Maternal Antibody Related Autism: Maternal Autoantibodies

Autism and the Immune System

A number of lines of evidence suggest that at least some forms of autism are associated with immune dysfunction. Individuals with autism have abnormal immune system function leading to inappropriate or ineffective immune response to pathogen challenges. Children with autism often have recurrent infections, suggesting that abnormal immune function may be present in a subset of these children. Moreover, several studies have shown peripheral immune abnormalities in individuals with autism, as well as inflammation in the central nervous system.

In addition to general immune system dysfunction seen in autism, recent evidence suggests that at least some cases of autism are associated with autoimmune disorders, and that autoimmune disorders are more common in family members of children with autism compared to typically developing controls. Moreover, autoantibodies directed against central nervous system proteins have been found in the serum of children with autism. It is important to note that while significantly higher levels of autoantibodies are detected in individuals with autism compared to controls, the pathogenic significance of these antibodies is not yet understood.

Autism and the Maternal Immune System

In addition to the presence of autoantibodies in children with autism, recent evidence raises the possibility that maternal antibodies to fetal brain proteins may play a role in the development of autism in a woman’s offspring. The first suggestion that maternal antibodies might be involved in autism came from studies showing that antibodies from serum of mothers who have children with an ASD reacted to antigens on lymphocytes from their affected children. Given that antigens expressed on lymphocytes are also found on cells of the central nervous system, the authors proposed that aberrant maternal immunity might be associated with the development of some cases of autism. More evidence of a link between maternal immunity and autism came from the demonstration of binding of maternal antibodies to adult rat cerebellar Purkinje cells. Furthermore, when these antibodies were injected into pregnant mice, the offspring exhibited some behavioral abnormalities. It was subsequently shown that plasma from several women with children with autism contained antibodies that recognized proteins in fetal rat brain.

Most recently, researchers at the University of California at Davis have identified a highly specific pattern of autoantibody reactivity to fetal human brain proteins in the serum of mothers who have a child with autism. Similar results were reported almost simultaneously from a group at Johns Hopkins University and the Kennedy Krieger Institute. It has also been reported in a prospective study using archived serum samples that similar antibodies exist in pregnant women whose children were subsequently diagnosed with autism. It is important to note that in this case the samples were collected during pregnancy, while in the other cases the samples were collected after the child was born and diagnosed.

Compelling data linking these maternal antibodies to the etiology of autism come from antibody transfer studies in primates. Briefly, antibodies purified from women with multiple children with autism were injected into pregnant rhesus monkeys, and the pregnancies were allowed to continue to term. The resultant offspring showed dramatically altered phenotypes, including hyperactivity, repetitive behavior patterns, and impaired social interactions, not unlike symptoms seen in children with autism. A similar study has now been published using a mouse model, with analogous results: offspring that were exposed in utero to antibodies taken from mothers of children with autism had a number of behaviors consistent with those seen in children with autism.

Collectively, the above studies suggest that in a significant percentage of the cases of autism, circulating maternal antibodies directed against certain fetal brain proteins might cross the placenta and bind to targets in the developing fetal brain. These antibodies may interfere with fetal neurodevelopment, potentially leading to neurodevelopmental disorders such as autism.

These observations suggest that detection of antibodies directed against fetal brain proteins can serve as valuable biomarkers to identify women who have an increased risk of having a child with autism.