It is likely that exposure to environmental factors and altered immune function can precipitate or exacerbate autism. Research into the interaction of genes and environment must proceed in parallel with the search for genetic risk factors.

1. Nearly 20 percent of Simons Simplex Collection families report significant improvement in autism symptoms when affected children experience a fever. Convincing anecdotal reports have accumulated from many other sources.
2. Maternal infection during the first trimester of pregnancy has been reported to increase the risk of autism.
3. Elevated levels of pro-inflammatory cytokines have been found in in the plasma of children with autism.
4. About 10 percent of mothers of children with autism have circulating anti-brain antibodies.
5. Rodent and primate models of maternal infection produce offspring that have deficits associated with autism in humans, including impairments in communication and social interaction.
6. Mice and rhesus monkeys exposed in utero to antibodies derived from mothers of children with autism later display autism-associated behaviors. Exposed monkeys also exhibit abnormal brain growth.
7. Glia, the non-neuronal cells that reside in the brain, influence neurogenesis and synaptic function in the normal brain. Studies of microglia provide evidence for cerebral immune attack in autism.
   Positron emission tomography has detected relatively large numbers of microglia in the brains of young males with autism.
   Bone-marrow transplantation, allowing the infiltration of healthy myeloid cells into the brain, in radiation-conditioned mice that lack the MeCP2 gene (a rodent model of Rett syndrome) alleviates classic symptoms of Rett syndrome.
8. Exposure during pregnancy to valproic acid, a therapy for epilepsy and bipolar disorder, among other disorders, increases the risk of autism in the child.

1. Are the beneficial effects of fever due to temperature-dependent neural processes or to pro-inflammatory cytokines (for instance, interleukin-6)?
2. How do trajectories and sex differences affect therapies and placebo responses?
3. What roles do microglia and astrocytes play in the evolution of autism-associated behaviors?
4. Are the distributions of activated microglia and astrocytes useful biomarkers for regions of the brain that are at risk in autism?
5. Can a cell culture system be developed to study the interactions among various combinations of wild-type and genetically modified neurons and glia?
6. Can effects of microglia and astrocytes be examined early in development, both prenatally and perinatally?
7. What antigens do maternal antibodies recognize?
8. How do maternal anti-brain antibodies affect the development of the fetal brain?
9. Can modulators of immune function alter the course of autism?

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