Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2)
Year: 2026
Type: article
Study design: Case Report
Abstract: Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.
DOI: 10.1084/jem.20251331
Authors: Conor Gruber, Meredith Ramba, Bineeta Debnath, Lorenzo Cuollo, Anna-Lena Neehus, Angelica Lee, Sofija Buta, Marta Martin-Fernandez, Jérémie Rosain, Laureline Berteloot, Philippe Drabent, Tom Le Voyer, Camille Soudée, Jessica Peel, Yoann Seeleuthner, Anne Puel, Shen-Ying Zhang, Michael J. Ciancanelli, Carlos A. Arango-Franco, Mélanie Migaud, Marie-Louise Frémond, Florence Renaldo, Odile Boespflug-Tanguy, Imen Dorboz, Beatrice Dubern, Tristan Fonteneau, Nima Parvaneh, Rasol Molatefi, Mohammad Shahrooei, Darragh Duffy, Vincent Bondet, Gillian I. Rice, Yanick J. Crow, Thierry Jo Molina, Nathalie Boddaert, Jean-Laurent Casanova, Veronique Houdouin, Isabelle Melki, Alice Hadchouel, Jacinta Bustamante, Dusan Bogunovic
Institutions: Children's Hospital of Philadelphia, Columbia University Irving Medical Center, Columbia University, Icahn School of Medicine at Mount Sinai, Hôpital Necker-Enfants Malades, Boston Children's Hospital, Harvard University, Inserm, Université Paris Cité, Dana-Farber Cancer Institute, Institut des Maladies Génétiques Imagine, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Instituto de Salud Carlos III, Instituto de Investigación de Enfermedades Raras, Assistance Publique – Hôpitaux de Paris, Rockefeller University, Hôpital Saint-Louis, Universidad de Antioquia, Sorbonne Université, Hôpital Armand-Trousseau, NeuroDiderot, Centre National de la Recherche Scientifique, Institut du Cerveau, Bicêtre Hospital, Université Pierre-et-Marie-Curie, Hôpital Robert-Debré, Children's Medical Center, Tehran University of Medical Sciences, Ardabil University of Medical Sciences, Institut Pasteur, University of Manchester, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Howard Hughes Medical Institute
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: St. Giles Foundation, European Molecular Biology Organization, Rockefeller University, Institut des maladies génétiques Imagine, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, National Institutes of Health, Medical Research Council, Inserm Transfert, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences, H2020 European Research Council
Awards: G2360709987, G250961418, G2659219095, G282427092, G3685082252, G4673943409, G5429587316, G546891718, Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection, G6917541615, G726382754, Genetic disorders of human neurological and immune function, Novel Mechanisms of Genetic Errors of Immunity, Genome-Wide Dissection of Mendelian Susceptibility to Mycobacterial Disease, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success
OpenAlex ID: W7169027947