The Presence of Specific Maternal IgG Antibodies Is Associated with Abnormal Brain Enlargement in ASD and in Nonhuman Primate Model of ASD

Saturday, May 19, 2012: 12:00 PM
Grand Ballroom East (Sheraton Centre Toronto)
10:15 AM
C. W. Nordahl1, M. Bauman1, D. Braunschweig1, A. M. Iosif2, P. Ashwood1, J. Van de Water1 and D. G. Amaral1, (1)UC Davis MIND Institute, Sacramento, CA, (2)Public Health Sciences, University of California , Davis, CA
Background: The immune system has been implicated in the pathogenesis of some forms of autism. Braunschweig et al. (2007) have demonstrated that 12% of mothers of children with autism have autoantibodies directed against fetal brain tissue. Nonhuman primate models are currently underway to further determine the pathologic significance of these antibodies.  

Objectives: We evaluated children born to mothers with these autism-specific IgG autoantibodies to determine whether they exhibit a distinct neural phenotype.  In a parallel line of research utilizing nonhuman primates, we evaluated brain and behavioral development of rhesus monkeys prenatally exposed to these autism-specific antibodies.

Methods: We examined total cerebral volume (TCV) in 152 male children (12 autism spectrum disorder [ASD] and 40 typically developing [TD] controls), at 3 years of age. Participants were enrolled in the MIND Institute Autism Phenome Project (APP). Mothers from both groups were screened for maternal IgG autoantibodies that are reactive to fetal brain proteins. We focused our efforts on antibodies that demonstrate the highest autism specificity, with reactivity to two fetal brain protein bands (37 and 73 kDa). In the nonhuman primate model, we prenatally exposed rhesus monkeys to a pool of 37/73 kDa IgG antibodies collected from a subset of the human mother participants and evaluated total brain volume (TBV) when the monkey offspring reached 2 years of age. 

Results: Of the 112 children in the ASD group, 10 (9%) were born to mothers with the autism-specific 37/73kDa IgG antibodies (ASD-POS). The remaining 102 ASD children were negative for the 37/73KDa IgG antibodies (ASD-NEG).  As expected, none of the mothers in the TD group exhibited these autoantibodies. Clinically, there were no differences in age, autism severity, or DQ in the two ASD groups. However, TCV in ASD-POS group is significantly larger than both ASD-NEG and TD groups (p = 0.0003). The magnitude of abnormal brain enlargement in ASD-NEG group relative to TD controls is 5%, consistent with previous reports of brain enlargement in ASD. However, the magnitude of enlargement in the ASD-POS group is much larger, at 12%. Parallel results obtained from the nonhuman primate model indicate that TBV in juvenile male monkeys prenatally exposed to autism-specific maternal antibodies is significantly larger than control groups (p = 0.04). 

Conclusions: These results suggest that there may be an underlying immunological etiology for megalencephaly/macrocephaly in autism. With the nonhuman primate model, we will be able to evaluate the cellular/molecular pathology associated with this pattern of abnormal brain growth. The translational nature of this multidisciplinary research can be used to further determine the pathological significance of the autism-specific antibodies, and may ultimately contribute to novel preventative and/or therapeutic measures.

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