Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Neuroscience Bulletin
Published in: Neuroscience Bulletin 2/2017

Open Access 01-04-2017 | Review

The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder

Authors: Anne Masi, Nicholas Glozier, Russell Dale, Adam J. Guastella

Published in: Neuroscience Bulletin | Issue 2/2017

Login to get access

Abstract

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by variable impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Heterogeneity of presentation is a hallmark. Investigations of immune system problems in ASD, including aberrations in cytokine profiles and signaling, have been increasing in recent times and are the subject of ongoing interest. With the aim of establishing whether cytokines have utility as potential biomarkers that may define a subgroup of ASD, or function as an objective measure of response to treatment, this review summarizes the role of the immune system, discusses the relationship between the immune system, the brain, and behavior, and presents previously-identified immune system abnormalities in ASD, specifically addressing the role of cytokines in these aberrations. The roles and identification of biomarkers are also addressed, particularly with respect to cytokine profiles in ASD.
Literature
1.
APA. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Washington, DC: American Psychiatric Association, 2013.
2.
Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 2008, 47: 921–929.PubMedCrossRef
3.
Mannion A, Leader G. An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with autism spectrum disorder: A two year follow-up. Res Autism Spectr Disord 2016, 22: 20–33.CrossRef
4.
Mannion A, Leader G. Comorbidity in autism spectrum disorder: A literature review. Res Autism Spectr Disord 2013b, 7: 1595–1616.CrossRef
5.
6.
Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, Croen LA. Immune mediated conditions in autism spectrum disorders. Brain Behav Immun 2015, 46: 232–236.PubMedPubMedCentralCrossRef
7.
Goines P, Van de Water J. The immune system’s role in the biology of autism. Curr Opin Neurol 2010, 23: 111–117.PubMedCrossRef
8.
Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry 2015, 20: 440–446.PubMedCrossRef
9.
Mead J, Ashwood P. Evidence supporting an altered immune response in ASD. Immunol Lett 2015, 163: 49–55.PubMedCrossRef
10.
Owen JA, Punt J, Stranford SA, Jones PP, Kuby J. Kuby Immunology. New York: W.H. Freeman, 2013.
11.
D’Elia RV, Harrison K, Oyston PC, Lukaszewski RA, Clark GC. Targeting the “cytokine storm” for therapeutic benefit. Clin Vaccine Immunol 2013, 20: 319–327.PubMedPubMedCentralCrossRef
12.
Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? the example of natural killer cells. Science 2011, 331: 44–49.PubMedPubMedCentralCrossRef
13.
Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2014, 1843: 2563–2582.
14.
Graves DT, Jiang Y. Chemokines, a family of chemotactic cytokines. Crit Rev Oral Biol Med 1995, 6: 109–118.PubMedCrossRef
15.
Depino MA, de los Angeles Robinson-Agramonte M. Understanding on neuroimmunology in autism spectrum disorder. Translational approaches to autism spectrum disorder. Springer International Publishing, 2015: 155–180.
16.
17.
Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular biology of the cell. 4th edition. New York: Garland Science; 2002. Helper T Cells and Lymphocyte Activation.
18.
Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol 1998, 85: 106–109.PubMedCrossRef
19.
Molloy CA, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K, Manning-Courtney P, et al. Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 2006, 172: 198–205.PubMedCrossRef
20.
21.
Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Cell Res 2006, 16: 126–133.PubMedCrossRef
22.
Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004, 75: 163–189.PubMedCrossRef
23.
Xu N, Li X, Zhong Y. Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediators Inflamm 2015, 2015: 10.
24.
Cavaillon JM. Pro- versus anti-inflammatory cytokines: Myth or reality. Cell Mol Biol (Noisy-le-grand) 2001, 47: 695–702.PubMed
25.
Filiano AJ, Gadani SP, Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res 2015, 1617: 18–27.PubMedCrossRef
26.
Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988, 12: 123–137.PubMedCrossRef
27.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008, 9: 46–56.PubMedPubMedCentralCrossRef
28.
29.
Dantzer R. Cytokine-Induced Sickness Behavior: Where Do We Stand? Brain Behav Immun 2001, 15: 7–24.PubMedCrossRef
30.
Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacology & therapeutics 2011, 130: 226–238.CrossRef
31.
Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987, 107: 293–300.PubMedCrossRef
32.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010, 67: 446–457.PubMedCrossRef
33.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011, 70: 663–671.PubMedPubMedCentralCrossRef
34.
Modabbernia A, Taslimi S, Brietzke E, Ashrafi M. Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 2013, 74: 15–25.PubMedCrossRef
35.
Capuron L, Castanon N. Role of inflammation in the development of neuropsychiatric symptom domains: evidence and mechanisms. Curr Top Behav Neurosci 2017, 31: 31–44.
36.
Mitchell RH, Goldstein BI. Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry 2014, 53: 274–296.PubMedCrossRef
37.
Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res 2007, 85: 2059–2070.PubMedCrossRef
38.
Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003, 2: 255–267.PubMedCrossRef
39.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015, 523: 337–341.PubMedPubMedCentralCrossRef
40.
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun 2011, 25: 840–849.PubMedCrossRef
41.
Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 2016, 535: 425–429.PubMedPubMedCentralCrossRef
42.
Forbes CE, Grafman J. The role of the human prefrontal cortex in social cognition and moral judgment. Annu Rev Neurosci 2010, 33: 299–324.PubMedCrossRef
43.
Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun 2009, 23: 124–133.PubMedCrossRef
44.
Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr 1977, 7: 49–55.PubMedCrossRef
45.
Meltzer A, Van de Water J. The role of the immune system in autism spectrum disorder. Neuropsychopharmacology 2017, 42: 284–298.PubMedCrossRef
46.
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.PubMedCrossRef
47.
Jiang HY, Xu LL, Shao L, Xia RM, Yu ZH, Ling ZX, 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..PubMedCrossRef
48.
Estes ML, McAllister AK. Maternal immune activation: Implications for neuropsychiatric disorders. Science 2016, 353: 772–777.PubMedCrossRef
49.
Krakowiak P, Goines PE, Tancredi DJ, Ashwood P, Hansen RL, Hertz-Picciotto I, et al. Neonatal cytokine profiles associated with autism spectrum disorder. Biol Psychiatry 2017, 81: 442–451..PubMedCrossRef
50.
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.PubMedCrossRef
51.
Suzuki K, Matsuzaki H, Iwata K, Kameno Y, Shimmura C, Kawai S. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One 2011, 6: e20470.PubMedPubMedCentralCrossRef
52.
Netea MG, Simon A, van de Veerdonk F, Kullberg B-J, Van der Meer JWM, Joosten LAB. IL-1β Processing in Host Defense: Beyond the Inflammasomes. PLoS Pathog 2010, 6: e1000661.PubMedPubMedCentralCrossRef
53.
Li L, Kim J, Boussiotis VA. IL-1beta-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol 2010, 185: 4148–4153.PubMedPubMedCentralCrossRef
54.
Verma ND, Hall BM, Plain KM, Robinson CM, Boyd R, Tran GT, et al. Interleukin-12 (IL-12p70) Promotes Induction of Highly Potent Th1-Like CD4(+)CD25(+) T Regulatory Cells That Inhibit Allograft Rejection in Unmodified Recipients. Front Immunol 2014, 5: 190.PubMedPubMedCentralCrossRef
55.
Ricci S, Businaro R, Ippoliti F, Lo Vasco VR, Massoni F, Onofri E, et al. Altered cytokine and BDNF levels in autism spectrum disorder. Neurotox Res 2013, 24: 491–501.PubMedCrossRef
56.
Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 2007, 36: 361–365.PubMedCrossRef
57.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011, 1813: 878–888.PubMedCrossRef
58.
Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M. Activation of the inflammatory response system in autism. Neuropsychobiology 2002, 45: 1–6.PubMedCrossRef
59.
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.PubMedCrossRef
60.
Li X, Chauhn A, Shiekh AM, Patil S, Chauhn V, Li X-M, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009, 207: 111–116.PubMedPubMedCentralCrossRef
61.
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 Neuroinflammation 2011, 8: 52.PubMedPubMedCentralCrossRef
62.
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 2011a, 25: 40–45.PubMedCrossRef
63.
Wei H, Chadman KK, McCloskey DP, Sheikh AM, Malik M, Brown WT, et al. Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochim Biophys Acta 2012, 1822: 831–842.PubMedCrossRef
64.
Miano S, Giannotti F, Cortesi F. Sleep disorders and autism spectrum disorder. In: Mazzone L, Vitiello B (Eds.). Psychiatric symptoms and comorbidities in autism spectrum disorder. Springer International Publishing, 2016: 111–128.
65.
Rohleder N, Aringer M, Boentert M. Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci 2012, 1261: 88–96.PubMedCrossRef
66.
McDougle CJ, Landino SM, Vahabzadeh A, O’Rourke J, Zurcher NR, Finger BC, et al. Toward an immune-mediated subtype of autism spectrum disorder. Brain Res 2015, 1617: 72–92.PubMedCrossRef
67.
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: 149–153.PubMedPubMedCentralCrossRef
68.
El Gohary TM, El Aziz NA, Darweesh M, Sadaa ES. Plasma level of transforming growth factor β 1 in children with autism spectrum disorder. Egyptian Journal of Ear, Nose, Throat and Allied Sciences 2015, 16: 69–73.CrossRef
69.
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 2011b, 232: 196–199.PubMedCrossRef
70.
Biber K, Vinet J, Boddeke HWGM. Neuron-microglia signaling: Chemokines as versatile messengers. J Neuroimmunol 2008, 198: 69–74.PubMedCrossRef
71.
Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol 2013, 36: 67–81.PubMedCrossRef
72.
Courchesne E. Brain development in autism: Early overgrowth followed by premature arrest of growth. Ment Retard Dev Disabil Res Rev 2004, 10: 106–111.PubMedCrossRef
73.
Bickel M. The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol 1993, 64: 456–460.PubMed
74.
Qazi BS, Tang K, Qazi A. Recent advances in underlying pathologies provide insight into interleukin-8 expression-mediated inflammation and angiogenesis. Int J Inflam 2011, 2011: 908468.PubMedPubMedCentralCrossRef
75.
Ashwood P, Corbett BA, Kantor A, Schulman H, Van de Water J, Amaral DG. In search of cellular immunophenotypes in the blood of children with autism. PLoS One 2011c, 6: e19299.PubMedCrossRef
76.
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.PubMedCrossRef
77.
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.PubMedPubMedCentralCrossRef
78.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001, 69: 89–95.CrossRef
79.
Banati R, Hickie IB. Therapeutic signposts: using biomarkers to guide better treatment of schizophrenia and other psychotic disorders. Med J Aust 2009, 190: S26.PubMed
80.
Ruggeri B, Sarkans U, Schumann G, Persico A. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology (Berl.) 2014, 231: 1201–1216.CrossRef
81.
Akhondzadeh S, Fallah J, Mohammadi MR, Imani R, Mohammadi M, Salehi B, et al. Double-blind placebo-controlled trial of pentoxifylline added to risperidone: effects on aberrant behavior in children with autism. Prog. Neuropsychopharmacol. Biol Psychiatry 2010, 34: 32–36.PubMedCrossRef
82.
Ghaleiha A, Rasa SM, Nikoo M, Farokhnia M, Mohammadi M-R, Akhondzadeh S. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res 2015, 229: 181–187.PubMedCrossRef
83.
Kobayashi T, Notoya K, Naito T, Unno S, Nakamura A, Martel-Pelletier J, et al. Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, reduces the progression of experimental osteoarthritis in guinea pigs. Arthritis Rheum 2005, 52: 479–487.PubMedCrossRef
84.
Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 2012, 32: 10117–10128.PubMedPubMedCentralCrossRef
85.
Asadabadi M, Mohammadi MR, Ghanizadeh A, Modabbernia A, Ashrafi M, Hassanzadeh E, et al. Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Psychopharmacology (Berl.) 2013, 225: 51–59.CrossRef
86.
Choi JE, Widjaja F, Careaga M, Bent S, Ashwood P, Hendren RL. Change in plasma cytokine levels during risperidone treatment in children with autism. J Child Adolesc Psychopharmacol 2014, 24: 586–589.PubMedPubMedCentralCrossRef
87.
Hayashi-Takagi A, Vawter MP, Iwamoto K. Peripheral biomarkers revisited: integrative profiling of peripheral samples for psychiatric research. Biol Psychiatry 2014, 75: 920–928.PubMedCrossRef
88.
Insel TR. The NIMH research domain criteria (RDoC) project: precision medicine for psychiatry. Am J Psychiatry 2014, 171: 395–397.PubMedCrossRef
89.
National Academy of Sciences. The national academies collection: reports funded by national institutes of health. Washington (DC): National Academies Press (US), 2011.
90.
91.
Derecki N, Privman E, Kipnis J. Rett syndrome and other autism spectrum disorders—brain diseases of immune malfunction? Mol Psychiatry 2010, 15: 355–363.PubMedPubMedCentralCrossRef
Metadata
Title
The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder
Authors
Anne Masi
Nicholas Glozier
Russell Dale
Adam J. Guastella
Publication date
01-04-2017
Publisher
Springer Singapore
Published in
Neuroscience Bulletin / Issue 2/2017
Print ISSN: 1673-7067
Electronic ISSN: 1995-8218
DOI
https://doi.org/10.1007/s12264-017-0103-8

Other articles of this Issue 2/2017

Neuroscience Bulletin 2/2017 Go to the issue

Original Article

Assessing the Accuracy of the Modified Chinese Autism Spectrum Rating Scale and Social Responsiveness Scale for Screening Autism Spectrum Disorder in Chinese Children

Review

An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options

Original Article

A Volumetric and Functional Connectivity MRI Study of Brain Arginine-Vasopressin Pathways in Autistic Children

Review

Cellular and Circuitry Bases of Autism: Lessons Learned from the Temporospatial Manipulation of Autism Genes in the Brain

Original Article

Chinese Norms for the Autism Spectrum Rating Scale

Review

Non-human Primate Models for Brain Disorders – Towards Genetic Manipulations via Innovative Technology