Autoimmunity a Player in Autism

Megan Brooks

September 06, 2013

A new study suggests that about 1 in 10 mothers of children with autism have antibodies that react with proteins in the brain of their children, and these antibrain antibodies correlate with maternal autoimmunity.

"This study strongly suggests that maternal antibrain antibodies associate with autism spectrum disorder [ASD] in the child, as others have also shown, and suggest that the presence of antibrain antibodies may be associated with other manifestations of autoimmunity in the mom," lead investigator Betty Diamond, MD, PhD, from the Center for Autoimmune and Musculoskeletal Diseases at the Feinstein Institute for Medical Research in Manhasset, New York, told Medscape Medical News.

The study found an increased prevalence of autoimmune disease, especially rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), in mothers with antibrain antibodies. This finding is "consistent with the hypothesis that autoimmune diseases may confer risk for ASD in the offspring of mothers with these disorders," the investigators say.

The study was published online August 20 in Molecular Psychiatry.

Antibrain Antibodies and ASD

The underlying etiology for autism remains unknown, although genetic and environmental factors, including in utero environmental factors, are thought to be involved.

There is mounting evidence that maternal antibodies can target the fetal brain. Several studies have identified the presence of antibodies that bind to human fetal brain tissue in mothers with an ASD child. When antibrain antibodies from mothers of an ASD child are administered to pregnant mice or pregnant monkeys, the offspring exhibit behavioral alterations akin to those seen in ASD children.

As reported by Medscape Medical News, several studies have linked maternal infections or inflammation during pregnancy to the development of ASD in offspring, suggesting that activation of the maternal immune system might lead to an increased risk of having a child with ASD.

To further examine ties between antibrain antibodies, autism, and autoimmunity, Dr. Diamond and colleagues screened plasma of 2431 mothers of an ASD child and 653 unselected women of childbearing age for antibrain antibodies.

Using immunohistology on mouse brain, they found that mothers of an ASD child were nearly 4 times more likely to harbor antibrain antibodies than unselected women of childbearing age (P < .00001).

In total, 10.7% of the plasma of mothers of an ASD child (260/2431) displayed strong reactivity to mouse brain antigens compared with 2.6% of the plasma from control women (17/653). Only 28% of plasma of mothers of an ASD child showed no binding compared with 64.7% of plasma from control women.

The researchers analyzed an additional 318 plasma samples of mothers of an ASD child from a separate cohort and found that 28 (8.8%) displayed strong reactivity to mouse brain antigens. Only 22.6% (72 samples) showed no binding.

Link to Autoimmunity

To test their hypothesis that brain reactivity would be associated with an autoimmune predisposition, the researchers tested for the presence of antinuclear antibodies, which are commonly present in individuals with many autoimmune diseases.

Confirming their hypothesis, they found that ASD mothers with antibrain antibodies were significantly more likely to harbor antinuclear autoantibodies than ASD mothers or unselected women who lacked antibrain antibodies (P < .0001).

In total, 53% of mothers of an ASD child with antibrain antibodies also had antinuclear autoantibodies compared with 13.4% of mothers of an ASD child without antibrain antibodies and 15% of control women.

"These data are consistent with a predisposition to more generalized autoimmunity in some mothers with anti-brain antibodies who have a child with ASD," Dr. Diamond and colleagues say. Self- reported autoimmune diseases, especially RA and SLE, were also more common in the mothers of an ASD child with antibrain antibodies.

"The possibility of autoimmune mechanisms being a contributing factor in ASD has been entertained as early studies suggested that individuals with ASD have a family history of autoimmune disease," the investigators note. A recent study examining autoimmune disorders in women, with data for more than 600,000 births, showed that women with either RA or celiac disease had an increased risk of having a child with ASD (Atladottir et al, Pediatrics 2009;124:687-694).

Link "Gaining Traction"

Dr. Diamond and colleagues say that work is under way to assess the etiologic role of antibrain antibodies in autism. "The detailed characterization of the antigenic specificity of these antibodies is likely to shed light on the neurobiology of autism as well as provide practical benefits to the management and prevention of this disorder," they write.

"This study should be confirmed, although our data do confirm other studies," Dr. Diamond told Medscape Medical News. "The hope is that these findings will begin to help assess risk of an ASD child for a woman, but this is just a beginning," she said.

In July, as reported by Medscape Medical News, a team led by Judy Van de Water, PhD, of the University of California–Davis MIND Institute, found that maternal antibodies that interfere with fetal brain proteins during pregnancy may be responsible for roughly one quarter of cases of ASD. They coined the term "maternal autoantibody–related," or MAR, autism for these cases.

Asked for her thoughts on this latest study, Dr. Van de Water said, "From my perspective, it supports other studies that these antibodies are really there, so this is gaining traction now." She said the maternal antibody research as it relates to autism is "probably the biggest piece of research that we have going on right now."

The finding that these women have more autoimmunity, or immune dysregulation, is not entirely unexpected. "Biologic factors are certainly important in autism," Dr. Van de Water added. She said it is also important to note that immune dysregulation "goes beyond maternal; a good proportion of autistic children have some kind of immune dysregulation."

The study was supported by the Simons Foundation and Autism Speaks. The authors have disclosed no relevant financial relationships. Dr. Van de Water has a patent on proteins used in her research of maternal antibrain antibodies and is a consultant for Pediatric Bioscience.

Mol Psychiatry. Published online August 20, 2013. Abstract

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