Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19

Abstract

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.

Neutralizing Autoantibodies to Type I Interferons in COVID-19 Convalescent Donor Plasma

“…Ongoing variation in the viral spike protein may necessitate the continued use of convalescent plasma, due to the slower pace of generation of recombinant monoclonal antibodies and possibly the emergence of vaccineresistance [5]. While we previously found non-hospitalized donors to be anti-IFN-α2 negative [4], the data presented here suggest that COVID-19 convalescent plasma from previously hospitalized patients may require screening for type I interferon autoantibodies. Alternatively, COVID-19 plasma donation could exclude those donors with a record of severe to critical pneumonia until future studies can address whether transfer of autoantibodies constitutes harm to recipients.…”

“…It remains to be determined whether administration of convalescent plasma containing type I interferon autoantibodies has any detrimental effect to patients, particularly when diluted in the recipients' blood volume. However, in our original report, plasma from most patients could neutralize the protective effect of IFN-α2 against SARS-CoV-2 in vitro even when diluted up to 10,000-fold [4]. In light of recent reports on varying efficacy of convalescent plasma for COVID-19 treatment, it is worth considering that in rare circumstances, the presence of autoantibodies in the donor plasma pool could explain some of the variance in clinical response.…”

“…Recently, neutralizing autoantibodies to type I interferons have been described in at least 10% of patients with critical COVID-19 pneumonia, while they were absent from infected individuals with asymptomatic or mild disease [3]. These autoantibodies are likely pre-existing and have an immunological impact early in the course of COVID-19 [3,4].…”

Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1

“…Autoantibodies against type-I-IFNs were reported in patients with severe COVID-19 (11), among whom a strong bias towards males (95%) and patients elder than 65 y/a (>50%) was also noted (11). Autoantibodies against type-I-IFNs in severe COVID-19 were confirmed in additional cohorts (14)(15)(16)(17). However, to date only cohorts collected for severe COVID-19 had been analysed (11,(15)(16)(17)(18).…”

“…Autoantibodies against type-I-IFNs in severe COVID-19 were confirmed in additional cohorts (14)(15)(16)(17). However, to date only cohorts collected for severe COVID-19 had been analysed (11,(15)(16)(17)(18). We are not aware of a prospective follow-up of patients with pre-existing autoantibodies against type-I-IFNs.…”