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Schizophrenia: the teratogenic antibody Hypothesis

  • P. Wright
  • P. Laing
  • P. T. Donaldson
  • R. M. Murray
Part of the Key Topics in Brain Research book series (KEYTOPICS)

Summary

Disease discordance of 50% in monozygotic twins implicates genetic and environmental factors in the aetiology of schizophrenia. Autoimmune diseases are HLA associated and are thought to occur when a genetically predisposed individual is exposed to an essential, probably viral, environmental trigger. We have reported an excess of autoimmune diseases in the first degree relatives of schizophrenic patients, an excess of second trimester influenza infections in the mothers of schizophrenic patients, and a deficiency of HLA DRB1*O4 alleles in the mothers of schizophrenic patients and in schizophrenic patients themselves. We have therefore hypothesised that maternal immunogenetic predisposition interacts with the influenza virus to cause neurodevelopmental lesions which manifest in adulthood as schizophrenia. Our work raises the possibility of an (immuno)genetic predisposition to schizophrenia at pedigree, maternal, and proband level.

Having a schizophrenic relative is the single most powerful risk factor for schizophrenia (Gottesman, 1991). However, disease discordance of about 50% in monozygotic twins (M2) both confirms the contribution of genes to the aetiology of schizophrenia and implicates non-genetic environmental factors (Gottesman, 1991; Walker et al., 1991; Torrey, 1992). One hypothesis that may encompass these genetic and environmental aetiological contributions suggests that schizophrenia occurs because of genetic susceptibility to an unidentified environmental agent. An increased frequency of autoimmune diseases has been found in the relatives of schizophrenic patients (MacSweeney et al., 1978; Ganguli et al., 1987; DeLisi et al., 1990 and we have reported an excess of both insulin dependent diabetes mellitus (IDDM) and of thyrotoxicosis in the first degree relatives of 101 psychotic patients when compared to 115 controls (Gilvarry et al, 1996), and an excess of IDDM (but not of thyrotoxicosis) in the relatives of 121 DSM-III-R schizophrenic patients (Wright et al, 1996a) when compared to controls. Given the apparent contributions of both genes and environmental factors to schizophrenia, these reports are of particular interest because autoimmune diseases are thought to occur when a genetically predisposed individual is exposed to an essential, probably viral, environmental trigger. Furthermore, disease discordance of about 50% in MZ twins has been reported for several autoimmune diseases (Knight et al, 1992).

In this paper we discuss how immunogene-viral interactions may explain some of the epidemiological features of schizophrenia and will review the evidence implicating prenatal influenza virus as one environmental aetiological factor. We also consider potential mechanisms by which influenza might increase risk for schizophrenia and propose a model — the teratogenic antibody hypothesis — which may explain a proportion of those cases of schizophrenia that appear to be related to prenatal influenza exposure.

Keywords

Influenza Virus Schizophrenic Patient Prenatal Exposure Influenza Infection Swine Influenza 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Adams W, Kendell RE, Hare EH, et al. (1993) Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia: an analysis of Scottish, English and Danish data. Br J Psychiatry 163: 522–534PubMedCrossRefGoogle Scholar
  2. Amagai M, Klaus Kovtun V, Stanley JR (1991) Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67: 869–870PubMedCrossRefGoogle Scholar
  3. Blackwood DH, Muir WJ, Stephenson A, Wentzel J, Ad’hiah A, Walker MJ, Papiha SS, StClair DM, Roberts DF (1996) Reduced expression of HLA B35 in schizophrenia. Psychiatr Genet 6: 51–59PubMedCrossRefGoogle Scholar
  4. Blaschuk OW, Pouliot Y, Holland PC (1990) Identification of a conserved region common to cadherins and influenza strain A haemagglutinins. J Mol Biol 211: 4, 679–682PubMedCrossRefGoogle Scholar
  5. Boos J, Esiri MM (1986) Viral encephalitis. Blackwell Scientific, Oxford, pp 1–365Google Scholar
  6. Boyd JH, Pulver AE, Stewart W (1986) Season of birth: schizophrenia and bipolar disorder. Schizophr Bull 12: 173–186PubMedCrossRefGoogle Scholar
  7. Bradbury TN, Miller GA (1985) Season of birth in schizophrenia: a review of evidence, methodology and etiology. Psychol Bull 98: 569–594PubMedCrossRefGoogle Scholar
  8. Buck C, Simpson H (1978) Season of birth among the sibs of schizophrenics. Br J Psychiatry 132: 358–360CrossRefGoogle Scholar
  9. Cannon M, Byrne M, Cotter D, et al. (1992) Further evidence for anomalies in the hand-prints of patients with schizophrenia: a study of secondary creases. Schizophr Res 13: 179–184CrossRefGoogle Scholar
  10. Cannon M, Cotter D, Sham PC, et al. (1994) Schizophrenia in an Irish sample following prenatal exposure to the 1957 influenza epidemic: a case-controlled prospective follow up study. Schizophr Res 11: 95Google Scholar
  11. Carter M, Watts CA (1971) Possible biological advantages among schizophrenics’relatives. Br J Psychiatry 118: 453–460PubMedCrossRefGoogle Scholar
  12. Coffey VP, Jessop WJE (1955) Congenital abnormalities — 6th series. Irish J Med Sci 349: 30–46PubMedGoogle Scholar
  13. Coffey VP, Jessop WJE (1959) Maternal influenza and congenital deformities. Lancet 2: 935–938PubMedCrossRefGoogle Scholar
  14. Cohen JA, Lisak RP (1987) Acute disseminated encephalomyelitis. In: Aarli JA, Behan WMH, Behan PO (eds) Clinical neuroimmunology. Blackwell, Oxford, pp 192–213Google Scholar
  15. Conrad AJ, Scheibel AB (1987) Schizophrenia and the hippocampus: the embryological hypothesis extended. Schizophr Bull 13: 577–587PubMedCrossRefGoogle Scholar
  16. Dalen P (1975) Season of birth: a study of schizophrenia and other mental disorders. North Holland Publishing Company, AmsterdamGoogle Scholar
  17. De Lisi LE, Boccio AM, Riordan H, et al. (1991) Familial thyroid disease and delayed language development in first admission patients with schizophrenia. Psychiatry Res 38: 39–50CrossRefGoogle Scholar
  18. DiBrino M, Tsuchida T, Turner R, et al. (1993) HLA Al and HLA A3 T cell epi-topes derived from influenza virus proteins predicted from peptide binding motifs. J Immunol 11: 5930–5935Google Scholar
  19. Eaton WW, Hayward C, Ram R (1992) Schizophrenia and rheumatoid arthritis: a review. Schizophr Res 6: 181–192PubMedCrossRefGoogle Scholar
  20. Edelman G (1984) Cell-adhesion molecules: a molecular basis for animal form. Sci Am 250: 4, 80–91CrossRefGoogle Scholar
  21. Fahy TA, Jones PB, Sham PC (1992) Schizophrenia in Afro-Caribbeans in the UK following prenatal exposure to the 1957 A2 influenza epidemic. Schizophr Res 6: 98–99CrossRefGoogle Scholar
  22. Ganguli R, Rabin BS, Kelly RH, et al. (1987) Clinical and laboratory evidence of autoimmunity in acute schizophrenia. Ann NY Acad Sci 496: 676–685PubMedCrossRefGoogle Scholar
  23. Gibson S, Hawi Z, Straub R, Kendler K, Walsh D, Gill M (1997) Frequency of HLA-DR4 and HLA-DQBl*0602 in familial schizophrenics and controls. Ir J Med Sci 165: S2, 27Google Scholar
  24. Gilvarry CM, Sham PC, Jones PB, Cannon M, Wright P, Lewis S, Bebbington P, Toone B, Murray RM (1996) Autoimmune diseases and psychosis: a case control family study. Schizophr Res 19(1): 33–40PubMedCrossRefGoogle Scholar
  25. Gottesman II (1991) Schizophrenia genesis: the origins of madness. WH Freeman, New York, pp 104–132Google Scholar
  26. Hare EH (1976) The season of birth of siblings of psychiatric patients. Br J Psychiatry 129: 49–954PubMedCrossRefGoogle Scholar
  27. Hare EH, Price JS, Slater E (1974) Mental disorder and season of birth: a national survey compared with the general population. Br J Psychiatry 152: 460–465Google Scholar
  28. Huxley J, Mayr E, Osmond H, et al. (1964) Schizophrenia as a genetic mor-phism. Nature 204: 4995, 220–221PubMedCrossRefGoogle Scholar
  29. Jameel SY (1993) Studies of virus induced autoimmunity to brain antigens in schizophrenia. Thesis, University of NottinghamGoogle Scholar
  30. Kaplan C, Dehan M, Tchernia G (1992) Fetal and neonatal thrombocytopenia. Platelets 3: 61–67PubMedCrossRefGoogle Scholar
  31. Kendell RE, Kemp IW (1989) Maternal influenza in the aetiology of schizophrenia. Arch Gen Psychiatry 46: 878–882PubMedCrossRefGoogle Scholar
  32. Knight J, Knight A, Ungvari G (1992) Can autoimmune mechanisms account for the genetic predisposition to schizophrenia? Br J Psychiatry 160: 533–540PubMedCrossRefGoogle Scholar
  33. Kunugi H, Nanko S, Takei N, et al. (1996) Schizophrenia following in utero exposure to 1957 influenza epidemics in Japan. Am J Psychiatry 152: 450–452Google Scholar
  34. Laing P, Knight JG, Hill JM, et al. (1989) Influenza viruses induce autoanti-bodies to a brain specific 37 kDa protein in rabbit. Proc Natl Acad Sci USA 86: 1998–2002PubMedCrossRefGoogle Scholar
  35. Laing P, Knight J, Wright P, et al. (1995) Disruption of foetal brain development by maternal antibodies as an aetiological factor in schizophrenia. In: Mednick SA, Hollister JM (eds) Neural development in schizophrenia: theory and research. NATO Plenum Press, New YorkGoogle Scholar
  36. Levitan IB, Kaczmarek LK (1991) The neuron: cell and molecular biology. Oxford University Press, New YorkGoogle Scholar
  37. Lewis MS (1989) Age incidence and schizophrenia, part I. The season of birth controversy. Schizophr Bull 15: 59–73PubMedCrossRefGoogle Scholar
  38. Lewis MS, Griffin TA (1981) An explanation for the season of birth effect in schizophrenia and certain other diseases. Psychol Bull 89: 589–596PubMedCrossRefGoogle Scholar
  39. Lynberg MC, Khoury MJ, Lu X, et al (1994) Maternal flu, fever, and the risk of neural tube defects: a population based case control study. Am J Epidemiol 140, 3: 244–255PubMedGoogle Scholar
  40. Machon RA, Mednick SA, Schulsinger F (1983) The interaction of seasonally, place of birth, genetic risk and subsequent schizophrenia in a high risk sample. Br J Psychiatry 143: 383–388PubMedCrossRefGoogle Scholar
  41. MacSweeney D, Timms P, Johnson A (1978) Thyroendocrine pathology, obstetric morbidity and schizophrenia: survey of 100 families with a schizophrenic proband. Psychol Med 8: 151–155PubMedCrossRefGoogle Scholar
  42. McGrath JJ, Pemberton M, Welham JL, et al. (1994) Schizophrenia and the influenza epidemics of 1954, 1957 and 1959: a southern hemisphere study. Schizophr Res 14: 1–8PubMedCrossRefGoogle Scholar
  43. McNeil T, Kaij L, Dzierzykray-Rogalska M (1976) Season of birth among siblings of schizophrenics. Acta Psychiatr Scand 54: 267–274PubMedCrossRefGoogle Scholar
  44. Mednick SA, Machon RA, Huttunen MO, et al. (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 45: 189–192PubMedCrossRefGoogle Scholar
  45. Mednick SA, Huttunen MO, Machon RA (1994) Prenatal influenza infection and adult schizophrenia. Schizophr Bull 20, 2: 263–267PubMedCrossRefGoogle Scholar
  46. Morrison J, Elvin J, Latron F, et al. (1992) Identification of the nonamer peptide from influenza A matrix protein and the role of pockets of HLA A2 in its recognition by cytotoxic T lymphocytes. Eur J Immunol 22: 903–907PubMedCrossRefGoogle Scholar
  47. Murphy BR, Webster RG (1990) Orthomyxoviruses. In: Fields BN, Knipe DM et al. (eds) Virology. Raven Press, New YorkGoogle Scholar
  48. O’Callaghan E, Sham PC, Takei N, et al. (1991) Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 337: 1248–1250PubMedCrossRefGoogle Scholar
  49. O’Callaghan E, Sham PC, Takei N, et al. (1994) The relationship of schizophrenic births to 16 infectious diseases. Br J Psychiatry 165: 353–356PubMedCrossRefGoogle Scholar
  50. O’Callaghan E, Cotter D, Colgan K, et al. (1995) Confinement of winter birth excess in schizophrenia to the urban born and its gender specificity. Br J Psychiatry 166: 51–54PubMedCrossRefGoogle Scholar
  51. Pallast EGM, Jongbloet PH, Hubb M, et al. (1994) Excess seasonally of births among patients with schizophrenia and seasonal ovopathy. Schizophr Bull 20, 2: 269–276PubMedCrossRefGoogle Scholar
  52. Parker G, Neilson M (1976) Mental disorder and season of birth: a southern hemisphere study. Br J Psychiatry 129: 355–361PubMedCrossRefGoogle Scholar
  53. Pulver AE, Kung-Lee Yiang, Wolyniec PS, et al. (1992) Season of birth of siblings of schizophrenic patients. Br J Psychiatry 160: 71–75PubMedCrossRefGoogle Scholar
  54. Safranek TJ, Lawrence DN, Kurland LT, et al. (1991) Reassessment of the association between Guillain-Barre syndrome and receipt of swine influenza vaccine in 1976-1977: results of a two state study. Am J Epidemiol 133: 940–946PubMedGoogle Scholar
  55. Sasaki T, Kuwata S, Dai XY, Nanko S, et al. (1994) HLA DR types in Japanese schizophrenica: analysis by group-specific PCR amplification. Schizophr Res 14: 9–14PubMedCrossRefGoogle Scholar
  56. Schwab GS, Knapp M, Freymann J, Albus M, et al. (1998) The HLA DRB1 gene locus in schizophrenia: an association study in 55 families with linkage to chromosome 6p. Schizophr Res 29, 1-2: 133CrossRefGoogle Scholar
  57. Selten JPCJ, Sleats JPJ (1994) Evidence against maternal influenza asa risk factor for schizophrenia. Br J Psychiatry 164: 674–676PubMedCrossRefGoogle Scholar
  58. Sham PC, O’Callaghan E, Takei N, et al. (1992) Schizophrenia following prenatal exposure to influenza epidemics between 1939 and I960. Br J Psychiatry 160: 461–466PubMedCrossRefGoogle Scholar
  59. Silver ML, Guo H-C, Strominger JL, et al. (1992) Atomic structure of human MHC molecule presenting an influenza virus peptide. Nature 360: 367–369PubMedCrossRefGoogle Scholar
  60. Stober G, Franzek E, Beckmann J (1992) The role of maternal infectious diseases during pregnancy in the aetiology of schizophrenia in offspring. Eur Psychiatry 7: 147–152Google Scholar
  61. Susser E, Lin SP, Brown AS, et al. (1994) No relation between risk of schizophrenia and prenatal exposure to influenza in Holland. Am J Psychiatry 151: 922–924PubMedGoogle Scholar
  62. Tadmor B, Putterman C, Naparstek Y (1992) Embryonal germ layer antigens: target for autoimmunity. Lancet 339: 975–978PubMedCrossRefGoogle Scholar
  63. Takei N, Murray RM (1994) Prenatal influenza and schizophrenia. Br J Psychiatry 165: 833–834PubMedCrossRefGoogle Scholar
  64. Takei N, Sham PC, O’Callaghan E, et al. (1994) Prenatal exposure to influenza and the development of schizophrenia: is the effect confined to females? Am J Psychiatry 151: 117–119PubMedGoogle Scholar
  65. Torrey FE (1992) Are we overestimating the genetic contribution to schizophrenia? Schizophr Bull 18: 159–170PubMedCrossRefGoogle Scholar
  66. Torrey EF, Bowler AE, Rawlings R (1991) An influenza epidemic and the sea-sonality of schizophrenic births. In: Kurstat K (ed) Psychiatry and biological factors. Plenum Press, New York, pp 106–116Google Scholar
  67. Waddington JL, O’Callaghan E, Larkin C (1990) Physical anomalies and neu-rodevelopmental abnormalities in schizophrenia: new clinical correlates. Schizophr Res 3: 90CrossRefGoogle Scholar
  68. Walker E, Downey G, Caspi A (1991) Twin studies of psychopathology: why do the concordance rates vary? Schizophr Res 5: 211–221PubMedCrossRefGoogle Scholar
  69. Watson CG, Kucala T, Tilleskjor C, et al. (1984) Schizophrenic birth seasonal-ity in relation to the incidence of infectious diseases and temperature extremes. Arch Gen Psychiatry 41: 85–95PubMedCrossRefGoogle Scholar
  70. Welham JL, Pemberton MR, McGrath JJ (1993) Schizophrenia: do seasonal birth rates vary between hemispheres? Schizophr Res 9: 142–143Google Scholar
  71. Wright P, Gill M, Murray RM (1993a) Schizophrenia: genetics and the maternal immune response to viral infection. Am J Med Genet 48: 40–46PubMedCrossRefGoogle Scholar
  72. Wright P, Murray RM (1993b) Schizophrenia: prenatal influenza and autoimmunity. Ann Med 25: 497–502PubMedCrossRefGoogle Scholar
  73. Wright P, Takei N, Rifkin L, Murray RM (1995a) Maternal influenza, obstetric complications and schizophrenia. Am J Psychiatry 152: 1714–1720PubMedGoogle Scholar
  74. Wright P, Donaldson P, Underhill J, Takei N, Rifkin L, Murray RM (1995b) Do maternal immunogenes mediate the’schizophrenogenic’effect of prenatal influenza exposure? Psychiatr Genet 5(1): 69Google Scholar
  75. Wright P, Sham PC, Gilvarry CM, Jones P, Cannon M, Sharma T, Murray RM (1996a) Autoimmune disorders in the first degree relatives of schizophrenic and control subjects. Schizophr Res 20: 261–267PubMedCrossRefGoogle Scholar
  76. Wright P, Donaldson PT, Underhill JA, Doherty DG, Choudhuri K, Murray RM (1996b) Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia. Am J Psychiatry 153: 1530–1533PubMedGoogle Scholar
  77. Wright P, Dawson E, Donaldson PT, Underhill JA, Sham PC, Zhao J, Gill M, Nanko S, Owen MJ, McGuffin P, Murray RM (1998) A transmission/disequilibrium study of the DRB1*O4 gene locus on chromosome 6p21.3 with schizophrenia. Schizophr Res 32: 75–80PubMedCrossRefGoogle Scholar
  78. Zamani MG, De Hert M, Spaepen M, Hermans M, Marynen P, Cassiman JJ, Peuskens J (1994) Study of the possible association of HLA Class II, CD4 and CD3 polymorphisms with schizophrenia. Am J Med Genet 54: 372–377PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • P. Wright
    • 1
  • P. Laing
    • 2
  • P. T. Donaldson
    • 3
  • R. M. Murray
    • 1
  1. 1.Department of Psychological MedicineInstitute of Psychiatry and King’s College HospitalLondonUK
  2. 2.Peptide Therapeutics Group PLCCambridgeUK
  3. 3.Institute of Liver StudiesKing’s College HospitalLondonUK

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