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.

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.

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.

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.

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.

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.

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.

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.

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.

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.