CLINICAL HANDBOOK OF SCHIZOPHRENIA

70 I. CORE SCIENCE AND BACKGROUND INFORMATIONwhich may have been due to a relatively small sample size (including 27 psychotic offspring,only 13 of whom were diagnosed with schizophrenia).With the exception of the parasite T. gondii, viral infections rarely cross the placenta;therefore, the damaging effects of fetal exposure to most viral infections likely involvemultiple molecular pathways, a primary one being the mother’s immune response to viralinfections. During pregnancy, many immunological changes to protect the fetus from themother mounting an immune response to a genetically dissimilar entity. Many of thesechanges involve signaling proteins called cytokines, which are considered the hormonesof the immune system and, among other functions, are essential in combating infections.Although there are exceptions, there seems to be a shift in immune functioning duringpregnancy, with preferential production of helper T cell (Type 2) T h 2 cytokines, such asinterleukin–4 (IL-4), interleukin–5 (IL-5), and interleukin–10 (IL-10), that are mainly involvedin the stimulation of B cells and antibody responses. The relative increase in T h 2cytokines during pregnancy has been associated with a down-regulation of T h 1 cytokines,such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) andinterleukin–2 (IL-2), which are involved in cell-mediated immunity and inflammation(proinflammatory cytokines), thereby potentially decreasing the mother’s ability to respondto viral infection.In addition to the possibility that the fetus is more vulnerable to infection due to ashift in maternal immune functioning, studies suggest that the maternal antiviral responsemay contribute directly to the neuronal abnormalities found in offspring exposed prenatallyto infection, with particular importance placed on the role of proinflammatorycytokines. Pregnant mice injected with a sham virus, capable of producing an antiviral reaction,had offspring with cognitive deficits similar to those found among patients withschizophrenia, such as deficits in prepulse inhibition (thought to be a measure ofsensorimotor gating). In concert with these findings, rats prenatally exposed to proinflammatorycytokines have a multitude of brain abnormalities similar to those foundamong patients with schizophrenia, such as abnormalities in the hippocampus and cortex.In humans, exposure to elevated cytokines during pregnancy has been associatedwith neurodevelopmental damage, such as periventricular leukomalacia, cerebral palsy,and mental retardation. In summary, these findings suggest that neuronal abnormalitiesassociated with prenatal infection may be related to elevated proinflammatory cytokineproduction, even in the absence of a genetic diathesis for schizophrenia.In addition to the direct neurotoxic effects of proinflammatory cytokines, growingevidence suggests a causal relationship between inflammation and multiple OCs found inthe histories of patients with schizophrenia, including preterm delivery, preeclampsia, andfetal oxygen deprivation (hypoxia). As discussed earlier, fetal hypoxia leads to a series ofneuronal abnormalities found among patients with schizophrenia, even in the absence ofinfection and in individuals at low genetic risk for schizophrenia. Therefore, fetalneuronal damage following exposure to inflammation may be in part a result of the damagingeffects of fetal hypoxia.Given the aforementioned studies, it is not surprising that investigators have begunto explore the possible relationship between fetal exposure to proinflammatory cytokinesand schizophrenia outcome. This area of research is somewhat complicated by the dynamicnature of the immune system. Specifically, cytokines typically aggregate around thesite of infection and/or injury; therefore, cytokine levels in blood serum typically do notaccurately reflect either the constantly changing state of the immune system or the interactionsbetween the mother’s immune system and the developing fetus. Nevertheless, twostudies have linked markers of inflammation from maternal serum to psychotic outcome