Skip to main content

Is Autism Spectrum Disorder Related to Immune Dysfunction(s)?

  • Chapter
  • First Online:
Immuno-Psychiatry

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by impairments in communication and social interactions as well as restricted patterns of interest or behavior. On top of genetic and environmental risk factors, various immuno-inflammatory processes have been associated with ASD, at all developmental stages raising hopes of the possibility of identifying homogenous subgroups and of innovative diagnostic strategies. In order to review the potential role of immune dysfunctions in autism, we will summarize data along a developmental perspective: from specific immuno-genetic backgrounds, to peri-natal factors such as auto-antibodies and early infections, to inflammation in childhood and adult dysimmune patterns.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. 1971;1(1):33–47.

    Article  CAS  PubMed  Google Scholar 

  2. Al-Haddad BJS, Jacobsson B, Chabra S, Modzelewska D, Olson EM, Bernier R, et al. Long-term risk of neuropsychiatric disease after exposure to infection in utero. JAMA Psychiatry. 2019;76(6):594.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, et al. Family history of autoimmune diseases is associated with an increased risk of autism in children: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2015;55:322–32.

    Article  PubMed  Google Scholar 

  4. Chen S, Zhong X, Jiang L, Zheng X, Xiong Y, Ma S, et al. Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behav Brain Res. 2016;296:61–9.

    Article  PubMed  Google Scholar 

  5. Abisror N, Mekinian A, Lachassinne E, Nicaise-Roland P, De Pontual L, Chollet-Martin S, et al. Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome. Semin Arthritis Rheum. 2013;43:348–51. https://doi.org/10.1016/j.semarthrit.2013.07.001.

    Article  CAS  PubMed  Google Scholar 

  6. Brown AS, Surcel HM, Hinkka-Yli-Salomaki S, Cheslack-Postava K, Bao Y, Sourander A. Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. Prog Neuro-Psychopharmacol Biol Psychiatry. 2015;57:86–92. https://doi.org/10.1016/j.pnpbp.2014.10.010.

    Article  CAS  Google Scholar 

  7. Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, et al. Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiat. 2015;72(5):415–23.

    Article  Google Scholar 

  8. Huguet G, Benabou M, Bourgeron T. The genetics of autism spectrum disorders. In: Sassone-Corsi P, Christen Y, editors. A time for metabolism and hormones. Cham (CH): Springer; 2016.

    Google Scholar 

  9. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359(6376):693–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Torres AR, Westover JB, Rosenspire AJ. HLA immune function genes in autism. Autism Res Treat. 2012;2012:959073. https://doi.org/10.1155/2012/959073.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tamouza R, Fernell E, Eriksson MA, Anderlid B-M, Manier C, Mariaselvam CM, et al. HLA polymorphism in regressive and non-regressive autism: a preliminary study. Autism Res. 2020;13:182–6.

    Article  PubMed  Google Scholar 

  13. Guerini FR, Bolognesi E, Chiappedi M, Ghezzo A, Canevini MP, Mensi MM, et al. An HLA-G(∗)14bp insertion/deletion polymorphism associates with the development of autistic spectrum disorders. Brain Behav Immun. 2015;44:207–12.

    Article  CAS  PubMed  Google Scholar 

  14. Deykin EY, Macmahon B. Viral exposure and autism. Am J Epidemiol. 1979;109(6):628–38.

    Article  CAS  PubMed  Google Scholar 

  15. Maeyama K, Tomioka K, Nagase H, Yoshioka M, Takagi Y, Kato T, et al. Congenital cytomegalovirus infection in children with autism spectrum disorder: systematic review and meta-analysis. J Autism Dev Disord. 2018;48(5):1483–91.

    Article  PubMed  Google Scholar 

  16. Atladóttir HÓ, Henriksen TB, Schendel DE, Parner ET. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics. 2012;130(6):e1447–54.

    Article  PubMed  Google Scholar 

  17. 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;45(12):4015–25.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lee BK, Magnusson C, Gardner RM, Blomström Å, Newschaffer CJ, Burstyn I, et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain Behav Immun. 2015;44:100–5.

    Article  PubMed  Google Scholar 

  19. Jiang H, Xu L, Shao L, Xia R, Yu Z, Ling Z, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: a systematic review and meta-analysis. Brain Behav Immun. 2016;58:165–72.

    Article  PubMed  Google Scholar 

  20. Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913–47.

    Article  CAS  PubMed  Google Scholar 

  21. Meyer U, Yee BK, Feldon J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? The Neuroscientist. 2007;13(3):241–56.

    Article  CAS  PubMed  Google Scholar 

  22. Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, et al. Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol. 2003;53(4):533–7.

    Article  PubMed  Google Scholar 

  23. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, et al. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology. 2008;29(2):226–31.

    CAS  PubMed  Google Scholar 

  24. Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol. 2008;194(1–2):165–72.

    Article  CAS  PubMed  Google Scholar 

  25. Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol Psychiatry. 2013;18(11):1171–7.

    Article  CAS  PubMed  Google Scholar 

  26. Jones KL, Van de Water J. Maternal autoantibody related autism: mechanisms and pathways. Mol Psychiatry. 2019;24(2):252–65.

    Article  CAS  PubMed  Google Scholar 

  27. Heuer L, Braunschweig D, Ashwood P, Van de Water J, Campbell DB. Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Transl Psychiatry. 2011;1:e48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nordahl CW, Braunschweig D, Iosif A-M, Lee A, Rogers S, Ashwood P, et al. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav Immun. 2013;30:61–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sabourin KR, Reynolds A, Schendel D, Rosenberg S, Croen LA, Pinto-Martin JA, et al. Infections in children with autism spectrum disorder: study to explore early development (SEED): autism spectrum disorder and infection. Autism Res. 2019;12(1):136–46.

    Article  PubMed  Google Scholar 

  30. Vojtechova I, Petrasek T, Maleninska K, Brozka H, Tejkalova H, Horacek J, et al. Neonatal immune activation by lipopolysaccharide causes inadequate emotional responses to novel situations but no changes in anxiety or cognitive behavior in Wistar rats. Behav Brain Res. 2018;349:42–53.

    Article  CAS  PubMed  Google Scholar 

  31. Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel H-M. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014;19(2):259–64.

    Article  CAS  PubMed  Google Scholar 

  32. Zerbo O, Traglia M, Yoshida C, Heuer LS, Ashwood P, Delorenze GN, et al. Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study. Translational Psychiatry. 2016;6(4):e783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Koks N, Ghassabian A, Greaves-Lord K, Hofman A, Jaddoe VWV, Verhulst FC, et al. Maternal C-reactive protein concentration in early pregnancy and child autistic traits in the general population: maternal CRP and child autistic traits. Paediatric Perinatal Epidemiol. 2016;30(2):181–9.

    Article  Google Scholar 

  34. Hsiao EY. Immune dysregulation in autism spectrum disorder. Int Rev Neurobiol. 2013;113:269–302.

    Article  CAS  PubMed  Google Scholar 

  35. Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27(40):10695–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016;351(6276):933–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 2017;549(7673):528–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, Hansen R, et al. Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol Autism. 2011;2(1):13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry. 2017;22(2):273–9.

    Article  CAS  PubMed  Google Scholar 

  40. Patterson PH. Maternal infection and autism. Brain Behav Immun. 2012;26(3):393.

    Article  PubMed  Google Scholar 

  41. Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, et al. Amniotic fluid chemokines and autism spectrum disorders: an exploratory study utilizing a Danish historic birth cohort. Brain Behav Immun. 2012;26(1):170–6.

    Article  CAS  PubMed  Google Scholar 

  42. Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011;25(3):514–23.

    Article  CAS  PubMed  Google Scholar 

  43. Piras IS, Haapanen L, Napolioni V, Sacco R, Van de Water J, Persico AM. Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with autism spectrum disorder. Brain Behav Immun. 2014;38:91–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gréa H, Scheid I, Gaman A, Rogemond V, Gillet S, Honnorat J, et al. Clinical and autoimmune features of a patient with autism spectrum disorder seropositive for anti-NMDA-receptor autoantibody. Dialogues Clin Neurosci. 2017;19(1):65–70.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bennabi M, Tarantino N, Gaman A, Scheid I, Krishnamoorthy R, Debré P, et al. Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events? Mol Autism. 2019;10:22.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pramparo T, Pierce K, Lombardo MV, Carter Barnes C, Marinero S, Ahrens-Barbeau C, et al. Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiat. 2015;72(4):386.

    Article  Google Scholar 

  47. Abdallah MW, Larsen N, Mortensen EL, Atladottir HO, Norgaard- Pedersen B, Bonefeld-Jorgensen EC, et al. 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. 2012;252:75–82.

    Article  CAS  PubMed  Google Scholar 

  48. Krakowiak P, Goines PE, Tancredi DJ, et al. Neonatal cytokine profiles associated with autism spectrum disorder. Biol Psychiatry. 2017;81(5):442–51. https://doi.org/10.1016/j.biopsych.2015.08.007.

    Article  CAS  PubMed  Google Scholar 

  49. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998;16:137–61.

    Article  CAS  PubMed  Google Scholar 

  50. Gomes FC, Sousa Vde O, Romao L. Emerging roles for TGF-beta1 in nervous system development. Int J Dev Neurosci. 2005;23(5):413–24.

    Article  CAS  PubMed  Google Scholar 

  51. Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen RL, Croen LA, et al. Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol. 2008;204:149–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Grigorenko EL, Han SS, Yrigollen CM, Leng L, Mizue Y, Anderson GM, et al. Macrophage migration inhibitory factor and autism spectrum disorders. Pediatrics. 2008;122(2):e438–45.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  54. Mostafa GA, Al-Ayadhi LY. The possible link between elevated serum levels of epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children. Behav Brain Funct. 2015;11:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 2014;133(5):872–83.

    Article  PubMed  Google Scholar 

  56. Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory Interleukin-10. J Clin Immunol. 2004 Nov;24(6):664–73.

    Article  CAS  PubMed  Google Scholar 

  57. Walker SJ, Fortunato J, Gonzalez LG, Krigsman A. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013;8(3):e58058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bennabi M, Delorme R, Oliveira J, Fortier C, Lajnef M, Boukouaci W, et al. Dectin-1 polymorphism: a genetic disease specifier in autism spectrum disorders? PLoS One. 2015;10(9):e0137339.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Bennabi M, Gaman A, Delorme R, Boukouaci W, Manier C, Scheid I, et al. HLA-class II haplotypes and autism spectrum disorders. Sci Rep. 2018;8(1):7639.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Sherwin E, Bordenstein SR, Quinn JL, Dinan TG, Cryan JF. Microbiota and the social brain. Science. 2019;366(6465):eaar2016.

    Article  CAS  PubMed  Google Scholar 

  61. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20(2):145–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xu M, Xu X, Li J, Li F. Association between gut microbiota and autism spectrum disorder: a systematic review and meta-analysis. Front Psych. 2019 Jul;17:10.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lejuste, F., Tamouza, R., Leboyer, M. (2021). Is Autism Spectrum Disorder Related to Immune Dysfunction(s)?. In: Berk, M., Leboyer, M., Sommer, I.E. (eds) Immuno-Psychiatry. Springer, Cham. https://doi.org/10.1007/978-3-030-71229-7_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-71229-7_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-71228-0

  • Online ISBN: 978-3-030-71229-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics