Advertisement

Molecular Neurobiology

, Volume 56, Issue 7, pp 5000–5008 | Cite as

Maternal Gestational Immune Response and Autism Spectrum Disorder Phenotypes at 7 Years of Age in the Seychelles Child Development Study

  • Jessica L. Irwin
  • Alison J. Yeates
  • Maria S. Mulhern
  • Emeir M. McSorley
  • J. J. Strain
  • Gene E. Watson
  • Katherine Grzesik
  • Sally W. Thurston
  • Tanzy M. Love
  • Tristram H. Smith
  • Daniel W. Mruzek
  • Conrad F. Shamlaye
  • Catriona Monthy
  • Gary J. Myers
  • Philip W. Davidson
  • Edwin van WijngaardenEmail author
Article

Abstract

Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers’ serum at 28 weeks’ gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7 years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to pro-inflammatory cytokines) was associated with fewer ASD symptoms (B = − 0.40; 95% CI = − 0.72, − 0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = − 0.18; 95% CI = − 0.35, − 0.01), but only after removal of outliers. No associations were observed for other markers. These findings suggest that a shift in the maternal immune balance during pregnancy may be associated with ASD symptomatology. While the use of well-established measures that capture ASD phenotypic variability is a strength of the study, measurement of peripheral immune markers only once during gestation is a limitation. Our results should be confirmed using maternal immune markers measured throughout gestation.

Keywords

Pregnancy Immune response Inflammation Autism Spectrum disorder Cytokines Chemokines 

Notes

Acknowledgements

We acknowledge with thanks the contribution of the nursing and laboratory teams in Seychelles. The study sponsors had no role in the design, collection, analysis, or interpretation of the data; in the writing of the report; or in the decision to submit the article for publication.

Funding information

This research was supported by grants R01-ES010219, P30-ES01247, R03-ES027514, T32-ES007271, and T32-ES007026 from the US National Institute of Environmental Health Sciences (National Institutes of Health) and in-kind by the Government of the Republic of Seychelles.

Compliance with ethical standards

The study was reviewed and approved by the Seychelles Ethics Board and the Research Subjects Review Board at the University of Rochester.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed). American Psychiatric Association, Arlington, VAGoogle Scholar
  2. 2.
    Baio J, Wiggins LD, Christensen DL, Maenner MJ, Daniels J, Warren Z, Kurzius-Spencer M, Zahorodny W et al (2018) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. Morb Mortal Wkly Rep Surveill Summ 67:1–23.  https://doi.org/10.15585/mmwr.ss6706a1 CrossRefGoogle Scholar
  3. 3.
    Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, Park BY, Snyder NW et al (2017) The changing epidemiology of autism spectrum disorders. Annu Rev Public Health 38:81–102.  https://doi.org/10.1146/annurev-publhealth-031816-044318 CrossRefPubMedGoogle Scholar
  4. 4.
    Gladysz D, Krzywdzińska A, Hozyasz KK (2018) Immune abnormalities in autism spectrum disorder—could they hold promise for causative treatment? Mol Neurobiol 55:1–49.  https://doi.org/10.1007/s12035-017-0822-x CrossRefGoogle Scholar
  5. 5.
    Aghaeepour N, Ganio EA, Mcilwain D, Tsai AS, Tingle M, van Gassen S, Gaudilliere DK, Baca Q et al (2017) An immune clock of human pregnancy. Sci Immunol 2:eaan2946.  https://doi.org/10.1126/sciimmunol.aan2946 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mosmann TR, Coffman RL (1989) ThI and Th2 CELLS: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immuno 7:145–173CrossRefGoogle Scholar
  7. 7.
    Saito S, Sakai M, Sasaki Y, Tanebe K, Tsuda H, Michimata T (1999) Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia. Clin Exp Immunol 117:550–555.  https://doi.org/10.1046/j.1365-2249.1999.00997.x CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sargent IL, Borzychowski AM, Redman CWG (2006) NK cells and human pregnancy—an inflammatory view. Trends Immunol 27:399–404.  https://doi.org/10.1016/j.it.2006.06.009 CrossRefPubMedGoogle Scholar
  9. 9.
    Wegmann TG, Lin H, Guilbert L, Mosmann TR (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14:353–356.  https://doi.org/10.1016/0167-5699(93)90235-D CrossRefPubMedGoogle Scholar
  10. 10.
    Mor G, Cardenas I, Abrahams V, Guller S (2011) Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 1221:80–87.  https://doi.org/10.1111/j.1749-6632.2010.05938.x CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Estes ML, McAllister AK (2016) Maternal immune activation: implications for neuropsychiatric disorders. Science (80- 353:772 LP–772777.  https://doi.org/10.1126/science.aag3194 CrossRefGoogle Scholar
  12. 12.
    Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, Toovey S, Prinssen EP (2014) Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 10:643–660.  https://doi.org/10.1038/nrneurol.2014.187 CrossRefPubMedGoogle Scholar
  13. 13.
    Racicot K, Kwon JY, Aldo P, Silasi M, Mor G (2014) Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol 72:107–116.  https://doi.org/10.1111/aji.12289 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bilbo SD, Block CL, Bolton JL, Hanamsagar R, Tran PK (2018) Beyond infection—maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Exp Neurol 299:241–251CrossRefGoogle Scholar
  15. 15.
    Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET (2010) Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord 40:1423–1430.  https://doi.org/10.1007/s10803-010-1006-y CrossRefPubMedGoogle Scholar
  16. 16.
    Zerbo O, Qian Y, Yoshida C, Grether JK, van de Water J, Croen LA (2015) Maternal infection during pregnancy and autism spectrum disorders. J Autism Dev Disord 45:4015–4025.  https://doi.org/10.1007/s10803-013-2016-3 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Patel S, Masi A, Dale RC, Whitehouse AJO, Pokorski I, Alvares GA, Hickie IB, Breen E et al (2017) Social impairments in autism spectrum disorder are related to maternal immune history profile. Mol Psychiatry 23:1794–1797.  https://doi.org/10.1038/mp.2017.201 CrossRefPubMedGoogle Scholar
  18. 18.
    Pardo CA, Meffert MK (2018) Animal models in autism research: the legacy of Paul H. Patterson Exp Neurol 299:197–198CrossRefGoogle Scholar
  19. 19.
    Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702.  https://doi.org/10.1523/JNEUROSCI.2178-07.2007 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH (2012) Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun 26:607–616.  https://doi.org/10.1016/j.bbi.2012.01.011 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel HM (2014) Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry 19:259–264.  https://doi.org/10.1038/mp.2012.197 CrossRefPubMedGoogle Scholar
  22. 22.
    Zerbo O, Traglia M, Yoshida C, Heuer LS, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M et al (2016) Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study. Transl Psychiatry 6:e783.  https://doi.org/10.1038/tp.2016.46 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, Hansen R, Kharrazi M, Ashwood P et al (2011) Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol Autism 2:13.  https://doi.org/10.1186/2040-2392-2-13 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, DeLorenze GN, Kharrazi M et al (2017) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry 22:273–279.  https://doi.org/10.1038/mp.2016.77 CrossRefPubMedGoogle Scholar
  25. 25.
    Abdallah MW, Larsen N, Mortensen EL, Atladóttir HÓ, Nørgaard-Pedersen B, Bonefeld-Jørgensen EC, Grove J, Hougaard DM (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 252:75–82.  https://doi.org/10.1016/j.jneuroim.2012.07.013 CrossRefPubMedGoogle Scholar
  26. 26.
    Abdallah MW, Larsen N, Grove J, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL (2013) Neonatal chemokine levels and risk of autism spectrum disorders: findings from a Danish historic birth cohort follow-up study. Cytokine 61:370–376.  https://doi.org/10.1016/j.cyto.2012.11.015 CrossRefPubMedGoogle Scholar
  27. 27.
    Abdallah MW, Mortensen EL, Greaves-Lord K, Larsen N, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, Hougaard DM, Grove J (2013) Neonatal levels of neurotrophic factors and risk of autism spectrum disorders. Acta Psychiatr Scand 128:61–69.  https://doi.org/10.1111/acps.12020 CrossRefPubMedGoogle Scholar
  28. 28.
    Krakowiak P, Goines PE, Tancredi DJ, Ashwood P, Hansen RL, Hertz-Picciotto I, van de Water J (2017) Neonatal cytokine profiles associated with autism spectrum disorder. Biol Psychiatry 81:442–451.  https://doi.org/10.1016/j.biopsych.2015.08.007 CrossRefPubMedGoogle Scholar
  29. 29.
    Zerbo O, Yoshida C, Grether JK, van de Water J, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M et al (2014) Neonatal cytokines and chemokines and risk of autism spectrum disorder: the early markers for autism (EMA) study: a case-control study. J Neuroinflammation 11:1–9.  https://doi.org/10.1186/1742-2094-11-113 CrossRefGoogle Scholar
  30. 30.
    Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM (2013) Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders. World J Biol Psychiatry 14:528–538.  https://doi.org/10.3109/15622975.2011.639803 CrossRefPubMedGoogle Scholar
  31. 31.
    Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM (2012) Amniotic fluid chemokines and autism spectrum disorders: an exploratory study utilizing a Danish historic birth cohort. Brain Behav Immun 26:170–176.  https://doi.org/10.1016/j.bbi.2011.09.003 CrossRefPubMedGoogle Scholar
  32. 32.
    Strain JJ, Yeates AJ, van Wijngaarden E, Thurston SW, Mulhern MS, McSorley EM, Watson GE, Love TM et al (2015) Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles. Am J Clin Nutr 101:530–537.  https://doi.org/10.3945/ajcn.114.100503 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Constantino JN, Gruber CP (2005) Social responsiveness scale (SRS): manual. Western Psychological Services, Los Angeles, CAGoogle Scholar
  34. 34.
    Rutter M, Bailey A, Lord C (2003) Social Communication Questionnaire. Manual. Western Psychological Services, Los Angeles, CAGoogle Scholar
  35. 35.
    Berument SK, Rutter M, Lord C, Pickles A, Bailey A (1999) Autism screening questionnaire: diagnostic validity. Br J Psychiatry 175:444–451.  https://doi.org/10.1192/bjp.175.5.444 CrossRefPubMedGoogle Scholar
  36. 36.
    Fu Q, Zhu J, Van Eyk JE (2010) Comparison of multiplex immunoassay platforms. Clin Chem 56:314–318.  https://doi.org/10.1373/clinchem.2009.135087 CrossRefPubMedGoogle Scholar
  37. 37.
    Diehl S, Rincón M (2002) The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 39:531–536.  https://doi.org/10.1016/S0161-5890(02)00210-9 CrossRefPubMedGoogle Scholar
  38. 38.
    Ogden TL (2010) Handling results below the level of detection. Ann Occup Hyg 54:255–256PubMedGoogle Scholar
  39. 39.
    Wang C, Geng H, Liu W, Zhang G (2017) Prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis. Med (United States) 96:e6696.  https://doi.org/10.1097/MD.0000000000006696 CrossRefGoogle Scholar
  40. 40.
    van Wijngaarden E, Thurston SW, Myers GJ, Strain JJ, Weiss B, Zarcone T, Watson GE, Zareba G et al (2013) Prenatal methyl mercury exposure in relation to neurodevelopment and behavior at 19 years of age in the Seychelles child development study. Neurotoxicol Teratol 39:19–25.  https://doi.org/10.1016/j.ntt.2013.06.003 CrossRefPubMedGoogle Scholar
  41. 41.
    Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): An overview. J Interf Cytokine Res 29:313–326.  https://doi.org/10.1089/jir.2008.0027 CrossRefGoogle Scholar
  42. 42.
    Arrode-Brusés G, Brusés JL (2012) Maternal immune activation by poly I:C induces expression of cytokines IL-1β and IL-13, chemokine MCP-1 and colony stimulating factor VEGF in fetal mouse brain. J Neuroinflammation 9:83.  https://doi.org/10.1186/1742-2094-9-83 CrossRefPubMedGoogle Scholar
  43. 43.
    Hinojosa AE, Garcia-Bueno B, Leza JC, Madrigal JLM (2011) CCL2/MCP-1 modulation of microglial activation and proliferation. J Neuroinflammation 8:77.  https://doi.org/10.1186/1742-2094-8-77 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Chow SSW, Craig ME, Jones CA, Hall B, Catteau J, Lloyd AR, Rawlinson WD (2008) Differences in amniotic fluid and maternal serum cytokine levels in early midtrimester women without evidence of infection. Cytokine 44:78–84.  https://doi.org/10.1016/j.cyto.2008.06.009 CrossRefPubMedGoogle Scholar
  45. 45.
    Murphy K, Weaver C (2016) Janeway’s immunobiology, 9th ed. Garland Science, New York, NYCrossRefGoogle Scholar
  46. 46.
    Lundström S, Chang Z, Råstam M, Gillberg C, Larsson H, Anckarsäter H, Lichtenstein P (2012) Autism spectrum disorders and autisticlike traits: Similar etiology in the extreme end and the normal variation. Arch Gen Psychiatry 69:46–52.  https://doi.org/10.1001/archgenpsychiatry.2011.144 CrossRefPubMedGoogle Scholar
  47. 47.
    Spiker D, Lotspeich LJ, Dimiceli S, Myers RM, Risch N (2002) Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient. Am J Med Genet - Neuropsychiatr Genet 114:129–136.  https://doi.org/10.1002/ajmg.10188 CrossRefGoogle Scholar
  48. 48.
    Dworzynski K, Ronald A, Bolton P, Happé F (2012) How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? J Am Acad Child Adolesc Psychiatry 51:788–797.  https://doi.org/10.1016/j.jaac.2012.05.018 CrossRefPubMedGoogle Scholar
  49. 49.
    Moody EJ, Reyes N, Ledbetter C, Wiggins L, DiGuiseppi C, Alexander A, Jackson S, Lee LC et al (2017) Screening for autism with the SRS and SCQ: variations across demographic, developmental and behavioral factors in preschool children. J Autism Dev Disord 47:3550–3561.  https://doi.org/10.1007/s10803-017-3255-5 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Evans SC, Boan AD, Bradley C, Carpenter LA (2018) Sex/gender differences in screening for autism Spectrum disorder: implications for evidence-based assessment. J Clin Child Adolesc Psychol:1–15.  https://doi.org/10.1080/15374416.2018.1437734 CrossRefGoogle Scholar
  51. 51.
    de Jager W, Bourcier K, Rijkers GT, Prakken BJ, Seyfert-Margolis V (2009) Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunol 10:52.  https://doi.org/10.1186/1471-2172-10-52 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jessica L. Irwin
    • 1
  • Alison J. Yeates
    • 2
  • Maria S. Mulhern
    • 2
  • Emeir M. McSorley
    • 2
  • J. J. Strain
    • 2
  • Gene E. Watson
    • 1
  • Katherine Grzesik
    • 1
  • Sally W. Thurston
    • 1
  • Tanzy M. Love
    • 1
  • Tristram H. Smith
    • 1
  • Daniel W. Mruzek
    • 1
  • Conrad F. Shamlaye
    • 3
  • Catriona Monthy
    • 4
  • Gary J. Myers
    • 1
  • Philip W. Davidson
    • 1
  • Edwin van Wijngaarden
    • 1
    Email author
  1. 1.Department of Public Health SciencesUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Nutrition Innovation Centre for Food and Health (NICHE)Ulster UniversityCo. LondonderryUK
  3. 3.Ministry of HealthMahéRepublic of Seychelles
  4. 4.Ministry of Education & Human Resource DevelopmentMahéRepublic of Seychelles

Personalised recommendations