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

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.

SUBMITTER: van der Wijst MGP

PROVIDER: S-EPMC8601717 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

van der Wijst Monique G P MGP Vazquez Sara E SE Hartoularos George C GC Bastard Paul P Grant Tianna T Bueno Raymund R Lee David S DS Greenland John R JR Sun Yang Y Perez Richard R Ogorodnikov Anton A Ward Alyssa A Mann Sabrina A SA Lynch Kara L KL Yun Cassandra C Havlir Diane V DV Chamie Gabriel G Marquez Carina C Greenhouse Bryan B Lionakis Michail S MS Norris Philip J PJ Dumont Larry J LJ Kelly Kathleen K Zhang Peng P Zhang Qian Q Gervais Adrian A Le Voyer Tom T Whatley Alexander A Si Yichen Y Byrne Ashley A Combes Alexis J AJ Rao Arjun Arkal AA Song Yun S YS Fragiadakis Gabriela K GK Kangelaris Kirsten K Calfee Carolyn S CS Erle David J DJ Hendrickson Carolyn C Krummel Matthew F MF Woodruff Prescott G PG Langelier Charles R CR Casanova Jean-Laurent JL Derisi Joseph L JL Anderson Mark S MS Ye Chun Jimmie CJ

Science translational medicine 20210824 612

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 periphe ...[more]

PMID: 34429372

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Project description:BackgroundNeutralizing anti-interferon (IFN)-γ autoantibodies are linked to adult-onset immunodeficiency and opportunistic infections.MethodsTo explore whether anti-IFN-γ autoantibodies are associated with disease severity of coronavirus disease 2019 (COVID-19), we examined the titers and functional neutralization of anti-IFN-γ autoantibodies in COVID-19 patients. In 127 COVID-19 patients and 22 healthy controls, serum titers of anti-IFN-γ autoantibodies were quantified using enzyme-linked immunosorbent assay, and the presence of autoantibodies was verified with immunoblotting assay. The neutralizing capacity against IFN-γ was evaluated with flow cytometry analysis and immunoblotting, and serum cytokines levels were determined using the MULTIPLEX platform.ResultsA higher proportion of severe/critical COVID-19 patients had positivity for anti-IFN-γ autoantibodies (18.0%) compared with non-severe patients (3.4%, p < 0.01) or healthy control (HC) (0.0%, p < 0.05). Severe/critical COVID-19 patients also had higher median titers of anti-IFN-γ autoantibodies (5.01) compared with non-severe patients (1.33) or HC (0.44). The immunoblotting assay could verify the detectable anti-IFN-γ autoantibodies and revealed more effective inhibition of signal transducer and activator of transcription (STAT1) phosphorylation on THP-1 cells treated with serum samples from anti-IFN-γ autoantibodies-positive patients compared with those from HC (2.21 ± 0.33 versus 4.47 ± 1.64, p < 0.05). In flow-cytometry analysis, sera from autoantibodies-positive patients could also significantly more effectively suppress the STAT1 phosphorylation (median,67.28%, interquartile range [IQR] 55.2-78.0%) compared with serum from HC (median,106.7%, IQR 100.0-117.8%, p < 0.05) or autoantibodies-negative patients (median,105.9%, IQR 85.5-116.3%, p < 0.05). Multivariate analysis revealed that the positivity and titers of anti-IFN-γ autoantibodies were significant predictors of severe/critical COVID-19. Compared with non-severe COVID-19 patients, we reveal that a significantly higher proportion of severe/critical COVID-19 patients are positive for anti-IFN-γ autoantibodies with neutralizing capacity.ConclusionOur results would add COVID-19 to the list of diseases with the presence of neutralizing anti-IFN-γ autoAbs. Anti-IFN-γ autoantibodies positivity is a potential predictor of severe/critical COVID-19.

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

Publications

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

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