Immunologic Study Links Certain Maternal Autoantibodies to Autism

HONOLULU – Certain maternal autoantibodies are associated with the development of autism spectrum disorders, results from a large ongoing analysis demonstrate.

The finding lays the groundwork for an eventual diagnostic test for autism, Judy Van de Water, Ph.D., said at the annual meeting of the American Academy of Neurology.

"Currently there is no biologic marker for autism," said Dr. Van de Water, an immunologist at the University of California, Davis. "It’s completely defined by behaviors."

The maternal immune response in autism is of interest to researchers because of its role in neurodevelopment. "Maternal IgG isotype antibodies readily cross the placenta and are known to persist for up to 6 months postnatally in the child," Dr. Van de Water said. "In addition, maternal antibodies have been shown to cause changes in fetal development in several known autoimmune disorders, such as SLE."

In 2002, Dr. Van de Water and her associates began to collect blood samples from families as part of the Childhood Autism Risk from Genetics and the Environment (CHARGE) study. They sampled the study population from three groups of children aged 2-5 years: children with autism (currently includes more than 800 families); typically developing children without autism or other developmental disabilities selected from the general population (currently 600 families enrolled); and children with developmental disabilities without autism (currently 220 families enrolled).

In the original experimental design, Western blots against human fetal brain protein were performed with 61 mothers of children with autism (36 regressive and 25 early onset), 40 mothers of children with developmental delay, and 62 mothers of typically developing children. The mothers were matched for age and parity (Neurotoxicology 2008;29:226-31). The investigators found that seven mothers of children with autism (12%) had IgG reactivity to fetal brain proteins at bands 37kDa and 73kDa. "We did not see this pattern in the typically developing controls or in the developmentally delayed population, so this seemed to be very specific for autism," Dr. Van de Water said.

Analysis of autoantibody profiles of an additional 458 mothers – 204 mothers of children diagnosed with autism, 71 mothers of children diagnosed with an autism spectrum disorder, and 183 mothers of typically developing children – continues to yield highly significant associations between the presence of IgG reactivity to fetal brain proteins at bands 37kDa and 73kDa and a diagnosis of full autism. Dr. Van de Water and her associates also discovered an association between the 39kDa and 73kDa bands and a diagnosis of the broader autism phenotype, "though this pattern is less frequent in the full autism group," she said. Some mothers had reactivity to fetal brain proteins at all three bands.

"We think we may have a very interesting biomarker, but is there a pathologic significance to these antibodies?" she asked. To find out, the researchers analyzed behavioral characteristics associated with maternal antibodies to fetal brain proteins. Children of mothers who demonstrated reactivity at bands 37kDa and 73kDa had less expressive language based on the Expressive Language Scale of the Mullen Scales of Early Learning. Similar results were seen in children of mothers who demonstrated reactivity at all three bands. In contrast, children of mothers who demonstrated reactivity at bands 39kDa and 73kDa had higher scores on the Aberrant Behavior Checklist irritability subscale, "so we can see that we’re starting to phenotypically separate these children."

A pilot study in monkeys conducted by Dr. Van de Water and her associates demonstrated behavioral changes in offspring following passive transfer of maternal IgG during the late first and early second trimesters (Brain Behav. Immun. 2008;22:806-16). Subsequent studies have confirmed that passive transfer of these antibodies into an animal model can recapitulate some behaviors characteristic of autism. More confirmatory studies are underway.

"We are currently verifying the identity of the protein antigens recognized by these autoantibodies," Dr. Van de Water said. "We intend to develop a preconception test to use for mothers at risk of having a second child with autism."

Dr. Van de Water disclosed that she has received personal compensation for activities with Pediatric Bioscience as a consultant, and holds stock and/or stock options in the company. She has also received royalty payments from the University of California, Davis.

HONOLULU – Certain maternal autoantibodies are associated with the development of autism spectrum disorders, results from a large ongoing analysis demonstrate.

The finding lays the groundwork for an eventual diagnostic test for autism, Judy Van de Water, Ph.D., said at the annual meeting of the American Academy of Neurology.

"Currently there is no biologic marker for autism," said Dr. Van de Water, an immunologist at the University of California, Davis. "It’s completely defined by behaviors."

The maternal immune response in autism is of interest to researchers because of its role in neurodevelopment. "Maternal IgG isotype antibodies readily cross the placenta and are known to persist for up to 6 months postnatally in the child," Dr. Van de Water said. "In addition, maternal antibodies have been shown to cause changes in fetal development in several known autoimmune disorders, such as SLE."

In 2002, Dr. Van de Water and her associates began to collect blood samples from families as part of the Childhood Autism Risk from Genetics and the Environment (CHARGE) study. They sampled the study population from three groups of children aged 2-5 years: children with autism (currently includes more than 800 families); typically developing children without autism or other developmental disabilities selected from the general population (currently 600 families enrolled); and children with developmental disabilities without autism (currently 220 families enrolled).

In the original experimental design, Western blots against human fetal brain protein were performed with 61 mothers of children with autism (36 regressive and 25 early onset), 40 mothers of children with developmental delay, and 62 mothers of typically developing children. The mothers were matched for age and parity (Neurotoxicology 2008;29:226-31). The investigators found that seven mothers of children with autism (12%) had IgG reactivity to fetal brain proteins at bands 37kDa and 73kDa. "We did not see this pattern in the typically developing controls or in the developmentally delayed population, so this seemed to be very specific for autism," Dr. Van de Water said.

Analysis of autoantibody profiles of an additional 458 mothers – 204 mothers of children diagnosed with autism, 71 mothers of children diagnosed with an autism spectrum disorder, and 183 mothers of typically developing children – continues to yield highly significant associations between the presence of IgG reactivity to fetal brain proteins at bands 37kDa and 73kDa and a diagnosis of full autism. Dr. Van de Water and her associates also discovered an association between the 39kDa and 73kDa bands and a diagnosis of the broader autism phenotype, "though this pattern is less frequent in the full autism group," she said. Some mothers had reactivity to fetal brain proteins at all three bands.

"We think we may have a very interesting biomarker, but is there a pathologic significance to these antibodies?" she asked. To find out, the researchers analyzed behavioral characteristics associated with maternal antibodies to fetal brain proteins. Children of mothers who demonstrated reactivity at bands 37kDa and 73kDa had less expressive language based on the Expressive Language Scale of the Mullen Scales of Early Learning. Similar results were seen in children of mothers who demonstrated reactivity at all three bands. In contrast, children of mothers who demonstrated reactivity at bands 39kDa and 73kDa had higher scores on the Aberrant Behavior Checklist irritability subscale, "so we can see that we’re starting to phenotypically separate these children."

A pilot study in monkeys conducted by Dr. Van de Water and her associates demonstrated behavioral changes in offspring following passive transfer of maternal IgG during the late first and early second trimesters (Brain Behav. Immun. 2008;22:806-16). Subsequent studies have confirmed that passive transfer of these antibodies into an animal model can recapitulate some behaviors characteristic of autism. More confirmatory studies are underway.

"We are currently verifying the identity of the protein antigens recognized by these autoantibodies," Dr. Van de Water said. "We intend to develop a preconception test to use for mothers at risk of having a second child with autism."

Dr. Van de Water disclosed that she has received personal compensation for activities with Pediatric Bioscience as a consultant, and holds stock and/or stock options in the company. She has also received royalty payments from the University of California, Davis.

HONOLULU – Certain maternal autoantibodies are associated with the development of autism spectrum disorders, results from a large ongoing analysis demonstrate.

The finding lays the groundwork for an eventual diagnostic test for autism, Judy Van de Water, Ph.D., said at the annual meeting of the American Academy of Neurology.

"Currently there is no biologic marker for autism," said Dr. Van de Water, an immunologist at the University of California, Davis. "It’s completely defined by behaviors."

The maternal immune response in autism is of interest to researchers because of its role in neurodevelopment. "Maternal IgG isotype antibodies readily cross the placenta and are known to persist for up to 6 months postnatally in the child," Dr. Van de Water said. "In addition, maternal antibodies have been shown to cause changes in fetal development in several known autoimmune disorders, such as SLE."

In 2002, Dr. Van de Water and her associates began to collect blood samples from families as part of the Childhood Autism Risk from Genetics and the Environment (CHARGE) study. They sampled the study population from three groups of children aged 2-5 years: children with autism (currently includes more than 800 families); typically developing children without autism or other developmental disabilities selected from the general population (currently 600 families enrolled); and children with developmental disabilities without autism (currently 220 families enrolled).

In the original experimental design, Western blots against human fetal brain protein were performed with 61 mothers of children with autism (36 regressive and 25 early onset), 40 mothers of children with developmental delay, and 62 mothers of typically developing children. The mothers were matched for age and parity (Neurotoxicology 2008;29:226-31). The investigators found that seven mothers of children with autism (12%) had IgG reactivity to fetal brain proteins at bands 37kDa and 73kDa. "We did not see this pattern in the typically developing controls or in the developmentally delayed population, so this seemed to be very specific for autism," Dr. Van de Water said.

Analysis of autoantibody profiles of an additional 458 mothers – 204 mothers of children diagnosed with autism, 71 mothers of children diagnosed with an autism spectrum disorder, and 183 mothers of typically developing children – continues to yield highly significant associations between the presence of IgG reactivity to fetal brain proteins at bands 37kDa and 73kDa and a diagnosis of full autism. Dr. Van de Water and her associates also discovered an association between the 39kDa and 73kDa bands and a diagnosis of the broader autism phenotype, "though this pattern is less frequent in the full autism group," she said. Some mothers had reactivity to fetal brain proteins at all three bands.

"We think we may have a very interesting biomarker, but is there a pathologic significance to these antibodies?" she asked. To find out, the researchers analyzed behavioral characteristics associated with maternal antibodies to fetal brain proteins. Children of mothers who demonstrated reactivity at bands 37kDa and 73kDa had less expressive language based on the Expressive Language Scale of the Mullen Scales of Early Learning. Similar results were seen in children of mothers who demonstrated reactivity at all three bands. In contrast, children of mothers who demonstrated reactivity at bands 39kDa and 73kDa had higher scores on the Aberrant Behavior Checklist irritability subscale, "so we can see that we’re starting to phenotypically separate these children."

A pilot study in monkeys conducted by Dr. Van de Water and her associates demonstrated behavioral changes in offspring following passive transfer of maternal IgG during the late first and early second trimesters (Brain Behav. Immun. 2008;22:806-16). Subsequent studies have confirmed that passive transfer of these antibodies into an animal model can recapitulate some behaviors characteristic of autism. More confirmatory studies are underway.

"We are currently verifying the identity of the protein antigens recognized by these autoantibodies," Dr. Van de Water said. "We intend to develop a preconception test to use for mothers at risk of having a second child with autism."

Dr. Van de Water disclosed that she has received personal compensation for activities with Pediatric Bioscience as a consultant, and holds stock and/or stock options in the company. She has also received royalty payments from the University of California, Davis.