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.

Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage haematopoiesis resulting from the gene corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes and no aberrant clonal expansion was observed after 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T-cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56 dim CD16 hi NK cells linked positively to circulating IL-15. CD8 + T cell activation was apparent without signs of exhaustion. While cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.

IntroductionWiskott-Aldrich syndrome (WAS, OMIM 301000) is a complex and severe X-linked disorder characterized by microthrombocytopenia, eczema, immunodeficiency, and increased risk in developing autoimmunity and lymphomas. WAS affects 1 to 10 of every 1 million male newborns; life expectancy is approximately 15 years for patients lacking WAS protein (WASP) expression. 1,2 The protein encoded by the WAS gene (WASP) is a hematopoietic specific regulator of actin nucleation in response to signals arising at the cell membrane. 3,4 Mutations impairing but not abolishing WASP expression can cause X-linked thrombocytopenia (XLT). This disease can be chronic 5 or intermittent 6 and is considered an attenuated form of WAS because it is characterized by low platelet counts with minimal or no immunodeficiency. Recently, gain-of-function mutations in the WAS gene, giving rise to a constitutively active protein, were found to cause a distinct pathology, X-linked neutropenia. X-linked neutropenia is characterized by low neutrophil counts and predisposition to myelodysplasia in the absence of thrombocytopenia and T-cell immunodeficiency. 7,8 The wide spectrum of clinical manifestations highlights the complex role of WASP in various cellular mechanisms. Clinical manifestations in WAS MicrothrombocytopeniaAmong clinical manifestations, hemorrhages are frequent (Ͼ 80% incidence) in WAS and XLT patients and range from nonlife-threatening (epistaxis, petechiae, purpura, oral bleeding) to severe manifestations, such as intestinal and intracranial bleeding. 9 Death of WAS patients is caused, in 21% of the cases, by hemorrhages. 9,10 Bleeding is the result of severe thrombocytopenia with reduced platelet size, which is the most common finding in WAS and XLT patients (100% incidence). Thrombocytopenia occurs irrespectively of the severity of the mutation and is possibly caused by instability of mutated WASP in platelets. 11 Despite intensive research, the mechanisms underlying WASPrelated thrombocytopenia and hemorrhages are not completely understood. Megakaryocyte numbers have been reported to be normal in the majority of WAS patients, 12-14 whereas proplatelet formation depending on actin polymerization and formation of branching structures is conserved when tested in in vitro and ex vivo cultures. 12 Peripheral destruction of platelets in the spleen is thought to play an important role in thrombocytopenia because a substantial correction of the platelet count and size after splenectomy has been reported. 15 The accelerated destruction could be caused by an intrinsic defect of WASP-deficient platelets, showing an increased surface exposure of phosphatidylserine, or could be mediated by autoimmune reaction because of the presence of antiplatelet antibodies reported in patients and in the murine knockout model, 13 although the latter hypothesis is still a matter of controversy in the field. Finally, defects in filopodia and podosomes could play an additional role in migration of megakaryocytes from the endosteal to the perivascular n...