Vol. 1 No. 1 (2024): International Journal for Autism Challenges & Solution
Articles

Maternal Immune Activation and Autism Spectrum Disorder: Complex Interactions and Therapeutic Possibilities

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  • Geir Bjørklund,
  • Ramesa Shafi Bhat,
  • Afaf El-Ansary

Published 2024-04-19

Keywords

  • Autism,
  • Maternal immune activation,
  • neurodevelopment,
  • cytokine dysregulation,
  • genetic susceptibility,
  • epigenetics
    • ...More
    Less

How to Cite

Maternal Immune Activation and Autism Spectrum Disorder: Complex Interactions and Therapeutic Possibilities. (2024). International Journal for Autism Challenges & Solution, 1(1), 39-50. https://doi.org/10.54878/bgxvwf58

Abstract

This review examines the intricate association between maternal immune activation (MIA) and autism spectrum disorder (ASD), emphasizing the impact of maternal infections during pregnancy. Epidemiological studies link viral and bacterial infections to an elevated risk of ASD, revealing the complex interplay between environmental factors and neurodevelopmental outcomes. Immunological mechanisms, including cytokine dysregulation and neuroinflammation, involve key players such as interleukin-6 and tumor necrosis factor-alpha, influencing fetal brain development and ASD risk. Genetic and environmental interactions contribute to individual susceptibility, with specific variants influencing MIA's impact on ASD risk. Epigenetic modifications provide a molecular link between environmental exposures, including MIA, and enduring neurodevelopmental changes. Recognizing critical periods during fetal neurodevelopment susceptible to MIA is crucial. Long-term studies highlight enduring consequences on behavior and cognition into childhood and adolescence. Exploring potential therapeutic interventions, including immunomodulatory strategies during pregnancy, offers hope for mitigating MIA's impact on ASD outcomes. Despite progress, knowledge gaps persist, motivating future research guided by emerging technologies and interdisciplinary approaches to unravel the intricate MIA-ASD relationship.

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References

  1. American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text rev.). American Psychiatric Publishing.
  2. Karimi P, Kamali E, Mousavi SM, Karahmadi M. Environmental factors influencing the risk of autism. J Res Med Sci. 2017 Feb 16;22:27. doi: 10.4103/1735-1995.200272.
  3. Thabault, M.; Turpin, V.; Maisterrena, A.; Jaber, M.; Egloff, M.; Galvan, L. Cerebellar and Striatal Implications in Autism Spectrum Disorders: From Clinical Observations to Animal Models. Int. J. Mol. Sci. 2022, 23, 2294. https://doi.org/10.3390/ijms23042294
  4. Damiano CR, Mazefsky CA, White SW, Dichter GS. Future directions for research in autism spectrum disorders. J Clin Child Adolesc Psychol. 2014;43(5):828-43. doi: 10.1080/15374416.2014.945214
  5. Han, V. X., Patel, S., Jones, H. F. & Dale, R. C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol.2021. 17, 564–579
  6. Ellul, P., Maruani, A., Vantalon, V. Humeau E, Amestoy A, Anchordoqui A, et al. Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder. Sci Rep 13, 17687 (2023). https://doi.org/10.1038/s41598-023- 45060-z.
  7. Zawadzka A, Cieślik M, Adamczyk A. The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment. Int J Mol Sci. 2021 Oct 26;22(21):11516. doi: 10.3390/ijms222111516
  8. Sotgiu S, Manca S, Gagliano A, Minutolo A, Melis MC, Pisuttu G, Scoppola C, Bolognesi E, Clerici M, Guerini FR, Carta A. Immune regulation of neurodevelopment at the mother- foetus interface: the case of autism. Clin Transl Immunology. 2020 Nov 13;9(11):e1211. doi: 10.1002/cti2.1211
  9. Girault JB, Piven J. The Neurodevelopment of Autism from Infancy Through Toddlerhood. Neuroimaging Clin N Am. 2020 Feb;30(1):97- 114. doi: 10.1016/j.nic.2019.09.009.
  10. Weir E., Allison C., Baron-Cohen S. Autistic adults have poorer quality healthcare and worse health based on self-report data. Mol. Autism. 2022;13:23. doi: 10.1186/s13229-022-00501-
  11. Pan YH, Wu N, Yuan XB. Toward a Better Understanding of Neuronal Migration Deficits in Autism Spectrum Disorders. Front Cell Dev Biol. 2019 Sep 20;7:205. doi: 10.3389/fcell.2019.00205.
  12. Wolff JJ, Jacob S, Elison JT. The journey to autism: Insights from neuroimaging studies of infants and toddlers. Dev Psychopathol. 2018 May;30(2):479-495. doi: 10.1017/S0954579417000980.
  13. Yang G, Shcheglovitov A. Probing disrupted neurodevelopment in autism using human stem cell-derived neurons and organoids: An outlook into future diagnostics and drug development. Dev Dyn. 2020 Jan;249(1):6-33. doi: 10.1002/dvdy.100.
  14. Marotta R, Risoleo MC, Messina G, Parisi L, Carotenuto M, Vetri L, Roccella M. The Neurochemistry of Autism. Brain Sci. 2020 Mar 13;10(3):163. doi: 10.3390/brainsci10030163.
  15. Hernandez LM, Rudie JD, Green SA, Bookheimer S, Dapretto M. Neural signatures of autism spectrum disorders: insights into brain network dynamics. Neuropsychopharmacology. 2015 Jan;40(1):171-89. doi: 10.1038/npp.2014.172. Epub 2014 Jul 11. PMID: 25011468; PMCID: PMC4262896.
  16. Estes ML, McAllister AK. Maternal immune activation: Implications for neuropsychiatric disorders. Science. 2016 Aug 19;353(6301):772- 7. doi: 10.1126/science.aag3194.
  17. Dutta S., Sengupta P. Defining pregnancy phases with cytokine shift. J. Pregnancy Reprod. 2017;1:1–3. doi: 10.15761/JPR.1000124.
  18. Yang F., Zheng Q., Jin L. Dynamic Function and Composition Changes of Immune Cells During Normal and Pathological Pregnancy at the Maternal-Fetal Interface. Front. Immunol. 2019;10:2317. doi: 10.3389/fimmu.2019.02317.
  19. Ochoa-Bernal M.A., Fazleabas A.T. Physiologic Events of Embryo Implantation and Decidualization in Human and Non-Human Primates. Int. J. Mol. Sci. 2020;21:1973. doi: 10.3390/ijms21061973.
  20. Yockey L.J., Iwasaki A. Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development. Immunity. 2018;49:397–412. doi: 10.1016/j.immuni.2018.07.017.
  21. Equils O., Kellogg C., McGregor J., Gravett M., Neal-Perry G., Gabay C. The role of the IL-1 system in pregnancy and the use of IL-1 system markers to identify women at risk for pregnancy complications. Biol. Reprod. 2020;103:684–694. doi: 10.1093/biolre/ioaa102.
  22. Zhao B., Schwartz J.P. Involvement of cytokines in normal CNS development and neurological diseases: Recent progress and perspectives. J. Neurosci. Res. 1998;52:7–16.
  23. Parker-Athill E.C., Tan J. Maternal immune activation and autism spectrum disorder: Interleukin-6 signaling as a key mechanistic pathway. Neuro-Signals. 2010;18:113–128. doi: 10.1159/000319828.
  24. Phillips NLH, Roth TL. Animal Models and Their Contribution to Our Understanding of the Relationship Between Environments, Epigenetic Modifications, and Behavior. Genes (Basel). 2019 Jan 15;10(1):47. doi: 10.3390/genes10010047. PMID: 30650619; PMCID: PMC6357183.
  25. Hussain T, Murtaza G, Kalhoro DH, Kalhoro MS, Yin Y, Chughtai MI, Tan B, Yaseen A, Rehman ZU. Understanding the Immune System in Fetal Protection and Maternal Infections during Pregnancy. J Immunol Res. 2022 Jun 24;2022:7567708. doi: 10.1155/2022/7567708.
  26. Huang N, Chi H, Qiao J. Role of Regulatory T Cells in Regulating Fetal-Maternal Immune Tolerance in Healthy Pregnancies and Reproductive Diseases. Front Immunol. 2020 Jun 26;11:1023. doi: 10.3389/fimmu.2020.01023.
  27. Woods RM, Lorusso JM, Fletcher J, ElTaher H, McEwan F, Harris I, Kowash HM, D'Souza SW, Harte M, Hager R, Glazier JD. Maternal immuneactivation and role of placenta in the prenatal programming of neurodevelopmental disorders. Neuronal Signal. 2023 May 31;7(2):NS20220064. doi: 10.1042/NS20220064.
  28. Oyesola OO, Souza COS, Loke P. The Influence of Genetic and Environmental Factors and Their Interactions on Immune Response to Helminth Infections. Front Immunol. 2022 Apr 29;13:869163. doi: 10.3389/fimmu.2022.869163.
  29. Lu-Culligan A, Iwasaki A. The Role of Immune Factors in Shaping Fetal Neurodevelopment. Annu Rev Cell Dev Biol. 2020 Oct 6;36:441-468. doi: 10.1146/annurev-cellbio-021120-033518.
  30. Li Z, Zhu YX, Gu LJ, Cheng Y. Understanding autism spectrum disorders with animal models: applications, insights, and perspectives. Zool Res. 2021 Nov 18;42(6):800-824. doi: 10.24272/j.issn.2095-8137.2021.251.
  31. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, et al Maternal antibrain antibodies in autism. Brain, Behavior, and Immunity. 2007;21(3):351–357. doi: 10.1016/j.bbi.2006.08.005
  32. Haddad FL, Patel SV, Schmid S Maternal immune activation by Poly I: C as a preclinical model for neurodevelopmental disorders: a focus on autism and schizophrenia. Neuroscience & Biobehavioral Reviews. 2020;113:546–567
  33. Elsworth JD, Jentsch JD, VandeVoort CA, Roth RH, Redmond DE Jr, Leranth C Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non- human primates. NeuroToxicology. 2013;35:113– 120. doi: 10.1016/j.neuro.2013.01.001
  34. Jiang HY, Xu LL, Shao L, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain Behav Immun. 2016;58:165-172. doi:10.1016/j.bbi.2016.06.005
  35. Shuid, A.N.; Jayusman, P.A.; Shuid, N.; Ismail, J.; Kamal Nor, N.; Mohamed, I.N. Association between Viral Infections and Risk of Autistic Disorder: An Overview. Int. J. Environ. Res. Public Health 2021, 18, 2817. https://doi.org/10.3390/ijerph18062817
  36. Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, Croen LA. Maternal Infection During Pregnancy and Autism Spectrum Disorders. J Autism Dev Disord. 2015 Dec;45(12):4015-25. doi: 10.1007/s10803-013-2016-3. PMID: 24366406; PMCID: PMC4108569.
  37. aminski VL, Michita RT, Ellwanger JH, Veit TD, Schuch JB, Riesgo RDS, Roman T, Chies JAB. Exploring potential impacts of pregnancy- related maternal immune activation and extracellular vesicles on immune alterations observed in autism spectrum disorder. Heliyon. 2023 Apr 29;9(5):e15593. doi: 10.1016/j.heliyon.2023.e15593..
  38. Hall MB, Willis DE, Rodriguez EL, Schwarz JM. Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: Considerations of timing, severity, individual differences, and sex in human and rodent studies. Front Neurosci. 2023 Apr 13;17:1135559. doi: 10.3389/fnins.2023.1135559. PMID: 37123361; PMCID: PMC10133487.
  39. Brown AS and Derkits EJ.Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 2010 167, 261–280. 10.1176/appi.ajp.2009.09030361
  40. Zerbo O. et al. Month of conception and risk of autism. Epidemiology 2011 22, 469– 47.1097/EDE.0b013e31821d0b53
  41. Lee BK et al. Maternal hospitalization with infection during pregnancy and risk of autismspectrum disorders. Brain Behav Immun 2015 44, 100–105. 10.1016/j.bbi.2014.09.001
  42. Robinson-Agramonte MLA, Noris García E, Fraga Guerra J, Vega Hurtado Y, Antonucci N, Semprún-Hernández N, Schultz S, Siniscalco D. Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It? Int J Mol Sci. 2022 Mar 11;23(6):3033. doi: 10.3390/ijms23063033. PMID: 35328471; PMCID: PMC8955336.
  43. Lipkin WI, Bresnahan M, Susser E. Cohort- guided insights into gene-environment interactions in autism spectrum disorders. Nat Rev Neurol. 2023 Feb;19(2):118-125. doi: 10.1038/s41582-022-00764-0. Epub 2023 Jan 16. PMID: 36646930; PMCID: PMC9841497.
  44. Patel S, Dale RC, Rose D, Heath B, Nordahl CW, Rogers S, Guastella AJ, Ashwood P. Maternal immune conditions are increased in males with autism spectrum disorders and are associated with behavioural and emotional but not cognitive co- morbidity. Transl Psychiatry. 2020 Aug 14;10(1):286. doi: 10.1038/s41398-020-00976-2.
  45. Chaste P, Leboyer M. Autism risk factors: genes, environment, and gene-environment interactions Dialogues Clin Neurosci. 2012 Sep;14(3):281-92. doi: 10.31887/DCNS.2012.14.3/pchaste
  46. Abu-Raya B, Michalski C, Sadarangani M, Lavoie PM. Maternal Immunological Adaptation During Normal Pregnancy. Front Immunol. 2020 Oct 7;11:575197. doi: 10.3389/fimmu.2020.575197.
  47. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011 Mar;1221(1):80-7. doi: 10.1111/j.1749-6632.2010.05938.x.
  48. Estes ML, McAllister AK. Maternal immune activation: Implications for neuropsychiatric disorders. Science. 2016 Aug 19;353(6301):772- 7. doi: 10.1126/science.aag3194. PMID: 27540164; PMCID: PMC5650490.
  49. Knuesel I, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nature reviews Neurology. 2014;10:643–660. [PubMed] [Google Scholar]
  50. Reisinger S, et al. The poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery. Pharmacol Ther. 2015;149:213–226. [PubMed] [Google Scholar]
  51. Selten JP, Frissen A, Lensvelt-Mulders G, Morgan VA. Schizophrenia and 1957 pandemic of influenza: meta-analysis. Schizophr Bull. 2010;36:219–228. [PMC free article] [PubMed] [Google Scholar]
  52. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nature reviews Neuroscience. 2015;16:469–486. [PMC free article] [PubMed] [Google Scholar]
  53. Blomstrom A, et al. Associations Between Maternal Infection During Pregnancy, Childhood Infections, and the Risk of Subsequent Psychotic Disorder--A Swedish Cohort Study of Nearly 2 Million Individuals. Schizophr Bull. 2016; 42:125–133.
  54. Zawadzka A, Cieślik M, Adamczyk A. The role of maternal immune activation in the pathogenesis of autism: a review of the evidence, proposed mechanisms and implications for treatment. Int J Mol Sci. (2021) 22:1516. 10.3390/ijms222111516
  55. Saghazadeh A, Ataeinia B, Keynejad K, Abdolalizadeh A, Hirbod-Mobarakeh A, Rezaei N, et al.. meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: Effects of age, gender, and latitude. J Psychiatr Res. (2019) 115:90–102. 10.1016/j.jpsychires.2019.05.019
  56. Koo JW, Wohleb ES. How stress shapes neuroimmune function: implications for the neurobiology of psychiatric disorders. Biol Psychiatry. (2021) 90:74–84. 10.1016/j.biopsych.2020.11.007
  57. Heuer LS, Croen LA, Jones KL, Yoshida CK, Hansen RL, Yolken R, et al.. An Exploratory Examination of neonatal cytokines and chemokines as predictors of autism risk: the early markers for autism study. Biol Psychiatry. (2019) 86:255–64. 10.1016/j.biopsych.2019.04.037
  58. Zhang, W., Xiao, D., Mao, Q. et al. Role of neuroinflammation in neurodegeneration development. Sig Transduct Target Ther 8, 267 (2023). https://doi.org/10.1038/s41392-023- 01486-5
  59. Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, Bonnot O, Weismann- Arcache C, Botbol M, Lauth B, Ginchat V, Roubertoux P, Barburoth M, Kovess V, Geoffray MM, Xavier J. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014 Aug 4;5:53. doi: 10.3389/fpsyt.2014.00053
  60. Rylaarsdam L, Guemez-Gamboa A. Genetic Causes and Modifiers of Autism Spectrum Disorder. Front Cell Neurosci. 2019 Aug 20;13:385. doi: 10.3389/fncel.2019.00385.
  61. Cheroni, C., Caporale, N. & Testa, G. Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology. Molecular Autism 11, 69 (2020). https://doi.org/10.1186/s13229-020- 00370-1
  62. Strathearn L, Momany A, Kovács EH, Guiler W, Ladd-Acosta C. The intersection of genome, epigenome and social experience in autism spectrum disorder: Exploring modifiable pathways for intervention. Neurobiol Learn Mem. 2023;202:107761. doi:10.1016/j.nlm.2023.107761
  63. Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N. Epigenetic findings in autism: new perspectives for therapy. Int J Environ Res Public Health. 2013 Sep 11;10(9):4261-73. doi: 10.3390/ijerph10094261.
  64. Bergdolt L, Dunaevsky A. Brain changes in a maternal immune activation model of neurodevelopmental brain disorders. Prog Neurobiol. 2019 Apr;175:1-19. doi: 10.1016/j.pneurobio.2018.12.002.
  65. Conway F, Brown AS. Maternal Immune Activation and Related Factors in the Risk of Offspring Psychiatric Disorders. Front Psychiatry. 2019 Jun 28;10:430. doi: 10.3389/fpsyt.2019.00430.
  66. Mattei D., Schweibold R. and Wolf S.A. Brain in flames - animal models of psychosis: utility and limitations. Neuropsychiatr. Dis. Treat. 2015 11, 1313–1329 10.2147/NDT.S65564
  67. Meyer U., Feldon J. and Yee B.K. A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr. Bull. 2009 35, 959–972 10.1093/schbul/sbn022]
  68. Rapoport J.C., Addington A.M. and Frangou S. The neurodevelopmental model of schizophrenia: update 2005. Mol. Psychiatry2005 10, 434–449 10.1038/sj.mp.4001642
  69. Ming, G.; Song, H. Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions. Neuron 2011, 70, 687–702
  70. Marzola, P.; Melzer, T.; Pavesi, E.; Gil-Mohapel, J.; Brocardo, P.S. Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration. Brain Sci. 2023, 13, 1610. https://doi.org/10.3390/brainsci13121610
  71. Leibovitz Z, Lerman-Sagie T, Haddad L. Fetal Brain Development: Regulating Processes and Related Malformations. Life (Basel). 2022 May 29;12(6):809. doi: 10.3390/life12060809.
  72. Gundacker A, Cuenca Rico L, Stoehrmann P, Tillmann KE, Weber-Stadlbauer U, Pollak DD. Interaction of the pre- and postnatal environment in the maternal immune activation model. Discov Ment Health. 2023;3(1):15. doi: 10.1007/s44192- 023-00042-5.
  73. Paulus FW, Ohmann S, Möhler E, Plener P, Popow C. Emotional Dysregulation in Children and Adolescents With Psychiatric Disorders. A Narrative Review. Front Psychiatry. 2021 Oct 25;12:628252. doi: 10.3389/fpsyt.2021.628252.
  74. Bucknor MC, Gururajan A, Dale RC, Hofer MJ. A comprehensive approach to modeling maternal immune activation in rodents. Front Neurosci. 2022 Dec 16;16:1071976. doi: 10.3389/fnins.2022.1071976. PMID: 36590294; PMCID: PMC9800799.
  75. Beversdorf DQ, Anagnostou E, Hardan A, Wang P, Erickson CA, Frazier TW, Veenstra- VanderWeele J. Editorial: Precision medicine approaches for heterogeneous conditions such as autism spectrum disorders (The need for a biomarker exploration phase in clinical trials - Phase 2m). Front Psychiatry. 2023 Jan 19;13:1079006. doi: 10.3389/fpsyt.2022.1079006.
  76. Grezenko H, Ekhator C, Nwabugwu NU, Ganga H, Affaf M, Abdelaziz AM, Rehman A, Shehryar A, Abbasi FA, Bellegarde SB, Khaliq AS. Epigenetics in Neurological and Psychiatric Disorders: A Comprehensive Review of Current Understanding and Future Perspectives. Cureus. 2023 Aug 23;15(8):e43960. doi: 10.7759/cureus.43960.
  77. Subramanian M, Wojtusciszyn A, Favre L, Boughorbel S, Shan J, Letaief KB, Pitteloud N, Chouchane L. Precision medicine in the era of artificial intelligence: implications in chronic disease management. J Transl Med. 2020 Dec 9;18(1):472. doi: 10.1186/s12967-020-02658-5.
  78. Johnson KB, Wei WQ, Weeraratne D, Frisse ME, Misulis K, Rhee K, Zhao J, Snowdon JL. Precision Medicine, AI, and the Future of Personalized Health Care. Clin Transl Sci. 2021 Jan;14(1):86-93. doi: 10.1111/cts.12884.