Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19.

van der Wijst, Monique G P; Vazquez, Sara E; Hartoularos, George C; Bastard, Paul; Grant, Tianna; Bueno, Raymund; Lee, David S; Greenland, John R; Sun, Yang; Perez, Richard; Ogorodnikov, Anton; Ward, Alyssa; Mann, Sabrina A; Lynch, Kara L; Yun, Cassandra; Havlir, Diane V; Chamie, Gabriel; Marquez, Carina; Greenhouse, Bryan; Lionakis, Michail S; Norris, Philip J; Dumont, Larry J; Kelly, Kathleen; Zhang, Peng; Zhang, Qian; Gervais, Adrian; Le Voyer, Tom; Whatley, Alexander; Si, Yichen; Byrne, Ashley; Combes, Alexis J; Rao, Arjun Arkal; Song, Yun S; Fragiadakis, Gabriela K; Kangelaris, Kirsten; Calfee, Carolyn S; Erle, David J; Hendrickson, Carolyn; Krummel, Matthew F; Woodruff, Prescott G; Langelier, Charles R; Casanova, Jean-Laurent; Derisi, Joseph L; Anderson, Mark S; Ye, Chun Jimmie

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN-specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non-COVID-19 controls revealed a lack of type I IFN-stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN-specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN-specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.