Mycobacteriosis, staphylococcosis, and candidiasis can be caused by inborn monogenic errors of IFN-γ, IL-6, and IL-17A/F, respectively, or by genetically modified autoimmune phenocopies of IFN-γ, IL-6, and IL-17A/F, generating autoAbs neutralising against these cytokines. IFNs Type I, first described in 1957, cytokines that contribute to both innate immunity (through their secretion by plasmacytoid dendritic cells and other leukocytes) and cell-intrinsic immunity (in most, if not all, types of cells) against viral infections are ubiquitously expressed. Their receptors are ubiquitously expressed and cause the induction, through phosphorylated STAT1-STAT2-IRF9 trimers, of IFN stimulated genes (ISGs). Form I I IFNs can be neutralised by IgG autoAbs in patients treated with IFN-ap2 or IFN-β and occur in almost all patients with type I autoimmune polyendocrinopathy syndrome (APS-1). They are also seen in women with erythematosus systemic lupus.
These results were publish in Science under title "Auto-antibodies against type I IFNs in patients with life threatening COVID-19".
The author said "We report that at least 101 out of 987 patients with life-threatening COVID-19 pneumonia, at the onset of critical disease, had IgG auto-Abs neutralisation against IFN-alpha (13 patients), 13 forms of IFN-alpha (36) or both (52); some even had autoAbs against the other three IFNs of type I. The auto-Abs neutralise the ability of the appropriate type I IFNs to in vitro block SARS-CoV-2 infection. In 663 individuals with asymptomatic or moderate SARS-CoV-2 infection, these auto-Abs were not observed and were present in just 4 out of 1,227 healthy individuals. The auto-Abs patients were 25 to 87 years of age and 95 were males. In at least 2.6 percent of women and 12.5 percent of males, life-threatening COVID-19 pneumonia is the basis of A B cell autoimmune phenocopy of inborn form I errors".
Further ELISA was also performed and the findings obtained were compatible with those obtained with technology from Luminex. We also observed that 11 and 14 of the 23 patients tested had low IgM and IgA auto-Abs levels against IFN-alpha2 and IFN-alpha2, respectively. In two unrelated patients for whom we had plasma samples collected prior to infection with SARS-CoV-2, auto-Abs against type I IFNs were observed, suggesting that these antibodies were present before infection with SARS-CoV-2 and were not caused by this infection. We reported that all 25 APS-1 patients tested had high auto-Abs levels against IFN-alpha-2 and IFN-alpha as a control. Overall, we found that 135 out of 987 (13.7 percent) patients with COVID-19 life threatening pneumonia had IgG auto-Abs versus at least one IFN type I.
Ten of the 17 Type I IFN encoding genes (IFN-alpha2, alpha5, alpha6, alpha8, alpha13, alpha14, alpha21, beta, alpha and alpha) have experienced heavy negative selection, implying that they play an important role in the general population, while the other seven IFN loci in the human genome also bear loss-of-function alleles. In comparison, the 13 subtypes of IFN-alpha and IFN-alpha are more closely related to each other than to the other three structurally and structurally related IFNs (IFN-β, IFN-ε and IFN-alpha),
Thus all patients with auto-Abs neutralisation against IFN-alpha2 tested (N=22) had auto-Abs against all 13 subtypes of IFN-alpha and three of the 22 patients tested (14%) had auto-Abs against 14 or more IFNs of type I.
In addition, during acute blood disease, IFN-alpha subtypes were undetectable in patients with auto-Abs against IFN-alpha, indicating a pre-existing or concomitant in vivo biological effect. Patients are also unlikely to be able to break self-tolerance and instal high IgG auto-Abs neutralisation titers against type I IFN within only one or even two weeks of infection. Finally, lifethreatening COVID-19 inborn errors of type I I IFNs in other previously healthy adults, including autosomal recessive IFNAR1 deficiency, are recorded in an accompanying article.
Collectively, these results indicate that auto-Abs against type I IFNs are a cause and not a consequence of severe SARS-Cov-2 infection, although the SARS-CoV-2-driven induction of type I IFNs can increase their titers and affinity. They also describe the strong sex bias seen in patients with life-threatening COVID-19, and maybe the rise in risk with age.
They explained "Our results have clear clinical consequences. Second, to identify individuals with auto-Abs at risk of developing life-threatening pneumonia, SARSCoV-2-infected patients can be screened. Those patients recovering from lifethreatening COVID-19 should also be exempt from donating convalescent plasma for ongoing clinical trials, or at least checked prior to approval of their plasma donations Second, this unexpected discovery paves the way for therapeutic intervention, including plasmapheresis, monoclonal plasma depleting Abs, and unique type I IFN-reactive B cell type IFN inhibition. Lastly, early treatment with IFN-al is unlikely to be successful in this patient population. However, injected or nebulized IFN-β therapy can have beneficial effects, as auto-Abs against IFN-β tend to be uncommon in patients with auto-Abs versus IFNs of type I ".