Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation

Abstract

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

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References

  1. 1

    American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Publishing: Arlington, VA, USA, 2013.

  2. 2

    Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, (CDC) CfDCaP. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morb Mort Wkly Report Surv (Washington, DC: 2002) 2014; 63: 1–21.

    Google Scholar 

  3. 3

    Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011; 68: 1095–1102.

    Article  Google Scholar 

  4. 4

    Gronborg TK, Schendel DE, Parner ET . Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr 2013; 167: 947–953.

    Article  Google Scholar 

  5. 5

    Kim YS, Leventhal BL . Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry 2015; 77: 66–74.

    CAS  Article  Google Scholar 

  6. 6

    Atladottir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 2009; 124: 687–694.

    Article  Google Scholar 

  7. 7

    Croen LA, Grether JK, Yoshida CK, Odouli R, Van de Water J . Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case–control study. Arch Pediatr Adolesc Med 2005; 159: 151–157.

    Article  Google Scholar 

  8. 8

    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: 322–332.

    Article  Google Scholar 

  9. 9

    Atladottir HO, Thorsen P, Ostergaard L, Schendel DE, Lemcke S, Abdallah M et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord 2010; 40: 1423–1430.

    Article  Google Scholar 

  10. 10

    Lee BK, Magnusson C, Gardner RM, Blomstrom A, Newschaffer CJ, Burstyn I et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain Behav Immun 2015; 44: 100–105.

    Article  Google Scholar 

  11. 11

    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: 4015–4025.

    Article  Google Scholar 

  12. 12

    Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009; 207: 111–116.

    CAS  Article  Google Scholar 

  13. 13

    Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 2010; 68: 368–376.

    Article  Google Scholar 

  14. 14

    Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 2013; 70: 49–58.

    Article  Google Scholar 

  15. 15

    Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA . Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57: 67–81.

    CAS  Article  Google Scholar 

  16. 16

    Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflamm 2011; 8: 52.

    CAS  Article  Google Scholar 

  17. 17

    Croonenberghs J, Wauters A, Devreese K, Verkerk R, Scharpe S, Bosmans E et al. Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med 2002; 32: 1457–1463.

    CAS  Article  Google Scholar 

  18. 18

    Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL et al. Increased IgG4 levels in children with autism disorder. Brain Behav Immun 2009; 23: 389–395.

    CAS  Article  Google Scholar 

  19. 19

    Heuer L, Ashwood P, Schauer J, Goines P, Krakowiak P, Hertz-Picciotto I et al. Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Res 2008; 1: 275–283.

    Article  Google Scholar 

  20. 20

    Sweeten TL, Posey DJ, McDougle CJ . High blood monocyte counts and neopterin levels in children with autistic disorder. Am J Psychiatry 2003; 160: 1691–1693.

    Article  Google Scholar 

  21. 21

    Mead J, Ashwood P . Evidence supporting an altered immune response in ASD. Immunol Lett 2015; 163: 49–55.

    CAS  Article  Google Scholar 

  22. 22

    Abdallah MW, Larsen N, Grove J, Bonefeld-Jorgensen EC, Norgaard-Pedersen B, Hougaard DM et al. Neonatal chemokine levels and risk of autism spectrum disorders: findings from a Danish historic birth cohort follow-up study. Cytokine 2013; 61: 370–376.

    CAS  Article  Google Scholar 

  23. 23

    Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J . Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 2011; 25: 40–45.

    CAS  Article  Google Scholar 

  24. 24

    Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J . Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol 2011; 232: 196–199.

    CAS  Article  Google Scholar 

  25. 25

    Zerbo O, Yoshida C, Grether JK, Van de Water J, Ashwood P, Delorenze GN et al. Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case–control study. J Neuroinflamm 2014; 11: 113.

    Article  Google Scholar 

  26. 26

    Braunschweig D, Van de Water J . Maternal autoantibodies in autism. Arch Neurol 2012; 69: 693–699.

    Article  Google Scholar 

  27. 27

    Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry 2013; 3: e277.

    CAS  Article  Google Scholar 

  28. 28

    Wegmann TG, Lin H, Guilbert L, Mosmann TR . Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol today 1993; 14: 353–356.

    CAS  Article  Google Scholar 

  29. 29

    Chaouat G . The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 2007; 29: 95–113.

    Article  Google Scholar 

  30. 30

    Zaretsky MV, Alexander JM, Byrd W, Bawdon RE . Transfer of inflammatory cytokines across the placenta. Obstet Gynecol 2004; 103: 546–550.

    CAS  Article  Google Scholar 

  31. 31

    Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN . The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psychiatry 2006; 11: 47–55.

    CAS  Article  Google Scholar 

  32. 32

    Samuelsson AM, Jennische E, Hansson HA, Holmang A . Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning. Am J Physiol Regul Integr Compar Physiol 2006; 290: R1345–R1356.

    CAS  Article  Google Scholar 

  33. 33

    Hauguel-de Mouzon S, Guerre-Millo M . The placenta cytokine network and inflammatory signals. Placenta 2006; 27: 794–798.

    CAS  Article  Google Scholar 

  34. 34

    Mehler MF, Kessler JA . Cytokines in brain development and function. Adv Protein Chem 1998; 52: 223–251.

    CAS  Article  Google Scholar 

  35. 35

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

    CAS  Article  Google Scholar 

  36. 36

    Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C . Prevalence of autism in a US metropolitan area. JAMA 2003; 289: 49–55.

    Article  Google Scholar 

  37. 37

    Matson JL, Shoemaker M . Intellectual disability and its relationship to autism spectrum disorders. Res Dev Disabil 2009; 30: 1107–1114.

    Article  Google Scholar 

  38. 38

    Abdallah MW, Larsen N, Grove J, Norgaard-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: 170–176.

    CAS  Article  Google Scholar 

  39. 39

    Abdallah MW, Larsen N, Grove J, Norgaard-Pedersen B, Thorsen P, Mortensen EL et al. Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders. World J Biol Psychiatry 2013; 14: 528–538.

    Article  Google Scholar 

  40. 40

    Chow SS, Craig ME, Jones CA, Hall B, Catteau J, Lloyd AR et al. Differences in amniotic fluid and maternal serum cytokine levels in early midtrimester women without evidence of infection. Cytokine 2008; 44: 78–84.

    CAS  Article  Google Scholar 

  41. 41

    Deverman BE, Patterson PH . Cytokines and CNS development. Neuron 2009; 64: 61–78.

    CAS  Article  Google Scholar 

  42. 42

    Stuart MJ, Baune BT . Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: a systematic review of biomarker studies. Neurosci Biobehav Rev 2014; 42: 93–115.

    CAS  Article  Google Scholar 

  43. 43

    Bilbo SD, Schwarz JM . The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 2012; 33: 267–286.

    CAS  Article  Google Scholar 

  44. 44

    Li L, Walker TL, Zhang Y, Mackay EW, Bartlett PF . Endogenous interferon gamma directly regulates neural precursors in the non-inflammatory brain. J Neurosci 2010; 30: 9038–9050.

    CAS  Article  Google Scholar 

  45. 45

    Robinson DP, Klein SL . Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 2012; 62: 263–271.

    CAS  Article  Google Scholar 

  46. 46

    Denney JM, Nelson EL, Wadhwa PD, Waters TP, Mathew L, Chung EK et al. Longitudinal modulation of immune system cytokine profile during pregnancy. Cytokine 2011; 53: 170–177.

    CAS  Article  Google Scholar 

  47. 47

    Goines PE, Ashwood P . Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol 2013; 36: 67–81.

    CAS  Article  Google Scholar 

  48. 48

    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.

    CAS  Article  Google Scholar 

  49. 49

    Zhou X, Fragala MS, McElhaney JE, Kuchel GA . Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research. Curr Opin Clin Nutr Metab care 2010; 13: 541–547.

    CAS  Article  Google Scholar 

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Acknowledgements

This study was supported by Grants 3R01ES016669 from National Institute of Environmental Health Sciences, 5R01MH072565 from the National Institute of Mental Health and the NICHD-funded IDDRC 054 (U54HD079125). We thank Yanjun Cui and Lori Haapanen for their data collection and management efforts. Banked specimens were provided by Project Baby’s Breath (M Kharrazi and G DeLorenze, Co-Principal Investigators) under the direction of the California Genetic Disease Screening Program. The views expressed are those of the authors and do not necessarily represent those of the California Department of Public Health.

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Jones, K., Croen, L., Yoshida, C. et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry 22, 273–279 (2017). https://doi.org/10.1038/mp.2016.77

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