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

  • Author(s): van der Wijst, Monique GP;
  • 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;
  • UCSF COMET consortium
  • et al.
Abstract

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.

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