Chapter 9. Immunological Factors in Autism and ASD

Abdallah MW. 2013. Neonatal chemokine levels and risk of autism spectrum disorders: findings from a Danish historic birth cohort follow-up study. Cytokine. 61(2):370-6. doi: 10.1016/j.cyto.2012.11.015.

Abdallah MW et al., 2012. Neonatal levels of cytokines and risk of autism spectrum disorders: an exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank. J Neuroimmunol. 252(1-2):75-82. doi: 10.1016/j.jneuroim.2012.07.013.

Allen JL et al., 2014. Developmental exposure to concentrated ambient ultrafine particulate matter air pollution in mice results in persistent and sex-dependent behavioral neurotoxicity and glial activation. Toxicol Sci. 140(1):160-78. doi: 10.1093/toxsci/kfu059

Allen JL et al., 2016. Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders. Neurotoxicology. 22. pii: S0161-813X(15)30048-6. doi:10.1016/j.neuro.2015.12.014.

Asser A and P Taba. 2015. Psychostimulants and movement disorders. Front Neurol. 6:75. doi: 10.3389/fneur.2015.00075.

Authier FJ et al., 2001. Central nervous system disease in patients with macrophagic myofasciitis. Brain. 124(Pt 5):974-83.

Authier FJ, et al., 2006. AlOH3-adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background. Neuromuscul Disord 16(5):347–52.10.1016/j.nmd.2006.02.004

Bauer AZ and D Kriebel D. 2013. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health. 12:41. doi: 10.1186/1476-069X-12-41.

Becker KG and ST Schultz. 2010. Similarities in features of autism and asthma and a possible link to acetaminophen use. Med Hypotheses. 74(1):7-11. doi: 10.1016/j.mehy.2009.08.033.

Bernhardt EB et al., 2011. Memantine for comorbid obsessive-compulsive disorder and Asperger disorder suggests a link in glutamatergic dysregulation. J Clin Psychopharmacol 31(5):673–5. doi:10. 1097/JCP.0b013e31822c92d4

Block M. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 8(1):57-69.

Bohm, HV and MG Stewart. 2009. Brief report: On the concordance percentages for autistic spectrum disorder of twins. Journal of Autism and Developmental Disorders 39(5):806-808.

Bilder, D et al., 2013. Maternal prenatal weight gain and autism spectrum disorders. Pediatrics 132, e1276–e1283. doi: 10.1542/peds.2013-1188.

Blaylock RL 2008. A possible central mechanism in autism spectrum disorders, part 1. Altern Ther Health Med. 14(6):46-53.

Blaylock RL. et al., 2009. A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity. Altern Ther Health Med. 15(1):60-7.

Bondy S, 2010. The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology. 31(5):575-81. doi: 10.1016/j.neuro.2010.05.009.

Branton WG et al., 2013. Brain microbial populations in HIV/AIDS: α-proteobacteria predominate independent of host immune status. PLoS One. 2013;8(1):e54673. doi: 10.1371/journal.pone.0054673.

Braunschweig D et al., 2008. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology. 29(2):226-31.

Buonaguro L and B Pulendran, 2011. Immunogenomics and systems biology of vaccines. Immunol Rev. 239(1):197-208. doi: 10.1111/j.1600-065X.2010.00971.x.

Cabanlit M et al., 2007. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann N Y Acad Sci. 1107:92-103.

Charleston JS 1996. Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure. Neurotoxicology. 17(1):127-38.

Choi GB et al., 2016. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 351(6276):933-9. doi: 10.1126/science.aad0314.

Connolly AM et al., 1999. Serum autoantibodies to brain in Landau-Kleffner variant, autism and other neurologic disorders. J Pediatr 134(5):607-13.

Connors, DE et al., 2005. β2-Adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins. Journal of Child Neurology 20:876–884.

Costello DA et al.,2011. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: A role for Toll-like receptor activation J Biol Chem 286: 34722–34732.

Croen LA et al., 2008. Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biol Psychiatry. 64(7):583-8. doi: 10.1016/j.biopsych.2008.05.006.

Croen, LA et al.,2011. Prenatal exposure to β2-adrenergic receptor agonists and risk of autism spectrum disorders. Journal of Neurodevelopmental Disorders. 3:307–315.

Cunningham CL et al., 2013. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 33(10):4216-33. doi: 10.1523/JNEUROSCI.3441-12.2013.

Dalton P et al., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol. 53:533–537.

Dodds, L et al.,2011. The role of prenatal, obstetric and neonatal factors in the development of autism. J. Autism Dev. Disord. 41:891–902. doi: 10.1007/s10803-010-1114-8

Downer EJ et al., 2010. A novel anti-inflammatory role of NCAM-derived mimetic peptide, FGL. Neurobiol Aging 3:118–128.

Davalos D et al., 2005. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 8(6):752-8.

Dello Russo C et al.,2009. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol. 78(9):1242-51. doi: 10.1016/j.bcp.2009.06.097.

Edlow AG et al., 2016. Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity. Am J Obstet Gynecol. 2016 May;214(5):623.e1-623.e10. doi:10.1016/j.ajog.2016.02.054.

Fujii K et al., 2012. Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccine. Pediatr Int. 54(4):539-41. doi: 10.1111/j.1442-200X.2011.03501.x.

Gardner RM et al., 2015. Maternal body mass index during early pregnancy, gestational weight gain and risk of autism spectrum disorders: Results from a Swedish total population and discordant sibling study. Int J Epidemiol. 44(3):870-83. doi: 10.1093/ije/dyv081.

Geier DA et al. 2009. A prospective study of prenatal mercury exposure from maternal dental amalgams and autism severity. Acta Neurobiol Exp (Wars). 69(2):189-97.

Gherardi RK et al., 2001. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain. 124(Pt 9):1821-31.

Gherardi R and Authier FJ. 2012. Macrophagic myofasciitis: characterization and pathophysiology. Lupus 21(2):184–9.10.1177/0961203311429557

Gherardi RK et al., 2015. Biopersistence and brain translocation of aluminum adjuvants of vaccines. Front Neurol. 6:4. doi: 10.3389/fneur.2015.00004.

Giovanoli S et al., 2015. Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies. Brain Behav Immun. pii: S0889-1591(15)30022-2. doi: 10.1016/j.bbi.2015.09.015.

Goines P, Van de Water J. 2010. The immune system’s role in the biology of autism. Curr Opin Neurol. 23(2):111-7. PMID: 20160651

Gold M et al., 2015. β-amyloid, microglia and the inflammasome in Alzheimer’s disease. Semin Immunopathol. 37(6):607-11. doi: 10.1007/s00281-015-0518-0.

Golub MS et al., 1999. Aluminum uptake and effects on transferrin mediated iron uptake in primary cultures of rat neurons, astrocytes and oligodendrocytes. Neurotoxicology. 20:961-70.

Griffiths MR et al., 2009. The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain. J Neuropathol Exp Neurol. 68:217-26. doi: 10.1097/NEN.0b013e3181996688.

Gupta S et al., 2014. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun. 5:5748. doi: 10.1038/ncomms6748.

Hartzwell, S and S Seneff. 2012. Impaired sulfate metabolism and epigenetics: is there a link in autism? Entropy 2012:1953-1977.

Hatfield T and JL McGaugh. 1999. Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task. Neurobiol Learn Mem. 71:232-9.

Jabara HH et al., 2011. Ligation of CD46 to CD40 inhibits CD40 signaling in B cells. Int Immunol. 23(3):215-21. doi: 10.1093/intimm/dxq474.

Kang SS et al., 2014. Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring. J Neuroinflammation. 11:156. doi: 10.1186/s12974-014-0156-9.

Katz J et al., 2016. Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism. Acta Psychiatr Scand. 134(1):31-9. doi: 10.1111/acps.12579.

Krakowiak, al.,2012. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics 129, e1121–e1128. doi: 10.1542/peds.2011-2583.

Krakowiak et al., 2016. Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Res. 2016 Jun 17. doi: 10.1002/aur.1657.

Libbey JE et al. 2008. Are there enhanced MBP autoantibodies in autism? J Autism Dev Disord. 38:324-32.

Lintas C et al., 2009. Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry. 14:705-18. doi: 10.1038/mp.2008.21.

Lyons A et al., 2007. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 27: 8309–8313.

Machicado JD et al., 2013. Acute disseminated encephalomyelitis following seasonal influenza vaccination in an elderly patient. Clin Vaccine Immunol. 20(9):1485-6. doi: 10.1128/CVI.00307-13.

Madsen-Bouterse SA et al. 2010. The transcriptome of the fetal inflammatory response syndrome. Am J Reprod Immunol 63:73–92.

Martino D et al., 2015. The role of immune mechanisms in Tourette syndrome. Brain Res. 1617:126-43. doi: 10.1016/j.brainres.2014.04.027.

Matullo CM et al., 2011. CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge. PLoS Pathog. 7:e1002462. doi: 10.1371/journal.ppat.1002462.

McIntyre CK and B. Roozendaal. 2007. Adrenal Stress Hormones and Enhanced Memory for Emotionally Arousing In: Bermúdez-Rattoni F, Editor. SourceNeural Plasticity and Memory: From Genes to Brain Imaging. Boca Raton (FL): CRC Press/Taylor & Francis; Chapter 13.

Morgan JT et al., 2010. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological Psychiatry 68:368–376.

Moss, B et al., 2014. Increased risk of very low birth weight, rapid postnatal growth and autism in underweight and obese mothers. Am. J. Health Promot. 28:181–188. doi: 10.4278/ajhp.120705-QUAN-325.

Nakamura N et al., 2003 Neurologic complications associated with influenza vaccination: two adult cases. Intern Med. 42:191-4.

Ni, M et al., 2010. Methylmercury induces acute oxidative stress, altering Nrf2 protein level in primary microglial cells. Toxicol Sci. 116:590-603. doi: 10.1093/toxsci/kfq126.

Ni, L et al., 2007. Toll-like receptor ligands and CD154 stimulate microglia to produce a factor(s) that promotes excess cholinergic differentiation in the developing rat basal forebrain: implications for neurodevelopmental disorders. Pediatr Res. 61:15-20.

O’Connor TG et al., 2014. Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence. Dev Psychopathol. 26(4 Pt 2):1567-76. doi: 10.1017/S0954579414001242.

Paolicelli RC et al., 2011. Synaptic pruning by microglia is necessary for normal brain development. Science. 333(6048):1456-8. doi: 10.1126/science.1202529.

Pardo et al., 2014 Immunological disarrangements in ASD are associated with biological processes and homeostatic mechanisms in ASD rather than autoimmunity or pathogenic inflammation

Parkhurst CN et al., 2013. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596-609. doi: 10.1016/j.cell.2013.11.030.

Peixoto F, 2005. Comparative effects of the Roundup and glyphosate on mitochondrial oxidative phosphorylation. Chemosphere. 61:1115-22.

Petrik MS et al., 2007. Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. Neuromolecular Med 9:83–100.

Philippi A et al. 2005. Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism. Mol. Psychiatry 10: 950–60. doi:10.1038/ PMID 16027742.

Piras IS 2014. Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder. Brain Behav Immun. 38:91-9. doi: 10.1016/j.bbi.2013.12.020.

Ponomarev ED et al., 2006. CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation. J Immunol. 176:1402-10.

Prakash D et al., 2013. Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. Neuromolecular Med. 15(1):192-208. doi: 10.1007/s12017-012-8210-1.

Ray B et al., 2016. Finding novel distinctions between the sAPPa-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue. Sci Rep. 2016 May 23;6:26052. doi: 10.1038/srep26052.

Roberts A et al., 2013. Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’ Health Study II participants. Environ Health Perspect. 121:978-84. doi: 10.1289/ehp.1206187.

Rodriguez JI and JK. Kern. 2011. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol. 7(2-4): 205–213. doi: 10.1017/S1740925X12000142

Reynolds, L et al.,2014. Maternal obesity and increased risk for autism and developmental delay among very preterm infants. J. Perinatol. 34:688–692. doi: 10.1038/jp.2014.80.

Rodier P et al., 2011. Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders? Am J Obstet Gynecol. 204:91-4. doi: 10.1016/j.ajog.2010.11.030.

Rodriguez JI and JK Kern. 2011. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol. 7(2-4):205-13. doi: 10.1017/S1740925X12000142.

Rose S, et al., 2012. Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res Treat. 2012:986519. doi: 10.1155/2012/986519.

Rossi CC et al., 2013. Brief Report: antibodies reacting to brain tissue in Basque Spanish children with Autism Spectrum Disorder and their mothers. J Autism Dev Disord: 10.1007/s10803-013-1859-y.

Rigolet M et al., 2014. Clinical features in patients with long-lasting macrophagic myofasciitis. Front Neurol. 5:230. doi: 10.3389/fneur.2014.00230.

Sacheli A and R Bauer. 2014. Influenza vaccine-induced CNS demyelination in a 50-year-old male. Am J Case 15:368-73. doi: 10.12659/AJCR.891416.

Sanders, TR et al., 2014. Maternal obesity and IL-6 lead to aberrant developmental gene expression and deregulated neurite growth in the fetal arcuate nucleus. Endocrinology 155, 2566–2577. doi: 10.1210/en.2013-1968.

Sadasivan S et al.,2012. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One. 7(3):e33693. doi: 10.1371/journal.pone.0033693.

Sarkar S et al., 2015. Oral administration of thioflavin T prevents beta amyloid plaque formation in double transgenic AD Mice. Curr Alzheimer Res. 12(9):837-46.

Sequeira JM et al., 2013. The diagnostic utility of folate receptor autoantibodies in blood. Clin Chem Lab Med. 51(3):545-54. doi: 10.1515/cclm-2012-0577.

Seneff S et al., 2015. Aluminum and glyphosate can synergistically induce pineal gland pathology: connection to gut dysbiosis and neurological disease. Agricultural Sciences 6:42-70.

Senter PD et al., 2002. Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc Natl Acad Sci USA. 99:144-9.

Shapira I et al.,2015. Folate receptor autoantibodies in pregnancy related complications. Birth Defects Res A Clin Mol Teratol. doi: 10.1002/bdra.23436.

Shaw CA and MS Petrik. 2009. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem. 103:1555-62. doi: 10.1016/j.jinorgbio.2009.05.019.

Shoamanesh A and A Traboulsee. 2011. Acute disseminated encephalomyelitis following influenza vaccination. Vaccine. 29:8182-5. doi: 10.1016/j.vaccine.2011.08.103.

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

Singh VK et al.,2002 . Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 9:359-64.

Singh VK. 2009. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann Clin Psychiatry. 21:148-61.

Slotkin TA 2013. Terbutaline impairs the development of peripheral noradrenergic projections: potential implications for autism spectrum disorders and pharmacotherapy of preterm labor. Neurotoxicol Teratol. 36:91-6. doi: 10.1016/

Smolders S et al., 2015. Maternal immune activation evoked by polyinosinic:polycytidylic acid does not evoke microglial cell activation in the embryo. Front Cell Neurosci. 9:301. doi: 10.3389/fncel.2015.00301.

Streit WJ. 2002. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia. 40:133-9.

Sullivan EL 2014. Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol Behav. 123:236-42. doi: 10.1016/j.physbeh.2012.07.014.

Sun J et al., 2015. IL-17A is implicated in lipopolysaccharide-induced neuroinflammation and cognitive impairment in aged rats via microglial activation. J Neuroinflammation. 12:165. doi: 10.1186/s12974-015-0394-5.

Suzuki K et al., 2013. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry. 70:49-58. doi: 10.1001/jamapsychiatry.2013.272.

Tan J et al., 1999. Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis. J Neuroimmunol. 97:77-85.

Tanaka, S. et al., 2009. Activation of microglia induced learning and memory deficits. In: Transmitters and Modulators in Health and Disease. Springer.

Vargas DL et al., 2005. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 57:67-81.

Vergilio CS et al., 2015. Mercury-induced dysfunctions in multiple organelles leading to cell death. Toxicol In Vitro. 29:63-71. doi: 10.1016/j.tiv.2014.09.006.

Williamson LL 2011. Microglia and memory: modulation by early-life infection. J Neurosci. 31:15511-21. doi: 10.1523/JNEUROSCI.3688-11.2011.

Xiang AH et al., 2015. Association of maternal diabetes with autism in offspring. JAMA 313:1425-34. doi: 10.1001/jama.2015.2707.

Xie L et al., 2014. mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol. 192(12):6009-19. doi: 10.4049/jimmunol.1303492.

Yuan CY et al., 2012. Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats. J Biomed Sci. 19:51. doi: 10.1186/1423-0127-19-51.

Zeng KW et al., 2012. Aluminum maltolate induces primary rat astrocyte apoptosis via over-activation of the class III PI3K/Beclin 1-dependent autophagy signal. Toxicol In Vitro. 26:215-20. doi: 10.1016/j.tiv.2011.11.010.

Zerrate MC et al., 2007. Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism. J Pharmacol Exp Ther 322:16-2.

Zhan Y et al., 2014. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 17:400-6. doi: 10.1038/nn.3641.

Zhou R et al., 2015. Alginate-derived oligosaccharide inhibits neuroinflammation and promotes microglial phagocytosis of β-Amyloid. Mar Drugs. 13:5828-46. doi: 10.3390/md13095828.