Abstract
There is growing evidence that immune dysfunction interacts with genetic predisposition to increase vulnerability to autism spectrum disorders (ASD). However, few studies have extensively profiled the autoantibody repertoire from children with ASD. Here, we utilized unbiased approaches to identify the antigenic targets of autoantibodies from cerebrospinal fluid (CSF) and blood collected from children with ASD compared to typically developing controls. In a cohort of children with ASD, we identified 6 of 61 participants (9.8%) harbored anti-neural autoantibodies in their CSF with distinct immunoreactivity patterns by tissue-based immunofluorescence screening on murine brain sections. In one participant, two CSF samples collected 2.3 years apart showed persistent anti-neural immunofluorescence. Phage display immunoprecipitation sequencing (PhIP-seq) and immunoprecipitation mass spectrometry (IP-MS) were utilized to screen for the antigenic targets of these CSF immunoreactivities, which revealed that each of these 6 cases have unique autoreactivities in their CSF as well as their peripheral blood. Our screening techniques identified several candidate autoantigens that have strong genetic associations with ASD, including ANK2/3, BCL11A, CHD3/8, NRXN1/2, RUNX1T1, and ZNF292. Broadly, these candidate autoantigens participate in several pathways that may contribute to ASD, including synaptic connectivity, neuronal scaffolding, and transcriptional regulation. While the autoantibody specificities remain to be validated through orthogonal assays, these data demonstrate the potential for parallel unbiased screens to identify autoantibodies with relevance to ASD.