Interferon-λ-neutralizing autoantibodies and common autoimmune disease autoantibodies in pediatric acute-onset neuropsychiatric syndrome

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by sudden onset obsessive-compulsive disorder (OCD) symptoms in conjunction with other neuropsychiatric manifestations including disturbances in sleep, cognition, and behavior. Studies have revealed high rates of autoimmune and inflammatory markers-as well as comorbid rheumatologic disease-in patients with PANS. While published studies have suggested autoantibodies are common in PANS patients, the molecular targets of these autoantibodies (AAbs) remain poorly characterized. Here, we profile the AAbs in 224 plasma samples taken from 166 PANS patients during periods of active disease, or flares, compared to 83 pediatric healthy controls using custom Luminex microbead panels conjugated with highly curated antigens from common autoimmune diseases as well as cytokines and chemokines. We find that PANS patients exhibit increased prevalence of AAbs against autoantigens known to be targeted in scleroderma and GI/endocrine autoimmune conditions. Furthermore, a subset of PANS patients exhibited AAbs against IFN-λ, an important line of defense against infections at anatomic barriers. Among the 11 tested PANS plasma samples with IFN-λ-binding AAbs, 9 showed detectable inhibition of IFN-λ signaling, and 4 met our predefined stringent threshold for IFN-λ-neutralizing activity, while no tested HC samples met this neutralization threshold. These findings support a link between autoimmunity and PANS, and may provide insight into a potential disease mechanism mediated by immune deficits at barrier surfaces in a subset of patients.