Eric Song, Christopher M. Bartley, Ryan D. Chow, Thomas T. Ngo, Ruoyi Jiang, Colin R. Zamecnik, Ravi Dandekar, Rita P. Loudermilk, Yile Dai, Feimei Liu, Sara Sunshine, Jamin Liu, Wesley Wu, Isobel A. Hawes, Bonny D. Alvarenga, Trung Huynh, Lindsay McAlpine, Nur-Taz Rahman, Bertie Geng, Jennifer Chiarella, Benjamin Goldman-Israelow, Chantal B.F. Vogels, Nathan D. Grubaugh, Arnau Casanovas-Massana, Brett S. Phinney, Michelle Salemi, Jessa R. Alexander, Juan A. Gallego, Todd Lencz, Hannah Walsh, Anne E. Wapniarski, Subhasis Mohanty, Carolina Lucas, Jon Klein, Tianyang Mao, Jieun Oh, Aaron Ring, Serena Spudich, Albert I. Ko, Steven H. Kleinstein, John Pak, Joseph L. DeRisi, Akiko Iwasaki, Samuel J. Pleasure, Michael R. Wilson, Shelli F. Farhadian Published: April 27, 2021 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00116-6 Highlights Immune cell scRNA-seq showed divergent T cell activation in the CNS during COVID-19 COVID-19 patients had a compartmentalized cytokine response in the CNS All COVID-19 patients had anti-SARS-CoV-2 antibodies in their CSF Five out of seven COVID-19 patients had anti-neural autoantibodies in their CSF Summary COVID-19 patients frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single cell RNA-seq and cytokine analyses of CSF and blood from COVID-19 patients with neurological symptoms, we find compartmentalized, CNS specific T cell activation and B cell responses. All COVID-19 cases had CSF anti-SARS-CoV-2 antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are found only during brain infection, and are not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from a COVID-19 patient, and find that these mAbs target both anti-viral and anti-neural antigens—including one mAb that reacted to both spike protein and neural tissue. Overall, CSF IgG from 5/7 patients contains anti-neural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of COVID-19 patients and suggests a role for autoimmunity in neurologic sequelae of COVID-19.