Despite increasing evidence that circulating maternal antibodies can produce disease in the fetus and that anti- brain antibodies are associated with an ever-expanding number of neurological and psychiatric disorders, there is little information concerning when and how antibodies enter the brain, particularly of the fetus during pregnancy. We have previously proposed that gestational exposure to maternal antibodies is associated with the development of autism spectrum disorder (ASD) in human offspring. To support this contention, we exposed pregnant rhesus monkeys to purified IgG obtained from mothers who harbor anti-fetal brain antibodies and have given birth to children with ASD. The rhesus offspring demonstrated behavioral and brain growth alterations that are consistent with ASD. Nonetheless, substantial skepticism remains with the notion that unusual maternal antibodies are pathogenic for ASD. This is due, in part, to the fact that there is so little evidence concernig the entry of antibodies into the fetal brain and the mechanisms by which they might alter brain development leading to ASD. In fact, while papers by Coe and colleagues indicate that maternal antibodies cross the placenta during the latter half of pregnancy in the rhesus monkey, we have not been able to find a single publication that determines whether and when these antibodies enter the fetal monkey brain. To investigate this issue, we have recruited a team of investigators with expertise in neuroscience, immunology, fetal development of the nonhuman primate, and positron emission tomography (PET) to carry out studies with the overarching goal of providing evidence for transplacental transfer of maternal antibodies and entry into the fetal brain. While there are several potential strategies for carrying out these studies, we have focused on PET imaging with the hope that this will establish expertise and a protocol for noninvasively evaluating antibody entry into the central nervous system of the nonhuman primate at various ages.
Specific Aim 1 will evaluate the occurrence of transplacental transport of 124I-labeled IgG into the fetal rhesus monkey brain at three developmental time points in the second and third trimesters. Entry of IgG into the brain will be assessed both by PET and by fetal tissue harvests followed by brain dissection and evaluation for radioactivity using a gamma counter. We will use a monoclonal antibody to GPM6A which is a tetraspan membrane protein abundant on neuronal surfaces in the central nervous system. Evaluation of gene and protein databases indicate that this protein is abundant throughout fetal life both in the nonhuman primate (www.blueprintnhpatlas.org) and in the human (www.brainspan.org/), and is a component of the human surfaceome.
Specific Aim 2 will carry out longitudinal PET scans to identify quantitative changes of IgG entry into the fetal brain from midgestation to near term. The studies described here are a first step towards developing a nonhuman primate model of antibody-induced psychiatric illness and establishing the mechanisms through which anti-brain antibodies might influence brain development, brain function and behavior.
Antibodies directed at one's own body cause a variety of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. During pregnancy, autoimmune disease can affect the fetus in syndromes such as Graves disease and myasthenia gravis. This application is for funding to study if, and when, antibodies in pregnant rhesus monkeys cross the placenta and ultimately enter the fetal brain. The outcome of this research will have important implications for our proposal that anti-brain antibodies may be one cause of psychiatric illnesses such as autism spectrum disorder.
