Heterozygous gain-of-function variants cause an autoinflammatory immunodeficiency.

Hirokazu Kanegane, Fabian Hauck, Tomohiro Morio, Christoph Klein, Kathleen E Sullivan, Graeme L Conn, Christoph Walz, Paul Gray, Meino Rohlfs, Michael H Albert, Matthias Griese, Karl Reiter, Davide Montin, Kazutoshi Cho, Thomas Magg, Debayan Dey, Brenda M Calderon, Esther N Park, Andrés Caballero-Oteyza, Ronald M Ferdman, Julia Ley-Zaporozhan, Francesco Licciardi, Jennifer Heimall, Kento Inoue, Samantha L Schwartz, Daniel F R Boehmer, Lars M Koenig, Tsubasa Okano

Journal: Science immunology 2022;6(60):eabf9564

PMID: 34145065

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Abstract

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 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.

Address: Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.; Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.; Graduate Program in Biochemistry, Cell and Developmental Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA.; Department of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pediatric and Public Health Sciences, University of Torino, Regina Margherita Children's Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy.; Department of Radiology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Centre for Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency (IFI), University Hospital Freiburg, Freiburg, Germany.; Maternity and Perinatal Care Center, Hokkaido University Hospital, Hokkaido, Japan.; German Center for Lung Research (DZL), Munich, Germany.; Department of Immunology and Infectious Disease, Sydney Children's Hospital, Sydney, NSW, Australia.; Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.; German Centre for Infection Research (DZIF), Munich, Germany.; Munich Centre for Rare Diseases (M-ZSE), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.; Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. [email protected] [email protected].; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. [email protected] [email protected].

DOI: 10.1126/sciimmunol.abf9564