Identifying Neurological Autoantibodies in COVID-19: mGluR2 as a Marker of Immune Dysregulation During the Omicron Outbreak in China

Aimed to comprehensively investigate the presence of neural autoantibodies in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients experiencing neurological complications during the Omicron wave in China. Forty consecutive COVID-19 patients with severe neurological complications and 15 disease controls (DC) were enrolled. Neural autoantibodies were detected using both the indirect immunofluorescence assay (IFA) on mouse brain tissue and the Brain-neuronal-antigen microarray. Our results indicated a significantly higher prevalence of neural autoantibodies in the CSF (62.16% vs. 0.0%) and plasma (38.71% vs. 13.33%) of COVID-19 patients compared to DC. Additionally, we identified 12 upregulated intrathecal IgG autoantibodies with differential levels between COVID-19 patients and DC, as well as 51 upregulated IgG autoantibodies in plasma. A high prevalence of anti-mGluR2 antibodies (13.33%) in COVID-19 patients was confirmed by cell-based assays. Western blot analysis showed these antibodies cross-react with both the nucleocapsid (N) and spike (S) proteins of SARS-CoV-2. Notably, strong binding to both the S protein's RBD-Fc and mGluR2 was observed, an association that was substantiated by bioinformatics analysis evaluating the similarity between SARS-CoV-2 proteins and the targeted antigens on the microarray. This finding hints at a potential cross-reactivity between anti-mGluR2 antibodies and the S protein in COVID-19 patients.