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Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis

Molecular Psychiatry volume 20, pages 440446 (2015) | Download Citation

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Abstract

The role of non-diagnostic features in the pathophysiology of autism spectrum disorders (ASDs) is unclear. Increasing evidence suggests immune system alterations in ASD may be implicated in the severity of behavioral impairment and other developmental outcomes. The primary objective of this meta-analysis was to investigate if there is a characteristic abnormal cytokine profile in ASD compared with healthy controls (HCs). We identified relevant studies following a search of MEDLINE, EMBASE, PsycINFO, Web of Knowledge and Scopus. A meta-analysis was performed on studies comparing plasma and serum concentrations of cytokines in unmedicated participants with ASD and HCs. Results were reported according to PRISMA statement. Seventeen studies with a total sample size of 743 participants with ASD and 592 HC were included in the analysis. Nineteen cytokines were assessed. Concentrations of interleukin (IL)-1beta (P<0.001), IL-6 (P=0.03), IL-8 (P=0.04), interferon-gamma (P=0.02), eotaxin (P=0.01) and monocyte chemotactic protein-1 (P<0.05) were significantly higher in the participants with ASD compared with the HC group, while concentrations of transforming growth factor-β1 were significantly lower (P<0.001). There were no significant differences between ASD participants and controls for the other 12 cytokines analyzed. The findings of our meta-analysis identified significantly altered concentrations of cytokines in ASD compared to HCs, strengthening evidence of an abnormal cytokine profile in ASD where inflammatory signals dominate.

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References

  1. 1.

    , , , , , . Defining the sleep phenotype in children with autism. Dev Neuropsychol 2009; 34: 560–573.

  2. 2.

    , . Autism spectrum disorders: from immunity to behavior. Methods Mol Biol 2012; 934: 219–240.

  3. 3.

    , , , , , . Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr 2006; 27: S128–S136.

  4. 4.

    , . Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 2011; 17: 290–314.

  5. 5.

    , , . The immune response in autism: a new frontier for autism research. J Leukoc Biol 2006; 80: 1–15.

  6. 6.

    , . Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol 2012; 36: 67–81.

  7. 7.

    , . Comparative immunogenetics of autism and schizophrenia. Genes Brain Behav 2011; 10: 689–701.

  8. 8.

    , , , . Maternal immune activation causes age-and region-specific changes in brain cytokines in offspring throughout development. Brain Behavior Immunity 2012; 31: 54–68.

  9. 9.

    , , , , . Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007; 27: 10695–10702.

  10. 10.

    , , , , , et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 2009; 124: 687–694.

  11. 11.

    , , , , . Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57: 67–81.

  12. 12.

    , , , , , et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflam 2011; 8: 52.

  13. 13.

    , , , , . Activation of the inflammatory response system in autism. Neuropsychobiology 2002; 45: 1–6.

  14. 14.

    , , , , , et al. Altered cytokine and BDNF levels in autism spectrum disorder. Neurotox Res 2013; 24: 491–501.

  15. 15.

    , , , , , et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE 2011; 6: e20470.

  16. 16.

    , , , , , . Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol 2011a; 232: 196–199.

  17. 17.

    , , , . Association between plasma levels of transforming growth factor-b1, IL-23 and IL-17 and the severity of autism in Egyptian children. Res Autism Spect Dis 2013; 7: 199–204.

  18. 18.

    . Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Design 2005; 11: 973–984.

  19. 19.

    , , , , . Central nervous system inflammation in disease related conditions: mechanistic prospects. Brain Res 2012; 1446: 144–155.

  20. 20.

    , , . Neuroinflammation: a common pathway in CNS diseases as mMediated at the blood-brain barrier. Neuroimmunomodulation 2012; 19: 121–130.

  21. 21.

    , , , , . Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 2007; 36: 361–365.

  22. 22.

    , , , , , et al. Decreased serum levels of transforming growth factor-(beta)1 in patients with autism. Prog Neuro-Psychopharmacol Biol Psychiatry 2007; 31: 187–190.

  23. 23.

    , , , , , et al. Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 2006; 172: 198–205.

  24. 24.

    , , , , , et al. Detection of IL-17 and IL-23 in plasma samples of children with autism. Am J Biochem Biotechnol 2008; 4: 114–120.

  25. 25.

    . Plasma increase of interleukin- 12 and interferon-gamma pathological significance in autism. J Neuroimmunol 1996; 66: 143–145.

  26. 26.

    , , , , , 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: 149–153.

  27. 27.

    , . Elevated serum levels of interleukin-17 A in children with autism. J Neuroinflamm 2012; 9: 158.

  28. 28.

    , , , , . Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr 2005; 146: 605–610.

  29. 29.

    , , , , , . Altered T cell responses in children with autism. Brain Behav Immun 2011; 25: 840–849.

  30. 30.

    , , , , , . Expression of inflammatory cytokines, Bc12 and cathepsin D are altered in lymphoblasts of autistic subjects. Immunobiology 2010; 216: 80–85.

  31. 31.

    , , , , , et al. An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children. Biol Psychiatry 2009; 66: 978–984.

  32. 32.

    , , , , , et al. Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15. J Neuroimmunol 2008; 205: 148–154.

  33. 33.

    , , , , , 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.

  34. 34.

    , . Cytokines and CNS development. Neuron 2009; 64: 61–78.

  35. 35.

    , , , , . Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci 2012; 109: 12776–12781.

  36. 36.

    , , , , . Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Bioi Psychiatry 2011; 70: 663–671.

  37. 37.

    , , , , , . Inflammatorycytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 2008; 63: 801–808.

  38. 38.

    , , , . Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 2013; 74: 15–25.

  39. 39.

    , , , , , et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457.

  40. 40.

    , , , , , et al. Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders. J Neuroimmunol 2009; 216: 126–129.

  41. 41.

    , , , , , et al. Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder. J Neuroinflam 2013; 10: 38.

  42. 42.

    , , , , . Altered neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. Pharmacopsychiatry 2012; 45: 241–243.

  43. 43.

    , , , . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151: 264–269.

  44. 44.

    , , , . Comprehensive meta-analysis version 2. Biostat: Englewood, NJ, 2005.

  45. 45.

    . Statistical Power Analysis for the Behavioral Sciences. Lawrence Erlbaum Associates: Hillsdale, NJ, 1988.

  46. 46.

    , . Statistical Methods for Meta-Analysis. Academic Press: Orlando, 1985.

  47. 47.

    , , , . Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629–634.

  48. 48.

    , . Quantifying heterogeneity in a meta-analysis. Statist Med 2002; 21: 1539–1558.

  49. 49.

    , , , . Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557–560.

  50. 50.

    . Pro-inflammatory cytokines in autistic children in central Saudi Arabia. Neurosciences 2005; 10: 155–158.

  51. 51.

    , . The proinflammatory cytokines in children with autism. Pak J Biol Sci 2006; 9: 2593–2599.

  52. 52.

    , , , , , . Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 2011b; 25: 40–45.

  53. 53.

    , , , . Plasma cytokine levels in children with autistic disorder and unrelated siblings. Int J Dev Neurosci 2012; 30: 121–127.

  54. 54.

    , , , . High nitric oxide production in autistic disorder: a possible role for interferon-γ. Biol Psychiatry 2004; 55: 434–437.

  55. 55.

    , . Neuroinflammation in autism spectrum disorders. J Neuroinflam 2012; 9: 1–9.

  56. 56.

    , , , . Interferon-γ: an overview of signals, mechanisms and functions. J Leukoc Biol 2004; 75: 163–189.

  57. 57.

    . Science commentary: Th1 and Th2 responses: what are they? Br Med J 2000; 321: 424–424.

  58. 58.

    , , . Emerging roles for TGF-β1 in nervous system development. Int J Dev Neurosci 2005; 23: 413–424.

  59. 59.

    , , , , . Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry 1993; 150: 1189–1193.

  60. 60.

    , . Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol 2006; 2: 619–626.

  61. 61.

    . The Pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998; 128: 127.

  62. 62.

    , , . Role of interleukin‐6 in stress, sleep, and fatigue. Ann New York Acad Sci 2012; 1261: 88–96.

  63. 63.

    , , , , , et al. Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endo 84: 203–2607.

  64. 64.

    , , , , , . Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology. Clin Chem 2005; 51: 1854–1866.

  65. 65.

    , , , , , et al. Effects of blood sample handling procedures on measurable inflammatory markers in plasma, serum and dried blood spot samples. J Immunol Methods 2008; 336: 78–84.

  66. 66.

    , , , , . Cytokine assays: An assessment of the preparation and treatment of blood and tissue samples. Methods 2013; 61: 10–17.

  67. 67.

    , , , , . Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J Immunol Methods 2005; 300: 124–135.

  68. 68.

    , , , , , et al. Multisite comparison of high-sensitvity multiplex cytokine assays. Clin vaccine immunol 2011; 18: 1229–1242.

  69. 69.

    , , . Hemoglobin stimulates the release of proinflammatory cytokines from leukocytes in whole blood. J Lab Clin Med 2000; 135: 263–269.

  70. 70.

    , , , , . Evidence for degradation of cytokines in the serum of patients with atopic dermatitis by calcium-dependent protease. Arch Dermatol Res 2000; 292: 391–396.

  71. 71.

    , , , , . Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC immunol 2009; 10: 52.

  72. 72.

    , , . The effects of 40 h of total sleep deprivation on inflammatory markers in healthy young adults. Brain Behav Immun 2007; 21: 1050–1057.

  73. 73.

    , , , , , et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009; 23: 887–897.

  74. 74.

    , , , , . Gender differences in inflammatory markers in children. Shock 2010; 33: 258–262.

  75. 75.

    , . The immune system's role in the biology of autism. Curr Opin Neurol 2010; 23: 111–117.

  76. 76.

    , , , , , et al. Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Psychopharmacology 2013; 225: 51–59.

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Acknowledgements

We thank Melanie Reuss for assisting with the independent screening of titles, abstracts and full-text articles and subsequent assessment of eligibility. We acknowledge the support of National Health and Medical Research Council project grant (1043664) and Career Development Fellowship (1061922) to Associate Professor Guastella and an Australia Fellowship (494914) to Professor Hickie.

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Affiliations

  1. Autism Clinic for Translational Research, Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia

    • A Masi
    • , D S Quintana
    • , N Glozier
    • , I B Hickie
    •  & A J Guastella
  2. Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia

    • A R Lloyd

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Competing interests

Ian B Hickie is a member of the Medical Advisory Panel for BUPA Health Insurance (Australia) and also a Board Member of Psychosis Australia Trust. From 2012, he is a Commissioner in Australia’s new National Mental Health Commission. He was until January 2012 a director of headspace: the national youth mental health foundation. Professor Hickie was previously the chief executive officer (till 2003) and clinical adviser (till 2006) of beyondblue, an Australian National Depression Initiative. He is supported principally for clinical research in depression and health services and population health initiatives related to anxiety and depression by an NHMRC Australian Medical Research Fellowship (2007–2012). He has led projects for health professionals and the community supported by governmental, community agency and pharmaceutical industry partners (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) for the identification and management of depression and anxiety. He has received honoraria for presentations of his own work at educational seminars supported by a number of non-government organizations and the pharmaceutical industry (including Pfizer, Servier and AstraZeneca). He has served on advisory boards convened by the pharmaceutical industry in relation to specific antidepressants, including nefazodone, duloxetine and desvenlafaxine. He leads a new investigator-initiated study of the effects of agomelatine on circadian parameters (supported in part by Servier but also by other NHMRC funding) and has participated in a multicentre clinical trial of the effects of agomelatine on sleep architecture in depression and a Servier-supported study of major depression and sleep disturbance in primary care settings. In addition to national and international government-based grant bodies, investigator-initiated mental health research at the BMRI, he has been supported by various pharmaceutical manufacturers (including Servier and Pfizer) and not-for-profit entities (including the Heart Foundation, beyondblue and the BUPA Foundation).

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Correspondence to A J Guastella.

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https://doi.org/10.1038/mp.2014.59

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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