Posted April 19, 2017

Betty Diamond, M.D., Feinstein Institute for Medical Research

Autism spectrum disorder (ASD) is a complex condition resulting from the combination of genetic and environmental factors. Recently, focus has been placed on the environmental factors of maternal immune contribution, and research suggests that maternal brain-reactive antibodies may play a major role in ASD. Maternal brain-reactive antibodies are molecules present in the maternal circulation that have the potential to profoundly and irreversibly alter development of the vulnerable fetal brain, which does not yet have the protection of a fully developed blood-brain barrier. These brain-reactive antibodies arise in adults due to immune responses provoked by autoimmune disease, infections, or the presence of tumors. Several studies have focused on understanding the role of the maternal brain-reactive antibodies in ASD, but these studies have had important limitations such as the use of polyclonal antibodies. Dr. Diamond, with support from a 2013 Autism Research Program Idea Development Award, developed a novel strategy to test a series of monoclonal anti-brain antibodies to demonstrate particular ASD characteristics associated with a specific antibody.

Dr. Diamond generated 40 monoclonal antibodies from memory B cells isolated from three mothers that were positive for brain-reactive antibodies and had a child with ASD. Memory B-cells, in particular, were used to generate the antibodies because 1) they have the ability to bind to human fetal brain cells, and 2) they persist in humans for years, which is critical because the blood may have been obtained from the mother years after pregnancy. Of the antibodies isolated, three antibodies (C6, A7, and C9) targeted Contactin-Associated Protein-like 2 (Caspr2), a protein critical to normal brain development.

The C6 antibody was extensively characterized, and the results were published in a 2016 article in Molecular Psychiatry. To demonstrate the contribution of C6 to ASD, mice were exposed, in utero, to isolated C6 antibody through maternal mouse blood. Abnormalities were found in the developing brains of the mice that translated to the ASD behavioral phenotypes of impaired social ability, diminished flexible learning, and increased repetitive behavior. The brain and behavioral defects were observed in male mice, but not female mice. In agreement with these results, when the original human blood, from which C6 was isolated, was administered to pregnant mice those fetuses also displayed developmental changes in the brain characteristic of ASD. What's more, depletion of C6 antibodies from the human blood prior to administration to pregnant mice resulted in normal brain development in the fetuses.

Dr. Diamond next investigated whether antibodies to Caspr2 are frequently present in women with an ASD child. Plasma from human mothers positive for brain-reactive antibodies having a child with ASD was analyzed and it was determined that 37% displayed robust anti-Caspr2 binding, compared to 12% in mothers lacking brain-reactive antibodies with an ASD child, and only 7.6% in mothers who did not have a child with ASD.

Dr. Diamond's research identifies a potential biomarker that could help identify pregnancies at an increased risk for an ASD child. Furthermore, by identifying pathways of neuronal development that are impaired by specific antibodies, preventative strategies during pregnancy can be developed to protect the developing brain from insults that give rise to ASD.

 

Publication:

Brimberg L, Mader S, Jeganathan V, et al. 2016. Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Molecular Psychiatry, 21(12):1663-1671.

 

Link:

Public and Technical Abstracts: Maternal Brain-Reactive Antibodies and Autism Spectrum Disorder

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