The Interaction between the Immune System and Epigenetics in the Etiology of Autism Spectrum Disorders

Recent studies have firmly established that the etiology of autism includes both genetic and environmental components. However, we are only just beginning to elucidate the environmental factors that might be involved in the development of autism, as well as the molecular mechanisms through which they function. Mounting epidemiological and biological evidence suggest that prenatal factors that induce a more activated immune state in the mother are involved in the development of autism. In parallel, molecular studies have highlighted the role of epigenetics in brain development as a process susceptible to environmental influences and potentially causative of autism spectrum disorders (ASD). In this review, we will discuss converging evidence for a multidirectional interaction between immune system activation in the mother during pregnancy and epigenetic regulation in the brain of the fetus that may cooperate to produce an autistic phenotype. This interaction includes immune factor-induced changes in epigenetic signatures in the brain, dysregulation of epigenetic modifications specifically in genomic regions that encode immune functions, and aberrant epigenetic regulation of microglia. Overall, the interaction between immune system activation in the mother and the subsequent epigenetic dysregulation in the developing fetal brain may be a main consideration for the environmental factors that cause autism.

[1]  A. Iosif,et al.  Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring , 2014, Biological Psychiatry.

[2]  James C. Cronk,et al.  Wild type microglia arrest pathology in a mouse model of Rett syndrome , 2012, Nature.

[3]  E. Reuveni,et al.  DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways , 2014, Translational Psychiatry.

[4]  E. Eichler,et al.  Epigenetics of Autism-related Impairment: Copy Number Variation and Maternal Infection , 2015, Journal of developmental and behavioral pediatrics : JDBP.

[5]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[6]  Stepan Melnyk,et al.  Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum , 2013, Translational Psychiatry.

[7]  R. Hoffmann,et al.  Interleukin-17 A induces glucocorticoid insensitivity in human bronchial epithelial cells , 2012 .

[8]  J. V. van Meurs,et al.  DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring , 2015, International journal of epidemiology.

[9]  Michael J. Yetman,et al.  Wild-type microglia do not reverse pathology in mouse models of Rett syndrome , 2015, Nature.

[10]  Jessica L. Crisci,et al.  Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons , 2012, PLoS biology.

[11]  J. Buxbaum,et al.  Genetics and genomics of autism spectrum disorder: embracing complexity. , 2015, Human molecular genetics.

[12]  William A. Catterall,et al.  Enhancement of Inhibitory Neurotransmission by GABAA Receptors Having α2,3-Subunits Ameliorates Behavioral Deficits in a Mouse Model of Autism , 2014, Neuron.

[13]  Alan S. Brown,et al.  Maternal Immune Activation Leads to Selective Functional Deficits in Offspring Parvalbumin Interneurons , 2015, Molecular Psychiatry.

[14]  A. Feinberg,et al.  Common DNA methylation alterations in multiple brain regions in autism , 2014, Molecular Psychiatry.

[15]  Izumi Maezawa,et al.  Rett Syndrome Microglia Damage Dendrites and Synapses by the Elevated Release of Glutamate , 2010, The Journal of Neuroscience.

[16]  C. J. Machado,et al.  Maternal Immune Activation in Nonhuman Primates Alters Social Attention in Juvenile Offspring , 2015, Biological Psychiatry.

[17]  Julie C Kiefer,et al.  Epigenetics in development , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[18]  B. Trask,et al.  Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. , 2002, Genomics.

[19]  Michael C O'Donovan,et al.  Methylomic trajectories across human fetal brain development , 2015, Genome research.

[20]  M. Szyf,et al.  Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi , 2015, Translational Psychiatry.

[21]  Christopher S. Poultney,et al.  Synaptic, transcriptional, and chromatin genes disrupted in autism , 2014, Nature.

[22]  I. Pogribny,et al.  Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum , 2014, Translational Psychiatry.

[23]  I. Waldman,et al.  The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis , 2014, Molecular Psychiatry.

[24]  C. Allis,et al.  Epigenetics: A Landscape Takes Shape , 2007, Cell.

[25]  X. Zhong,et al.  Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: A systematic review and meta-analysis , 2016, Behavioural Brain Research.

[26]  S. Chess,et al.  Autism in children with congenital rubella , 1971, Journal of autism and childhood schizophrenia.

[27]  Juan I. Young,et al.  The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1 , 2012, Autism research : official journal of the International Society for Autism Research.

[28]  T. Dinan,et al.  Mind-altering Microorganisms: the Impact of the Gut Microbiota on Brain and Behaviour , 2022 .

[29]  A. Hannan,et al.  The Role of Epigenetic Change in Autism Spectrum Disorders , 2015, Front. Neurol..

[30]  R. Hoffmann,et al.  Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells , 2011, European Respiratory Journal.

[31]  J. Hutton.  Does Rubella Cause Autism: A 2015 Reappraisal? , 2016, Front. Hum. Neurosci..

[32]  C. Lintas,et al.  Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects , 2016, Journal of Neurodevelopmental Disorders.

[33]  Peter A. Jones,et al.  The Role of DNA Methylation in Mammalian Epigenetics , 2001, Science.

[34]  E. Fombonne,et al.  Increased Risk of Autism Spectrum Disorders in Children Born to Women With Systemic Lupus Erythematosus: Results From a Large Population‐Based Cohort , 2015, Arthritis & rheumatology.

[35]  Tom R. Gaunt,et al.  Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age , 2014, Environmental health perspectives.

[36]  P. Sparén,et al.  Parental Autoimmune Diseases Associated With Autism Spectrum Disorders in Offspring , 2010, Epidemiology.

[37]  C. Baker,et al.  Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. , 2016, American journal of human genetics.

[38]  M J Wright,et al.  Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population , 2015, Molecular Psychiatry.

[39]  Boris Yamrom,et al.  The contribution of de novo coding mutations to autism spectrum disorder , 2014, Nature.

[40]  W. Farrar,et al.  IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase. , 2007, Cancer genomics & proteomics.

[41]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[42]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[43]  Stephen T. C. Wong,et al.  MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription , 2008, Science.

[44]  Hein Putter,et al.  Persistent epigenetic differences associated with prenatal exposure to famine in humans , 2008, Proceedings of the National Academy of Sciences.

[45]  A. Pillai,et al.  Ubiquitin-proteasome dependent degradation of GABAAα1 in autism spectrum disorder , 2014, Molecular Autism.

[46]  S. Chess.  Follow-up report on autism in congenital rubella , 1977, Journal of autism and childhood schizophrenia.

[47]  Kenji Mori,et al.  Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument , 2011, Journal of autism and developmental disorders.

[48]  C. Zang,et al.  Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. , 2010, Immunity.

[49]  H. Peeters,et al.  DISC1 duplication in two brothers with autism and mild mental retardation , 2010, Clinical genetics.

[50]  J. Davie.  Inhibition of histone deacetylase activity by butyrate. , 2003, The Journal of nutrition.

[51]  A. Sawa,et al.  A Review of Disrupted-in-Schizophrenia-1 (disc1): Neurodevelopment, Cognition, and Mental Conditions , 2006, Biological Psychiatry.

[52]  Erik T Parner,et al.  Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders , 2010, Journal of autism and developmental disorders.

[53]  A. Sawa,et al.  Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood , 2010, Behavioural Brain Research.

[54]  G. Dussor,et al.  Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity , 2014, Molecular pain.

[55]  P. Sham,et al.  Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain , 2014, Translational Psychiatry.

[56]  M. Szyf,et al.  DNA methylation mediates the effect of maternal cognitive appraisal of a disaster in pregnancy on the child’s C-peptide secretion in adolescence: Project Ice Storm , 2018, PloS one.

[57]  D. Dunger,et al.  Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  B. Aleksic,et al.  Copy‐number variation in the pathogenesis of autism spectrum disorder , 2014, Psychiatry and clinical neurosciences.

[59]  A. Guidotti,et al.  Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex , 2015, Epigenetics.

[60]  J. LaSalle.  Licensee Oa Publishing London 2013. Creative Commons Attribution License (cc-by) , 2022 .

[61]  S. Horvath,et al.  Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology , 2011, Nature.

[62]  K. Mirnics,et al.  Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6 , 2007, The Journal of Neuroscience.

[63]  J. Gordon,et al.  Human nutrition, the gut microbiome and the immune system , 2011, Nature.

[64]  Andreas M. Grabrucker,et al.  Environmental Factors in Autism , 2013, Front. Psychiatry.

[65]  Dai Zhang,et al.  Evidence for association between Disrupted-in-schizophrenia 1 (DISC1) gene polymorphisms and autism in Chinese Han population: a family-based association study , 2011, Behavioral and Brain Functions.

[66]  Ryan J Kast,et al.  Epigenetic changes at gene promoters in response to immune activation in utero , 2013, Brain, Behavior, and Immunity.

[67]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[68]  W. Byrd,et al.  Transfer of Inflammatory Cytokines Across the Placenta , 2004, Obstetrics and gynecology.

[69]  Jay Shendure,et al.  Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development , 2014, Cell.

[70]  P. Patterson,et al.  Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism , 2012, Brain, Behavior, and Immunity.

[71]  Michel Botbol,et al.  Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms , 2014, Front. Psychiatry.

[72]  Sarah E. Reese,et al.  Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns , 2016, Nature Communications.

[73]  Louise V Wain,et al.  Copy number variation. , 2011, Methods in molecular biology.

[74]  R. Jirtle,et al.  Environmental epigenomics and disease susceptibility , 2007, Nature Reviews Genetics.

[75]  Shannon E. Ellis,et al.  Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism , 2014, Nature Communications.

[76]  P. Mortensen,et al.  Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders , 2009, Pediatrics.

[77]  Hyunju Kim,et al.  The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring , 2016, Science.

[78]  Flora Tassone,et al.  Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. , 2012, The American journal of clinical nutrition.

[79]  Tom R. Gaunt,et al.  The Avon Longitudinal Study of Parents and Children (ALSPAC): an update on the enrolled sample of index children in 2019 , 2019, Wellcome open research.

[80]  Jakob Grove,et al.  Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population , 2015, Nature Genetics.

[81]  Per Magnus,et al.  Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. , 2013, JAMA.

[82]  Igor Burstyn,et al.  Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders , 2015, Brain, Behavior, and Immunity.

[83]  A. Ting,et al.  Brain Transcriptional and Epigenetic Associations with Autism , 2012, PloS one.

[84]  Cathleen K. Yoshida,et al.  Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. , 2005, Archives of pediatrics & adolescent medicine.

[85]  E. Elliott,et al.  Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model , 2016, Neuropharmacology.

[86]  P. Heinrich,et al.  Principles of interleukin (IL)-6-type cytokine signalling and its regulation. , 2003, The Biochemical journal.

[87]  Yi-Ju Li,et al.  Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. , 2014, Human molecular genetics.

[88]  Yi-Ju Li,et al.  Epigenetic dysregulation of SHANK 3 in brain tissues from individuals with autism spectrum disorders , 2014 .

[89]  Izumi Maezawa,et al.  CX3CR1 ablation ameliorates motor and respiratory dysfunctions and improves survival of a Rett syndrome mouse model , 2017, Brain, Behavior, and Immunity.

[90]  J. LaSalle,et al.  The landscape of DNA methylation amid a perfect storm of autism aetiologies , 2016, Nature Reviews Neuroscience.

[91]  Jing Shang,et al.  Interleukin-18 directly protects cortical neurons by activating PI3K/AKT/NF-κB/CREB pathways. , 2014, Cytokine.

[92]  Kathryn Roeder,et al.  Most genetic risk for autism resides with common variation , 2014, Nature Genetics.

[93]  Marco Gobbetti,et al.  Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified , 2013, PloS one.

[94]  G. Hitman,et al.  Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring. , 2015, Human molecular genetics.

[95]  C. Connor,et al.  Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome , 2012, Schizophrenia Research.