Recent evidence implicates the immune system in some cases of autism spectrum disorders. Researchers at the University of California, Davis, Johns Hopkins, and the Kennedy Krieger Institute have found that some mothers of children with autism produce autoantibodies that target the developing fetal brain (Braunschweig, Ashwood et al. 2007; Zimmerman, Connors et al. 2007; Croen, Braunschweig et al. 2008). When these maternal autoantibodies are injected into pregnant monkeys or mice, the offspring show behavioral abnormalities that resemble aspects of autism (Martin, Ashwood et al. 2008; Singer, Morris et al. 2009). Subsets of children with autism also have immunological differences from their typically developing peers (Ashwood, Wills et al. 2006; Enstrom, Van de Water et al. 2009). These findings present an exciting opportunity for a deeper understanding of these enigmatic disorders.
Autism and the Immune System
Autism is on the rise, with the latest estimates of 1 in 100 children diagnosed each year. Though autism has received extensive attention, the biological underpinnings of the disorders are not well understood. It is generally accepted that genetics play a large role, though several avenues of research suggest that additional factors are involved. For decades, unique immunological phenomena have been described in people with autism and their family members. Findings include altered maternal immune activity during pregnancy, as well as immunological changes in the child with autism. The role of the immune system in autism has been historically controversial. However, several recent large-scale studies have provided credibility to the connection between autism and immunity. A particular area of interest involves a potential role for antibodies directed towards brain proteins in autism.
Autism and the Maternal Immune System
Some of the most intriguing immune-related findings involve mothers of children with autism. Independent studies have shown that subsets of these women harbor autoantibodies in their bloodstream that react with protein targets in the fetal brain. These autoantibodies are found in about 12-14% of mothers of children with autism. Most importantly, these autoantibodies have never been observed in mothers of typically developing children.
What Are Antibodies and Autoantibodies?
Antibodies are specialized proteins made by the immune system. They work by marking unwanted assailants in the body for destruction and removal. Antibodies do not react with the body itself under normal circumstances. This is important to prevent misdirected and potentially damaging immune responses. However, on occasion the immune system mistakenly produces antibodies that target tissues within the body. This phenomenon is called “autoimmunity,” and is observed in diseases like multiple sclerosis, rheumatoid arthritis, and systemic lupus. Antibodies that target self-tissues are known as “autoantibodies.” The autoantibodies found in mothers of children with ASD target the developing human brain.
Why do Maternal Antibodies Matter in Pregnancy?
During pregnancy, the developing fetus does not have a functional immune system. The maternal immune system is therefore responsible for protecting the child in addition to the mother. To accomplish this, antibodies produced by the mother’s immune system are passed across the placenta into fetal circulation. These maternal antibodies protect the child during gestation and for months after birth, until the child’s own immune system matures. If the mother has autoantibodies in her circulation during pregnancy, the fetus will receive them as well. Children born to mothers with autoimmune diseases like systemic lupus are susceptible to damage mediated by these maternal autoantibodies. The autoantibodies which are found in mothers of children with autism are also passed to the fetus, where they may interfere with brain development and function.
Animal Models: Demonstrating the Pathogenic Significance of Autoantibodies
Animal models have been used to explore the developmental consequences of in-utero exposure to the autoantibodies found in mothers of children with autism. It is difficult to model autism behaviors in animals; though monkeys and mice demonstrate numerous observable forms of anxiety, learning impediments, and social difficulties that can be likened to autism. Antibodies were obtained from mothers of children with autism and injected into pregnant Rhesus monkeys and mice. For comparison, antibodies from mothers of typically developing children were injected into separate groups of pregnant animals. The results of these studies have been fascinating. Monkeys exposed in utero to antibodies from mothers of children with autism behaved very differently from the control animals. They showed unique repetitive behaviors which overwhelmed their desire to interact with their mothers during testing. Mice also behaved differently when exposed to these antibodies during fetal development.
Remaining Questions and Future Directions
There are several questions that remain unanswered. First, the precise targets of these maternal autoantibodies in the fetal brain are not fully characterized. Determining the nature of the target proteins will allow for a better understanding of their significance in autism. Second, it is unclear how the maternal autoantibodies impact fetal development. They may initiate damaging immune reactions in the brain of the developing child, or interfere with important developmental and functional processes. Further research is needed to delineate their exact mode of action. Third, it is unclear whether these autoantibodies will lead to treatment options. In children born to mothers with conditions like myasthenia gravis and systemic lupus, immune-mediated damage can be ameliorated by various pre and post-natal interventions including plasmaphoresis. The findings among mothers of children with autism are too preliminary to know if similar options would be beneficial. Regardless of future treatment options, these antibodies may serve as a valuable biomarker of autism susceptibility in mothers. A newly formed company, Pediatric Bioscience, now offers a test for these maternal autoantibodies commercially.
In addition to our work on maternal autoantibodies, we have a strong interest in the immune function of children with autism and, in particular, their response to immune challenge. These studies are still in their infancy, though preliminary data suggests that there are immunological differences in subgroups of children with autism. We are also working on the development of a device that will enable us to measure immune function in infants using a very small blood sample. This may help us determine which children may have difficulties with future immune challenges. Continued research will surely lead to a greater understanding of ASD, and may provide options for early interventions and therapy.
Dr. Judy Van de Water, PhD has been involved in researching the immunobiology of autism spectrum disorders for 10 years. She is with the Department of Internal Medicine and works in collaboration with the MIND (Medical Investigation of Neurodevelopmental Diseases) institute at the University of California, Davis. Paula Goines is a PhD candidate in Immunology, and has been working with Dr. Van de Water since 2005 to delineate the connection between autism and immunity.
References
Ashwood, P., S. Wills, et al. (2006). “The immune response in autism: a new frontier for autism research.” J Leukoc Biol 80(1): 1-15.
Braunschweig, D., P. Ashwood, et al. (2007). “Autism: Maternally derived antibodies specific for fetal brain proteins.” Neurotoxicology.
Croen, L. A., D. Braunschweig, et al. (2008). “Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study.” Biol Psychiatry 64(7): 583-588.
Enstrom, A. M., J. A. Van de Water, et al. (2009). “Autoimmunity in autism.” Curr Opin Investig Drugs 10(5): 463-473.
Martin, L. A., P. Ashwood, et al. (2008). “Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism.” Brain Behav Immun.
Singer, H. S., C. Morris, et al. (2009). “Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: A pregnant dam mouse model.” J Neuroimmunol 211(1-2): 39-48.
Zimmerman, A. W., S. L. Connors, et al. (2007). “Maternal antibrain antibodies in autism.” Brain Behav Immun 21(3): 351-357.
