Anti-neuronal and anti-microbial immunity link CaMKII and autism spectrum disorder with pediatric acute-onset neuropsychiatric syndrome

Autism spectrum disorders (ASD) may be associated with neuropsychiatric symptoms such as tics, obsessive-compulsive behaviors, and other symptoms characteristic of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). Abnormal anti-neuronal autoantibody responses against the basal ganglia are elevated in neuropsychiatric disorders such as PANDAS. Our study suggests that anti-neuronal autoantibodies in ASD may be associated with the presence of PANDAS and investigates microbial polysaccharides as potential inducers of anti-neuronal autoantibodies in children with confirmed ASD or ASD/PANDAS. Functional anti-neuronal autoantibodies which signal CaMKII and induce excess dopamine release were found in ASD/PANDAS serum. Autoantibody signaling or reactivity was inhibited by 3 common microbial antigens, by a group of neuronal antigens, or by anti-IgG beads which significantly reduced CaMKII activation in ASD/PANDAS sera. Interestingly, a CamKII mutation has recently been associated with autistic symptoms in animal models and also in ASD in humans. Children with ASD/PANDAS had significantly elevated anti-neuronal autoantibodies by ELISA, and strong IgG responses against the group A streptococcal epitope GlcNAc were observed in ASD/PANDAS. Our study links three common microbial antigens to anti-neuronal antibody responses in ASD/PANDAS and suggests that molecular mimicry between host and pathogen may play a role in development of the autoantibodies and potentially lead to neuropsychiatric symptoms in ASD/PANDAS. Thus, ASD may be complicated by anti-neuronal antibodies which can develop during infections and may contribute to the co-morbid symptoms of PANDAS in ASD.