Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Distinct genes encode 6 human receptors for IgG (hFc␥Rs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFc␥Rs for the 4 human IgG subclasses is unknown. This information is critical for antibodybased immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3, and IgG4 to Fc␥RI; Fc␥RIIA, IIB, and IIC; Fc␥RIIIA and IIIB; and all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found that (1) IgG1 and IgG3 bind to all hFc␥Rs; (2) IgG2 bind not only to Fc␥RIIA H131 , but also, with a lower affinity, to Fc␥RIIA R131 4 Other FcRs are inserted in the outer layer of the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and contain no signaling motif. 5 FcRs have been associated with many antibodydependent diseases 6 and are key molecules in antibody-based immunotherapy. These include the treatment, for instance, of non-Hodgkin lymphomas by mouse/human chimeric IgG1 anti-CD20 antibodies 7 and the prevention of hemolytic disease of the newborn by a mixture of polyclonal IgG1 and IgG3 anti-RhD antibodies (eg, Rophylac). Therapeutic antibodies are, however, potentially harmful, as exemplified by a recent clinical trial using IgG4 anti-CD28 antibodies.Four human subclasses of IgG are produced in different amounts in response to various antigens. T-dependent protein antigens elicit primarily IgG1 and IgG3 antibodies, whereas T-independent carbohydrate antigens elicit primarily IgG2 antibodies. Chronic antigen stimulation, as in allergic desensitization, elicits IgG4 antibodies. The biological activities of each subclass of IgG are poorly known. IgG receptors (Fc␥Rs) are strikingly numerous in humans. They comprise high-affinity and low-affinity receptors. 8 Both high-affinity and low-affinity Fc␥Rs bind IgGimmune complexes with a high avidity, but only high-affinity Fc␥Rs bind monomeric IgG. There is one high-affinity IgG receptor in humans, hFc␥RI (CD64), and 2 families of low-affinity IgG receptors, hFc␥RIIA, IIB, and IIC (CD32), and hFc␥RIIIA and IIIB (CD16). hFc␥RI and hFc␥RIIIA are FcR␥-associated activating receptors, hFc␥RIIA and hFc␥RIIC are single-chain activating receptors, hFc␥RIIB are single-chain inhibitory receptors, and hFc␥RIIIB are GPI-anchored receptors whose function is uncertain. 1 The multiplicity of hFc␥Rs is further increased by a series of polymorphisms in their extracellular domains (reviewed in van Sorge et al 9 ). Two alleles of the gene encoding hFc␥RIIA generate 2 variants differing at position 131, named low-responder (H 131 ) and high-responder (R 131 ). 10 The H 131 and R 131 alleles are differentially distributed in whites, Japanese, and Chinese. 11 Two alleles of the gene-encoding hFc␥RIIIA generate 2 variants differing at 23 and hFc␥RIIIB NA2 to SLE in Japanese people. 24 The subclass specificity of hFc␥Rs has been investigated since the 1980s, that is, at a time when the complexity of hFc␥R...

Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems.

Mouse IgG subclasses display a hierarchy of in vivo activities, with IgG2a and IgG2b showing the greatest protective and pathogenic properties. These enhanced activities result, in part, from their ability to bind to a novel, gamma chain-dependent, activating IgG Fc receptor, FcgammaRIV. FcgammaRIV maps in the 75 kb genomic interval between FcgammaRII and FcgammaRIII; its expression is restricted to myeloid lineage cells, and it binds to IgG2a and IgG2b with intermediate affinity. No binding to IgG1 or IgG3 was observed. Blocking FcgammaRIV binding to pathogenic anti-platelet antibodies is sufficient to protect mice from antibody-induced thrombocytopenia. Thus, the FcgammaR system has evolved distinct activation receptors displaying selectivity for IgG subclasses, with IgG1 antibodies exclusively dependent on FcgammaRIII, whereas IgG2a and IgG2b show preferential dependence on FcgammaRIV activation. These distinct binding affinities for the IgG subclasses to FcgammaRs account for their differential protective and pathogenic activities in vivo.