Review
Maternal infection and immune involvement in autism

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Recent studies have highlighted a connection between infection during pregnancy and the increased risk of autism in the offspring. Parallel studies of cerebral spinal fluid, blood and postmortem brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult autism subjects. There are also indications of gastrointestinal problems in at least a subset of autistic children. Work on the maternal infection risk factor using animal models indicates that aspects of brain and peripheral immune dysregulation can begin during fetal development and continue through adulthood. The offspring of infected or immune-activated dams also display cardinal behavioral features of autism, as well as neuropathology consistent with that seen in human autism. These rodent models are proving useful for the study of pathogenesis and gene–environment interactions as well as for the exploration of potential therapeutic strategies.

Section snippets

Maternal infection and autism

There is little public awareness that infection during pregnancy significantly increases the probability of the offspring becoming schizophrenic. In fact, it has been estimated that if viral (influenza, Herpes simplex virus, rubella), bacterial (urinary tract) and parasitic (toxoplasma) infections could be prevented in pregnant women, >30% of schizophrenia cases could be eliminated [1]. The public health implications are enormous, but not widely recognized [2]. Similarly, there is little public

Immune-related abnormalities in autism

A variety of organ systems exhibit inflammatory-like changes in autism. Evidence comes from quantifying immune-related proteins and RNAs, as well as immunohistochemistry. Findings from epidemiology are also relevant.

Animal models of the maternal infection risk factor

The maternal infection risk factor is currently being studied in mice, rats and monkeys. These experiments involve infecting the mother or simply activating her immune system in the absence of pathogens.

Gene–environment interactions

Many mental disorders have been attributed in part to genes that increase susceptibility to environmental risk factors. To date, however, there is little evidence for such gene–environment interactions. Therefore, it is of interest that mice heterozygous for the tuberous sclerosis 2 (Tsc2) gene display a social interaction deficit only when they are born to mothers treated with poly(I:C) [37]. That is, this behavioral deficit is most severe when the MIA environmental risk factor is combined

Therapeutic manipulations

The findings summarized above demonstrate that the maternal infection and MIA models display face (similar symptoms) and construct (similar cause) values for both autism and schizophrenia. These models can have a predictive value as well. For example, the manipulation of cytokines during pregnancy can prevent the development of abnormal behaviors in the offspring in the poly(I:C) and LPS models. In addition, pretreatment of pregnant rats with N-acetyl-cysteine, which increases calcium influx

Concluding remarks

A variety of techniques has been used to demonstrate the presence of a subclinical, inflammatory-like state in the brain, CSF and peripheral immune system in many ASD samples. There is also evidence of abnormalities in the GI tract, although the prevalence and precise phenotype in that system remain to be determined. Mouse and rat models that mimic the autism maternal infection risk factor display face, construct and predictive validity for ASD. Many of the symptoms in these rodent models are

Acknowledgments

The work cited from the author's laboratory was supported by the National Institute of Mental Health, the California Institute of Regenerative Medicine and the Autism Speaks and Binational Science foundations. Owing to space limitations, reviews are cited rather than primary research articles wherever possible.

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