2026/07/16 by Conor Gruber, Meredith Ramba, Bineeta Debnath +38 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Immunodeficiency and Autoimmune Disorders #Inflammasome and immune disorders #interferon and immune responses
paper · doi:10.1084/jem.20251331
openalex publication_date 2026/07/16 · openalex created_date 2026/07/17 · openalex updated_date 2026/07/27
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.