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

Abstract

Description Type I interferon autoantibodies in patients with COVID-19 are associated with poor interferon responses and increased LAIR1 abundance in leukocytes. Interfering with interferons A subset of patients diagnosed with coronavirus disease 2019 (COVID-19) present with autoantibodies specific to type I interferons (IFNs). However, the systemic impacts of type I IFN–specific autoantibodies are not fully understood. Here, van der Wijst et al. longitudinally evaluated the relationship between type I IFN–specific autoantibody abundance and changes to the immune system of individuals with COVID-19. Using single-cell transcriptomics, the authors found that the presence of type I IFN autoantibodies correlated with reduced type I IFN–stimulated gene (ISG) expression in patients with critical COVID-19. Reduced ISG expression, in turn, correlated with increased expression of the inhibitory receptor, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), on monocytes. Together, these findings suggest that early evidence of type I IFN autoantibodies and increased LAIR1 expression may help distinguish severe cases of COVID-19. 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.