title: A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction.
abstract: We propose a unifying hypothesis of schizophrenia to help reconcile findings from many different disciplines. This hypothesis proposes that schizophrenia often involves pre- or perinatal exposure to adverse factors that produce a latent immune vulnerability. When this vulnerability is manifested, beginning around puberty with changes in immune function and involution of the thymus, individuals become more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Our hypothesis suggests theoretical bridges between different lines of evidence on schizophrenia and offers explanations for many puzzling findings about schizophrenia. For example, the hypothesis helps account for why schizophrenia patients tend to have had increased exposure to neurotropic infections, but most individuals with such exposure do not develop schizophrenia, and why prenatal hardships increase risk for schizophrenia, but the onset of symptoms typically does not occur until after puberty. The hypothesis also explains another paradox: lower socioeconomic status and poor prenatal care increase risk for schizophrenia at the same geographic site, but international comparisons indicate that countries with higher per capita incomes and better prenatal care actually tend to have higher schizophrenia prevalences. As the hypothesis predicts, (1) prenatal adversity, which increases risk for schizophrenia, also impairs post-pubertal immune competence, (2) schizophrenia patients experience elevated morbidity from infectious and auto-immune diseases, (3) genetic and environmental risk factors for schizophrenia increase vulnerability to these diseases, (4) factors that exacerbate schizophrenic symptoms also tend to impair immune function, (5) many anti-psychotic medications combat infection, (6) effects of early infections may not appear until after puberty, when they can produce neurologic and psychiatric symptoms, and (7) immune dysfunctions, such as imbalances of pro- and anti-inflammatory cytokines, may contribute to the onset of psychotic symptoms and the progressive loss of brain tissue in schizophrenia. The disruptive effects of prenatal adversity on the development of the immune system may often combine with adverse effects on prenatal brain development to produce schizophrenia. This paper focuses on the adverse immune system effects, because effects on the brain have been extensively discussed in neurodevelopmental theories of schizophrenia. We propose new tests of scientific predictions. We also point out potential clinical implications of the hypothesis; for example, individuals with schizophrenia may often have underlying infections or immune dysfunctions, such as imbalances in inflammatory cytokines, that contribute to the illness. This possibility could be tested experimentally--e.g., by clinical trials in which patients' exposure to infection is reduced or immune function is normalized.
authors.affiliation: Genetics Laboratory, Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, United States. dr.dkinney@gmail.com
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Kinney
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hintz
authors.forename: Erika M
authors.initials: EM
authors.lastname: Shearer
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Barch
authors.forename: Catherine
authors.initials: C
authors.lastname: Riffin
authors.forename: Katherine
authors.initials: K
authors.lastname: Whitley
authors.forename: Robert
authors.initials: R
authors.lastname: Butler
mesh_terms: D001927:Brain Diseases / Q000276:immunology*; D002980:Climate; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology*; D007239:Infections / Q000276:immunology*; D018448:Models, Immunological; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D011627:Puberty / Q000276:immunology; D012559:Schizophrenia / Q000276:immunology*; D013315:Stress, Psychological / Q000276:immunology*