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Psychoneuroimmunology pp 219–240Cite as

Autism Spectrum Disorders: From Immunity to Behavior

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 934))

Abstract

Autism spectrum disorders (ASD) are complex and heterogeneous with a spectrum of diverse symptoms. Mounting evidence from a number of disciplines suggests a link between immune function and ASD. Although the causes of ASD have yet to be identified, genetic studies have uncovered a host of candidate genes relating to immune regulation that are altered in ASD, while epidemiological studies have shown a relationship with maternal immune disturbances during pregnancy and ASD. Moreover, decades of research have identified numerous systemic and cellular immune abnormalities in individuals with ASD and their families. These include changes in immune cell number, differences in cytokine and chemokine production, and alterations of cellular function at rest and in response to immunological challenge. Many of these changes in immune responses are associated with increasing impairment in behaviors that are core features of ASD. Despite this evidence, much remains to be understood about the precise mechanism by which the immune system alters neurodevelopment and to what extent it is involved in the pathogenesis of ASD. With estimates of ASD as high as 1% of children, ASD is a major public health issue. Improvements in our understanding of the interactions between the nervous and immune system during early neurodevelopment and how this interaction is different in ASD will have important therapeutic implications with wide ranging benefits.

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References

  1. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  2. Fombonne E (2003) Epidemiological surveys of autism and other pervasive developmental disorders: an update. J Autism Dev Disord 33:365–382

    PubMed  Google Scholar 

  3. King M, Bearman P (2009) Diagnostic change and the increased prevalence of autism. Int J Epidemiol 38:1224–1234

    PubMed  Google Scholar 

  4. Money J, Bobrow NA, Clarke FC (1971) Autism and autoimmune disease: a family study. J Autism Child Schizophr 1:146–160

    PubMed  CAS  Google Scholar 

  5. Cooper GS, Bynum ML, Somers EC (2009) Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun 33:197–207

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  7. Atladottir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, Parner ET (2009) Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124:687–694

    PubMed  Google Scholar 

  8. Valicenti-McDermott MD, McVicar K, Cohen HJ, Wershil BK, Shinnar S (2008) Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatr Neurol 39:392–398

    PubMed  Google Scholar 

  9. Keil A, Daniels JL, Forssen U, Hultman C, Cnattingius S, Soderberg KC, Feychting M, Sparen P (2010) Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology 21:805–808

    PubMed  Google Scholar 

  10. Mouridsen SE, Rich B, Isager T, Nedergaard NJ (2007) Autoimmune diseases in parents of children with infantile autism: a case–control study. Dev Med Child Neurol 49:429–432

    PubMed  Google Scholar 

  11. Mostafa GA, Kitchener N (2009) Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr Neurol 40:107–112

    PubMed  Google Scholar 

  12. Molloy CA, Morrow AL, Meinzen-Derr J, Dawson G, Bernier R, Dunn M, Hyman SL, McMahon WM, Goudie-Nice J, Hepburn S, Minshew N, Rogers S, Sigman M, Spence MA, Tager-Flusberg H, Volkmar FR, Lord C (2006) Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA study. J Autism Dev Disord 36:317–324

    PubMed  Google Scholar 

  13. Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ (2003) Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics 112:e420

    PubMed  Google Scholar 

  14. Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN (1999) Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 14:388–394

    PubMed  CAS  Google Scholar 

  15. Mor G, Cardenas I (2010) The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 63:425–433

    PubMed  CAS  Google Scholar 

  16. Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261–280

    PubMed  Google Scholar 

  17. Chess S (1977) Follow-up report on autism in congenital rubella. J Autism Child Schizophr 7:69–81

    PubMed  CAS  Google Scholar 

  18. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS (2005) Autistic disorder and viral infections. J Neurovirol 11:1–10

    PubMed  Google Scholar 

  19. Sweeten TL, Posey DJ, McDougle CJ (2004) Brief report: autistic disorder in three children with cytomegalovirus infection. J Autism Dev Disord 34:583–586

    PubMed  Google Scholar 

  20. Atladottir HO, Thorsen P, Ostergaard 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

    PubMed  Google Scholar 

  21. Wiznitzer M (2004) Autism and tuberous sclerosis. J Child Neurol 19:675–679

    PubMed  Google Scholar 

  22. Ehninger D, Sano Y, de Vries PJ, Dies K, Franz D, Geschwind DH, Kaur M, Lee YS, Li W, Lowe JK, Nakagawa JA, Sahin M, Smith K, Whittemore V, Silva AJ (2012) Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice. Mol Psychiatry 17(1):62–70

    PubMed  CAS  Google Scholar 

  23. Smith SEP, Hsiao E, Patterson PH (2010) Activation of the maternal immune system as a risk factor for neuropsychiatric disorders. In: Zimmerman AW, Connors SL (eds) Maternal influences on fetal neurodevelopment. Springer, New York, pp 97–115

    Google Scholar 

  24. Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C (2002) Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology 26:204–215

    PubMed  CAS  Google Scholar 

  25. Gilmore JH, Jarskog LF, Vadlamudi S (2005) Maternal poly I:C exposure during pregnancy regulates TNF alpha, BDNF, and NGF expression in neonatal brain and the maternal-fetal unit of the rat. J Neuroimmunol 159:106–112

    PubMed  CAS  Google Scholar 

  26. Hsiao EY, Patterson PH (2011) Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav Immun 25(4):604–615

    PubMed  CAS  Google Scholar 

  27. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J (2008) Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 22:469–486

    PubMed  CAS  Google Scholar 

  28. Jonakait GM (2007) The effects of maternal inflammation on neuronal development: possible mechanisms. Int J Dev Neurosci 25:415–425

    PubMed  CAS  Google Scholar 

  29. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702

    PubMed  CAS  Google Scholar 

  30. Parker-Athill E, Luo D, Bailey A, Giunta B, Tian J, Shytle RD, Murphy T, Legradi G, Tan J (2009) Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol 217:20–27

    PubMed  CAS  Google Scholar 

  31. Zalcman SS (2002) Interleukin-2-induced increases in climbing behavior: inhibition by dopamine D-1 and D-2 receptor antagonists. Brain Res 944:157–164

    PubMed  CAS  Google Scholar 

  32. Ponzio NM, Servatius R, Beck K, Marzouk A, Kreider T (2007) Cytokine levels during pregnancy influence immunological profiles and neurobehavioral patterns of the offspring. Ann N Y Acad Sci 1107:118–128

    PubMed  CAS  Google Scholar 

  33. Abazyan B, Nomura J, Kannan G, Ishizuka K, Tamashiro KL, Nucifora F, Pogorelov V, Ladenheim B, Yang C, Krasnova IN (2010) Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry 68:1172–1181

    PubMed  CAS  Google Scholar 

  34. Lasala N, Zhou H (2007) Effects of maternal exposure to LPS on the inflammatory response in the offspring. J Neuroimmunol 189:95–101

    PubMed  CAS  Google Scholar 

  35. Surriga O, Ortega A, Jadeja V, Bellafronte A, Lasala N, Zhou H (2009) Altered hepatic inflammatory response in the offspring following prenatal LPS exposure. Immunol Lett 123:88–95

    PubMed  CAS  Google Scholar 

  36. Mandal M, Marzouk AC, Donnelly R, Ponzio NM (2010) Preferential development of Th17 cells in offspring of immunostimulated pregnant mice. J Reprod Immunol 87:97–100

    PubMed  CAS  Google Scholar 

  37. Mandal M, Marzouk AC, Donnelly R, Ponzio NM (2011) Maternal immune stimulation during pregnancy affects adaptive immunity in offspring to promote development of TH17 cells. Brain Behav Immun 25:863–871

    PubMed  CAS  Google Scholar 

  38. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J (2011) Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol 232(1–2):196–199

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  40. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J (2011) Altered T cell responses in children with autism. Brain Behav Immun 25(5):840–849

    PubMed  CAS  Google Scholar 

  41. Enstrom AM, Onore CE, Van de Water JA, Ashwood P (2010) Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun 24:64–71

    PubMed  CAS  Google Scholar 

  42. Heuer L, Ashwood P, Schauer J, Goines P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J (2008) Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Res 1:275–283

    PubMed  Google Scholar 

  43. Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM (2000) Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol 15:429–435

    PubMed  CAS  Google Scholar 

  44. Tincani A, Rebaioli CB, Frassi M, Taglietti M, Gorla R, Cavazzana I, Faden D, Taddei F, Lojacono A, Motta M, Trepidi L, Meroni P, Cimaz R, Ghirardello A, Doria A, Pisoni MP, Muscara M, Brucato A (2005) Pregnancy and autoimmunity: maternal treatment and maternal disease influence on pregnancy outcome. Autoimmun Rev 4:423–428

    PubMed  CAS  Google Scholar 

  45. Lee JY, Huerta PT, Zhang J, Kowal C, Bertini E, Volpe BT, Diamond B (2009) Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat Med 15:91–96

    PubMed  CAS  Google Scholar 

  46. Neri F, Chimini L, Bonomi F, Filippini E, Motta M, Faden D, Lojacono A, Rebaioli CB, Frassi M, Danieli E, Tincani A (2004) Neuropsychological development of children born to patients with systemic lupus erythematosus. Lupus 13:805–811

    PubMed  CAS  Google Scholar 

  47. McAllister DL, Kaplan BJ, Edworthy SM, Martin L, Crawford SG, Ramsey-Goldman R, Manzi S, Fries JF, Sibley J (1997) The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends. J Int Neuropsychol Soc 3:370–376

    PubMed  CAS  Google Scholar 

  48. Tincani A, Danieli E, Nuzzo M, Scarsil M, Motta M, Cimaz R, Lojacono A, Nacinovich R, Taddei F, Doria A, Brucato A, Meroni P (2006) Impact of in utero environment on the offspring of lupus patients. Lupus 15:801–807

    PubMed  CAS  Google Scholar 

  49. Fu J, Jiang Y, Liang L, Zhu H (2005) Risk factors of primary thyroid dysfunction in early infants born to mothers with autoimmune thyroid disease. Acta Paediatr 94:1043–1048

    PubMed  Google Scholar 

  50. Rolim A, Castro M, Santiago M (2006) Neonatal antiphospholipid syndrome. Lupus 15:301

    Google Scholar 

  51. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J (2008) Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 29:226–231

    PubMed  CAS  Google Scholar 

  52. Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, Vicente AM (2004) Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol 152:176–182

    PubMed  CAS  Google Scholar 

  53. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, Pearce DA (2007) Maternal antibrain antibodies in autism. Brain Behav Immun 21:351–357

    PubMed  CAS  Google Scholar 

  54. Klauck SM, Poustka A (2006) Animal models of autism. Drug Discov Today Dis Models 3:313–318

    Google Scholar 

  55. Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG (2008) Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun 22:806–816

    PubMed  CAS  Google Scholar 

  56. Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M (2009) Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: a pregnant dam mouse model. J Neuroimmunol 211:39–48

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  58. Silverman MN, Pearce BD, Biron CA, Miller AH (2005) Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 18:41–78

    PubMed  CAS  Google Scholar 

  59. Schwartz M, Kipnis J (2011) A conceptual revolution in the relationships between the brain and immunity. Brain Behav Immun 25(5):817–819

    PubMed  Google Scholar 

  60. Strous RD, Shoenfeld Y (2006) Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun 27:71–80

    PubMed  CAS  Google Scholar 

  61. Murphy TK, Kurlan R, Leckman J (2010) The immunobiology of Tourette’s disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward. J Child Adolesc Psychopharmacol 20:317–331

    PubMed  Google Scholar 

  62. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    PubMed  CAS  Google Scholar 

  63. Eaton WW, Pedersen MG, Nielsen PR, Mortensen PB (2010) Autoimmune diseases, bipolar disorder, and non-affective psychosis. Bipolar Disord 12:638–646

    PubMed  Google Scholar 

  64. Careaga M, Van de Water J, Ashwood P (2010) Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics 7:283–292

    PubMed  CAS  Google Scholar 

  65. Enstrom AM, Van de Water JA, Ashwood P (2009) Autoimmunity in autism. Curr Opin Investig Drugs 10:463–473

    PubMed  CAS  Google Scholar 

  66. Goines P, Van de Water J (2010) The immune system’s role in the biology of autism. Curr Opin Neurol 23:111–117. doi:110.1097/WCO.1090b1013e3283373514

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  68. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li X-M, Ji L, Brown T, Malik M (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116

    PubMed  CAS  Google Scholar 

  69. Ashwood P, Anthony A, Torrente F, Wakefield AJ (2004) Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol 24:664–673

    PubMed  CAS  Google Scholar 

  70. Jyonouchi H, Sun S, Le H (2001) Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 120:170–179

    PubMed  CAS  Google Scholar 

  71. Singh VK, Warren RP, Odell JD, Cole P (1991) Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children. Clin Immunol Immunopathol 61:448–455

    PubMed  CAS  Google Scholar 

  72. Singh VK (1996) Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. J Neuroimmunol 66:143–145

    PubMed  CAS  Google Scholar 

  73. Ashwood P, Wakefield AJ (2006) Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol 173:126–134

    PubMed  CAS  Google Scholar 

  74. Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen RL, Croen LA, Ozonoff S, Pessah IN, Van de Water J (2008) Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol 204:149–153

    PubMed  CAS  Google Scholar 

  75. Okada K, Hashimoto K, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Sugiyama T, Kawai M, Minabe Y, Takei N, Mori N (2007) Decreased serum levels of transforming growth factor-beta1 in patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 31:187–190

    PubMed  CAS  Google Scholar 

  76. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P (2010) Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry 167:1349–1356

    PubMed  Google Scholar 

  77. Saresella M, Marventano I, Guerini FR, Mancuso R, Ceresa L, Zanzottera M, Rusconi B, Maggioni E, Tinelli C, Clerici M (2009) An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children. Biol Psychiatry 66:978–984

    PubMed  Google Scholar 

  78. Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117:145–152

    PubMed  CAS  Google Scholar 

  79. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    PubMed  CAS  Google Scholar 

  80. Palis J, Yoder MC (2001) Yolk-sac hematopoiesis: the first blood cells of mouse and man. Exp Hematol 29:927–936

    PubMed  CAS  Google Scholar 

  81. Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141:775–785

    PubMed  CAS  Google Scholar 

  82. Derecki NC, Quinnies KM, Kipnis J (2011) Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice. Brain Behav Immun 25(3):379–385

    PubMed  CAS  Google Scholar 

  83. Cacci E, Claasen JH, Kokaia Z (2005) Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res 80:789–797

    PubMed  CAS  Google Scholar 

  84. Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059

    PubMed  CAS  Google Scholar 

  85. Widera D, Mikenberg I, Elvers M, Kaltschmidt C, Kaltschmidt B (2006) Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling. BMC Neurosci 7:64

    PubMed  Google Scholar 

  86. Banks WA, Farr SA, La Scola ME, Morley JE (2001) Intravenous human interleukin-1 alpha impairs memory processing in mice: dependence on blood–brain barrier transport into posterior division of the septum. J Pharmacol Exp Ther 299:536–541

    PubMed  CAS  Google Scholar 

  87. Depino AM, Alonso M, Ferrari C, del Rey A, Anthony D, Besedovsky H, Medina JH, Pitossi F (2004) Learning modulation by endogenous hippocampal IL-1: blockade of endogenous IL-1 facilitates memory formation. Hippocampus 14:526–535

    PubMed  CAS  Google Scholar 

  88. Goshen I, Yirmiya R (2009) Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocrinol 30:30–45

    PubMed  CAS  Google Scholar 

  89. Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO (1998) A neuromodulatory role of interleukin-1beta in the hippocampus. Proc Natl Acad Sci U S A 95:7778–7783

    PubMed  CAS  Google Scholar 

  90. Baier PC, May U, Scheller J, Rose-John S, Schiffelholz T (2009) Impaired hippocampus-dependent and -independent learning in IL-6 deficient mice. Behav Brain Res 200:192–196

    PubMed  CAS  Google Scholar 

  91. Harden LM, du Plessis I, Poole S, Laburn HP (2008) Interleukin (IL)-6 and IL-1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Brain Behav Immun 22:838–849

    PubMed  CAS  Google Scholar 

  92. Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen RL, Pessah IN, Hertz-Picciotto I, Van de Water JA, Sharp FR, Ashwood P (2009) Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun 23:124–133

    PubMed  CAS  Google Scholar 

  93. Warren RP, Foster A, Margaretten NC (1987) Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry 26:333–335

    PubMed  CAS  Google Scholar 

  94. Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K, Hirani K, Neubrander J, Woeller KN, O’Hara N, Usman A, Schneider C, Hebroni F, Berookhim J, McCandless J (2008) Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15. J Neuroimmunol 205:148–154

    PubMed  CAS  Google Scholar 

  95. Ashwood P, Corbett BA, Kantor A, Schulman H, Van de Water J, Amaral DG (2011) In search of cellular immunophenotypes in the blood of children with autism. PLoS One 6:e19299

    PubMed  CAS  Google Scholar 

  96. Wilson EH, Weninger W, Hunter CA (2010) Trafficking of immune cells in the central nervous system. J Clin Invest 120:1368–1379

    PubMed  CAS  Google Scholar 

  97. Lima FRS, da Fonseca ACC, Faria GP, Dubois LGF, Alves TR, Faria J, Neto VM (2010) The origin of microglia and the development of the brain. In: Ulrich H (ed) Perspectives of stem cells. Springer, Netherlands, pp 171–189

    Google Scholar 

  98. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, Geschwind DH (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380–384

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  100. Jyonouchi H, Sun S, Itokazu N (2002) Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology 46:76–84

    PubMed  CAS  Google Scholar 

  101. Jyonouchi H, Geng L, Cushing-Ruby A, Quraishi H (2008) Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study. J Neuroinflammation 5:52

    PubMed  Google Scholar 

  102. Rosen NJ, Yoshida CK, Croen LA (2007) Infection in the first 2 years of life and autism spectrum disorders. Pediatrics 119:e61–e69

    PubMed  Google Scholar 

  103. Moynihan JA, Santiago FM (2007) Brain behavior and immunity: twenty years of T cells. Brain Behav Immun 21:872–880

    PubMed  CAS  Google Scholar 

  104. Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275

    PubMed  CAS  Google Scholar 

  105. Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M (2004) T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A 101:8180–8185

    PubMed  CAS  Google Scholar 

  106. Serpe CJ, Coers S, Sanders VM, Jones KJ (2003) CD4+ T, but not CD8+ or B, lymphocytes mediate facial motoneuron survival after facial nerve transection. Brain Behav Immun 17:393–402

    PubMed  Google Scholar 

  107. Deboy CA, Xin J, Byram SC, Serpe CJ, Sanders VM, Jones KJ (2006) Immune-mediated neuroprotection of axotomized mouse facial motoneurons is dependent on the IL-4/STAT6 signaling pathway in CD4(+) T cells. Exp Neurol 201:212–224

    PubMed  CAS  Google Scholar 

  108. Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067–1080

    PubMed  CAS  Google Scholar 

  109. Fairweather D, Cihakova D (2009) Alternatively activated macrophages in infection and autoimmunity. J Autoimmun 33:222–230

    PubMed  CAS  Google Scholar 

  110. Stubbs EG (1976) Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. J Autism Child Schizophr 6:269–274

    PubMed  CAS  Google Scholar 

  111. Warren RP, Margaretten NC, Pace NC, Foster A (1986) Immune abnormalities in patients with autism. J Autism Dev Disord 16:189–197

    PubMed  CAS  Google Scholar 

  112. Ashwood P, Anthony A, Pellicer AA, Torrente F, Walker-Smith JA, Wakefield AJ (2003) Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol 23:504–517

    PubMed  Google Scholar 

  113. Plioplys AV, Greaves A, Kazemi K, Silverman E (1994) Lymphocyte function in autism and Rett syndrome. Neuropsychobiology 29:12–16

    PubMed  CAS  Google Scholar 

  114. Gupta S, Aggarwal S, Rashanravan B, Lee T (1998) Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol 85:106–109

    PubMed  CAS  Google Scholar 

  115. Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M, Parvaneh N, Abolhassani H, Pourpak Z, Moin M (2009) IgA deficiency: correlation between clinical and immunological phenotypes. J Clin Immunol 29:130–136

    PubMed  CAS  Google Scholar 

  116. Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Daniels WW, Torres AR (1997) Brief report: immunoglobulin A deficiency in a subset of autistic subjects. J Autism Dev Disord 27:187–192

    PubMed  CAS  Google Scholar 

  117. Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL, Van de Water JA, Ashwood P (2009) Increased IgG4 levels in children with autism disorder. Brain Behav Immun 23:389–395

    PubMed  CAS  Google Scholar 

  118. Croonenberghs J, Wauters A, Devreese K, Verkerk R, Scharpe S, Bosmans E, Egyed B, Deboutte D, Maes M (2002) Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med 32:1457–1463

    PubMed  CAS  Google Scholar 

  119. Grether JK, Croen LA, Anderson MC, Nelson KB, Yolken RH (2010) Neonatally measured immunoglobulins and risk of autism. Autism Res 3:323–332

    PubMed  Google Scholar 

  120. Qaqish BF, Prisayanh P, Qian Y, Andraca E, Li N, Aoki V, Hans-Filho G, dos Santos V, Rivitti EA, Diaz LA (2009) Development of an IgG4-based predictor of endemic pemphigus foliaceus (fogo selvagem). J Invest Dermatol 129:110–118

    PubMed  CAS  Google Scholar 

  121. Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J (2007) Autoantibodies in autism spectrum disorders (ASD). Ann N Y Acad Sci 1107:79–91

    PubMed  CAS  Google Scholar 

  122. Todd RD, Ciaranello RD (1985) Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proc Natl Acad Sci U S A 82:612–616

    PubMed  CAS  Google Scholar 

  123. Connolly AM, Chez M, Streif EM, Keeling RM, Golumbek PT, Kwon JM, Riviello JJ, Robinson RG, Neuman RJ, Deuel RM (2006) Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biol Psychiatry 59:354–363

    PubMed  CAS  Google Scholar 

  124. Singh VK, Warren RP, Odell JD, Warren WL, Cole P (1993) Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun 7:97–103

    PubMed  CAS  Google Scholar 

  125. Singh VK, Warren R, Averett R, Ghaziuddin M (1997) Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol 17:88–90

    PubMed  CAS  Google Scholar 

  126. Libbey JE, Coon HH, Kirkman NJ, Sweeten TL, Miller JN, Stevenson EK, Lainhart JE, McMahon WM, Fujinami RS (2008) Are there enhanced MBP autoantibodies in autism? J Autism Dev Disord 38:324–332

    PubMed  Google Scholar 

  127. Kirkman NJ, Libbey JE, Sweeten TL, Coon HH, Miller JN, Stevenson EK, Lainhart JE, McMahon WM, Fujinami RS (2008) How relevant are GFAP autoantibodies in autism and Tourette syndrome? J Autism Dev Disord 38:333–341

    PubMed  Google Scholar 

  128. Morris CM, Zimmerman AW, Singer HS (2009) Childhood serum anti-fetal brain antibodies do not predict autism. Pediatr Neurol 41:288–290

    PubMed  Google Scholar 

  129. Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L, Hansen R, Hertz-Picciotto I, Ashwood P, Van de Water J (2011) Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun 25(3):514–523

    PubMed  CAS  Google Scholar 

  130. Wills S, Rossi CC, Bennett J, Cerdeno VM, Ashwood P, Amaral DG, Van de Water J (2011) Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism. Mol Autism 2:5

    PubMed  Google Scholar 

  131. Torrente F, Anthony A, Heuschkel RB, Thomson MA, Ashwood P, Murch SH (2004) Focal-enhanced gastritis in regressive autism with features distinct from Crohn’s and Helicobacter pylori gastritis. Am J Gastroenterol 99:598–605

    PubMed  Google Scholar 

  132. Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH (2002) Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry 7(375–382):334

    Google Scholar 

  133. Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH (2001) Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr 138:366–372

    PubMed  CAS  Google Scholar 

  134. de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, Bravaccio C (2010) Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr 51:418–424

    PubMed  Google Scholar 

  135. D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O (1996) Abnormal intestinal permeability in children with autism. Acta Paediatr 85:1076–1079

    PubMed  Google Scholar 

  136. Wang LW, Tancredi DJ, Thomas DW (2011) The prevalence of gastrointestinal problems in children across the United States with autism spectrum disorders from families with multiple affected members. J Dev Behav Pediatr 32:351–360

    PubMed  Google Scholar 

  137. Buie T, Campbell DB, Fuchs GJ III, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H (2010) Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125(suppl 1):S1–S18

    PubMed  Google Scholar 

  138. Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11:22

    PubMed  Google Scholar 

  139. Genuis SJ, Bouchard TP (2010) Celiac disease presenting as autism. J Child Neurol 25(1):114–119

    PubMed  Google Scholar 

  140. Constantino JN, Todd RD (2000) Genetic structure of reciprocal social behavior. Am J Psychiatry 157:2043–2045

    PubMed  CAS  Google Scholar 

  141. Ronald A, Happe F, Bolton P, Butcher LM, Price TS, Wheelwright S, Baron-Cohen S, Plomin R (2006) Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry 45:691–699

    PubMed  Google Scholar 

  142. Kolevzon A, Smith CJ, Schmeidler J, Buxbaum JD, Silverman JM (2004) Familial symptom domains in monozygotic siblings with autism. Am J Med Genet B Neuropsychiatr Genet 129B:76–81

    PubMed  Google Scholar 

  143. Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R, Reiss AL, Pearlson GD (2004) Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. Am J Psychiatry 161:539–546

    PubMed  Google Scholar 

  144. Jorde LB, Hasstedt SJ, Ritvo ER, Mason-Brothers A, Freeman BJ, Pingree C, McMahon WM, Petersen B, Jenson WR, Mo A (1991) Complex segregation analysis of autism. Am J Hum Genet 49:932–938

    PubMed  CAS  Google Scholar 

  145. Stubbs EG, Magenis RE (1980) HLA and autism. J Autism Dev Disord 10:15–19

    PubMed  CAS  Google Scholar 

  146. Daniels WW, Warren RP, Odell JD, Maciulis A, Burger RA, Warren WL, Torres AR (1995) Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology 32:120–123

    PubMed  CAS  Google Scholar 

  147. Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD, Zimmerman AW (2006) HLA-DR4 in families with autism. Pediatr Neurol 35:303–307

    PubMed  Google Scholar 

  148. Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D (2002) The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum Immunol 63:311–316

    PubMed  CAS  Google Scholar 

  149. Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, DeWitt CW, McCullough M (1992) Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics 36:203–207

    PubMed  CAS  Google Scholar 

  150. Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD (2008) Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 4:e1000024

    PubMed  Google Scholar 

  151. Guerini FR, Bolognesi E, Manca S, Sotgiu S, Zanzottera M, Agliardi C, Usai S, Clerici M (2009) Family-based transmission analysis of HLA genetic markers in Sardinian children with autistic spectrum disorders. Hum Immunol 70:184–190

    PubMed  CAS  Google Scholar 

  152. Guerini FR, Bolognesi E, Chiappedi M, De Silvestri A, Ghezzo A, Zanette M, Rusconi B, Manca S, Sotgiu S, Agliardi C, Clerici M (2011) HLA polymorphisms in Italian children with autism spectrum disorders: results of a family based linkage study. J Neuroimmunol 230:135–142

    PubMed  CAS  Google Scholar 

  153. Mascart-Lemone F, Hauptmann G, Goetz J, Duchateau J, Delespesse G, Vray B, Dab I (1983) Genetic deficiency of C4 presenting with recurrent infections and a SLE-like disease. Genetic and immunologic studies. Am J Med 75:295–304

    PubMed  CAS  Google Scholar 

  154. Odell D, Maciulis A, Cutler A, Warren L, McMahon WM, Coon H, Stubbs G, Henley K, Torres A (2005) Confirmation of the association of the C4B null allele in autism. Hum Immunol 66:140–145

    PubMed  CAS  Google Scholar 

  155. Warren RP, Burger RA, Odell D, Torres AR, Warren WL (1994) Decreased plasma concentrations of the C4B complement protein in autism. Arch Pediatr Adolesc Med 148:180–183

    PubMed  CAS  Google Scholar 

  156. Warren RP, Yonk J, Burger RW, Odell D, Warren WL (1995) DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology 31:53–57

    PubMed  CAS  Google Scholar 

  157. Mostafa GA, Shehab AA (2010) The link of C4B null allele to autism and to a family history of autoimmunity in Egyptian autistic children. J Neuroimmunol 223:115–119

    PubMed  CAS  Google Scholar 

  158. Corbett BA, Kantor AB, Schulman H, Walker WL, Lit L, Ashwood P, Rocke DM, Sharp FR (2007) A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol Psychiatry 12:292–306

    PubMed  CAS  Google Scholar 

  159. Grigorenko EL, Han SS, Yrigollen CM, Leng L, Mizue Y, Anderson GM, Mulder EJ, de Bildt A, Minderaa RB, Volkmar FR, Chang JT, Bucala R (2008) Macrophage migration inhibitory factor and autism spectrum disorders. Pediatrics 122:e438–e445

    PubMed  Google Scholar 

  160. Correll PH, Morrison AC, Lutz MA (2004) Receptor tyrosine kinases and the regulation of macrophage activation. J Leukoc Biol 75:731–737

    PubMed  CAS  Google Scholar 

  161. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P (2006) A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A 103:16834–16839

    PubMed  CAS  Google Scholar 

  162. Lintas C, Sacco R, Garbett K, Mirnics K, Militerni R, Bravaccio C, Curatolo P, Manzi B, Schneider C, Melmed R, Elia M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM (2009) Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry 14:705–718

    PubMed  CAS  Google Scholar 

  163. Serajee FJ, Zhong H, Mahbubul Huq AH (2006) Association of Reelin gene polymorphisms with autism. Genomics 87:75–83

    PubMed  CAS  Google Scholar 

  164. Zhang H, Liu X, Zhang C, Mundo E, Macciardi F, Grayson DR, Guidotti AR, Holden JJ (2002) Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry 7:1012–1017

    PubMed  CAS  Google Scholar 

  165. Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER, DeLong GR, Moore JH, McCauley JL, Sutcliffe JS, Ashley-Koch AE, Cuccaro ML, Folstein SE, Gilbert JR, Pericak-Vance MA (2005) Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 10:563–571

    PubMed  CAS  Google Scholar 

  166. Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A (2007) Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am J Med Genet A 143:589–593

    PubMed  Google Scholar 

  167. Splawski I, Timothy KW, Priori SG, Napolitano C, Bloise R (1993) Timothy syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K (eds) GeneReviews. University of Washington, Seattle, WA

    Google Scholar 

  168. Nagarajan RP, Patzel KA, Martin M, Yasui DH, Swanberg SE, Hertz-Picciotto I, Hansen RL, Van de Water J, Pessah IN, Jiang R, Robinson WP, LaSalle JM (2008) MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res 1:169–178

    PubMed  Google Scholar 

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  1. Department of Medical Microbiology and Immunology and the M.I.N.D. Institute, University of California at Davis, Davis, CA, USA

    Milo Careaga & Paul Ashwood

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    Qing Yan

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Careaga, M., Ashwood, P. (2012). Autism Spectrum Disorders: From Immunity to Behavior. In: Yan, Q. (eds) Psychoneuroimmunology. Methods in Molecular Biology, vol 934. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-071-7_12

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  • DOI: https://doi.org/10.1007/978-1-62703-071-7_12

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