Autism: Maternally derived antibodies specific for fetal brain proteins

Abstract

Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73kDa and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands correlated with a diagnosis of behavioral regression in the child when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09 -15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.

Maternal Mid-Pregnancy Autoantibodies to Fetal Brain Protein: The Early Markers for Autism Study

“…On the basis of results reported from evaluations of specimens obtained after the child's diagnosis (18)(19)(20), we elected to begin the search for maternal biologic markers by focusing on autoantibodies to human fetal brain proteins measured in mid-pregnancy peripheral blood. With modest sample size for this first study, we found that the frequency of specific bands and band patterns differed some-what by study group and by autism onset type.…”

“…This study also demonstrated that immunoreactivity persisted in maternal circulation for up to 18 years after delivery. Finally, we recently reported that autoantibodies to human fetal brain proteins at 37 kDa and 73 kDa were significantly more often present in the plasma of mothers of children with autism compared with control mothers (20). In that study, maternal plasma was collected on average 3.5 years after the birth of the study child.…”

Immune Dysfunction in Autism: A Pathway to Treatment

“…The maternal transfer of autoantibodies from the mother to child during pregnancy is well documented, and is associated with a number of factors that can affect both pregnancy and neonatal outcome. 11 The presence of autoantibodies directed against critical neuronal components of fetal brain extracts in a subset of mothers of ASD children provides supporting evidence that one potential mechanism linking maternal immune components with ASD involves the transfer of autoantibodies from mother to the developing fetus during pregnancy 15,16,17,20 (Table 2).…”

“…Future studies will need to better characterize the behavioral changes evoked by these antibodies and their relevance to core features or symptoms of ASD, as well as the potential cellular targets of these antibodies. Although the frequency at which potential autoantibodies are present in mothers who have children with ASD is low, the significance of carrying these antibodies may be substantial 16 and presents an exciting avenue for screening and therapy.…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…Anti-fetal antibodies can pass the blood-brain barrier which is not fully developed during the prenatal period [73]. Braunschweig et al identified that anti-fetal brain antibodies, IgG, were found in ~11.5% of mothers of children with ASD, but not in mothers of children of typical development and mothers of children with development delay [74]. Injections of IgG collected from mothers of children with ASD into pregnant rhesus monkeys during the first and second trimesters led to altered brain volume and social behavior development in the offspring [75].…”