Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies.

Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

Depression as an evolutionary strategy for defense against infection.

Recent discoveries relating depression to inflammation and immune function may help to solve an important evolutionary puzzle: If depression carries with it so many negative consequences, including notable costs to survival and reproduction, then why is it common and heritable? What countervailing force or compensatory advantage has allowed susceptibility genes for depression to persist in the population at such high rates? A priori, compensatory advantages in combating infection are a promising candidate, given that infection has been the major cause of mortality throughout human history. Emerging evidence on deeply rooted bidirectional pathways of communication between the nervous and immune systems further supports this notion. Here we present an updated review of the "infection-defense hypothesis" of depression, which proposes that moods-with their ability to orchestrate a wide array of physical and behavioral responses-have played an adaptive role throughout human history by helping individuals fight existing infections, as well as helping both individuals and their kin avoid new ones. We discuss new evidence that supports several key predictions derived from the hypothesis, and compare it with other major evolutionary theories of depression. Specifically, we discuss how the infection-defense hypothesis helps to explain emerging data on psychoimmunological features of depression, as well as depression's associations with a diverse array of conditions and illnesses-including nutritional deficiencies, seasonal changes, hormonal fluctuations, and chronic diseases-that previous evolutionary theories of depression have not accounted for. Finally, we note the potential implications of the hypothesis for the treatment and prevention of depression.

An evolutionary hypothesis of suicide: why it could be biologically adaptive and is so prevalent in certain occupations.

From an evolutionary perspective, suicide is a puzzle, because it has serious adverse effects, yet is remarkably common and heritable. An hypothesis is proposed to explain this puzzle, by explaining how suicide could be adaptive through reducing risk that individuals will transmit infections to kin. Empirical evidence supports four predictions from the hypothesis. There are well-established mechanisms by which infections and immune factors increase risk for mental disorders that contribute to suicide. Suicide is more prevalent in occupations with greater exposure to infection and immune-compromising factors and at higher latitudes, where key environmental factors increase vulnerability to infection. In several other highly social species, suicide-like behaviors have evolved to reduce transmission of infections. If the hypothesis is correct, detection and treatment of underlying infections and immune dysfunction should help predict and prevent suicidal behavior, while also combating spread of infectious diseases.

Association of hypomelanotic skin disorders with autism: links to possible etiologic role of vitamin-D levels in autism?

Vitamin D is crucial for several key physiological processes, including brain development, DNA repair, and regulation of many genes. Much evidence indicates prenatal and early postnatal vitamin-D deficiency increases autism risk, probably through multiple effects, including impaired brain development and increased de novo mutations. High autism rates in several genetically based hypomelanotic skin disorders are puzzling, because ultraviolet-B radiation (UVB) in sunlight acting on skin is a key source of vitamin-D, and lighter skin protects against vitamin-D deficiency, especially at high latitudes. We consider two hypotheses to help explain autism's co-morbidity with hypomelanosis. 1) Because genetic and epigenetic variants that produce hypomelanosis help protect against vitamin-D deficiency, they increase reproductive fitness of individuals who also have other autism risk factors. 2) Hypomelanotic children have increased autism risk because photosensitivity and skin-cancer concerns lead families to excessively reduce children's sun exposure. Hypothesis testing could involve studies comparing genomes, epigenetic markers, skin pigmentation, and vitamin-D levels in autistic individuals with and without hypomelanosis, their relatives and controls. Conducting such studies in samples from regions that differ widely in UVB availability would provide particularly valuable data. Support for either hypothesis would elucidate vitamin-D's role in autism and suggest vitamin-D enhancement may aid treatment and prevention of autism.

Associations of hypomelanotic skin disorders with autism: Do they reflect the effects of genetic mutations and epigenetic factors on vitamin-D metabolism in individuals at risk for autism?

Vitamin D is crucial for full functioning in many genes, and vitamin-D deficiency interferes with many processes, including brain development and DNA repair. Several lines of evidence suggest that prenatal and early postnatal vitamin-D deficiency increases risk for autism, probably through multiple effects that include impaired brain development and increased de novo mutations. High rates of autism in several genetically based hypomelanotic skin disorders present a puzzle, because ultraviolet-B (UVB) radiation acting on skin is the major natural source of vitamin D, and lighter skin, which increases UVB penetration, helps protect against vitamin-D deficiency, especially at higher latitudes. Understanding autism's association with hypomelanosis may elucidate autism's etiology. We consider two hypotheses that may help explain autism's association with hypomelanotic disorders. Hypothesis 1) Because genetic and epigenetic variants that produce hypomelanotic conditions may help protect against vitamin-D deficiency, especially at higher latitudes, these variants may tend to decrease mortality - and increase the fertility - of individuals who also carry genetic or epigenetic factors that increase vulnerability to autism. Hypothesis 2) Children with hypomelanotic conditions will be more likely to develop autism, because children's photosensitivity and parental concerns about sunburn and skin cancer lead them to excessively reduce children's sun exposure and resultant vitamin-D levels. One approach to testing these hypotheses would involve comparing the genomes, epigenetic markers, skin pigmentation, and serum and brain levels of the active form of vitamin D in autistic individuals, with and without co-morbid hypomelanoses, as well as in their relatives and controls. Because availability of UVB radiation varies widely around the world, epidemiological and genetic studies of the co-morbidity in different regions would provide complementary means of testing the hypotheses. If test results support either hypothesis, they will add important evidence for an etiologic role of vitamin-D deficiency in autism, as well as supporting investigation of whether vitamin-D enhancement may aid treatment and prevention of autism.

Environmental risk factors for autism: do they help cause de novo genetic mutations that contribute to the disorder?

Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors--mercury, cadmium, nickel, trichloroethylene, and vinyl chloride--are established mutagens. Another four--including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation--are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress--a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism--and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches--which we suggest--to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.

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.

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.

An evolutionary hypothesis of depression and its symptoms, adaptive value, and risk factors.

Major depression is an evolutionary paradox: it carries great disadvantages for survival and reproduction of both patients and their relatives, yet it is common and has significant heritability. We propose a new hypothesis to help explain many of depression's symptoms and its risk factors, most of them not explained by previous evolutionary theories. We hypothesize that the evolutionary costs of depression are offset by its benefits in combating existing infections and avoiding new ones. As our hypothesis predicts, depression can be elicited by various infections as well as by environmental stressors that compromise immune function. Moreover, many depressive symptoms tend to aid immune function and reduce exposure to new infections and stressors. The hypothesis makes many predictions about the epidemiology and physiology of depression that are supported by available evidence. The hypothesis also suggests that possible underlying infectious and immune factors deserve greater consideration in prevention and treatment of depression.

Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: a role for prenatal vitamin d deficiency and infections?

Previous surveys found a large (>10-fold) variation in schizophrenia prevalence at different geographic sites and a tendency for prevalence to increase with latitude. We conducted meta-analyses of prevalence studies to investigate whether these findings pointed to underlying etiologic factors in schizophrenia or were the result of methodological artifacts or the confounding of sites' latitude with level of healthcare at those sites. We found that these patterns were still present after controlling for an index of healthcare--infant mortality--and focusing on 49 studies that used similar diagnostic and ascertainment methods. The tendencies for schizophrenia prevalence to increase with both latitude and colder climate were still large and significant and present on several continents. The increase in prevalence with latitude was greater for groups with low fish consumption, darker skin, and higher infant mortality--consistent with a role of prenatal vitamin D deficiency in schizophrenia. Previous research indicates that poor prenatal healthcare and nutrition increase risk for schizophrenia within the same region. These adverse conditions are more prevalent in developing countries concentrated near the equator, but schizophrenia prevalence is lowest at sites near the equator. This suggests that schizophrenia-producing environmental factors associated with higher latitude may be so powerful they overwhelm protective effects of better healthcare in industrialized countries. The observed patterns of correlations of risk factors with prevalence are consistent with an etiologic role for prenatal vitamin D deficiency and exposure to certain infectious diseases. Research to elucidate environmental factors that underlie variations in schizophrenia prevalence deserves high priority.

Prenatal stress and risk for autism.

This paper reviews several converging lines of research that suggest that prenatal exposure to environmental stress may increase risk for Autistic Disorder (AD). We first discuss studies finding that prenatal exposure to stressful life events is associated with significantly increased risk of AD, as well as other disorders, such as schizophrenia and depression. We then review evidence from animal and human studies that prenatal stress can produce both (a) abnormal postnatal behaviors that resemble the defining symptoms of AD, and (b) other abnormalities that have elevated rates in AD, such as learning deficits, seizure disorders, perinatal complications, immunologic and neuroinflammatory anomalies, and low postnatal tolerance for stress. We explain why an etiologic role for prenatal stress is compatible with genetic factors in AD, and describe how stress can disrupt fetal brain development. Finally, we discuss implications for understanding underlying processes in AD, including potential gene-environment interactions, and developing new therapies and early prevention programs.

Autism prevalence following prenatal exposure to hurricanes and tropical storms in Louisiana.

Hurricanes and tropical storms served as natural experiments for investigating whether autism is associated with exposure to stressful events during sensitive periods of gestation. Weather service data identified severe storms in Louisiana from 1980 to 1995 and parishes hit by storm centers during this period. Autism prevalences in different cohorts were calculated using anonymous data on birth dates and parishes of children diagnosed with autism in the state mental health system, together with corresponding census data on all live births in Louisiana. Prevalence increased in dose-response fashion with severity of prenatal storm exposure, especially for cohorts exposed near the middle or end of gestation (p < 0.001). Results complement other evidence that factors disrupting development during sensitive gestational periods may contribute to autism.