Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 60, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abf9564
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Funding
- Care-for-Rare Foundation (C4R) [160073]
- German Centre for Infection Research (DZIF) [TTU 07.909]
- Else Kroner-Fresenius Stiftung (EKFS) [2017_A110, 2017_A50]
- German Federal Ministry of Education and Research (BMBF) [01GM1910C]
- JSPS [26293244, 18H02778, 19K23861, 20K16847]
- AMED Rare/Intractable Disease Project [1010139]
- Health and Labor Science Research Grant [201911006B, 201911013B]
- German Research Foundation (DFG, Gottfried Wilhelm Leibniz program)
- Deutsche Forschungsgemeinschaft (DFG
- German Research Foundation) [442265435]
- Friedrich-Baur-Stiftung [48/17]
- NIH [R01-AI144067, T32-GM008367, F31-AI133950]
- Emory University Research Council
- Emory University School of Medicine Bridge Funding Program
- Atlanta Chapter of the ARCS Foundation
- Cystic Fibrosis Foundation [DEY18F0]
- BMBF
- European Cooperation in Science and Technology [COST A16125]
- Deutsche Forschungsgemeinschaft (DFG) [Gr970-9/1]
- European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases [739543]
- Grants-in-Aid for Scientific Research [20K16847, 18H02778, 26293244, 19K23861] Funding Source: KAKEN
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This study identified novel OAS1 gain-of-function variants causing a polymorphic autoinflammatory immunodeficiency characterized by a range of symptoms and independent activity towards RNA. By controlling RNase L expression, the disorder can be modulated, while allogeneic hematopoietic cell transplantation can cure this disease.
Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.
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