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.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

No abstract

“X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia” (XMEN) disease is an inborn error of glycosylation and immunity caused by loss of function mutations in the magnesium transporter 1 ( MAGT1 ) gene. It is a multisystem disease that strongly affects certain immune cells. MAGT1 is now confirmed as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates Asparagine (N)-linked glycosylation of specific substrates, making XMEN a congenital disorder of glycosylation manifesting as a combined immune deficiency. The clinical disease has variable expressivity and impaired glycosylation of key MAGT1-dependent glycoproteins in addition to Mg 2+ abnormalities can explain some of the immune manifestations. NKG2D, an activating receptor critical for cytotoxic function against EBV, is poorly glycosylated and invariably decreased on CD8 + T cells and natural killer (NK) cells from XMEN patients. It is the best biomarker of the disease. The characterization of EBV-naïve XMEN patients has clarified features of the genetic disease that were previously attributed to EBV infection. Extra-immune manifestations, including hepatic and neurological abnormalities have recently been reported. EBV-associated lymphomas remain the main cause of severe morbidity. Unfortunately, treatment options to address the underlying mechanism of disease remain limited and Mg 2+ supplementation has not proven successful. Here, we review the expanding clinical phenotype and recent advances in glycobiology that have increased our understanding of XMEN disease. We also propose updating XMEN to “ X -linked M AGT1 deficiency with increased susceptibility to E BV-infection and N -linked glycosylation defect” in light of these novel findings.

Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55 leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin (Ig) wasting in the intestine. We report in vivo human data that we accumulated using the complement C5 inhibitor eculizumab for the medical treatment of CHAPLE patients and observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized Ig concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued Ig replacement and other treatments, and exhibited catch-up growth. Thus, we show blockade of C5 by eculizumab effectively re-establishes the regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

No abstract

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6−/− mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)–containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6−/− mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.

No abstract