Skip to main content
SpringerLink
Log in

Maternally Acting Alleles in Autism and Other Neurodevelopmental Disorders: The Role of HLA-DR4 Within the Major Histocompatibility Complex

  • Chapter
  • First Online:
Maternal Influences on Fetal Neurodevelopment

  • 837 Accesses

Abstract

Autism is a common and devastating neurodevelopmental disorder that begins in early childhood and whose causes are believed to be the interactions of multiple genes with environmental factors. These genes are usually thought of as acting in the individual with autism. In this chapter, an additional category of genes is considered: maternal genes that act in the mothers (most likely) during pregnancy to contribute to the autism phenotype of their affected offspring.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Johnson WG (2003) Teratogenic alleles and neurodevelopmental disorders. Bioessays 25:464–477.

    Article  PubMed  CAS  Google Scholar 

  2. Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, Mitchell LE (2002) Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet 71(5):1222–1226.

    Article  PubMed  CAS  Google Scholar 

  3. Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-Santiago MF et al (2007) Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med 161(4):356–361.

    PubMed  Google Scholar 

  4. Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, Williams TA et al (2009) HLA-DR4 as a risk allele for autism, acting in mothers of probands possibly during pregnancy. Arch Pediatr Adolesc Med 163(6):542–546.

    Article  PubMed  Google Scholar 

  5. Fisher RA (1944) An “incomplete” antibody in human serum. Nature 153:771–772, cited by Race RR.

    Article  Google Scholar 

  6. Komrower GM, Sardharwalla IB, Coutts JM, Ingham D (1979) Management of maternal phenylketonuria: an emerging clinical problem. Br Med J 1(6175):1383–1387.

    Article  PubMed  CAS  Google Scholar 

  7. Hollister JM, Laing P, Mednick SA (1996) Rhesus incompatibility as a risk factor for schizophrenia in male adults. Arch Gen Psychiatry 53:19–24.

    Article  PubMed  CAS  Google Scholar 

  8. Palmer CG, Turunen JA, Sinsheimer JS, Minassian S, Paunio T, Lonnqvist J et al (2002) RHD maternal–fetal genotype incompatibility increases schizophrenia susceptibility. Am J Hum Genet 71(6):1312–1319.

    Article  PubMed  CAS  Google Scholar 

  9. Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, Mills JL et al (2002) A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet 71(5):1207–1215.

    Article  PubMed  CAS  Google Scholar 

  10. Chen D, Hu Y, Yang F, Li Z, Wu B, Fang Z et al (2005) Cytochrome P450 gene polymorphisms and risk of low birth weight. Genet Epidemiol 28(4):368–375.

    Article  PubMed  Google Scholar 

  11. Jensen LE, Hoess K, Mitchell LE, Whitehead AS (2006) Loss of function polymorphisms in NAT1 protect against spina bifida. Hum Genet 120(1):52–57.

    Article  PubMed  CAS  Google Scholar 

  12. Jensen LE, Etheredge AJ, Brown KS, Mitchell LE, Whitehead AS (2006) Maternal genotype for the monocyte chemoattractant protein 1 A(-2518)G promoter polymorphism is associated with the risk of spina bifida in offspring. Am J Med Genet A 140(10):1114–1118.

    PubMed  Google Scholar 

  13. Descamps OS, Bruniaux M, Guilmot PF, Tonglet R, Heller FR (2004) Lipoprotein concentrations in newborns are associated with allelic variations in their mothers. Atherosclerosis 172(2):287–298.

    Article  PubMed  CAS  Google Scholar 

  14. Carroll WD, Lenney W, Child F, Strange RC, Jones PW, Fryer AA (2005) Maternal glutathione S-transferase GSTP1 genotype is a specific predictor of phenotype in children with asthma. Pediatr Allergy Immunol 16(1):32–39.

    Article  PubMed  CAS  Google Scholar 

  15. Martinelli M, Scapoli L, Pezzetti F, Carinci F, Carinci P, Stabellini G et al (2001) C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers? Am J Med Genet 98(4):357–360.

    Article  PubMed  CAS  Google Scholar 

  16. van Beynum IM, Kapusta L, den Heijer M, Vermeulen SH, Kouwenberg M, Daniels O et al (2006) Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J 27(8):981–987.

    Article  PubMed  CAS  Google Scholar 

  17. Rai AK, Singh S, Mehta S, Kumar A, Pandey LK, Raman R (2006) MTHFR C677T and A1298C polymorphisms are risk factors for Down’s syndrome in Indian mothers. J Hum Genet 51(4):278–283.

    Article  PubMed  CAS  Google Scholar 

  18. Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD et al (2006) HLA-DR4 in families with autism. Pediatr Neurol 35(5):303–307.

    Article  PubMed  Google Scholar 

  19. Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL et al (1991) Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol 83:438–440.

    Article  PubMed  CAS  Google Scholar 

  20. ten Wolde S, Breedveld FC, de Vries RR, D’Amaro J, Rubenstein P, Schreuder GM et al (1993) Influence of non-inherited maternal HLA antigens on occurrence of rheumatoid arthritis. Lancet 341(8839):200–202.

    Article  PubMed  Google Scholar 

  21. van der Horst-Bruinsma I, Hazes JM, Schreuder GM, Radstake TR, Barrera P, van de Putte LB et al (1998) Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis. Ann Rheum Dis 57(11):672–675.

    Article  PubMed  Google Scholar 

  22. Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Daniels WW et al (1996) Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J Neuroimmunol 67:97–102.

    Article  PubMed  CAS  Google Scholar 

  23. Zusterzeel PL, Nelen WL, Roelofs HM, Peters WH, Blom HJ, Steegers EA (2000) Polymorphisms in biotransformation enzymes and the risk for recurrent early pregnancy loss. Mol Hum Reprod 6(5):474–478.

    Article  PubMed  CAS  Google Scholar 

  24. De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Cama A et al (2001) Polymorphisms in genes involved in folate metabolism as risk factors for NTDs. Eur J Pediatr Surg 11(Suppl 1):S14–S17.

    Article  PubMed  Google Scholar 

  25. O’Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M et al (2002) MTRR and MTHFR polymorphism: link to Down syndrome? Am J Med Genet 107(2):151–155.

    Article  PubMed  Google Scholar 

  26. van Rooij IA, Wegerif MJ, Roelofs HM, Peters WH, Kuijpers-Jagtman AM, Zielhuis GA et al (2001) Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene–environment interaction. Epidemiology 12(5):502–507.

    Article  PubMed  Google Scholar 

  27. Gonzalez-Herrera LJ, Flores-Machado MP, Castillo-Zapata IC, Garcia-Escalante MG, Pinto-Escalante D, Gonzalez-Del Angel A (2002) Interaction of C677T and A1298C polymorphisms in the MTHFR gene in association with neural tube defects in the State of Yucatan, Mexico. Am J Hum Genet 71(4):367 (abstract).

    Google Scholar 

  28. Sata F, Yamada H, Kondo T, Gong Y, Tozaki S, Kobashi G et al (2003) Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss. Mol Hum Reprod 9(3):165–169.

    Article  PubMed  CAS  Google Scholar 

  29. Johnson WG, Stenroos ES, Spychala J, Buyske S, Chatkupt S, Ming X (2004) A new 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) – a risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet 124A(4):339–345.

    Article  PubMed  Google Scholar 

  30. Suryanarayana V, Deenadayal M, Singh L (2004) Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population. Hum Reprod 19(11):2648–2652.

    Article  PubMed  CAS  Google Scholar 

  31. Johnson WG, Scholl TO, Spychala JR, Buyske S, Stenroos ES, Chen X (2005) Common dihydrofolate reductase 19 bp deletion allele: a novel risk factor for preterm delivery. Am J Clin Nutr 81:664–668.

    PubMed  CAS  Google Scholar 

  32. Scala I, Granese B, Sellitto M, Salome S, Sammartino A, Pepe A et al (2006) Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring. Genet Med 8(7):409–416.

    Article  PubMed  CAS  Google Scholar 

  33. Johnson WG, Sreenath M, Buyske S, Stenroos ES (2008) Teratogenic alleles in autism and other neurodevelopmental disorders. In: Zimmerman A (ed) Autism: current theories and evidence. Humana, Totowa, pp 41–68.

    Google Scholar 

  34. Levine P, Stetson RE (1939) An unusual case of intragroup agglutination. JAMA 113:126–127.

    Article  Google Scholar 

  35. Levine P, Burnham L, Katzin EM, Vogel P (1941) The role of iso-immunization in the pathogenesis of erythroblastosis fetalis. Am J Obstet Gynecol 42:925–937.

    Google Scholar 

  36. Flegel WA (2006) Molecular genetics of RH and its clinical application. Transfus Clin Biol 13(1–2):4–12.

    Article  PubMed  CAS  Google Scholar 

  37. Yan L, Wu J, Zhu F, Hong X, Xu X (2007) Molecular basis of D variants in Chinese persons. Transfusion 47(3):471–477.

    Article  PubMed  CAS  Google Scholar 

  38. Westgren M, Ek S, Remberger M, Ringden O, Stangenberg M (1995) Cytokines in fetal blood and amniotic fluid in Rh-immunized pregnancies. Obstet Gynecol 86(2):209–213.

    Article  PubMed  CAS  Google Scholar 

  39. Guttler F, Azen C, Guldberg P, Romstad A, Hanley WB, Levy HL et al (1999) Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study. Pediatrics 104(2 Pt 1):258–262.

    Article  PubMed  CAS  Google Scholar 

  40. Koch R, Levy HL, Matalon R, Rouse B, Hanley WB, Trefz F et al (1994) The international collaborative study of maternal phenylketonuria: status report 1994. Acta Paediatr Suppl 407:111–119.

    Article  PubMed  CAS  Google Scholar 

  41. Allen RJ, Brunberg J, Schwartz E, Schaefer AM, Jackson G (1994) MRI characterization of cerebral dysgenesis in maternal PKU. Acta Paediatr Suppl 407:83–85.

    Article  PubMed  CAS  Google Scholar 

  42. Menkes JH (1990) Textbook of child neurology, 4th edn. Lea & Febiger, Philadelphia.

    Google Scholar 

  43. Buyske S (2008) Maternal genotype effects can alias case genotype effects in case-control studies. Eur J Hum Genet 16(7):783–785.

    Article  PubMed  Google Scholar 

  44. Tiwari HK, Barnholtz-Sloan J, Wineinger N, Padilla MA, Vaughan LK, Allison DB (2008) Review and evaluation of methods correcting for population stratification with a focus on underlying statistical principles. Hum Hered 66(2):67–86.

    Article  PubMed  Google Scholar 

  45. Shi M, Umbach DM, Vermeulen SH, Weinberg CR (2008) Making the most of case-mother/control-mother studies. Am J Epidemiol 168(5):541–547.

    Article  PubMed  CAS  Google Scholar 

  46. Mitchell LE (1997) Differentiating between fetal and maternal genotypic effects, using the transmission test for linkage disequilibrium. Am J Hum Genet 60:1006–1007.

    PubMed  CAS  Google Scholar 

  47. Johnson WG (1999) The DNA polymorphism-diet-cofactor-development hypothesis and the gene-teratogen model for schizophrenia and other developmental disorders. Am J Med Genet (Neuropsychiatr Genet) 88:311–323.

    Article  CAS  Google Scholar 

  48. Weinberg CR, Wilcox AJ, Lie RT (1998) A log–linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 62(4):969–978.

    Article  PubMed  CAS  Google Scholar 

  49. Wilcox AJ, Weinberg CR, Lie RT (1998) Distinguishing the effects of maternal and offspring genes through studies of “case-parent triads”. Am J Epidemiol 148(9):893–901.

    Article  PubMed  CAS  Google Scholar 

  50. Weinberg CR, Wilcox AJ (1999) Re: “Distinguishing the effects of maternal and offspring genes through studies of ‘case-parent triads’” and “a new method for estimating the risk ratio in studies using case-parental control design”. Am J Epidemiol 150(4):428–429.

    Article  PubMed  CAS  Google Scholar 

  51. Weinberg CR (1999) Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Hum Genet 65(1):229–235.

    Article  PubMed  CAS  Google Scholar 

  52. Starr JR, Hsu L, Schwartz SM (2005) Assessing maternal genetic associations: a comparison of the log–linear approach to case-parent triad data and a case-control approach. Epidemiology 16(3):294–303.

    Article  PubMed  Google Scholar 

  53. Minassian SL, Palmer CG, Sinsheimer JS (2005) An exact maternal–fetal genotype incompatibility (MFG) test. Genet Epidemiol 28(1):83–95.

    Article  PubMed  Google Scholar 

  54. Mitchell LE, Weinberg CR (2005) Evaluation of offspring and maternal genetic effects on disease risk using a family-based approach: the “pent” design. Am J Epidemiol 162(7):676–685.

    Article  PubMed  Google Scholar 

  55. Mitchell LE, Starr JR, Weinberg CR, Sinsheimer JS, Mitchell LE, Murray JC (2005) Maternal genetic effects. Presented at Annual meeting, Concurrent invited sessions I, #14, American Society of Human Genetics, Salt Lake City UT, Wed, Oct 26, 8–10 pm, 2005, Moderator, Laura E Mitchell.

    Google Scholar 

  56. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, D.C.

    Google Scholar 

  57. Rapin I (1997) Autism. N Engl J Med 337:97–104.

    Article  PubMed  CAS  Google Scholar 

  58. Muhle R, Trentacoste SV, Rapin I (2004) The genetics of autism. Pediatrics 113(5): e472–e486.

    Article  PubMed  Google Scholar 

  59. Szatmari P (2003) The causes of autism spectrum disorders. Br Med J 326(7382):173–174.

    Article  Google Scholar 

  60. Lawler CP, Croen LA, Grether JK, Van de Water J (2004) Identifying environmental contributions to autism: provocative clues and false leads. Ment Retard Dev Disabil Res Rev 10(4):292–302.

    Article  PubMed  Google Scholar 

  61. Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J (1996) Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370:247–261.

    Article  PubMed  CAS  Google Scholar 

  62. Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C (1994) Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 36:351–356.

    Article  PubMed  CAS  Google Scholar 

  63. Piven J, O’Leary D (1999) Neuroimaging in autism. Child Adolesc Psychiatr Clin N Am 6:305–323.

    Google Scholar 

  64. Casanova MF, Buxhoeveden D, Gomez J (2003) Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist 9(6):496–507.

    Article  PubMed  Google Scholar 

  65. Casanova MF, Buxhoeveden DP, Switala AE, Roy E (2002) Minicolumnar pathology in autism. Neurology 58(3):428–432.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  68. 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(4):311–316.

    Article  PubMed  CAS  Google Scholar 

  69. (1990) HLA typing. In: Zachary AA, Teresi GA (eds). ASHI laboratory manual, American Society for Histocompatibility and Immunogenetics, New York, p 195.

    Google Scholar 

  70. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516.

    PubMed  CAS  Google Scholar 

  71. 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.

    Article  PubMed  CAS  Google Scholar 

  72. Sadeharju K, Knip M, Hiltunen M, Akerblom HK, Hyoty H (2003) The HLA-DR phenotype modulates the humoral immune response to enterovirus antigens. Diabetologia 46(8):1100–1105.

    Article  PubMed  CAS  Google Scholar 

  73. Holladay SD, Sharova LV, Punareewattana K, Hrubec TC, Gogal RM Jr, Prater MR et al (2002) Maternal immune stimulation in mice decreases fetal malformations caused by teratogens. Int Immunopharmacol 2(2–3):325–332.

    Article  PubMed  CAS  Google Scholar 

  74. Sharova L, Sura P, Smith BJ, Gogal RM Jr, Sharov AA, Ward DL et al (2000) Nonspecific stimulation of the maternal immune system. II. Effects on gene expression in the fetus. Teratology 62(6):420–428.

    Article  PubMed  CAS  Google Scholar 

  75. Holladay SD, Sharova L, Smith BJ, Gogal RM Jr, Ward DL, Blaylock BL (2000) Nonspecific stimulation of the maternal immune system. I. Effects On teratogen-induced fetal malformations. Teratology 62(6):413–419.

    Article  PubMed  CAS  Google Scholar 

  76. Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I et al (2006) The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci 26(18):4752–4762.

    Article  PubMed  CAS  Google Scholar 

  77. Serajee FJ, Zhong H, Mahbubul Huq AH (2006) Association of Reelin gene polymorphisms with autism. Genomics 87(1):75–83.

    Article  PubMed  CAS  Google Scholar 

  78. Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER et al (2005) Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 10(6):563–571.

    Article  PubMed  CAS  Google Scholar 

  79. Fatemi SH, Stary JM, Egan EA (2002) Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol 22(2):139–152.

    Article  PubMed  CAS  Google Scholar 

  80. Fatemi SH, Stary JM, Halt AR, Realmuto GR (2001) Dysregulation of reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord 31(6):529–535.

    Article  PubMed  CAS  Google Scholar 

  81. Patterson PH, Xu W, Smith SEP, Devarman BE (2008) Maternal immune activation, cytokines and autism. In: Zimmerman AW (ed) Autism. Current theories and evidence. Humana, Totowa, NJ, pp 289–307.

    Google Scholar 

  82. Serajee FJ, Nabi R, Zhong H, Huq M (2004) Polymorphisms in xenobiotic metabolism genes and autism. J Child Neurol 19(6):413–417.

    PubMed  Google Scholar 

  83. Buyske S, Williams TA, Mars AE, Stenroos ES, Ming SX, Wang R et al (2006) Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism. BMC Genet 7(1):8.

    Article  PubMed  CAS  Google Scholar 

  84. Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH, Buyske S (2010) Genetic variant of glutathione peroxidase 1 in autism. Brain Dev 32(2):105–109.

    Article  PubMed  Google Scholar 

  85. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW et al (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80(6):1611–1617.

    PubMed  CAS  Google Scholar 

  86. Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC (2005) Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 73(5):379–384.

    Article  PubMed  CAS  Google Scholar 

  87. Ling S, Li Z, Borschukova O, Xiao L, Pumpens P, Holoshitz J (2007) The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway. Arthritis Res Ther 9(1):R5.

    Article  PubMed  CAS  Google Scholar 

  88. Feitsma AL, Worthington J, van der Helm-van Mil AH, Plant D, Thomson W, Ursum J et al (2007) Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis development. Proc Natl Acad Sci U S A 104(50):19966–19970.

    Article  PubMed  CAS  Google Scholar 

  89. de LB I, Battini L, Simonelli M, Clemente F, Brunori E, Mariotti ML et al (2000) Increased HLA-DR homozygosity associated with pre-eclampsia. Hum Reprod 15(8):1807–1812.

    Article  Google Scholar 

  90. Jonakait GM (2007) The effects of maternal inflammation on neuronal development: possible mechanisms. Int J Dev Neurosci 25(7):415–425.

    Article  PubMed  CAS  Google Scholar 

  91. Bauer S, Kerr BJ, Patterson PH (2007) The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 8(3):221–232.

    Article  PubMed  CAS  Google Scholar 

  92. Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN (2006) The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psychiatry 11(1):47–55.

    Article  PubMed  CAS  Google Scholar 

  93. Bell MJ, Hallenbeck JM, Gallo V (2004) Determining the fetal inflammatory response in an experimental model of intrauterine inflammation in rats. Pediatr Res 56(4):541–546.

    Article  PubMed  CAS  Google Scholar 

  94. Urakubo A, Jarskog LF, Lieberman JA, Gilmore JH (2001) Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res 47(1):27–36.

    Article  PubMed  CAS  Google Scholar 

  95. 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(1–2):106–112.

    Article  PubMed  CAS  Google Scholar 

  96. Molloy CA, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K, Manning-Court P et al (2006) Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 172(1–2):198–205.

    Article  PubMed  CAS  Google Scholar 

  97. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131(6):1164–1178.

    Article  PubMed  CAS  Google Scholar 

  98. Goddard CA, Butts DA, Shatz CJ (2007) Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci U S A 104(16):6828–6833.

    Article  PubMed  Google Scholar 

  99. Wekerle H (2005) Planting and pruning in the brain: MHC antigens involved in synaptic plasticity? Proc Natl Acad Sci U S A 102(1):3–4.

    Article  PubMed  CAS  Google Scholar 

  100. Thams S, Oliveira A, Cullheim S (2008) MHC class I expression and synaptic plasticity after nerve lesion. Brain Res Rev 57(1):265–269.

    Article  PubMed  CAS  Google Scholar 

  101. Larsson HE, Lynch K, Lernmark B, Nilsson A, Hansson G, Almgren P et al (2005) Diabetes-associated HLA genotypes affect birthweight in the general population. Diabetologia 48(8):1484–1491.

    Article  PubMed  CAS  Google Scholar 

  102. Hummel M, Marienfeld S, Huppmann M, Knopff A, Voigt M, Bonifacio E et al (2007) Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions. Diabetologia 50(4):850–858.

    Article  PubMed  CAS  Google Scholar 

  103. Larsson HE, Lynch K, Lernmark B, Hansson G, Lernmark A, Ivarsson SA (2007) Relationship between increased relative birthweight and infections during pregnancy in children with a high-risk diabetes HLA genotype. Diabetologia 50(6):1161–1169.

    Article  PubMed  CAS  Google Scholar 

  104. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA et al (2008) Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 29(2):226–231.

    PubMed  CAS  Google Scholar 

  105. Morris CM, Pletnikov M, Zimmerman AW, Singer HS (2008) Maternal antibodies and the placental–fetal IgG transfer theory. In: Zimmerman AW (ed) Autism. Current theories and evidence. Humana, Totowa, pp 309–328.

    Google Scholar 

  106. Heuer L, Ashwood P, Van de Water J (2008) The immune system in autism. Is there a connection? In: Zimmerman AW (ed) Autism. Current theories and evidence. Humana, Totowa, NJ, pp 271–288.

    Google Scholar 

  107. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA et al (2007) Maternal antibrain antibodies in autism. Brain Behav Immun 21(3):351–357.

    Article  PubMed  CAS  Google Scholar 

  108. Saruhan-Direskeneli G, Uyar FA, Bas F, Gunoz H, Bundak R, Saka N et al (2000) HLA-DR and -DQ associations with insulin-dependent diabetes mellitus in a population of Turkey. Hum Immunol 61(3):296–302.

    Article  PubMed  CAS  Google Scholar 

  109. Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA (1996) The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet 59(5):1134–1148.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 671 Hoes Lane, Piscataway, NJ, 08854, USA

    William G. Johnson

  2. Center for Childhood Neurotoxicology & Exposure Assessment, UMDNJ-Robert Wood Johnson Medical School, 671 Hoes Lane, Piscataway, 08854, NJ, USA

    William G. Johnson

Authors
  1. William G. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven Buyske
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward S. Stenroos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George H. Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William G. Johnson .

Editor information

Editors and Affiliations

  1. Kennedy Krieger Institute, Center for Autism and Related Disorders, Johns Hopkins University, N. Broadway 707, Baltimore, 21205, Maryland, USA

    Andrew W. Zimmerman

  2. Massachusetts General Hospital for Child, Lurie Family Autism Center / LADDERS Cli, 1 Maguire Rd., Lexington, 02421, Massachusetts, USA

    Susan L. Connors

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Johnson, W.G., Buyske, S., Stenroos, E.S., Lambert, G.H. (2010). Maternally Acting Alleles in Autism and Other Neurodevelopmental Disorders: The Role of HLA-DR4 Within the Major Histocompatibility Complex. In: Zimmerman, A., Connors, S. (eds) Maternal Influences on Fetal Neurodevelopment. Springer, New York, NY. https://doi.org/10.1007/978-1-60327-921-5_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-921-5_9

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-60327-920-8

  • Online ISBN: 978-1-60327-921-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation