This proposal focuses on the role of in utero exposure to maternal autoimmunity indetermining neurodevelopmental outcomes of the offspring. Our preliminary data provide strongsupport for the hypothesis that anti-brain antibodies in mothers have a contributory role in thedevelopment of autism spectrum disorders (ASD). We focus particularly on ASD, in partbecause the incidence of this disorder has increased dramatically over the past few decades.While many environmental triggers have been suggested, growing evidence indicates roles formaternal autoimmunity and maternal immune activation. There is evidence from animal studiesthat exposure in utero to maternal anti-brain antibodies plays a role in disease pathogenesis.When serum or purified IgG from women with brain-reactive antibodies and a child with ASD areadministered to pregnant mice or monkeys, the offspring exhibit abnormalities in socialbehavior, increased anxiety or increased motor activity. In cross sectional studies, we haveshown that women with a child with ASD are 4-5 times more likely to have brain-reactiveserology than unselected women of child-bearing age. These antibodies are enriched in womenwith autoimmunity, and autoimmunity in a mother has been shown to predispose to ASDoutcome. Despite these intriguing observations, there is a lack of prospective data in humansshowing a relationship between autoimmunity and/or inflammation during gestation and thepresence of neurodevelopmental abnormalities in offspring. This project will investigate aprospective cohort to address this issue by enriching for mothers who have evidence ofautoimmunity, and comparing the incidence of neurodevelopmental disorders in their children tothe children of control mothers without evidence of autoimmunity. In specific aim 1, we will testthe hypothesis that clinical or subclinical autoimmunity in the mother at the time of pregnancypredisposes to a child with ASD. We will monitor ASD related outcomes in a cohort of 4,500mothers who are enriched for the presence of autoimmune disease. In specific aim 2, we willtest the hypothesis that the presence of maternal anti-brain antibodies during pregnancypredisposes to a greater risk of a child with ASD or neurodevelopmental problems. In specificaim 3, we will test the hypothesis that maternal immune activation or increased cytokine levelsat during pregnancy predisposes to ASD in the child. We will follow cytokine levels and modularpatterns of maternal whole blood gene expression in the second and third trimesters in order toassess the contribution of maternal immune and inflammatory factors to ASD-relatedphenotypes in offspring. Prospective data supporting a role for intrauterine environment on riskfor ASD will fundamentally alter our understanding of ASD pathogenesis and will lead directly topotential diagnostics as well as new approaches to disease prevention.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
