Van de Water J, Anders TF, Gershwin ME: Genetic and immunologic considerations in autism. Neurobiol Dis 2002 Mar;9(2):107-25.

Abstract:

Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, California 95616, USA.

According to recent epidemiological surveys, autistic spectrum disorders have become recognized as common childhood psychopathologies. These life-lasting conditions demonstrate a strong genetic determinant consistent with a polygenic mode of inheritance for which several autism susceptibility regions have been identified. Parallel evidence of immune abnormalities in autistic patients argues for an implication of the immune system in pathogenesis. This review summarizes advances in the molecular genetics of autism, as well as recently emerging concerns addressing the disease incidence and triggering factors. The neurochemical and immunologic findings are analyzed in the context of a neuroimmune hypothesis for autism. Studies of disorders with established neuroimmune nature indicate multiple pathways of the pathogenesis; herein, we discuss evidence of similar phenomena in autism.

Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M: Activation of the inflammatory response system in autism. Neuropsychobiology 2002;45(1):1-6.

Abstract:

University Center of Child and Adolescent Psychiatry, Antwerp, Belgium.

BACKGROUND/AIM: There is now some evidence that autism may be accompanied by abnormalities in the inflammatory response system (IRS). Products of the IRS, such as proinflammatory cytokines, may induce some of the behavioral symptoms of autism, such as social withdrawal, resistance to novelty and sleep disturbances. The main aim of the present study was to examine whether autism is accompanied by an activation of the IRS. METHODS: We measured the production of interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA), interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by whole blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R) and IL-1RA. RESULTS: This study showed a significantly increased production of IFN-gamma and IL-1RA and a trend toward a significantly increased production of IL-6 and TNF-alpha by whole blood of autistic children. There were no significant differences in the serum concentrations of IL-6, IL-2R and IL-1RA between autistic and normal children. CONCLUSIONS: These results suggest that autism may be accompanied by an activation of the monocytic (increased IL-1RA) and Th-1-like (increased IFN-gamma) arm of the IRS. It is hypothesized that increased production of proinflammatory cytokines could play a role in the pathophysiology of autism.

Malek-Ahmadi P: Cytokines and etiopathogenesis of pervasive developmental disorders. Med Hypotheses 2001 Mar;56(3):321-4.

Abstract:

Department of Neuropsychiatry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.

Autistic disorder, also known as early infantile autism, is a developmental disorder of unknown etiology. However, there is some evidence to suggest that abnormalities of the immune system mediate the pathophysiology of autistic disorder. Cytokines, which play a pivotal role in initiating and maintaining immune responses, have been implicated in the etiopathogenesis of major neuropsychiatric disorders including autism. Cytokines are synthesized in the periphery, as well as in the central nervous system, and exert their effects by binding to their receptors in the nervous tissues. It is suggested that, in genetically predisposed individuals, overproduction or decreased synthesis of certain cytokines may result in neurodevelopmental arrest and/or neurotoxicity.

Jyonouchi H, Sun S, Le H.: Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 2001 Nov 1;120(1-2):170-9

Abstract:
Department of Pediatrics, University of Minnesota, MMC 610 FUMC, 420 Delaware Street SE, Minneapolis, MN 55455, USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.

Jyonouchi, H., Sun, S., Itokazu, N.: Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder Neuropsychobiology 2002;46(2):76-84.

Abstract:

Department of Pediatrics, University of Minnesota, Minneapolis, Minn., USA.

Objectives: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. Methods: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. Results: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. Conclusion: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria.

Hornig M, Lipkin WI: Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models. Ment Retard Dev Disabil Res Rev 2001;7(3):200-10.

Abstract:

Emerging Diseases Laboratory, Gillespie Neuroscience Research Facility, University of California, Irvine, California 92697-4292, USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

Both genetic and environmental factors contribute to the pathogenesis of a wide variety of neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of clinical disease expression may be influenced by the environment. In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease. Elucidation of the mechanisms guiding this intricate interplay between host response genes, environmental agents, and the neurodevelopmental context within which these interactions occur, is necessary to understand the continuum of clinical outcomes. This chapter will review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline areas for future research.

Bernard S, Enayati A, Redwood L, Roger H, Binstock T: Autism: a novel form of mercury poisoning. Med Hypotheses 2001 Apr;56(4):462-71.

Abstract:

ARC Research, Cranford, New Jersey 07901, USA.

Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and US government data suggests that: (i) many cases of idiopathic autism are induced by early mercury exposure from thimerosal; (ii) this type of autism represents an unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors establish a predisposition whereby thimerosal's adverse effects occur only in some children.

Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo MT, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Baldi A, Keller F: Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies. Am J Med Genet 2000 Dec 4;96(6):784-90.

Abstract:

Laboratory of Neuroscience, Department of Physiology and Neuroscience, Libera Universita Campus Bio-Medico, Rome, Italy.

Adenosine deaminase ( ADA ) plays a relevant role in purine metabolism, immune responses, and peptidase activity, which may be altered in some autistic patients. Codominant ADA1 and ADA2 alleles code for ADA1 and ADA2 allozymes, the most frequent protein isoforms in the general population. Individuals carrying one copy of the ADA2 allele display 15 to 20% lower catalytic activity compared to ADA1 homozygotes. Recent preliminary data suggest that ADA2 alleles may be more frequent among autistic patients than healthy controls. The present study was undertaken to replicate these findings in a new case-control study, to test for linkage/association using a family-based design, and to characterize ADA2-carrying patients by serotonin blood levels, peptiduria, and head circumference. ADA2 alleles were significantly more frequent in 91 Caucasian autistic patients of Italian descent than in 152 unaffected controls (17.6% vs. 7.9%, P = 0.018), as well as among their fathers. Family-based tests involving these 91 singleton families, as well as 44 additional Caucasian-American trios, did not support significant linkage/association. However, the observed preferential maternal transmission of ADA2 alleles, if replicated, may point toward linkage disequilibrium between the ADA2 polymorphism and an imprinted gene variant located in its vicinity. Racial and ethnic differences in ADA allelic distributions, together with the low frequency of the ADA2 allele, may pose methodological problems to future linkage/association studies. Direct assessments of ADA catalytic activity in autistic individuals and unaffected siblings carrying ADA1/ADA1 vs ADA1/ADA2 genotypes may provide stronger evidence of ADA2 contributions to autistic disorder.

Megson MN: Is autism a G-alpha protein defect reversible with natural vitamin A? Med Hypotheses 2000 Jun;54(6):979-83.

Abstract:

Pediatric and Adolescent Ability Center, Richmond, VA 23226, USA.

Autism may be a disorder linked to the disruption of the G-alpha protein, affecting retinoid receptors in the brain. A study of 60 autistic children suggests that autism may be caused by inserting a G-alpha protein defect, the pertussis toxin found in the DPT vaccine, into genetically at-risk children. This toxin separates the G-alpha protein from retinoid receptors. Those most at risk report a family history of at least one parent with a pre-existing G-alpha protein defect, including night blindness, pseudohypoparathyroidism or adenoma of the thyroid or pituitary gland.Natural vitamin A may reconnect the retinoid receptors critical for vision, sensory perception, language processing and attention. Autism spectrum disorders have increased from 1 in 10 000 in 1978 to 1 in 300 in some US communities in 1999. Recent evidence indicates that autism is a disorder of the nervous system and the immune system, affecting multiple metabolic pathways.

Gupta S: Immunological treatments for autism. J Autism Dev Disord 2000 Oct;30(5):475-9.

Abstract:

Division of Basic and Clinical Immunology, Medical Sciences I, University of California, Irvine 92697, USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

Several investigators, including ourselves, have reported significant changes in various immune responses in children with autism. These changes demonstrate dysregulation of the immune system (deficiency in some components of the immune system and excesses in others). In addition, certain genes in the major histocompatibility complex (that regulates immune responses) appear to be involved in autism. Based upon immunological abnormalities, various treatment modalities have been applied to children with autism. In this brief review, these immunological changes and various biological therapies are analyzed and summarized.

Hornig M, Weissenbock H, Horscroft N, Lipkin WI: An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci USA 1999 Oct 12; 96(21):12102-7.

Abstract:

Emerging Diseases Laboratory, Department of Microbiology, University of California, Irvine, CA 92697-4292, USA.

Perinatal exposure to infectious agents and toxins is linked to the pathogenesis of neuropsychiatric disorders, but the mechanisms by which environmental triggers interact with developing immune and neural elements to create neurodevelopmental disturbances are poorly understood. We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. Infection results in abnormal righting reflexes, hyperactivity, inhibition of open-field exploration, and stereotypic behaviors. Architecture is markedly disrupted in hippocampus and cerebellum, with reduction in granule and Purkinje cell numbers. Neurons are lost predominantly by apoptosis, as supported by increased mRNA levels for pro-apoptotic products (Fas, caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in situ labeling of fragmented DNA. Although inflammatory infiltrates are observed transiently in frontal cortex, glial activation (microgliosis > astrocytosis) is prominent throughout the brain and persists for several weeks in concert with increased levels of proinflammatory cytokine mRNAs (interleukins 1alpha, 1beta, and 6 and tumor necrosis factor alpha) and progressive hippocampal and cerebellar damage. The resemblance of these functional and neuropathologic abnormalities to human neurodevelopmental disorders suggests the utility of this model for defining cellular, biochemical, histologic, and functional outcomes of interactions of environmental influences with the developing central nervous system.

Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK: Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr 1999 May;134(5):607-13.

Abstract:

Departments of Neurology and Pediatrics, Washington University, St. Louis Children's Hospital, St Louis, Missouri, USA.

OBJECTIVE: Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children. DESIGN: We collected sera from a cohort of children with (1) pure Landau-Kleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV, n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with non-neurologic illnesses (NNIs), and 20 children with other neurologic disorders (ONDs). We identified brain autoantibodies by immunostaining of human temporal cortex and antinuclear autoantibodies using commercially available kits. RESULTS: IgG anti-brain autoantibodies were present in 45% of sera from children with LKSV, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with LKSV, and 15% with ONDs compared with 0% of control sera. Labeling studies identified one antigenic target to be endothelial cells. Antinuclear antibodies with titers >/=1:80 were more common in children with ASD and control children with ONDs. CONCLUSION: Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.

Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN: Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 1999 Jun;14(6):388-94.

Abstract:

Johns Hopkins Hospital, Division of Pediatric Neurology, Baltimore, MD 21212, USA. This email address is being protected from spambots. You need JavaScript enabled to view it.

Autism is an age-dependent neurologic disorder that is often associated with autoimmune disorders in the patients' relatives. To evaluate the frequency of autoimmune disorders, as well as various prenatal and postnatal events in autism, we surveyed the families of 61 autistic patients and 46 healthy controls using questionnaires. The mean number of autoimmune disorders was greater in families with autism; 46% had two or more members with autoimmune disorders. As the number of family members with autoimmune disorders increased from one to three, the risk of autism was greater, with an odds ratio that increased from 1.9 to 5.5, respectively. In mothers and first-degree relatives of autistic children, there were more autoimmune disorders (16% and 21%) as compared to controls (2% and 4%), with odds ratios of 8.8 and 6.0, respectively. The most common autoimmune disorders in both groups were type 1 diabetes, adult rheumatoid arthritis, hypothyroidism, and systemic lupus erythematosus. Forty-six percent of the autism group reported having relatives with rheumatoid diseases, as compared to 26% of the controls. Prenatal maternal urinary tract, upper respiratory, and vaginal infections; asphyxia; prematurity, and seizures were more common in the autistic group, although the differences were not significant. Thirty-nine percent of the controls, but only 11% of the autistic, group, reported allergies. An increased number of autoimmune disorders suggests that in some families with autism, immune dysfunction could interact with various environmental factors to play a role in autism pathogenesis.

Singh V, Lin S, Yang V.Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clinical Immunology and Immunopathology 1998:89;105-108.

College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065, USA.

Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism. Copyright 1998 Academic Press.

Van Gent T, Heijnen CJ, Treffers PD: Autism and the immune system. J Child Psychol Psychiatry 1997 Mar;38(3):337-49.

Abstract:

University of Leijden, The Netherlands.

As our knowledge of the interactions of the immune, nervous and endocrine systems progresses, complex links with the origin and course of psychopathology in childhood are revealed. In this article the neuroimmunological literature on autism is reviewed. Relevant aspects of immune functioning and the neuroendocrine-immune network are described. We present the immunological findings in autistic patients within two related conceptual frameworks: a viral and an autoimmune hypothesis. Interpretation of data is hampered by conceptual and methodological differences between studies. Both the clinical significance of the immune changes and the causal connection between immune changes and psychopathological phenomena in autism remain to be elucidated. Recommendations for further research are given.

Warren RP, Singh VK, Averett RE, Odell JD, Maciulis A, Burger RA, Daniels WW, Warren WL: Immunogenetic studies in autism and related disorders. Mol Chem Neuropathol 1996 May-Aug;28(1-3):77-81.

Abstract:

Utah State University, Logan 84322, USA.

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 frequently 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 DR beta 1 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 DR beta 1 gene also had significantly increased representation in the autistic subjects.

Warren RP, Singh VK: Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology 1996;34(2):72-5.

Abstract:

Center for Persons with Disabilities, Utah State University, Logan 84322, USA.

Two of the most consistently observed biological findings in autism are increased serotonin levels in the blood and immunological abnormalities (including autoreactivity with tissues of the central nervous system). The purpose of this investigation was to determine if any relationship exists between these two sets of observations. Our laboratory has found and confirmed associations of the major histocompatibility complex (MHC) with autism. Since the MHC is known to regulate the immune system and is also associated with autoimmune disorders, we studied serum serotonin levels in 20 autistic subjects with or without MHC types previously found to be associated with autism. A positive relationship was observed between elevated serotonin levels and the MHC types previously associated with autism.

Singh VK: Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. J Neuroimmunol 1996 May;66(1-2):143-5.

Abstract:

Department of Psychiatry, University of Michigan, School of Medicine, Ann Arbor 48109-0656, USA.

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.

Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B: Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist Super Sanita 1996;32(3):351-9.

Abstract:

Servizio di Psichiatria, Istituto OASI per lo Studio del Ritardo Mentale e l'Involuzione Cerebrale, Troina (Enna), Italy.

The emerging concept of opioid peptides as a new class of chemical messengers of the neuroimmune axis and the presence of a number of immunological abnormalities in infantile autism prompted us to correlate biological (hormonal and immunological) determinations and behavioural performances during treatment with the potent opiate antagonist, naltrexone (NAL). Twelve autistic patients ranging from 7 to 15 years, diagnosed according to DSM-III-R, entered a double-blind crossover study with NAL at the doses of 0.5, 1.0 and 1.5 mg/kg every 48 hours. The behavioural evaluation was conducted using the specific BSE and CARS rating scales NAL treatment produced a significant reduction of the autistic symptomatology in seven ("responders") out of 12 children. The behavioural improvement was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels. It is suggested that the mechanisms underlying opioid-immune interactions are altered in this population of autistic children and that an immunological screening may have prognostic value for the pharmacological therapy with opiate antagonists.

Gupta S, Aggarwal S, Heads C: Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord 1996 Aug;26(4):439-52. [No abstract available]

Warren RP, Yonk J, Burger RW, Odell D, Warren WL: DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology 1995;31(2):53-7.

Abstract:

Center for Persons with Disabilities, Utah State University, Logan 84322 , USA.

Autism is a developmental disorder characterized by severe communication, social and behavioral abnormalities. Over the past several years a fair amount of evidence has accumulated suggesting that some cases of autism may be associated with immune abnormalities and with products of the HLA complex including the C4B gene located in the class III region of HLA. This study sought additional evidence for an association of autoimmune processes with autism by investigating the presence of activated T cells in 26 autistic subjects. Fourteen of the autistic subjects had DR+ T cells, an indicator of activated T cells, but none of the autistic subjects had T cells expressing the interleukin-2 receptor, another indicator of T cell activation. Similar findings of incomplete or partial T cell activation have been reported in autoimmune disorders and in a recent study of autism. In the current investigation, the DR+ T cells were not found to be associated with age of the autistic patients but were inversely correlated with a decreased plasma level of the C4B protein. In conclusion, this study provides additional evidence for the involvement of an autoimmune mechanism in autism.

Daniels WW, Warren RP, Odell JD, Maciulis A, Burger RA, Warren WL, Torres AR: Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology 1995;32(3):120-3.

Abstract:

Center for Persons with Disabilities, Utah State University, Logan 84322, USA.

Autism likely results from several different etiologies or a combination of pathological mechanisms. Recent studies suggest that this disorder may be associated with immune abnormalities, pathogen-autoimmune processes and perhaps the major histocompatibility complex (MHC). In a preliminary study we found that 22 autistic subjects had an increased frequency of the extended or ancestral MHC haplotype B44-SC30-DR4. The current study attempted to confirm this observation by studying 23 additional randomly chosen autistic subjects, most of their parents and 64 unrelated normal subjects. In agreement with earlier findings B44-SC30-DR4 was associated with autism. In combining the data from the original and current studies, B44-SC30-DR4 or a substantial fragment of this extended haplotype was represented in 40% of the autistic subjects and/or their mothers as compared to about 2% of the unrelated subjects. It is concluded that one or more genes of the MHC is (are) involved in the development of some cases of autism.

Singh V. K., Warren R. P., Odell J. D. Warren W. L., Cole P.:Antibodies to Myelin Basic Protein in Children with Autistic Behavior. Brain, Behavior, and Immunity 7, 97 - 103, 1993.

Abstract: Biomedical Division, Center for Persons with Disabilities, Logan, Utah.

Based on a possible pathological relationship of autoimmunity to autism, antibodies reactive with myelin basic protein (anti-MBP) were investigated in the sera of autistic children. Using a screening serum dilution of 1:400 in the protein-immunoblotting technique, approximately 58% (19 of 33) sera of autistic children (< or = 10 years of age) were found to be positive for anti-MBP. This result in autistics was significantly (p < or =.0001) different from the controls (8 of 88 or only 9% positive), which included age-matched children with normal health, idiopathic mental retardation (MR) and Down syndrome (DS), and normal adults of 20 to 40 years of age. Since autism is a syndrome of unknown etiology, it is possible that anti-MBP antibodies are associated with the development of autistic behavior.

Singh V.K., Warren R.P Odell J.D., and Cole P.: Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children. Immunology and Immunopathology 61, 448-455, 1991.

Abstract:

Neuroimmunology Laboratory, Utah State University, Logan 84322-6800.

Immune abnormalities in autistic children led us to study for indirect evidence of immune activation as measured by the serum analysis of soluble interleukin-2 (sIL-2), interleukin-2 receptor (sIL-2R), T8 antigen (sT8), and interleukin-1 (sIL-1). The serum concentration of these soluble antigens was quantitated by enzyme-linked immunosorbent assays. The concentration of sIL-2 and sT8, but not of sIL-2R and sIL-1, antigens was significantly (P less than 0.05) increased in the sera of autistic children over that in the control healthy children or children with mental retardation (non-Down's syndrome). This finding indirectly indicates that the activation of a subpopulation of T cells occurs in some children with autism.

Yonk, L.J., Warren, R.P., Burger, R.A., Cole, P., Odell, J.D., Warren,W.L., White, E., and Singh, V.K.: CD4+ helper T cell depression in autism. Immunol. Lett. 25, 341 - 346, 1990.

Abstract:

Developmental Center for Handicapped Persons, Utah State University, Logan 84322-6800.

CD4+ (helper) T cells are a heterogenous population of lymphocytes including at least two distinct subpopulations. To investigate the possibility that immune abnormalities in some subjects with autism may involve abnormal distributions of CD4+ and/or CD8+ cells, (suppressor) T cells, peripheral blood lymphocytes of 25 autistic subjects were characterized with monoclonal antibodies and flow cytometry. The autistic subjects had a significantly lower percentage and number of CD4+ cells, a lower number of T cells (CD2+ cells) and B cells (CD20+ cells), and a lower percentage and number of total lymphocytes than siblings and normal subjects. The level of blood values for female subjects appeared lower than those for males as compared to normal subjects of the same sex. These results suggest that a decrease in CD4+ cells is associated with autism.

Warren, R. P.,Yonk, L. J., Burger, R. A., Cole, P., Odell, J.D., Warren, W.L., White, E., and Singh, V.K.: Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism. Immunol. Invest. 19, 245-251, 1990.

Abstract:

Developmental Center for Handicapped Persons, Utah State University, Logan 84322.

CD4+ cells are a heterogenous population of lymphocytes including at least two distinct subpopulations: CD45RA+ cells, inducers of suppressor T cells and CDw29+ cells, inducers of helper function for antibody production. To investigate the possibility that immune abnormalities in autism may involve abnormal distribution of these helper subpopulations, monoclonal antibodies were used in flow cytometric analysis to characterize peripheral blood lymphocytes of 36 subjects with autism. The autistic subjects as compared to a group of 35 healthy age-matched subjects had a significantly reduced number of lymphocytes, a decreased number of CD2+ T cells and reduced numbers of CD4+ and CD4+CD45RA+ lymphocytes. The numbers of B (CD20+) cells, suppressor T (CD8+) cells, inducers of helper function (CD4+CDw29+) and natural killer (CD56+) cells were not altered in the autistic subjects. Our results suggest that an alteration in the suppressor-inducer T-cell subset is associated with autism.

Warren R. P., Cole P., Odell J. D., Pingree C., Warren L., White E., Yonk J., Singh V. K.: Detection of Maternal Antibodies in Infantile Autism. J. Am. Acad. Child Adolesc. Psychiatry, 29:6, November 1990.

Abstract:

Developmental Center for Handicapped Persons, Utah State University, Logan 84322.

Maternal antibodies reactive with antigenic proteins expressed on the cell surface of paternal lymphocytes can be detected in couples with histories of more than one miscarriage or stillbirth. It is possible, but not proven, that these antibodies also react with tissues of the fetus and result in fetal death. Since many mothers of autistic children have a history of pregnancy disorder, antibodies were studied in 11 mothers of autistic children who were 6 years of age or younger. Six of the mothers had antibodies that reacted with lymphocytes of the autistic child. Five of these six mothers had a history of pregnancy disorder. Since antigens expressed on lymphocytes are found on cells of the central nervous system and, perhaps, other tissues of the developing embryo, it is suggested that aberrant maternal immunity may be associated with the development of some cases of infantile autism.

Root-Bernstein RS, Westall FC:Serotonin binding sites. II. Muramyl dipeptide binds to serotonin binding sites on myelin basic protein, LHRH, and MSH-ACTH 4-10. Brain Res Bull 1990 Dec;25(6):827-41.

Abstract:

Department of Physiology, Michigan State University, East Lansing 48824.

Previously, we reported the existence of structurally similar serotonin binding sites on myelin basic protein, LHRH, and MSH-ACTH 4-10. We now report that the adjuvant peptide, muramyl dipeptide (N-acetyl-muramyl-L-Ala-D-isoGln) also binds to these sites. This observation may help to explain previous observations of serotonin-like activity by muramyl peptides, including the promotion of slow-wave sleep and fever induction. The observation may also provide an important link between the immune system and the nervous system that may explain the role of muramyl dipeptide adjuvants in causing autoimmune diseases to serotonin-regulated proteins and their receptors, as well as the alterations in serotonin levels that are often observed in autoimmune diseases. The observation provides concrete evidence for a dual-antigen hypothesis for the induction of autoimmune diseases by an adjuvant-peptide complex. Application of such a mechanism for induction of autoimmunity may be of importance in understanding a number of postinfectious and postvaccinal neuropathies, and suggests a possible etiology for autism, in which many patients have high blood serotonin levels, autoimmune reactions to myelin basic protein, and antibodies to serotonin binding sites. Finally, the observation suggests that glycopeptides may act as neurotransmitters.

Singh, V.K, Fudenberg, H. H., Emerson, D. and Coleman, M. : Immunodiagnosis and immunotherapy in autistic children. Ann. N. Y. Acad. Sci. 540, 602-604, 1988. [No abstract available]

Meulen Ter Volker: Autoimmune Reactions Against Myelin Basic Protein Induced by Corona and Measles Viruses. Annals of The New York Academy of Sciences, Advances in Neuroimmunology, Vol. 540, 1988. [No abstract available]

Ferrari P, Marescot MR, Moulias R, Bursztejn C, Deville Chabrolle A, Thiollet M, Lesourd B, Braconnier A, Dreux C, Zarifian E, et al: Immune status in infantile autism. Correlation between the immune status, autistic symptoms and levels of serotonin [Article in French]. Encephale 1988 Sep-Oct;14(5):339-44.

Abstract:

Service de Psychotherapie, l'Enfant et de l'Adolescent, Hopital Robert Debre, Reims.

In sixteen autistic children high values of IgG and a high level of lymphocyte stimulation with PHA were observed. Principal component analysis showed: 1) a significant correlation between basic lymphocyte mitogenic activity and the clinical symptoms opposition and hyperactivity, 2) a significant correlation between high Ig levels, high PHA stimulation responses and the main autistic symptoms (withdrawal, inaffectivity, hypoactivity, mannerism, stereotypy and negatively echolalia), 3) a significant correlation with serotonin uptake by platelets and high immunological responses. Such correlations are strongly in favor of an immunologic component in autistic disease.

Warren RP, Foster A, Margaretten NC: Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry 1987 May;26(3):333-5. [No abstract available]

Warren RP, Margaretten NC, Pace NC, Foster A: Immune abnormalities in patients with autism. J Autism Dev Disord 1986 Jun;16(2):189-97.

Abstract:

We have begun an investigation on the immune systems of patients with autism in attempt to determine if immune mechanisms are involved in the development of this severe developmental disorder. A study of 31 autistic patients has revealed several immune-system abnormalities, including reduced responsiveness in the lymphocyte blastogenesis assay to phytohemagglutinin, concanavalin A, and pokeweed mitogen; decreased numbers of T lymphocytes; and an altered ratio of helper to suppressor T cells. Immune-system abnormalities may be directly related to underlying biologic processes of autism, or these changes may be an indirect reflection of the actual pathologic mechanism.

Todd RD: Pervasive developmental disorders and immunological tolerance. Psychiatr Dev 1986 Summer;4(2):147-65.

Abstract:

A wide range of studies in man and other species suggest that early compromise of immunological tolerance (both maternal-fetal and self) may lead to severe and varied cognitive deficits. This article briefly reviews what is known of the genesis and maintenance of normal tolerance and current ideas on pathological deviances in tolerance. These ideas are discussed in relation to risk factor, family, twin, biochemical, anatomical, and immunological studies of pervasive developmental disorders (particularly infantile autism). A range of immunological injury hypotheses for the genesis of the pervasive developmental disorders are considered and technical problems in deciding among them are presented.

Weizman, A., Weizman, R., Szekely, G.A., Wijsenbeek, H., and Livni, E: Abnormal immune response to brain tissue antigen in the syndrome of autism. Am. J. Psychiatry 7, 1462-1465, 1982.

Abstract:

Cell-mediated immune response to human myelin basic protein was studied by the macr, ophage migration inhibition factor test in 17 autistic patients and a control group of 11 patie, nts suffering from other mental diseases included in the differential diagnosis of the syndrome of autism. Of the 17 autistic patients, 13 demonstrated inhibition of macrophage migration, whereas none of the nonautistic patients showed such a response. The results indicate the existence of a cell-mediated immune response to brain tissue in the syndrome of autism.

Stubbs EG, Crawford ML: Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr 1977 Mar;7(1):49-55.

Abstract:

Although there are associations linking autism with prenatal rubella, cytomegalovirus, syphilis, and varicella, the etiology of the autistic state remains obscure. Host defense against the etiologic agents postulated to be responsible for the autism-associated syndromes is believed to be primarily of the cell-mediated type. In this preliminary study, cellular immune function was assessed in vitro by phytohemagglutinin (PHA) stimulation of lymphocyte cultures. Twelve autistic children and 13 control subjects were compared. The autistic group exhibited a depressed lymphocyte transformation response to PHA when compared to the control subjects (p less than.01).

Stubbs EG: Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. J Autism Child Schizophr 1976 Sep;6(3):269-74.

Abstract:

The etiology of autism is unknown, but autism has been associated with a number of diseases, including prenatal rubella. Rubella vaccine challenge was used in an attempt to retrospectively diagnose prenatal rubella in autistic children. This test was selected because unresponsiveness of antibody titer has been reported as helpful in retrospective diagnosing of prenatal rubella. Fifteen autistic children and 8 controls matched for age were challenged with rubella vaccine. Rubella vaccine challenge did not differentiate autistic children from the control subjects. However, 5 of 13 autistic children had undetectable titers despite previous vaccine; all control subjects had detectable titers. This finding of undetectable titers in autistic children suggests these children may have an altered immune response.

updated 05/17/05

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Lisa S. Lewis, Ph.D.

Lisa S. Lewis, Ph.D. Lisa S. Lewis, Ph.D. is the author of Special Diets For Special Kids I & II, the foremost books on gluten and casein-free diets for children with disabilities.

Karyn Seroussi

Karyn Seroussi Karyn Seroussi is the author of Unraveling the Mystery of Autism and PDD, the story of her son's autism recovery through dietary and other biomedical interventions.

Helping since 1995

Together Lewis and Seroussi created the Autism Network for Dietary Intervention (ANDI.) Since 1995, ANDI has been helping and supporting parents using dietary and biomedical interventions for autism spectrum disorders. Last year, Lisa and Karyn again joined forces and put the sum of their knowledge in a new book, The Encyclopedia of Dietary Interventions. They continue to write and speak on the topic of dietary intervention, and to support other parents around the world.