Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

1.
Kanner L: Autistic disturbances of affective contact. Nerv Child 1943; 2: 217–250.
2.
DSM-5 diagnostic classification; in: Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association, 2013. DOI: 10.1176/appi.books.9780890425596.x00 DiagnosticClassification.
3.
Huerta M, Lord C: Diagnostic evaluation of autism spectrum disorders. Pediatr Clin North Am 2012; 103–111.
4.
Gadia CA, Tuchman R, Rotta NT: Autismo e doenças invasivas de desenvolvimento. J Pediatr 2004;S83–S94.
5.
Rapin I, Tuchman RF: Autism: definition, neurobiology, screening, diagnosis. Pediatr Clin North Am 2008; 55: 1129–1146.
6.
Tonhajzerova I, Ondrejka I, Mestanik M, Mikolka P, Hrtanek I, Mestanikova A, et al: Inflammatory activity in autism spectrum disorder. Adv Exp Med Biol 2015; 861: 93–98.
7.
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.
8.
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium: Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism 2017; 8: 21.
9.
Lintas C, Sacco R, Persico AM: Genome-wide expression studies in autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiol Dis 2012; 45: 57–68.
10.
Skafidas E, Testa R, Zantomio D, Chana G, Everall IP, Pantelis C: Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Mol Psychiatry 2014; 19: 504–510.
11.
Christensen DL, Baio J, Braun KVN, Bilder D, Charles J, Constantino JN, et al: Prevalence and characteristics of autism spectrum disorder among children aged 8 years – Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ 2016; 65: 1–23.
12.
Smith V, Brown N: Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. Arch Dis Child Educ Pract Ed 2014; 99: 198.
13.
Roullet FI, Lai JKY, Foster JA: In utero exposure to valproic acid and autism – a current review of clinical and animal studies. Neurotoxicol Teratol 2013; 36: 47–56.
14.
Ranger P, Ellenbroek BA: Perinatal influences of valproate on brain and behaviour: an animal model for autism. Curr Top Behav Neurosci 2016; 29: 363–386.
15.
Christianson AL, Chester N, Kromberg JGR: Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol 1994; 36: 361–369.
16.
Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, et al: A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000; 37: 489–497.
17.
Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH: Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001; 43: 202–206.
18.
Williams PG, Hersh JH: A male with fetal valproate syndrome and autism. Dev Med Child Neurol 1997; 39: 632–634.
19.
Bambini-Junior V, Rodrigues L, Behr GA, Moreira JCF, Riesgo R, Gottfried C: Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain Res 2011; 1408: 8–16.
20.
Schneider T, Przewłocki R: Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005; 30: 80–89.
21.
Schneider T, Roman A, Basta-Kaim A, Kubera M, Budziszewska B, Schneider K, et al: Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology 2008; 33: 728–740.
22.
Roullet FI, Wollaston L, Decatanzaro D, Foster JA: Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience 2010; 170: 514–522.
23.
Baronio D, Castro K, Gonchoroski T, de Melo GM, Nunes GDF, Bambini-Junior V, et al: Effects of an H3R antagonist on the animal model of autism induced by prenatal exposure to valproic acid. PLoS One 2015; 10:e0116363.
24.
Favre MR, Barkat TR, Lamendola D, Khazen G, Markram H, Markram K: General developmental health in the VPA-rat model of autism. Front Behav Neurosci 2013; 7: 88.
25.
Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T: Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 2013; 16: 91–103.
26.
Zhubi A, Cook EH, Guidotti A, Grayson DR: Epigenetic mechanisms in autism spectrum disorder. Int Rev Neurobiol 2014; 115: 203–244.
27.
Uher R: Gene-environment interactions in severe mental illness. Front Psychiatry 2014; 5: 48.
28.
Misztak P, Pańczyszyn-Trzewik P, Sowa-Kućma M: Histone deacetylases (HDACs) as therapeutic target for depressive disorders. Pharmacol Reports 2018; 70: 398–408.
29.
Koprinarova M, Schnekenburger M, Diederich M: Role of histone acetylation in cell cycle regulation. Curr Top Med Chem 2015; 16: 732–744.
30.
Nadal S, Raj R, Mohammed S, Davis BG: Synthetic post-translational modification of histones. Curr Opin Chem Biol 2018; 45: 35–47.
31.
Hu Y, Suliman BA: Roles of HDACs in the responses of innate immune cells and as targets in inflammatory diseases. Adv Exp Med Biol 2017; 1024: 91–110.
32.
Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C, et al: Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol 2000; 165: 7017–24.
33.
Kroesen M, Gielen PR, Brok IC, Armandari I, Hoogerbrugge PM, Adema GJ: HDAC inhibitors and immunotherapy; a double-edged sword? Oncotarget 2014; 5: 6558–6572.
34.
Kawanai T, Ago Y, Watanabe R, Inoue A, Taruta A, Onaka Y, et al: prenatal exposure to histone deacetylase inhibitors affects gene expression of autism-related molecules and delays neuronal maturation. Neurochem Res 2016; 41: 2574–2584.
35.
Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria K, et al: Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 2017; 22: 820–835.
36.
Kazlauskas N, Campolongo M, Lucchina L, Zappala C, Depino AM: Postnatal behavioral and inflammatory alterations in female pups prenatally exposed to valproic acid. Psychoneuroendocrinology 2016; 72: 11–21.
37.
Lee HJ, Dreyfus C, DiCicco-Bloom E: Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat. Dev Neurobiol 2016; 76: 780–798.
38.
Perisic T, Zimmermann N, Kirmeier T, Asmus M, Tuorto F, Uhr M, et al: Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes. Neuropsychopharmacology 2010; 35: 792–805.
39.
Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, et al: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20: 6969–6978.
40.
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.
41.
Louveau A, Harris TH, Kipnis J: Revisiting the mechanisms of CNS immune privilege. Trends Immunol 2015; 36: 569–577.
42.
Daneman R, Prat A: The blood-brain barrier. Cold Spring Harb Perspect Biol 2015; 7:a020412.
43.
Wang Y, Rattner A, Zhou Y, Williams J, Smallwood PM, Nathans J: Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 2012; 151: 1332–1344.
44.
Zhou Y, Nathans J: Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical Wnt signaling. Dev Cell 2014; 31: 248–256.
45.
Zhou Y, Wang Y, Tischfield M, Williams J, Smallwood PM, Rattner A, et al: Canonical WNT signaling components in vascular development and barrier formation. J Clin Invest 2014; 124: 3825–3846.
46.
Hagan N, Ben-Zvi A: The molecular, cellular, and morphological components of blood-brain barrier development during embryogenesis. Semin Cell Dev Biol 2015; 38: 7–15.
47.
Zhao Z, Nelson AR, Betsholtz C, Zlokovic B V: establishment and dysfunction of the blood-brain barrier. Cell 2015; 163: 1064–1078.
48.
Daneman R, Zhou L, Kebede AA, Barres BA: Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 2010; 468: 562–566.
49.
Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, et al: Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 2010; 68: 409–427.
50.
Li Q, Barres BA: Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 2018; 18: 225–242.
51.
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al: Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 2014; 17: 131–143.
52.
Bohlen CJ, Bennett FC, Tucker AF, Collins HY, Mulinyawe SB, Barres BA: Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 2017; 94: 759–773.e8.
53.
Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312–318.
54.
Raivich G, Banati R: Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res Rev 2004; 46: 261–281.
55.
Nimmerjahn A, Kirchhoff F, Helmchen F: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314–1318.
56.
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J: Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 2009; 29: 3974–3980.
57.
Olson JK, Miller SD: Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004; 173: 3916–3924.
58.
Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski NR, Gautier EL, et al: Sall1 is a transcriptional regulator defining microglia identity and function. Nat Immunol 2016; 17: 1397–1406.
59.
Parisi C, Napoli G, Pelegrin P, Volonté C: M1 and m2 functional imprinting of primary microglia: role of P2X7 activation and miR-125b. Mediators Inflamm 2016; 2016: 2989548.
60.
Hanisch U-K, Prinz M, Angstwurm K, Hausler KG, Kann O, Kettenmann H, et al: The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls. Eur J Immunol 2001; 31: 2104–2115.
61.
Häusler KG, Prinz M, Nolte C, Weber JR, Schumann RR, Kettenmann H, et al: Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages. Eur J Neurosci 2002; 16: 2113–2122.
62.
Škuljec J, Sun H, Pul R, Bénardais K, Ragancokova D, Moharregh-Khiabani D, et al: CCL5 induces a pro-inflammatory profile in microglia in vitro. Cell Immunol 2011; 270: 164–171.
63.
Zarruk JG, Greenhalgh AD, David S: Microglia and macrophages differ in their inflammatory profile after permanent brain ischemia. Exp Neurol 2018; 301: 120–132.
64.
Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al: Microglial and macrophage polarization – new prospects for brain repair. Nat Rev Neurol 2015; 11: 56–64.
65.
Hanisch U-K, Kettenmann H: Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007; 10: 1387–1394.
66.
Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, et al: Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep 2018; 22: 832–847.
67.
Koyama R, Ikegaya Y: Microglia in the pathogenesis of autism spectrum disorders. Neurosci Res 2015; 100: 1–5.
68.
Hansen DV, Hanson JE, Sheng M: Microglia in Alzheimer’s disease. J Cell Biol 2018; 217: 459–472.
69.
Lucchinetti CF, Popescu BFG, Bunyan RF, Moll NM, Roemer SF, Lassmann H, et al: Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011; 365: 2188–2197.
70.
Antonietta Ajmone-Cat M, Mancini M, De Simone R, Cilli P, Minghetti L: Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures. Glia 2013; 61: 1698–1711.
71.
Serhan CN, Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 2005; 6: 1191–1197.
72.
Herz J, Filiano AJ, Smith A, Yogev N, Kipnis J: Myeloid cells in the central nervous system. Immunity 2017; 46: 943–956.
73.
Serrats J, Schiltz JC, García-Bueno B, van Rooijen N, Reyes TM, Sawchenko PE: Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 2010; 65: 94–106.
74.
Williams K, Alvarez X, Lackner AA: Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 2001; 36: 156–164.
75.
He H, Mack JJ, Güç E, Warren CM, Squadrito ML, Kilarski WW, et al: Perivascular macrophages limit permeability. Arterioscler Thromb Vasc Biol 2016; 36: 2203–2212.
76.
Shechter R, London A, Schwartz M: Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol 2013; 13: 206–218.
77.
Quintana E, Fernández A, Velasco P, de Andrés B, Liste I, Sancho D, et al: DNGR-1+ dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia 2015; 63: 2231–2248.
78.
Meeker RB, Williams K, Killebrew DA, Hudson LC: Cell trafficking through the choroid plexus. Cell Adh Migr 2012; 6: 390–396.
79.
Mendez-Gomez HR, Galera-Prat A, Meyers C, Chen W, Carrion-Vazquez M, Muzyczka N: Crossing the blood-cerebrospinal fluid barrier in the mouse choroid plexus with an engineered receptor/ligand system. Mol Ther 2015; 23:S65.
80.
Kierdorf K, Prinz M, Gomez Perdiguero E: Development and function of tissue resident macrophages in mice. Semin Immunol 2015; 27: 369–378.
81.
Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB: Transcranial amelioration of inflammation and cell death after brain injury. Nature 2014; 505: 223–228.
82.
Mildner A, Mack M, Schmidt H, Brück W, Djukic M, Zabel MD, et al: CCR2+Ly-6χ monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 2009; 132: 2487–2500.
83.
Dong H, Zhang X, Qian Y: Mast cells and neuroinflammation. Med Sci Monit Basic Res 2014; 20: 200–206.
84.
Prinz M, Priller J: The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 2017; 20: 136–144.
85.
Nau R, Zettl U, Gerber J, Trostdorf F, Michel U, Böttcher T, et al: Granulocytes in the subarachnoid space of humans and rabbits with bacterial meningitis undergo apoptosis and are eliminated by macrophages. Acta Neuropathol 1998; 96: 472–480.
86.
McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B: Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res 2003; 313: 259–269.
87.
Chinnery HR, Ruitenberg MJ, McMenamin PG: Novel characterization of monocyte-derived cell populations in the meninges and choroid plexus and their rates of replenishment in bone marrow chimeric mice. J Neuropathol Exp Neurol 2010; 69: 896–909.
88.
Anandasabapathy N, Victora GD, Meredith M, Feder R, Dong B, Kluger C, et al: Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J Exp Med 2011; 208: 1695–1705.
89.
Prendergast CT, Anderton SM: Immune cell entry to central nervous system – current understanding and prospective therapeutic targets. Endocr Metab Immune Disord Drug Targets 2009; 9: 315–327.
90.
Fabis MJ, Phares TW, Kean RB, Koprowski H, Hooper DC: Blood-brain barrier changes and cell invasion differ between therapeutic immune clearance of neurotrophic virus and CNS autoimmunity. Proc Natl Acad Sci USA 2008; 105: 15511–15516.
91.
Arima Y, Kamimura D, Sabharwal L, Yamada M, Bando H, Ogura H, et al: Regulation of immune cell infiltration into the CNS by regional neural inputs explained by the gate theory. Mediators Inflamm 2013; 2013: 898165.
92.
Dendrou CA, Fugger L, Friese MA: Immunopathology of multiple sclerosis. Nat Rev Immunol 2015; 15: 545–558.
93.
da Fonseca ACC, Matias D, Garcia C, Amaral R, Geraldo LH, Freitas C, et al: The impact of microglial activation on blood-brain barrier in brain diseases. Front Cell Neurosci 2014; 8: 362.
94.
Phares TW, Kean RB, Mikheeva T, Hooper DC: Regional differences in blood-brain barrier permeability changes and inflammation in the apathogenic clearance of virus from the central nervous system. J Immunol 2006; 114: 1761–1765.
95.
Bilbo SD, Block CL, Bolton JL, Hanamsagar R, Tran PK: Beyond infection – maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Exp Neurol 2018; 299: 241–251.
96.
Ashwood P, Wills S, Van de Water J: The immune response in autism: a new frontier for autism research. J Leukoc Biol 2006; 80: 1–15.
97.
Turner MD, Nedjai B, Hurst T, Pennington DJ: Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 2014; 1843: 2563–2582.
98.
Masi A, Glozier N, Dale R, Guastella AJ: The immune system, cytokines, and biomarkers in autism spectrum disorder. Neurosci Bull 2017; 33: 194–204.
99.
Ramesh G, MacLean AG, Philipp MT: Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm 2013; 2013: 480739.
100.
Biber K, Vinet J, Boddeke HWGM: Neuron-microglia signaling: chemokines as versatile messengers. J Neuroimmunol 2008; 198: 69–74.
101.
Réaux-Le Goazigo A, Van Steenwinckel J, Rostène W, Mélik Parsadaniantz S: Current status of chemokines in the adult CNS. Prog Neurobiol 2013; 104: 67–92.
102.
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ (eds): Immunobiology: The Immune System in Health and Disease, ed 5. New York, Garland Science, 2001.
103.
Metz DP, Bottomly K: Function and regulation of memory CD4 T cells. Immunol Res 1999; 19: 127–141.
104.
Amedei A, Prisco D, D’Elios M: Multiple sclerosis: the role of cytokines in pathogenesis and in therapies. Int J Mol Sci 2012; 13: 13438–13460.
105.
Vijayakumar NT, Judy MV: Autism spectrum disorders: integration of the genome, transcriptome and the environment. J Neurol Sci 2016; 364: 167–176.
106.
Erta M, Giralt M, Esposito FL, Fernandez-Gayol O, Hidalgo J: Astrocytic IL-6 mediates locomotor activity, exploration, anxiety, learning and social behavior. Horm Behav 2015; 73: 64–74.
107.
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.
108.
Bluthé RM, Michaud B, Poli V, Dantzer R: Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice. Physiol Behav 2000; 70: 367–73.
109.
Lucchina L, Depino AM: Altered peripheral and central inflammatory responses in a mouse model of autism. Autism Res 2013; 7: 273–289.
110.
Gottfried C, Bambini-Junior V, Francis F, Riesgo R, Savino W: the impact of neuroimmune alterations in autism spectrum disorder. Front Psychiatry 2015; 6: 121.
111.
Musolino C, Allegra A, Innao V, Allegra AG, Pioggia G, Gangemi S: Inflammatory and anti-inflammatory equilibrium, proliferative and antiproliferative balance: the role of cytokines in multiple myeloma. Mediators Inflamm 2017; 2017: 1852517.
112.
Dinarello CA: Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 2009; 27: 519–550.
113.
Gray SM, Bloch MH: Systematic review of proinflammatory cytokines in obsessive-compulsive disorder. Curr Psychiatry Rep 2012; 14: 220–228.
114.
Manzardo AM, Henkhaus R, Dhillon S, Butler MG: Plasma cytokine levels in children with autistic disorder and unrelated siblings. Int J Dev Neurosci 2012; 30: 121–127.
115.
Suzuki K, Matsuzaki H, Iwata K, Kameno Y, Shimmura C, Kawai S, et al: Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One 2011; 6: 1–6.
116.
Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, et al: Low-grade endotoxemia in patients with severe autism. Neurosci Lett 2010; 471: 162–165.
117.
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.
118.
Enstrom AM, Onore CE, Van de Water JA, Ashwood P: Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun 2010; 24: 64–71.
119.
Jyonouchi H, Sun S, Le H: Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 2001; 120: 170–179.
120.
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.
121.
Abdallah MW, Larsen N, Mortensen EL, Atladóttir HÓ, Nørgaard-Pedersen B, Bonefeld-Jørgensen 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.
122.
Theije CGM, Wu J, Koelink PJ, Korte-Bouws GAH, Borre Y, Kas MJH, et al: Autistic-like behavioural and neurochemical changes in a mouse model of food allergy. Behav Brain Res 2014; 261: 265–274.
123.
Wu H, Wang X, Gao J, Liang S, Hao Y, Sun C, et al: Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism. Life Sci 2017; 173: 43–54.
124.
Hegazy HG, Ali EHA, Elgoly AHM: Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model. Cytokine 2015; 71: 173–180.
125.
Kelly E, Won A, Refaeli Y, Van Parijs L: IL-2 and related cytokines can promote T cell survival by activating AKT. J Immunol 2002; 168: 597–603.
126.
Malek TR: The main function of IL-2 is to promote the development of T regulatory cells. J Leukoc Biol 2003; 74: 961–965.
127.
Fukuda T, Fukushima Y, Numao T, Ando N, Arima M, Nakajima H, et al: Role of interleukin-4 and vascular cell adhesion molecule-1 in selective eosinophil migration into the airways in allergic asthma. Am J Respir Cell Mol Biol 1996; 14: 84–94.
128.
Abdallah MW, Larsen N, Grove J, Nørgaard-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; 528–538.
129.
Greenfeder S, Umland SP, Cuss FM, Chapman RW, Egan RW: Th2 cytokines and asthma. The role of interleukin-5 in allergic eosinophilic disease. Respir Res 2001; 2: 71–79.
130.
Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH: Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007; 27: 10695–10702.
131.
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: 1–10.
132.
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.
133.
Bickel M: The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol 1993; 64: 456–460.
134.
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.
135.
Ma X, Yan W, Zheng H, Du Q, Zhang L, Ban Y, et al: Regulation of IL-10 and IL-12 production and function in macrophages and dendritic cells. F1000Res 2015; 4:pii F1000.
136.
Gee K, Guzzo C, Che Mat NF, Ma W, Kumar A: The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets 2009; 8: 40–52.
137.
Bao K, Reinhardt RL: The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 2015; 75: 25–37.
138.
Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T: The role of IL-17 and related cytokines in inflammatory autoimmune diseases. Mediators Inflamm 2017; 2017: 1–11.
139.
Zhong F, Cui D, Tao H, Du H, Xing C: IL-17A-producing T cells and associated cytokines are involved in the progression of gastric cancer. Oncol Rep 2015; 34: 2365–2374.
140.
Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim S V, et al: The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 2016; 351: 933–939.
141.
AL-Ayadhi LY, Mostafa GA: Elevated serum levels of interleukin-17A in children with autism. J Neuroinflamm 2012; 9: 595.
142.
Toussirot E: The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm Allergy Drug Targets 2012; 11: 159–68.
143.
Fischer K, Przepiera-Będzak H, Sawicki M, Walecka A, Brzosko I, Brzosko M: Serum interleukin-23 in Polish patients with systemic lupus erythematosus: association with lupus nephritis, obesity, and peripheral vascular disease. Mediators Inflamm 2017; 2017: 9401432.
144.
Ziblat A, Nuñez SY, Raffo Iraolagoitia XL, Spallanzani RG, Torres NI, Sierra JM, et al: Interleukin (IL)-23 stimulates IFN-γ secretion by CD56bright natural killer cells and enhances IL-18-driven dendritic cell activation. Front Immunol 2018; 8: 1959.
145.
Jyonouchi H, Sun S, Itokazu N: Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology 2002; 46: 76–84.
146.
Mah AY, Cooper MA: Metabolic regulation of natural killer cell IFN-γ production. Crit Rev Immunol 2016; 36: 131–147.
147.
Tostes MHFS, Teixeira HC, Gattaz WF, Brandão MAF, Raposo NRB: Altered neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. Pharmacopsychiatry 2012; 45: 241–243.
148.
Gutiérrez IL, González-Prieto M, García-Bueno B, Caso JR, Feinstein DL, Madrigal JLM: CCL2 induces the production of β2 adrenergic receptors and modifies astrocytic responses to noradrenaline. Mol Neurobiol 2018; 1–14.
149.
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.
150.
Fichna M, Żurawek M, Budny B, Komarowska H, Niechciał E, Fichna P, et al: Elevated serum RANTES chemokine in autoimmune Addison’s disease. Polish Arch Intern Med 2018; 128: 216–221.
151.
Cheng SS, Lukacs NW, Kunkel SL: Eotaxin/CCL11 suppresses IL-8/CXCL8 secretion from human dermal microvascular endothelial cells. J Immunol 2002; 168: 2887–2894.
152.
Ahmad SF, Zoheir KMA, Ansari MA, Nadeem A, Bakheet SA, AL-Ayadhi LY, et al: Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. Mol Neurobiol 2017; 54: 4390–4400.
153.
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; 24: 664–673.
154.
Enstrom AM, Onore CE, Van de Water JA, Ashwood P: Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun 2010; 24: 64–71.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.