The Peripheral Immunophenotype in Neurodevelopmental Disorders

Abstract

The factors contributing to the severity of the neurodevelopmental disorders autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are largely unknown. Previous studies have indicated immune abnormalities in these disorders, such as increased inflammation and altered immune cell numbers. We, in collaboration with the Province of Ontario Neurodevelopmental Disorder (POND) Network, analyzed markers of intestinal permeability and inflammation in children diagnosed with ASD or ADHD, as well as typically developing controls. Plasma from these participants was used to investigate levels of soluble inflammation, denoted by circulating acute phase proteins, as well as circulating levels of markers of intestinal epithelial damage and bacterial translocation. Peripheral blood mononuclear cells were isolated from these participants and used to construct an immunophenotype of ASD and ADHD, focusing on monocytes and monocyte activation and maturation. These data were then compared with scores of behaviour severity to identify associations between inflammation and behaviour in these disorders. We identified increased soluble inflammation in ASD, indicated by increased circulating C-reactive protein. We associated this inflammation with intestinal permeability, indicated by increased circulating LPS. Classical monocyte frequency was significantly lower in ASD and these monocytes displayed an altered migratory phenotype, indicated by a reduction in CCR2 expression. Furthermore, we have identified potential maladaptive monocyte responses to soluble inflammation in both ASD and ADHD, with altered monocyte phenotypes in response to inflammatory mediators compared to typically developing controls. Finally, we identified that changes in monocyte phenotype are associated with more severe behaviours in both ASD and ADHD. These findings imply that inflammation and immune abnormalities contribute to the severity of neurodevelopmental disorders.