Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of <i>STAT2</i> (TIMS2)

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.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2026-07-16
DOI
https://doi.org/10.1084/jem.20251331
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.00

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article

Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2)

Laureline Berteloot, Isabelle Melki, Yanick Joseph Crow, Odile Boespflug‐Tanguy et al.
The Journal of Experimental Medicine
interferon and immune responses
article

Familial pulmonary alveolar proteinosis and type I interferonopathy by mutation of STAT2 (TIMS2)

Laureline Berteloot, Isabelle Melki, Yanick Joseph Crow, Odile Boespflug‐Tanguy, Tristan Fonteneau, Béatrice Dubern, Jessica N. Peel, Florence Renaldo, Michael J. Ciancanelli, Darragh Duffy, Camille Soudée, Nima Parvaneh, Alice Hadchouel, Yoann Seeleuthner, Philippe Drabent, Sofija Buta, Marta Martín-Fernández, Nathalie Boddaert, Jean‐Laurent Casanova, Jérémie Rosain, Carlos A. Arango-Franco, Mélanie Migaud, Marie‐Louise Frémond, Tom Le Voyer, Anne Puel, Rasol Molatefi, Dusan Bogunovic, Anna‐Lena Neehus, Vincent Bondet, Shen‐Ying Zhang, Gillian Rice, Jacinta Bustamante, Thierry Jo Molina, Mohammad Shahrooei, Conor Gruber, Imen Dorboz, Lorenzo Cuollo, Meredith Ramba, Angelica E. Lee, Véronique Houdouin, Bineeta Debnath
article en

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.

The Journal of Experimental MedicineVol. 223(8)
Shahed University (IR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Children's Hospital of Philadelphia (US), Howard Hughes Medical Institute (US), Inserm (FR), Institut Pasteur (FR), University of Shahrood (IR), Université Paris Cité (FR), Columbia University Irving Medical Center (US), Manchester Academic Health Science Centre (GB), Instituto de Salud Carlos III (ES), University of Manchester (GB), Ardabil University of Medical Sciences (IR), Universidad de Antioquia (CO), Sorbonne Université (FR), Hospital for Sick Children Pediatric Center (US), Hôpital Armand-Trousseau (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Children's Medical Center (IR), Dana-Farber Cancer Institute (US), Hôpital Robert-Debré (FR), Hôpital Saint-Louis (FR), Pediatrics and Genetics (US), Institut du Cerveau (FR), Institute of Genetics and Cancer (GB), Instituto de Investigación de Enfermedades Raras (ES), Bicêtre Hospital (FR), Institut des Maladies Génétiques Imagine (FR), Tehran University of Medical Sciences (IR), Columbia University (US), Rockefeller University (US), Icahn School of Medicine at Mount Sinai (US)
St. Giles Foundation, European Molecular Biology Organization, Rockefeller University, Institut des maladies génétiques Imagine, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Medical Research Council, Inserm Transfert, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences, H2020 European Research Council
Gender equality
Openalex Percentile: Top 14%
interferon and immune responses
DOISourceOpenAlex
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