Skip to main content
SpringerLink
Log in

Schizophrenia: the teratogenic antibody Hypothesis

  • Conference paper
Psychiatry, Psychoimmunology, and Viruses

Part of the book series: Key Topics in Brain Research ((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.

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 109.99
Price excludes VAT (USA)
  • Compact, lightweight 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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • 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: 522–534

    Article  PubMed  CAS  Google Scholar 

  • Amagai M, Klaus Kovtun V, Stanley JR (1991) Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67: 869–870

    Article  PubMed  CAS  Google Scholar 

  • 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: 51–59

    Article  PubMed  CAS  Google Scholar 

  • 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, 679–682

    Article  PubMed  CAS  Google Scholar 

  • Boos J, Esiri MM (1986) Viral encephalitis. Blackwell Scientific, Oxford, pp 1–365

    Google Scholar 

  • Boyd JH, Pulver AE, Stewart W (1986) Season of birth: schizophrenia and bipolar disorder. Schizophr Bull 12: 173–186

    Article  PubMed  CAS  Google Scholar 

  • Bradbury TN, Miller GA (1985) Season of birth in schizophrenia: a review of evidence, methodology and etiology. Psychol Bull 98: 569–594

    Article  PubMed  CAS  Google Scholar 

  • Buck C, Simpson H (1978) Season of birth among the sibs of schizophrenics. Br J Psychiatry 132: 358–360

    Article  Google Scholar 

  • 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: 179–184

    Article  Google Scholar 

  • 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: 95

    Google Scholar 

  • Carter M, Watts CA (1971) Possible biological advantages among schizophrenics’relatives. Br J Psychiatry 118: 453–460

    Article  PubMed  CAS  Google Scholar 

  • Coffey VP, Jessop WJE (1955) Congenital abnormalities — 6th series. Irish J Med Sci 349: 30–46

    PubMed  Google Scholar 

  • Coffey VP, Jessop WJE (1959) Maternal influenza and congenital deformities. Lancet 2: 935–938

    Article  PubMed  CAS  Google Scholar 

  • Cohen JA, Lisak RP (1987) Acute disseminated encephalomyelitis. In: Aarli JA, Behan WMH, Behan PO (eds) Clinical neuroimmunology. Blackwell, Oxford, pp 192–213

    Google Scholar 

  • Conrad AJ, Scheibel AB (1987) Schizophrenia and the hippocampus: the embryological hypothesis extended. Schizophr Bull 13: 577–587

    Article  PubMed  CAS  Google Scholar 

  • Dalen P (1975) Season of birth: a study of schizophrenia and other mental disorders. North Holland Publishing Company, Amsterdam

    Google Scholar 

  • 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: 39–50

    Article  Google Scholar 

  • 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: 5930–5935

    Google Scholar 

  • Eaton WW, Hayward C, Ram R (1992) Schizophrenia and rheumatoid arthritis: a review. Schizophr Res 6: 181–192

    Article  PubMed  CAS  Google Scholar 

  • Edelman G (1984) Cell-adhesion molecules: a molecular basis for animal form. Sci Am 250: 4, 80–91

    Article  Google Scholar 

  • 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: 98–99

    Article  Google Scholar 

  • Ganguli R, Rabin BS, Kelly RH, et al. (1987) Clinical and laboratory evidence of autoimmunity in acute schizophrenia. Ann NY Acad Sci 496: 676–685

    Article  PubMed  CAS  Google Scholar 

  • 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, 27

    Google Scholar 

  • 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): 33–40

    Article  PubMed  CAS  Google Scholar 

  • Gottesman II (1991) Schizophrenia genesis: the origins of madness. WH Freeman, New York, pp 104–132

    Google Scholar 

  • Hare EH (1976) The season of birth of siblings of psychiatric patients. Br J Psychiatry 129: 49–954

    Article  PubMed  CAS  Google Scholar 

  • 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: 460–465

    Google Scholar 

  • Huxley J, Mayr E, Osmond H, et al. (1964) Schizophrenia as a genetic mor-phism. Nature 204: 4995, 220–221

    Article  PubMed  CAS  Google Scholar 

  • Jameel SY (1993) Studies of virus induced autoimmunity to brain antigens in schizophrenia. Thesis, University of Nottingham

    Google Scholar 

  • Kaplan C, Dehan M, Tchernia G (1992) Fetal and neonatal thrombocytopenia. Platelets 3: 61–67

    Article  PubMed  CAS  Google Scholar 

  • Kendell RE, Kemp IW (1989) Maternal influenza in the aetiology of schizophrenia. Arch Gen Psychiatry 46: 878–882

    Article  PubMed  CAS  Google Scholar 

  • Knight J, Knight A, Ungvari G (1992) Can autoimmune mechanisms account for the genetic predisposition to schizophrenia? Br J Psychiatry 160: 533–540

    Article  PubMed  CAS  Google Scholar 

  • Kunugi H, Nanko S, Takei N, et al. (1996) Schizophrenia following in utero exposure to 1957 influenza epidemics in Japan. Am J Psychiatry 152: 450–452

    Google Scholar 

  • 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: 1998–2002

    Article  PubMed  CAS  Google Scholar 

  • 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 York

    Google Scholar 

  • Levitan IB, Kaczmarek LK (1991) The neuron: cell and molecular biology. Oxford University Press, New York

    Google Scholar 

  • Lewis MS (1989) Age incidence and schizophrenia, part I. The season of birth controversy. Schizophr Bull 15: 59–73

    Article  PubMed  CAS  Google Scholar 

  • Lewis MS, Griffin TA (1981) An explanation for the season of birth effect in schizophrenia and certain other diseases. Psychol Bull 89: 589–596

    Article  PubMed  CAS  Google Scholar 

  • 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: 244–255

    PubMed  CAS  Google Scholar 

  • 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: 383–388

    Article  PubMed  CAS  Google Scholar 

  • MacSweeney D, Timms P, Johnson A (1978) Thyroendocrine pathology, obstetric morbidity and schizophrenia: survey of 100 families with a schizophrenic proband. Psychol Med 8: 151–155

    Article  PubMed  CAS  Google Scholar 

  • 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: 1–8

    Article  PubMed  CAS  Google Scholar 

  • McNeil T, Kaij L, Dzierzykray-Rogalska M (1976) Season of birth among siblings of schizophrenics. Acta Psychiatr Scand 54: 267–274

    Article  PubMed  CAS  Google Scholar 

  • Mednick SA, Machon RA, Huttunen MO, et al. (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 45: 189–192

    Article  PubMed  CAS  Google Scholar 

  • Mednick SA, Huttunen MO, Machon RA (1994) Prenatal influenza infection and adult schizophrenia. Schizophr Bull 20, 2: 263–267

    Article  PubMed  CAS  Google Scholar 

  • 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: 903–907

    Article  PubMed  CAS  Google Scholar 

  • Murphy BR, Webster RG (1990) Orthomyxoviruses. In: Fields BN, Knipe DM et al. (eds) Virology. Raven Press, New York

    Google Scholar 

  • O’Callaghan E, Sham PC, Takei N, et al. (1991) Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 337: 1248–1250

    Article  PubMed  Google Scholar 

  • O’Callaghan E, Sham PC, Takei N, et al. (1994) The relationship of schizophrenic births to 16 infectious diseases. Br J Psychiatry 165: 353–356

    Article  PubMed  Google Scholar 

  • 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: 51–54

    Article  PubMed  Google Scholar 

  • Pallast EGM, Jongbloet PH, Hubb M, et al. (1994) Excess seasonally of births among patients with schizophrenia and seasonal ovopathy. Schizophr Bull 20, 2: 269–276

    Article  PubMed  CAS  Google Scholar 

  • Parker G, Neilson M (1976) Mental disorder and season of birth: a southern hemisphere study. Br J Psychiatry 129: 355–361

    Article  PubMed  CAS  Google Scholar 

  • Pulver AE, Kung-Lee Yiang, Wolyniec PS, et al. (1992) Season of birth of siblings of schizophrenic patients. Br J Psychiatry 160: 71–75

    Article  PubMed  CAS  Google Scholar 

  • 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: 940–946

    PubMed  CAS  Google Scholar 

  • 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: 9–14

    Article  PubMed  CAS  Google Scholar 

  • 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: 133

    Article  Google Scholar 

  • Selten JPCJ, Sleats JPJ (1994) Evidence against maternal influenza asa risk factor for schizophrenia. Br J Psychiatry 164: 674–676

    Article  PubMed  CAS  Google Scholar 

  • 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: 461–466

    Article  PubMed  CAS  Google Scholar 

  • Silver ML, Guo H-C, Strominger JL, et al. (1992) Atomic structure of human MHC molecule presenting an influenza virus peptide. Nature 360: 367–369

    Article  PubMed  CAS  Google Scholar 

  • 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: 147–152

    Google Scholar 

  • 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: 922–924

    PubMed  CAS  Google Scholar 

  • Tadmor B, Putterman C, Naparstek Y (1992) Embryonal germ layer antigens: target for autoimmunity. Lancet 339: 975–978

    Article  PubMed  CAS  Google Scholar 

  • Takei N, Murray RM (1994) Prenatal influenza and schizophrenia. Br J Psychiatry 165: 833–834

    Article  PubMed  CAS  Google Scholar 

  • 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: 117–119

    PubMed  CAS  Google Scholar 

  • Torrey FE (1992) Are we overestimating the genetic contribution to schizophrenia? Schizophr Bull 18: 159–170

    Article  PubMed  CAS  Google Scholar 

  • 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 106–116

    Google Scholar 

  • Waddington JL, O’Callaghan E, Larkin C (1990) Physical anomalies and neu-rodevelopmental abnormalities in schizophrenia: new clinical correlates. Schizophr Res 3: 90

    Article  Google Scholar 

  • Walker E, Downey G, Caspi A (1991) Twin studies of psychopathology: why do the concordance rates vary? Schizophr Res 5: 211–221

    Article  PubMed  CAS  Google Scholar 

  • 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: 85–95

    Article  PubMed  CAS  Google Scholar 

  • Welham JL, Pemberton MR, McGrath JJ (1993) Schizophrenia: do seasonal birth rates vary between hemispheres? Schizophr Res 9: 142–143

    Google Scholar 

  • Wright P, Gill M, Murray RM (1993a) Schizophrenia: genetics and the maternal immune response to viral infection. Am J Med Genet 48: 40–46

    Article  PubMed  CAS  Google Scholar 

  • Wright P, Murray RM (1993b) Schizophrenia: prenatal influenza and autoimmunity. Ann Med 25: 497–502

    Article  PubMed  CAS  Google Scholar 

  • Wright P, Takei N, Rifkin L, Murray RM (1995a) Maternal influenza, obstetric complications and schizophrenia. Am J Psychiatry 152: 1714–1720

    PubMed  CAS  Google Scholar 

  • 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): 69

    Google Scholar 

  • 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: 261–267

    Article  PubMed  CAS  Google Scholar 

  • 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: 1530–1533

    PubMed  CAS  Google Scholar 

  • 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: 75–80

    Article  PubMed  CAS  Google Scholar 

  • 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: 372–377

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychological Medicine, Institute of Psychiatry and King’s College Hospital, De Crespigny Park, London, UK

    Dr. P. Wright & R. M. Murray

  2. Peptide Therapeutics Group PLC, 321 Cambridge Science Park, Milton Road, Cambridge, UK

    P. Laing

  3. Institute of Liver Studies, King’s College Hospital, Bessemer Road, London, UK

    P. T. Donaldson

Authors
  1. Dr. P. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Laing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. T. Donaldson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. M. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Psychiatrische Klinik und Poliklinik, Ludwig-Maximilians-Universität München, Nußbaumstraße 7, D-80336, München, Germany

    Norbert Müller

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Wien

About this paper

Cite this paper

Wright, P., Laing, P., Donaldson, P.T., Murray, R.M. (1999). Schizophrenia: the teratogenic antibody Hypothesis. In: Müller, N. (eds) Psychiatry, Psychoimmunology, and Viruses. Key Topics in Brain Research. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6404-4_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-6404-4_10

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-211-83249-3

  • Online ISBN: 978-3-7091-6404-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation