Examining the Autoimmune Hypothesis in Paediatric New-Onset Psychosis: A Pilot Study

Abstract

Introduction: Disease states involving psychosis are responsible for significant morbidity but remain incompletely understood. The dopamine and glutamate hypotheses explain the pathophysiology of psychosis in terms of defects in neurotransmission. Autoantibodies directed against proteins expressed on the surface of neuronal cells have been detected by a number of studies in recent years, and suggest that immune-mediated mechanisms may define a biological subgroup within psychosis. This study examined, for the first time, a cohort of children presenting with a first episode of psychosis (FEP) for the presence of antibodies to dopamine-2 receptor (D2R) and the NR1 subunit of the N-methyl-D-aspartate receptor (NMDAR). Methods: Serum taken during the acute presentation of 43 children with FEP and serum from 43 paediatric control subjects was assessed for the presence of IgG, IgM, and IgA antibodies to human D2R and NR1 using a flow cytometry live cell-based assay and immunolabeling of murine primary neurons. Immunoaffinity purification and immunoabsorption was used to assess the specificity of antibody binding. An ELISA assay was developed and trialled for the detection of antibodies to D2R. Results: Positive immunoglobulin binding to D2R was found in 3 of 43 psychosis patients (3 IgG, 1 IgM, 0 IgA) and to NMDAR in 6 of 43 patients (5 IgG, 1 IgM, 1 IgA). Positive binding was not detected to either receptor in any control patient serum, as compared with 8 of 43 FEP patients (p<0.0001). Specificity of binding was confirmed. ELISA assays did not reproduce the results of flow cytometry live cell-based assay. Conclusions: For the first time, antibodies to surface human D2R and NR1 were detected in paediatric patients with isolated psychosis, which supports the hypothesis that a subgroup of children presenting with psychosis may have immune-mediated pathologies.