Abstract
Antibodies directed against fetal brain proteins of 37 and 73 kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman primate model. IgG was isolated from mothers of children with ASD (IgG-ASD) and of typically developing children (IgG-CON). The purified IgG was administered to two groups of female rhesus monkeys (IgG-ASD; n=8 and IgG-CON; n=8) during the first and second trimesters of pregnancy. Another control group of pregnant monkeys (n=8) was untreated. Brain and behavioral development of the offspring were assessed for 2 years. Behavioral differences were first detected when the macaque mothers responded to their IgG-ASD offspring with heightened protectiveness during early development. As they matured, IgG-ASD offspring consistently deviated from species-typical social norms by more frequently approaching familiar peers. The increased approach was not reciprocated and did not lead to sustained social interactions. Even more striking, IgG-ASD offspring displayed inappropriate approach behavior to unfamiliar peers, clearly deviating from normal macaque social behavior. Longitudinal magnetic resonance imaging analyses revealed that male IgG-ASD offspring had enlarged brain volume compared with controls. White matter volume increases appeared to be driving the brain differences in the IgG-ASD offspring and these differences were most pronounced in the frontal lobes.
Highlights
Autism spectrum disorder (ASD) affects over 1% of the children in the United States,[1] yet there remains relatively little understanding of its underlying causes
Serum was collected and immunoglobulin G (IgG) purified from mothers of children with autism who exhibited maternal autoantibody reactivity to fetal brain proteins at 37 and 73 kDa (n 1⁄4 4), or from mothers of typically developing children, who were devoid of these antibodies (n 1⁄4 5)
The IgG-ASD37/73kDa offspring were more frequently approached by their mothers (Po0.01), they were more commonly in close proximity (P 1⁄4 0.03) to them, and they were more often contacted (Po0.01) by their mothers (Figure 1; Table 3; Supplementary Table S3)
Summary
Autism spectrum disorder (ASD) affects over 1% of the children in the United States,[1] yet there remains relatively little understanding of its underlying causes. Maternal immunoglobulin G (IgG) isotype antibodies normally cross the placenta and protect the immunologically naive fetus.[3] in addition to protective antibodies, autoantibodies that react to fetal ‘self’-proteins can cross the placenta resulting in a number of neonatal conditions.[4,5,6,7] We know that in approximately 12% of women who have a child with autism, maternal antibodies exist that are reactive to fetal brain proteins at 73 and 37 kDa.[7,8] To date, this pattern of reactivity has not been observed in any mothers of typically developing children
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