Paula Goines

BACKGROUND: Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders. METHODS: Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis. RESULTS: Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism. CONCLUSION: The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.

PURPOSE OF REVIEW: The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism. RECENT FINDINGS: The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. Although studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions. SUMMARY: In summary, the exciting research regarding the role of the immune system in autism spectrum disorders may have profound implications for diagnosis and treatment of this devastating disease.

OBJECTIVES: To assay if plasma antibody levels in children with autism or developmental delays (DD) differ from those with typical development as an indicator of immune function and to correlate antibody levels with severity of behavioral symptoms. METHODS: Plasma was collected from children with autistic disorder (AU; n=116), DD but not autism (n=32), autism spectrum disorder but not full autism (n=27), and age-matched typically developing (TD) controls (n=96). Samples were assayed for systemic levels of immunoglobulin (IgG, IgM, IgA, and IgE) by enzyme-linked immunosorbent assay. Subjects with autism were evaluated using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, and all subjects were scored on the Aberrant Behavior Checklist (ABC) by the parents. Numerical scores for each of the ABC subscales as well as the total scores were then correlated with Ig levels. RESULTS: Children with AU have a significantly reduced level of plasma IgG (5.39+/-0.29 mg/mL) compared to the TD (7.72+/-0.28 mg/mL; P<0.001) and DD children (8.23+/-0.49 mg/mL; P<0.001). Children with autism also had a reduced level of plasma IgM (0.670.06 mg/mL) compared to TD (0.79+/-0.05 mg/mL; P<0.05). Ig levels were negatively correlated with ABC scores for all children (IgG: r=-0.334, P<0.0001; IgM: r=-0.167, P=0.0285). CONCLUSION: Children with AU have significantly reduced levels of plasma IgG and IgM compared to both DD and TD controls, suggesting an underlying defect in immune function. This reduction in specific Ig levels correlates with behavioral severity, where those patients with the highest scores in the behavioral battery have the most reduced levels of IgG and IgM.